Urinary tract infections (UTIs) account for 8.3 million doctor visits, 1 million emergency department (ED) visits, and 100,000 hospitalizations annually, with an estimated cost of $1 billion annually in the U.S.¹ Urnary tract infections are the most common bacterial infections found in nursing home residents, accounting for 50% of reported infections in Norwegian nursing homes, 30% to 50% in U.S. nursing homes, and 25% of all infections in the noninstitutionalized elderly in the U.S.^2-4 In the geriatric population, UTIs are often found incidentally at the time of hospitalization for other admitting diagnoses, such as mentation changes or falls.⁵ Asymptomatic pyuria was found in 14.8% of community residents aged ≥ 80 years.⁶ Woodford and colleague found that 37% of geriatric patients admitted through an ED diagnosed with UTIs had no dysuria or urinary frequency.⁷

The incidence of UTIs is higher in the elderly due to genitourinary abnormalities, urolithiasis, dehydration, and diabetes, among other causes. These are considered complicated UTIs, defined as those in the presence of factors that predispose to persistent or relapsing infection, such as foreign bodies (calculi, indwelling catheters), obstruction, renal failure, and urinary retention.⁸

In elderly men, prostate enlargement causes bladder outlet obstruction predisposing them to urinary stasis and UTIs.² Urinary tract infections are prone to recur when urinary tract abnormalities persist or treatment ineffectively eradicates resistant bacteria. Urinary tract infections are considered recurrent when ≥ 3 occur within 1 year or ≥ 2 occur in a 6-month period. The anticipated recurrence rate of complicated UTIs at 4 to 6 weeks following completion of therapy is 40% to 60%.⁴

Current practice standards recommend not treating asymptomatic UTIs to avoid contributing to bacterial antibiotic resistance.⁹ The frequent use of antibiotics, such as quinolones, which are increasingly inactive against these organisms, contributes to the overgrowth of bacteria in the gastrointestinal tract and their appearance in the genitourinary tract.^10,11

As UTI-causing bacteria become more resistant to available antibiotics, the need to explore new strategies for managing UTIs is clear.¹² The spread of extended spectrum beta-lactamase (ESBL), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE), among other emerging bacterial resistance factors, present increasing treatment cost and poor patient outcomes. This challenge is occurring at a time when the discovery and development of new anti-infective agents is slowing down.¹³

The European Commission Scientific Committee on Health and Environmental Risk reported that in patients receiving up to 4,000 mg/d methenamine for preventive long-term treatment of UTIs, no adverse effects (AEs) were noted (Figure).¹⁷

Complicated UTIs in the elderly are difficult to treat due to bacterial resistance. The off-label use of methenamine hippurate for treatment/prophylaxis of MDR-recurrent UTIs is a compelling option, explored further in the following case studies. Four case studies using methenamine for treatment and prevention of recurrent MDR UTIs in geriatric patients are presented.

Treating UTI Patients

Case Study 1
A man aged > 89 years, symptomatic with nocturia due to benign prostatic hypertrophy (BPH) with bladder outlet obstruction had 8 symptomatic UTIs over 15 months. His urine culture tested positive for MDR Providencia stuartia (resistant to ampicillin, chephazolin, gentamycin, tigecycline, tobramycin and sulfamethizole) and Staphylococcus haemolyticus (resistant to ciprofloxacin, levofloxacin, and nitrofurantoin). Postvoid residual urine was identified as the cause for his recurrent UTIs. Self-catheterization was recommended, but the patient declined. Due to his advanced age and preference, surgical intervention was not pursued. His renal function was within normal limits.

Treatment with methenamine hippurate 500 mg bid with 1,000 mg ascorbic acid to acidify the urine was initiated. This reduced dose of 500 mg bid (rather than 1,000 mg bid) was prescribed due to his advanced age and a choice to “err on the side of caution.” Two months later, urinalysis was negative for leukocyte esterase and nitrates, and the growth culture tested negative. Three- and 6-month urinalyses also showed no growth. The patient’s renal function remained stable. He experienced no AEs from the methenamine.

Due to his urinary retention, formaldehyde was able to collect in his bladder for longer than 2 hours, achieving bactericidal levels and effectively preventing recurrence of MDR UTIs.

Case Study 2
A man aged > 89 years with BPH and urinary incontinence managed with an external urinary device worn continuously had a history of 4 UTIs within a 6-month period. His renal function was normal with a creatinine clearance of 37 mg/dL. He was diagnosed with a symptomatic UTI culturing > 100,000 CFU Proteus mirabilis (resistant to ciprofloxacin, nitrofurantoin, and septra).

Due to resistance of the organism to available oral antibiotics, the patient’s desire to avoid hospitalization, and his caregiver’s inability to learn to administer IV antibiotics in the home, methenamine hippurate 500 mg bid was initiated. Within 21 days, the patient’s urinalysis was negative, indicating no bacterial growth. He was treated for 4 months with no recurrence of a UTI. No symptomatic UTIs recurred during the ongoing methenamine treatment.

Case Study 3
A man aged > 89 years with end-stage renal disease and a history of bladder cancer declined dialysis, indicating that his goals for care were palliative. He was followed at home by a hospice team. He had 3 recurrent symptomatic MRSA UTIs in a 9-month period (resistant to ciprofloxacin, levofloxin, penicillin, and oxacillin). The antibiotics the bacteria was sensitive to, nitrofurantoin and septra, could not be given because his creatinine clearance was merely 8 mg/dL. He was prescribed 500 mg methenamine with 1,000 mg ascorbic acid bid. Within 4 weeks, his urinalysis had changed from > 100,000 CFU to > 50,000 CFU (< 100,000 CFU). One month later with the only treatment the methenamine and ascorbic acid, there was no bacterial growth in the patient’s urine culture. He had no recurrence of a symptomatic UTI while receiving methenamine.

Case Study 4
An 89-year-old man with BPH and recurrent MRSA UTIs had 3 hospitalizations within 1 year. He had stage 3 chronic kidney disease with a creatinine clearance of 43 mg/dL. The patient had a symptomatic UTI > 100,000 CFU MRSA. He was treated with 500 mg methenamine and 1,000 mg ascorbic acid bid. Urinalysis results 2 months later revealed the bacterial count had dropped to the colonization range (< 50,000 CFU). His urinalysis was positive for leukocyte esterase with high white blood cell (WBC) counts, but it was negative for nitrites. He continued without recurrent UTIs while receiving the medication.

Discussion

Patients with similar profiles to those discussed in this report were treated with less dramatic results. Several remained free of symptomatic UTIs with urine cultures showing bacterial counts in the colonization range of < 50,000 CFU, as noted in case 4. Frequently, patients treated with methenamine have urinalyses with negative nitrites, positive leukocyte esterase, high WBCs, and few bacteria, but cultures show no growth. Some patients who did not reliably take medications as prescribed had recurrent symptomatic UTIs. Some had a subsequent UTI culturing a different organism or a change in the sensitivity profile of the same organism. This phenomenon suggests that formaldehyde disrupts the manufacture and transmission of the proteins and enzymes responsible for bacterial resistance factors.

Freeman and colleagues conducted a prospective study of 249 men with bacteruria followed for up to 10 years.¹⁸ Continuous therapy with methenamine delayed recurrence of bacteruria. Nilsson found that recurrent UTIs were reduced by 25% with long-term treatment (> 3 months) with methenamine.¹⁹

Bacteria do not develop resistance to methenamine.²⁰ Reports of AEs are low, and drug interactions are limited to sulfamethizole, which can cause crystallization in the urine. Daily dosing used in studies ranged from 1 g to 4 g daily.²¹ Nilsson conducted research over 16 months with geriatric patients and found no changes in renal function or crystallization in urine.¹⁹

Severe hepatic impairment is also a contraindication, as methenamine can be hydrolyzed to ammonia. Studies have shown a reduced effectiveness with lower urinary tract abnormalities, although those studies administered the medication for short periods of time.²¹ Because the action of the medication relies on ≥ 2 hours of exposure to urine in the bladder, patients with indwelling catheters or patients who urinate frequently experience little benefit.²² Ideal candidates for methenamine are those with urinary retention and recurrent UTIs.

Although the use of methenamine has increased in Norway and Sweden by 24% since 2000, the use of methenamine in the U.S. remains low, perhaps because of conflicting reports in the literature regarding effectiveness and use with limited populations (ie, noncatheterized patients, those able to retain urine for ≥ 2 hours, and a creatinine clearance > 50 mg/dL).³

Some health care providers use methenamine for UTI prophylaxis, but this practice is less common in the U.S. than it is in Scandinavian countries.³ However, no published studies have explored the action of methenamine on MRSA, ESBL, and VRE bacteria or on the enzymes and proteins that enable and transmit bacterial resistance factors.

Elderly patients with complicated recurrent UTIs due to resistant bacteria are often left with no oral antibiotic options. Costs escalate rapidly when IV antibiotics are given. Administration generally requires hospitalization with close monitoring of renal function and drug levels and the placement of a PICC or midline IV access. If there is no caregiver, then hospitalization followed by an admission to a skilled nursing facility is required.

Lee and colleagues concluded that there is a need for further studies to explore long-duration therapy with methenamine.²¹ No studies have addressed its use in the geriatric population for long-term use of prevention of recurrent UTIs. No studies have been done on its use for primary treatment of MDR UTIs. The benefits of this drug with a low AE profile and low cost ($60/month for 1 g bid), which has been proven to reduce the incidence and/or delay recurrence of UTIs, is well worth further examination.

Conclusion

Multiple studies over 60 years have shown methenamine hippurate to be a well-tolerated and safe medication. Little data are available about the use of this medication in the elderly in the U.S., despite its wide use in Scandinavian countries. Use of methenamine for MDR UTIs in the geriatric population has been shown to be safe and effective, as presented in these case studies. Substantial cost savings were realized with the use of methenamine in these geriatric patients by reducing hospitalizations and complications due to recurrent MDR UTIs. The use of methenamine for treating MDR UTIs and the prevention of recurrent UTIs in the geriatric population warrants further clinical use and research.

The very interesting changes noted in sensitivity of the same bacteria in subsequent UTIs in patients treated with methenamine raises questions about the action of formaldehyde in the bladder on bacterial resistance factors. Given the worldwide increase in bacterial resistance to currently available antibiotics, this is a most compelling action that demands further study.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Urinary tract infections (UTIs) account for 8.3 million doctor visits, 1 million emergency department (ED) visits, and 100,000 hospitalizations annually, with an estimated cost of $1 billion annually in the U.S.¹ Urnary tract infections are the most common bacterial infections found in nursing home residents, accounting for 50% of reported infections in Norwegian nursing homes, 30% to 50% in U.S. nursing homes, and 25% of all infections in the noninstitutionalized elderly in the U.S.^2-4 In the geriatric population, UTIs are often found incidentally at the time of hospitalization for other admitting diagnoses, such as mentation changes or falls.⁵ Asymptomatic pyuria was found in 14.8% of community residents aged ≥ 80 years.⁶ Woodford and colleague found that 37% of geriatric patients admitted through an ED diagnosed with UTIs had no dysuria or urinary frequency.⁷

The incidence of UTIs is higher in the elderly due to genitourinary abnormalities, urolithiasis, dehydration, and diabetes, among other causes. These are considered complicated UTIs, defined as those in the presence of factors that predispose to persistent or relapsing infection, such as foreign bodies (calculi, indwelling catheters), obstruction, renal failure, and urinary retention.⁸

In elderly men, prostate enlargement causes bladder outlet obstruction predisposing them to urinary stasis and UTIs.² Urinary tract infections are prone to recur when urinary tract abnormalities persist or treatment ineffectively eradicates resistant bacteria. Urinary tract infections are considered recurrent when ≥ 3 occur within 1 year or ≥ 2 occur in a 6-month period. The anticipated recurrence rate of complicated UTIs at 4 to 6 weeks following completion of therapy is 40% to 60%.⁴

Current practice standards recommend not treating asymptomatic UTIs to avoid contributing to bacterial antibiotic resistance.⁹ The frequent use of antibiotics, such as quinolones, which are increasingly inactive against these organisms, contributes to the overgrowth of bacteria in the gastrointestinal tract and their appearance in the genitourinary tract.^10,11

As UTI-causing bacteria become more resistant to available antibiotics, the need to explore new strategies for managing UTIs is clear.¹² The spread of extended spectrum beta-lactamase (ESBL), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE), among other emerging bacterial resistance factors, present increasing treatment cost and poor patient outcomes. This challenge is occurring at a time when the discovery and development of new anti-infective agents is slowing down.¹³

The European Commission Scientific Committee on Health and Environmental Risk reported that in patients receiving up to 4,000 mg/d methenamine for preventive long-term treatment of UTIs, no adverse effects (AEs) were noted (Figure).¹⁷

Complicated UTIs in the elderly are difficult to treat due to bacterial resistance. The off-label use of methenamine hippurate for treatment/prophylaxis of MDR-recurrent UTIs is a compelling option, explored further in the following case studies. Four case studies using methenamine for treatment and prevention of recurrent MDR UTIs in geriatric patients are presented.

Treating UTI Patients

Case Study 1
A man aged > 89 years, symptomatic with nocturia due to benign prostatic hypertrophy (BPH) with bladder outlet obstruction had 8 symptomatic UTIs over 15 months. His urine culture tested positive for MDR Providencia stuartia (resistant to ampicillin, chephazolin, gentamycin, tigecycline, tobramycin and sulfamethizole) and Staphylococcus haemolyticus (resistant to ciprofloxacin, levofloxacin, and nitrofurantoin). Postvoid residual urine was identified as the cause for his recurrent UTIs. Self-catheterization was recommended, but the patient declined. Due to his advanced age and preference, surgical intervention was not pursued. His renal function was within normal limits.

Treatment with methenamine hippurate 500 mg bid with 1,000 mg ascorbic acid to acidify the urine was initiated. This reduced dose of 500 mg bid (rather than 1,000 mg bid) was prescribed due to his advanced age and a choice to “err on the side of caution.” Two months later, urinalysis was negative for leukocyte esterase and nitrates, and the growth culture tested negative. Three- and 6-month urinalyses also showed no growth. The patient’s renal function remained stable. He experienced no AEs from the methenamine.

Due to his urinary retention, formaldehyde was able to collect in his bladder for longer than 2 hours, achieving bactericidal levels and effectively preventing recurrence of MDR UTIs.

Case Study 2
A man aged > 89 years with BPH and urinary incontinence managed with an external urinary device worn continuously had a history of 4 UTIs within a 6-month period. His renal function was normal with a creatinine clearance of 37 mg/dL. He was diagnosed with a symptomatic UTI culturing > 100,000 CFU Proteus mirabilis (resistant to ciprofloxacin, nitrofurantoin, and septra).

Due to resistance of the organism to available oral antibiotics, the patient’s desire to avoid hospitalization, and his caregiver’s inability to learn to administer IV antibiotics in the home, methenamine hippurate 500 mg bid was initiated. Within 21 days, the patient’s urinalysis was negative, indicating no bacterial growth. He was treated for 4 months with no recurrence of a UTI. No symptomatic UTIs recurred during the ongoing methenamine treatment.

Case Study 3
A man aged > 89 years with end-stage renal disease and a history of bladder cancer declined dialysis, indicating that his goals for care were palliative. He was followed at home by a hospice team. He had 3 recurrent symptomatic MRSA UTIs in a 9-month period (resistant to ciprofloxacin, levofloxin, penicillin, and oxacillin). The antibiotics the bacteria was sensitive to, nitrofurantoin and septra, could not be given because his creatinine clearance was merely 8 mg/dL. He was prescribed 500 mg methenamine with 1,000 mg ascorbic acid bid. Within 4 weeks, his urinalysis had changed from > 100,000 CFU to > 50,000 CFU (< 100,000 CFU). One month later with the only treatment the methenamine and ascorbic acid, there was no bacterial growth in the patient’s urine culture. He had no recurrence of a symptomatic UTI while receiving methenamine.

Case Study 4
An 89-year-old man with BPH and recurrent MRSA UTIs had 3 hospitalizations within 1 year. He had stage 3 chronic kidney disease with a creatinine clearance of 43 mg/dL. The patient had a symptomatic UTI > 100,000 CFU MRSA. He was treated with 500 mg methenamine and 1,000 mg ascorbic acid bid. Urinalysis results 2 months later revealed the bacterial count had dropped to the colonization range (< 50,000 CFU). His urinalysis was positive for leukocyte esterase with high white blood cell (WBC) counts, but it was negative for nitrites. He continued without recurrent UTIs while receiving the medication.

Discussion

Patients with similar profiles to those discussed in this report were treated with less dramatic results. Several remained free of symptomatic UTIs with urine cultures showing bacterial counts in the colonization range of < 50,000 CFU, as noted in case 4. Frequently, patients treated with methenamine have urinalyses with negative nitrites, positive leukocyte esterase, high WBCs, and few bacteria, but cultures show no growth. Some patients who did not reliably take medications as prescribed had recurrent symptomatic UTIs. Some had a subsequent UTI culturing a different organism or a change in the sensitivity profile of the same organism. This phenomenon suggests that formaldehyde disrupts the manufacture and transmission of the proteins and enzymes responsible for bacterial resistance factors.

Freeman and colleagues conducted a prospective study of 249 men with bacteruria followed for up to 10 years.¹⁸ Continuous therapy with methenamine delayed recurrence of bacteruria. Nilsson found that recurrent UTIs were reduced by 25% with long-term treatment (> 3 months) with methenamine.¹⁹

Bacteria do not develop resistance to methenamine.²⁰ Reports of AEs are low, and drug interactions are limited to sulfamethizole, which can cause crystallization in the urine. Daily dosing used in studies ranged from 1 g to 4 g daily.²¹ Nilsson conducted research over 16 months with geriatric patients and found no changes in renal function or crystallization in urine.¹⁹

Severe hepatic impairment is also a contraindication, as methenamine can be hydrolyzed to ammonia. Studies have shown a reduced effectiveness with lower urinary tract abnormalities, although those studies administered the medication for short periods of time.²¹ Because the action of the medication relies on ≥ 2 hours of exposure to urine in the bladder, patients with indwelling catheters or patients who urinate frequently experience little benefit.²² Ideal candidates for methenamine are those with urinary retention and recurrent UTIs.

Although the use of methenamine has increased in Norway and Sweden by 24% since 2000, the use of methenamine in the U.S. remains low, perhaps because of conflicting reports in the literature regarding effectiveness and use with limited populations (ie, noncatheterized patients, those able to retain urine for ≥ 2 hours, and a creatinine clearance > 50 mg/dL).³

Some health care providers use methenamine for UTI prophylaxis, but this practice is less common in the U.S. than it is in Scandinavian countries.³ However, no published studies have explored the action of methenamine on MRSA, ESBL, and VRE bacteria or on the enzymes and proteins that enable and transmit bacterial resistance factors.

Elderly patients with complicated recurrent UTIs due to resistant bacteria are often left with no oral antibiotic options. Costs escalate rapidly when IV antibiotics are given. Administration generally requires hospitalization with close monitoring of renal function and drug levels and the placement of a PICC or midline IV access. If there is no caregiver, then hospitalization followed by an admission to a skilled nursing facility is required.

Lee and colleagues concluded that there is a need for further studies to explore long-duration therapy with methenamine.²¹ No studies have addressed its use in the geriatric population for long-term use of prevention of recurrent UTIs. No studies have been done on its use for primary treatment of MDR UTIs. The benefits of this drug with a low AE profile and low cost ($60/month for 1 g bid), which has been proven to reduce the incidence and/or delay recurrence of UTIs, is well worth further examination.

Conclusion

Multiple studies over 60 years have shown methenamine hippurate to be a well-tolerated and safe medication. Little data are available about the use of this medication in the elderly in the U.S., despite its wide use in Scandinavian countries. Use of methenamine for MDR UTIs in the geriatric population has been shown to be safe and effective, as presented in these case studies. Substantial cost savings were realized with the use of methenamine in these geriatric patients by reducing hospitalizations and complications due to recurrent MDR UTIs. The use of methenamine for treating MDR UTIs and the prevention of recurrent UTIs in the geriatric population warrants further clinical use and research.

The very interesting changes noted in sensitivity of the same bacteria in subsequent UTIs in patients treated with methenamine raises questions about the action of formaldehyde in the bladder on bacterial resistance factors. Given the worldwide increase in bacterial resistance to currently available antibiotics, this is a most compelling action that demands further study.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Urinary tract infections (UTIs) account for 8.3 million doctor visits, 1 million emergency department (ED) visits, and 100,000 hospitalizations annually, with an estimated cost of $1 billion annually in the U.S.¹ Urnary tract infections are the most common bacterial infections found in nursing home residents, accounting for 50% of reported infections in Norwegian nursing homes, 30% to 50% in U.S. nursing homes, and 25% of all infections in the noninstitutionalized elderly in the U.S.^2-4 In the geriatric population, UTIs are often found incidentally at the time of hospitalization for other admitting diagnoses, such as mentation changes or falls.⁵ Asymptomatic pyuria was found in 14.8% of community residents aged ≥ 80 years.⁶ Woodford and colleague found that 37% of geriatric patients admitted through an ED diagnosed with UTIs had no dysuria or urinary frequency.⁷

The incidence of UTIs is higher in the elderly due to genitourinary abnormalities, urolithiasis, dehydration, and diabetes, among other causes. These are considered complicated UTIs, defined as those in the presence of factors that predispose to persistent or relapsing infection, such as foreign bodies (calculi, indwelling catheters), obstruction, renal failure, and urinary retention.⁸

In elderly men, prostate enlargement causes bladder outlet obstruction predisposing them to urinary stasis and UTIs.² Urinary tract infections are prone to recur when urinary tract abnormalities persist or treatment ineffectively eradicates resistant bacteria. Urinary tract infections are considered recurrent when ≥ 3 occur within 1 year or ≥ 2 occur in a 6-month period. The anticipated recurrence rate of complicated UTIs at 4 to 6 weeks following completion of therapy is 40% to 60%.⁴

Current practice standards recommend not treating asymptomatic UTIs to avoid contributing to bacterial antibiotic resistance.⁹ The frequent use of antibiotics, such as quinolones, which are increasingly inactive against these organisms, contributes to the overgrowth of bacteria in the gastrointestinal tract and their appearance in the genitourinary tract.^10,11

As UTI-causing bacteria become more resistant to available antibiotics, the need to explore new strategies for managing UTIs is clear.¹² The spread of extended spectrum beta-lactamase (ESBL), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE), among other emerging bacterial resistance factors, present increasing treatment cost and poor patient outcomes. This challenge is occurring at a time when the discovery and development of new anti-infective agents is slowing down.¹³

The European Commission Scientific Committee on Health and Environmental Risk reported that in patients receiving up to 4,000 mg/d methenamine for preventive long-term treatment of UTIs, no adverse effects (AEs) were noted (Figure).¹⁷

Complicated UTIs in the elderly are difficult to treat due to bacterial resistance. The off-label use of methenamine hippurate for treatment/prophylaxis of MDR-recurrent UTIs is a compelling option, explored further in the following case studies. Four case studies using methenamine for treatment and prevention of recurrent MDR UTIs in geriatric patients are presented.

Treating UTI Patients

Case Study 1
A man aged > 89 years, symptomatic with nocturia due to benign prostatic hypertrophy (BPH) with bladder outlet obstruction had 8 symptomatic UTIs over 15 months. His urine culture tested positive for MDR Providencia stuartia (resistant to ampicillin, chephazolin, gentamycin, tigecycline, tobramycin and sulfamethizole) and Staphylococcus haemolyticus (resistant to ciprofloxacin, levofloxacin, and nitrofurantoin). Postvoid residual urine was identified as the cause for his recurrent UTIs. Self-catheterization was recommended, but the patient declined. Due to his advanced age and preference, surgical intervention was not pursued. His renal function was within normal limits.

Treatment with methenamine hippurate 500 mg bid with 1,000 mg ascorbic acid to acidify the urine was initiated. This reduced dose of 500 mg bid (rather than 1,000 mg bid) was prescribed due to his advanced age and a choice to “err on the side of caution.” Two months later, urinalysis was negative for leukocyte esterase and nitrates, and the growth culture tested negative. Three- and 6-month urinalyses also showed no growth. The patient’s renal function remained stable. He experienced no AEs from the methenamine.

Due to his urinary retention, formaldehyde was able to collect in his bladder for longer than 2 hours, achieving bactericidal levels and effectively preventing recurrence of MDR UTIs.

Case Study 2
A man aged > 89 years with BPH and urinary incontinence managed with an external urinary device worn continuously had a history of 4 UTIs within a 6-month period. His renal function was normal with a creatinine clearance of 37 mg/dL. He was diagnosed with a symptomatic UTI culturing > 100,000 CFU Proteus mirabilis (resistant to ciprofloxacin, nitrofurantoin, and septra).

Due to resistance of the organism to available oral antibiotics, the patient’s desire to avoid hospitalization, and his caregiver’s inability to learn to administer IV antibiotics in the home, methenamine hippurate 500 mg bid was initiated. Within 21 days, the patient’s urinalysis was negative, indicating no bacterial growth. He was treated for 4 months with no recurrence of a UTI. No symptomatic UTIs recurred during the ongoing methenamine treatment.

Case Study 3
A man aged > 89 years with end-stage renal disease and a history of bladder cancer declined dialysis, indicating that his goals for care were palliative. He was followed at home by a hospice team. He had 3 recurrent symptomatic MRSA UTIs in a 9-month period (resistant to ciprofloxacin, levofloxin, penicillin, and oxacillin). The antibiotics the bacteria was sensitive to, nitrofurantoin and septra, could not be given because his creatinine clearance was merely 8 mg/dL. He was prescribed 500 mg methenamine with 1,000 mg ascorbic acid bid. Within 4 weeks, his urinalysis had changed from > 100,000 CFU to > 50,000 CFU (< 100,000 CFU). One month later with the only treatment the methenamine and ascorbic acid, there was no bacterial growth in the patient’s urine culture. He had no recurrence of a symptomatic UTI while receiving methenamine.

Case Study 4
An 89-year-old man with BPH and recurrent MRSA UTIs had 3 hospitalizations within 1 year. He had stage 3 chronic kidney disease with a creatinine clearance of 43 mg/dL. The patient had a symptomatic UTI > 100,000 CFU MRSA. He was treated with 500 mg methenamine and 1,000 mg ascorbic acid bid. Urinalysis results 2 months later revealed the bacterial count had dropped to the colonization range (< 50,000 CFU). His urinalysis was positive for leukocyte esterase with high white blood cell (WBC) counts, but it was negative for nitrites. He continued without recurrent UTIs while receiving the medication.

Discussion

Patients with similar profiles to those discussed in this report were treated with less dramatic results. Several remained free of symptomatic UTIs with urine cultures showing bacterial counts in the colonization range of < 50,000 CFU, as noted in case 4. Frequently, patients treated with methenamine have urinalyses with negative nitrites, positive leukocyte esterase, high WBCs, and few bacteria, but cultures show no growth. Some patients who did not reliably take medications as prescribed had recurrent symptomatic UTIs. Some had a subsequent UTI culturing a different organism or a change in the sensitivity profile of the same organism. This phenomenon suggests that formaldehyde disrupts the manufacture and transmission of the proteins and enzymes responsible for bacterial resistance factors.

Freeman and colleagues conducted a prospective study of 249 men with bacteruria followed for up to 10 years.¹⁸ Continuous therapy with methenamine delayed recurrence of bacteruria. Nilsson found that recurrent UTIs were reduced by 25% with long-term treatment (> 3 months) with methenamine.¹⁹

Bacteria do not develop resistance to methenamine.²⁰ Reports of AEs are low, and drug interactions are limited to sulfamethizole, which can cause crystallization in the urine. Daily dosing used in studies ranged from 1 g to 4 g daily.²¹ Nilsson conducted research over 16 months with geriatric patients and found no changes in renal function or crystallization in urine.¹⁹

Severe hepatic impairment is also a contraindication, as methenamine can be hydrolyzed to ammonia. Studies have shown a reduced effectiveness with lower urinary tract abnormalities, although those studies administered the medication for short periods of time.²¹ Because the action of the medication relies on ≥ 2 hours of exposure to urine in the bladder, patients with indwelling catheters or patients who urinate frequently experience little benefit.²² Ideal candidates for methenamine are those with urinary retention and recurrent UTIs.

Although the use of methenamine has increased in Norway and Sweden by 24% since 2000, the use of methenamine in the U.S. remains low, perhaps because of conflicting reports in the literature regarding effectiveness and use with limited populations (ie, noncatheterized patients, those able to retain urine for ≥ 2 hours, and a creatinine clearance > 50 mg/dL).³

Some health care providers use methenamine for UTI prophylaxis, but this practice is less common in the U.S. than it is in Scandinavian countries.³ However, no published studies have explored the action of methenamine on MRSA, ESBL, and VRE bacteria or on the enzymes and proteins that enable and transmit bacterial resistance factors.

Elderly patients with complicated recurrent UTIs due to resistant bacteria are often left with no oral antibiotic options. Costs escalate rapidly when IV antibiotics are given. Administration generally requires hospitalization with close monitoring of renal function and drug levels and the placement of a PICC or midline IV access. If there is no caregiver, then hospitalization followed by an admission to a skilled nursing facility is required.

Lee and colleagues concluded that there is a need for further studies to explore long-duration therapy with methenamine.²¹ No studies have addressed its use in the geriatric population for long-term use of prevention of recurrent UTIs. No studies have been done on its use for primary treatment of MDR UTIs. The benefits of this drug with a low AE profile and low cost ($60/month for 1 g bid), which has been proven to reduce the incidence and/or delay recurrence of UTIs, is well worth further examination.

Conclusion

Multiple studies over 60 years have shown methenamine hippurate to be a well-tolerated and safe medication. Little data are available about the use of this medication in the elderly in the U.S., despite its wide use in Scandinavian countries. Use of methenamine for MDR UTIs in the geriatric population has been shown to be safe and effective, as presented in these case studies. Substantial cost savings were realized with the use of methenamine in these geriatric patients by reducing hospitalizations and complications due to recurrent MDR UTIs. The use of methenamine for treating MDR UTIs and the prevention of recurrent UTIs in the geriatric population warrants further clinical use and research.

The very interesting changes noted in sensitivity of the same bacteria in subsequent UTIs in patients treated with methenamine raises questions about the action of formaldehyde in the bladder on bacterial resistance factors. Given the worldwide increase in bacterial resistance to currently available antibiotics, this is a most compelling action that demands further study.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Transcription factors prompt

stem cells to form endothelium

(green), then blood cells (red)

Credit: Irina Elcheva

and Akhilesh Kumar

Researchers have reported a new method for creating human blood cells in the lab, and they believe the approach is safer and more reliable than its predecessors.

The team determined how blood cells are made at the earliest stages of development; namely, 2 genetic programs are responsible for turning pluripotent stem cells into blood cells.

This discovery gave the researchers the tools to make an array of blood cells themselves, using transcription factors.

“This is the first demonstration of the production of different kinds of cells from human pluripotent stem cells using transcription factors,” said Igor Slukvin, MD, PhD, of the University of Wisconsin-Madison.

He and his colleagues described this method in Nature Communications.

During development, blood cells emerge in the aorta. There, blood cells, including hematopoietic stem cells, are generated by budding from hemogenic endothelial cells.

Dr Slukvin and his colleagues found that 2 distinct groups of transcription factors—pan-myeloid (ETV2 and GATA2) and erythro-megakaryocytic (GATA2 and TAL1)—directly convert human pluripotent stem cells into hemogenic endothelial cells.

These cells then develop into blood cells with pan-myeloid or erythro-megakaryocytic potential.

“By overexpressing just 2 transcription factors, we can, in the laboratory dish, reproduce the sequence of events we see in the embryo,” Dr Slukvin said.

Furthermore, the method could produce blood cells in abundance. For every million stem cells, the researchers were able to produce 30 million blood cells.

The team noted that a critical aspect of this work is the use of modified messenger RNA to direct stem cells toward particular developmental fates.

This approach makes it possible to induce cells without introducing any genetic artifacts. So this method of blood cell production is safer than other methods, according to the researchers.

“You can do it without a virus, and genome integrity is not affected,” Dr Slukvin noted.

He added that his group is still working on a method for producing hematopoietic stem cells in the lab.

“We still don’t know how to do that,” he said. “But our new approach to making blood cells will give us an opportunity to model their development in a dish and identify novel hematopoietic stem cell factors.”

Transcription factors prompt

stem cells to form endothelium

(green), then blood cells (red)

Credit: Irina Elcheva

and Akhilesh Kumar

Researchers have reported a new method for creating human blood cells in the lab, and they believe the approach is safer and more reliable than its predecessors.

The team determined how blood cells are made at the earliest stages of development; namely, 2 genetic programs are responsible for turning pluripotent stem cells into blood cells.

This discovery gave the researchers the tools to make an array of blood cells themselves, using transcription factors.

“This is the first demonstration of the production of different kinds of cells from human pluripotent stem cells using transcription factors,” said Igor Slukvin, MD, PhD, of the University of Wisconsin-Madison.

He and his colleagues described this method in Nature Communications.

During development, blood cells emerge in the aorta. There, blood cells, including hematopoietic stem cells, are generated by budding from hemogenic endothelial cells.

Dr Slukvin and his colleagues found that 2 distinct groups of transcription factors—pan-myeloid (ETV2 and GATA2) and erythro-megakaryocytic (GATA2 and TAL1)—directly convert human pluripotent stem cells into hemogenic endothelial cells.

These cells then develop into blood cells with pan-myeloid or erythro-megakaryocytic potential.

“By overexpressing just 2 transcription factors, we can, in the laboratory dish, reproduce the sequence of events we see in the embryo,” Dr Slukvin said.

Furthermore, the method could produce blood cells in abundance. For every million stem cells, the researchers were able to produce 30 million blood cells.

The team noted that a critical aspect of this work is the use of modified messenger RNA to direct stem cells toward particular developmental fates.

This approach makes it possible to induce cells without introducing any genetic artifacts. So this method of blood cell production is safer than other methods, according to the researchers.

“You can do it without a virus, and genome integrity is not affected,” Dr Slukvin noted.

He added that his group is still working on a method for producing hematopoietic stem cells in the lab.

“We still don’t know how to do that,” he said. “But our new approach to making blood cells will give us an opportunity to model their development in a dish and identify novel hematopoietic stem cell factors.”

Transcription factors prompt

stem cells to form endothelium

(green), then blood cells (red)

Credit: Irina Elcheva

and Akhilesh Kumar

Researchers have reported a new method for creating human blood cells in the lab, and they believe the approach is safer and more reliable than its predecessors.

The team determined how blood cells are made at the earliest stages of development; namely, 2 genetic programs are responsible for turning pluripotent stem cells into blood cells.

This discovery gave the researchers the tools to make an array of blood cells themselves, using transcription factors.

“This is the first demonstration of the production of different kinds of cells from human pluripotent stem cells using transcription factors,” said Igor Slukvin, MD, PhD, of the University of Wisconsin-Madison.

He and his colleagues described this method in Nature Communications.

During development, blood cells emerge in the aorta. There, blood cells, including hematopoietic stem cells, are generated by budding from hemogenic endothelial cells.

Dr Slukvin and his colleagues found that 2 distinct groups of transcription factors—pan-myeloid (ETV2 and GATA2) and erythro-megakaryocytic (GATA2 and TAL1)—directly convert human pluripotent stem cells into hemogenic endothelial cells.

These cells then develop into blood cells with pan-myeloid or erythro-megakaryocytic potential.

“By overexpressing just 2 transcription factors, we can, in the laboratory dish, reproduce the sequence of events we see in the embryo,” Dr Slukvin said.

Furthermore, the method could produce blood cells in abundance. For every million stem cells, the researchers were able to produce 30 million blood cells.

The team noted that a critical aspect of this work is the use of modified messenger RNA to direct stem cells toward particular developmental fates.

This approach makes it possible to induce cells without introducing any genetic artifacts. So this method of blood cell production is safer than other methods, according to the researchers.

“You can do it without a virus, and genome integrity is not affected,” Dr Slukvin noted.

He added that his group is still working on a method for producing hematopoietic stem cells in the lab.

“We still don’t know how to do that,” he said. “But our new approach to making blood cells will give us an opportunity to model their development in a dish and identify novel hematopoietic stem cell factors.”

Alzheimer disease (AD) and other forms of dementia are pressing public health issues. They diminish quality of life for older adults and their families and impose significant financial costs on individuals and society. Dementia prevention and the development of treatments for dementia are important goals, and as a consequence, the VA Geriatric Research Education and Clinical Centers (GRECCs) have been conducting innovative research for the treatment and prevention of AD and related dementias.

Research conducted at the VISN 20 GRECC at the VA Puget Sound Health Care System (PSHCS) has helped increase clinicians’ understanding of the role of insulin in the development of AD and has evaluated the potential of treatment approaches based on the insulin-related research. More recently, this research has provided the basis for a pilot study aimed at dementia prevention for high-risk patients and for educational outreach about prevention within the VA.

Dementia Studies

The hormone insulin is required for efficient use of glucose throughout the body, including the brain. Insulin may also play a role in regulating cerebral amyloid, which is directly involved in the development of AD neuropathology and in maintaining healthy vascular function and lipid metabolism, both of which are required for brain health.¹ Research over the past decade has shown that patients with AD have reduced levels of brain insulin, and individuals with insulin resistance have an increased risk of developing AD. Insulin resistance also has been shown to be related to reduced cerebral glucose metabolism, even in individuals who did not have a memory disorder.²

One recent study, led by Suzanne Craft, PhD, and colleagues at PSHCS, tested the potential of intranasal insulin to treat cognitive impairment.³ Participants with either AD or milder memory deficits used a specially designed device to deliver insulin or a placebo to the nose twice a day. Insulin provided in this way reaches the brain quickly without entering the lungs or affecting glucose metabolism elsewhere in the body. Participants who received the insulin experienced improvements in delayed memory and functional abilities compared with those who received the placebo.

Studies at the same laboratory investigated the role of diet and exercise in insulin metabolism and cognitive function. In a diet-related study, older adults with normal memory and those with mild memory impairment received either a high saturated fat, high glycemic index (GI) diet or a low saturated fat, low GI diet for 4 weeks.⁴ Plasma insulin levels decreased and delayed visual memory improved for participants who received the low-fat, low-GI diet. AD-related markers in cerebrospinal fluid, however, improved only among participants with mild memory impairment, not among healthy individuals.

In an exercise-related study, older adults with glucose intolerance participated in a 6-month aerobic exercise program.⁵ Although memory did not improve, cardiorespiratory fitness, executive function, and insulin sensitivity improved for participants in the aerobic exercise program compared with those in a stretching program. The relationship of diet and exercise and cognitive function is complex and likely involves insulin regulation, vascular function, and lipid metabolism, among other factors. More research is needed to fully understand the relationships among diet, exercise, and dementia, but these results suggest that lifestyle modifications may play a role in prevention of dementia.

When patients have problems with memory, attention, or executive function, they may have difficulty managing their medications, making good nutritional choices, and monitoring blood pressure and blood glucose.⁶ Given the importance of controlling vascular risk factors, helping patients manage their medical conditions may help them prevent or delay the onset of AD.

Pilot Study

A VA-funded pilot study with the goal of dementia prevention among high-risk patients was recently conducted at the PSHCS. This study focused on veterans at significantly elevated risk of dementia: those with both diabetes and hypertension, with poor control of either or both conditions, and who had some degree of memory or attentional impairment. Participants were randomly assigned to continue their usual care or to add a 6-month care management intervention to their usual care.

A registered nurse who helped the veterans overcome the barriers to controlling their medical conditions led the intervention. Barriers ranged from relatively simple problems, such as appropriate use of insulin, to more complex issues, such as learning about healthy nutrition and exercise for people with diabetes. The intervention was adapted to meet each participant’s cognitive level, and family involvement was encouraged, with the veteran’s permission. Preliminary results of this study were presented at the annual meeting of the Gerontological Society of America in 2011 and the Alzheimer’s Association International conference in July 2013.^7,8

The VISN 20 GRECC also developed a “Dementia Roadshow” in which GRECC clinicians present educational, research-based lectures on dementia-related topics at VAMCs in VISN 20. One lecture in this series incorporates this recent research about prevention of dementia through control of diabetes and hypertension, as well as depression, posttraumatic stress disorder, and other risk factors; the lecture is presented to frontline clinicians who can then use this information to guide their work with high-risk patients.

The GRECCs are at the forefront of understanding the causes of dementia and how to prevent it. This work will help the VA to develop more effective ways of reducing the public health burden of this disease. 

Acknowledgments
The author wishes to thank Debby Tsuang, MD, Stephen Thielke, MD, and Julie Moorer, RN, for helpful feedback on the initial draft of this manuscript. The pilot project described was funded by VA VISN 20.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the Department of Veterans Affairs, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Alzheimer disease (AD) and other forms of dementia are pressing public health issues. They diminish quality of life for older adults and their families and impose significant financial costs on individuals and society. Dementia prevention and the development of treatments for dementia are important goals, and as a consequence, the VA Geriatric Research Education and Clinical Centers (GRECCs) have been conducting innovative research for the treatment and prevention of AD and related dementias.

Research conducted at the VISN 20 GRECC at the VA Puget Sound Health Care System (PSHCS) has helped increase clinicians’ understanding of the role of insulin in the development of AD and has evaluated the potential of treatment approaches based on the insulin-related research. More recently, this research has provided the basis for a pilot study aimed at dementia prevention for high-risk patients and for educational outreach about prevention within the VA.

Dementia Studies

The hormone insulin is required for efficient use of glucose throughout the body, including the brain. Insulin may also play a role in regulating cerebral amyloid, which is directly involved in the development of AD neuropathology and in maintaining healthy vascular function and lipid metabolism, both of which are required for brain health.¹ Research over the past decade has shown that patients with AD have reduced levels of brain insulin, and individuals with insulin resistance have an increased risk of developing AD. Insulin resistance also has been shown to be related to reduced cerebral glucose metabolism, even in individuals who did not have a memory disorder.²

One recent study, led by Suzanne Craft, PhD, and colleagues at PSHCS, tested the potential of intranasal insulin to treat cognitive impairment.³ Participants with either AD or milder memory deficits used a specially designed device to deliver insulin or a placebo to the nose twice a day. Insulin provided in this way reaches the brain quickly without entering the lungs or affecting glucose metabolism elsewhere in the body. Participants who received the insulin experienced improvements in delayed memory and functional abilities compared with those who received the placebo.

Studies at the same laboratory investigated the role of diet and exercise in insulin metabolism and cognitive function. In a diet-related study, older adults with normal memory and those with mild memory impairment received either a high saturated fat, high glycemic index (GI) diet or a low saturated fat, low GI diet for 4 weeks.⁴ Plasma insulin levels decreased and delayed visual memory improved for participants who received the low-fat, low-GI diet. AD-related markers in cerebrospinal fluid, however, improved only among participants with mild memory impairment, not among healthy individuals.

In an exercise-related study, older adults with glucose intolerance participated in a 6-month aerobic exercise program.⁵ Although memory did not improve, cardiorespiratory fitness, executive function, and insulin sensitivity improved for participants in the aerobic exercise program compared with those in a stretching program. The relationship of diet and exercise and cognitive function is complex and likely involves insulin regulation, vascular function, and lipid metabolism, among other factors. More research is needed to fully understand the relationships among diet, exercise, and dementia, but these results suggest that lifestyle modifications may play a role in prevention of dementia.

When patients have problems with memory, attention, or executive function, they may have difficulty managing their medications, making good nutritional choices, and monitoring blood pressure and blood glucose.⁶ Given the importance of controlling vascular risk factors, helping patients manage their medical conditions may help them prevent or delay the onset of AD.

Pilot Study

A VA-funded pilot study with the goal of dementia prevention among high-risk patients was recently conducted at the PSHCS. This study focused on veterans at significantly elevated risk of dementia: those with both diabetes and hypertension, with poor control of either or both conditions, and who had some degree of memory or attentional impairment. Participants were randomly assigned to continue their usual care or to add a 6-month care management intervention to their usual care.

A registered nurse who helped the veterans overcome the barriers to controlling their medical conditions led the intervention. Barriers ranged from relatively simple problems, such as appropriate use of insulin, to more complex issues, such as learning about healthy nutrition and exercise for people with diabetes. The intervention was adapted to meet each participant’s cognitive level, and family involvement was encouraged, with the veteran’s permission. Preliminary results of this study were presented at the annual meeting of the Gerontological Society of America in 2011 and the Alzheimer’s Association International conference in July 2013.^7,8

The VISN 20 GRECC also developed a “Dementia Roadshow” in which GRECC clinicians present educational, research-based lectures on dementia-related topics at VAMCs in VISN 20. One lecture in this series incorporates this recent research about prevention of dementia through control of diabetes and hypertension, as well as depression, posttraumatic stress disorder, and other risk factors; the lecture is presented to frontline clinicians who can then use this information to guide their work with high-risk patients.

The GRECCs are at the forefront of understanding the causes of dementia and how to prevent it. This work will help the VA to develop more effective ways of reducing the public health burden of this disease. 

Acknowledgments
The author wishes to thank Debby Tsuang, MD, Stephen Thielke, MD, and Julie Moorer, RN, for helpful feedback on the initial draft of this manuscript. The pilot project described was funded by VA VISN 20.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the Department of Veterans Affairs, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Alzheimer disease (AD) and other forms of dementia are pressing public health issues. They diminish quality of life for older adults and their families and impose significant financial costs on individuals and society. Dementia prevention and the development of treatments for dementia are important goals, and as a consequence, the VA Geriatric Research Education and Clinical Centers (GRECCs) have been conducting innovative research for the treatment and prevention of AD and related dementias.

Research conducted at the VISN 20 GRECC at the VA Puget Sound Health Care System (PSHCS) has helped increase clinicians’ understanding of the role of insulin in the development of AD and has evaluated the potential of treatment approaches based on the insulin-related research. More recently, this research has provided the basis for a pilot study aimed at dementia prevention for high-risk patients and for educational outreach about prevention within the VA.

Dementia Studies

The hormone insulin is required for efficient use of glucose throughout the body, including the brain. Insulin may also play a role in regulating cerebral amyloid, which is directly involved in the development of AD neuropathology and in maintaining healthy vascular function and lipid metabolism, both of which are required for brain health.¹ Research over the past decade has shown that patients with AD have reduced levels of brain insulin, and individuals with insulin resistance have an increased risk of developing AD. Insulin resistance also has been shown to be related to reduced cerebral glucose metabolism, even in individuals who did not have a memory disorder.²

One recent study, led by Suzanne Craft, PhD, and colleagues at PSHCS, tested the potential of intranasal insulin to treat cognitive impairment.³ Participants with either AD or milder memory deficits used a specially designed device to deliver insulin or a placebo to the nose twice a day. Insulin provided in this way reaches the brain quickly without entering the lungs or affecting glucose metabolism elsewhere in the body. Participants who received the insulin experienced improvements in delayed memory and functional abilities compared with those who received the placebo.

Studies at the same laboratory investigated the role of diet and exercise in insulin metabolism and cognitive function. In a diet-related study, older adults with normal memory and those with mild memory impairment received either a high saturated fat, high glycemic index (GI) diet or a low saturated fat, low GI diet for 4 weeks.⁴ Plasma insulin levels decreased and delayed visual memory improved for participants who received the low-fat, low-GI diet. AD-related markers in cerebrospinal fluid, however, improved only among participants with mild memory impairment, not among healthy individuals.

In an exercise-related study, older adults with glucose intolerance participated in a 6-month aerobic exercise program.⁵ Although memory did not improve, cardiorespiratory fitness, executive function, and insulin sensitivity improved for participants in the aerobic exercise program compared with those in a stretching program. The relationship of diet and exercise and cognitive function is complex and likely involves insulin regulation, vascular function, and lipid metabolism, among other factors. More research is needed to fully understand the relationships among diet, exercise, and dementia, but these results suggest that lifestyle modifications may play a role in prevention of dementia.

When patients have problems with memory, attention, or executive function, they may have difficulty managing their medications, making good nutritional choices, and monitoring blood pressure and blood glucose.⁶ Given the importance of controlling vascular risk factors, helping patients manage their medical conditions may help them prevent or delay the onset of AD.

Pilot Study

A VA-funded pilot study with the goal of dementia prevention among high-risk patients was recently conducted at the PSHCS. This study focused on veterans at significantly elevated risk of dementia: those with both diabetes and hypertension, with poor control of either or both conditions, and who had some degree of memory or attentional impairment. Participants were randomly assigned to continue their usual care or to add a 6-month care management intervention to their usual care.

A registered nurse who helped the veterans overcome the barriers to controlling their medical conditions led the intervention. Barriers ranged from relatively simple problems, such as appropriate use of insulin, to more complex issues, such as learning about healthy nutrition and exercise for people with diabetes. The intervention was adapted to meet each participant’s cognitive level, and family involvement was encouraged, with the veteran’s permission. Preliminary results of this study were presented at the annual meeting of the Gerontological Society of America in 2011 and the Alzheimer’s Association International conference in July 2013.^7,8

The VISN 20 GRECC also developed a “Dementia Roadshow” in which GRECC clinicians present educational, research-based lectures on dementia-related topics at VAMCs in VISN 20. One lecture in this series incorporates this recent research about prevention of dementia through control of diabetes and hypertension, as well as depression, posttraumatic stress disorder, and other risk factors; the lecture is presented to frontline clinicians who can then use this information to guide their work with high-risk patients.

The GRECCs are at the forefront of understanding the causes of dementia and how to prevent it. This work will help the VA to develop more effective ways of reducing the public health burden of this disease. 

Acknowledgments
The author wishes to thank Debby Tsuang, MD, Stephen Thielke, MD, and Julie Moorer, RN, for helpful feedback on the initial draft of this manuscript. The pilot project described was funded by VA VISN 20.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the Department of Veterans Affairs, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Drugs in vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) is alerting healthcare professionals not to use sterile drugs produced by Unique Pharmaceuticals Ltd., as they may be contaminated.

Healthcare professionals should immediately check their medical supplies and quarantine any sterile drug products from Unique Pharmaceuticals, a compounding outsourcing facility in Temple, Texas.

Administration of a non-sterile product may result in serious infection or death.

Unique Pharmaceuticals’ products were distributed nationwide. Most of the product labels include: “Unique Pharmaceuticals, Temple TX USA 76502.”

FDA investigators conducted 2 recent inspections of the Unique Pharmaceuticals facility and observed unsanitary conditions that resulted in a lack of sterility assurance.

The inspections revealed sterility failures in several lots of products intended to be sterile, recurring environmental contamination problems, and poor sterile production practices.

The FDA previously asked the company to recall all non-expired lots of sterile drug products, but the company refused to do so. The FDA has now issued a formal request for Unique Pharmaceuticals to recall all non-expired lots of its sterile products currently on the market.

The FDA has also asked the company to cease sterile compounding operations until sufficient corrections are made at its facility. Unique Pharmaceuticals has refused this request as well.

To date, the FDA is not aware of reports of illness associated with the use of Unique Pharmaceuticals’ products.

Patients who have received any drug product produced by Unique Pharmaceuticals and have concerns should contact their healthcare professional.

Professionals and consumers may report adverse events or quality problems associated with the use of Unique Pharmaceuticals’ products to the FDA’s MedWatch Adverse Event Reporting Program.

Unique Pharmaceuticals is registered under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) as an outsourcing facility. The Drug Quality and Security Act, signed into law on November 27, 2013, added a new section 503B to the FDCA. Under section 503B, a compounder can elect to become an outsourcing facility.

Outsourcing facilities must comply with current good manufacturing practice requirements, will be subject to inspection by the FDA according to a risk-based schedule, and must meet certain other requirements, such as reporting adverse events and providing the FDA with certain information about the products they compound.

Drugs in vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) is alerting healthcare professionals not to use sterile drugs produced by Unique Pharmaceuticals Ltd., as they may be contaminated.

Healthcare professionals should immediately check their medical supplies and quarantine any sterile drug products from Unique Pharmaceuticals, a compounding outsourcing facility in Temple, Texas.

Administration of a non-sterile product may result in serious infection or death.

Unique Pharmaceuticals’ products were distributed nationwide. Most of the product labels include: “Unique Pharmaceuticals, Temple TX USA 76502.”

FDA investigators conducted 2 recent inspections of the Unique Pharmaceuticals facility and observed unsanitary conditions that resulted in a lack of sterility assurance.

The inspections revealed sterility failures in several lots of products intended to be sterile, recurring environmental contamination problems, and poor sterile production practices.

The FDA previously asked the company to recall all non-expired lots of sterile drug products, but the company refused to do so. The FDA has now issued a formal request for Unique Pharmaceuticals to recall all non-expired lots of its sterile products currently on the market.

The FDA has also asked the company to cease sterile compounding operations until sufficient corrections are made at its facility. Unique Pharmaceuticals has refused this request as well.

To date, the FDA is not aware of reports of illness associated with the use of Unique Pharmaceuticals’ products.

Patients who have received any drug product produced by Unique Pharmaceuticals and have concerns should contact their healthcare professional.

Professionals and consumers may report adverse events or quality problems associated with the use of Unique Pharmaceuticals’ products to the FDA’s MedWatch Adverse Event Reporting Program.

Unique Pharmaceuticals is registered under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) as an outsourcing facility. The Drug Quality and Security Act, signed into law on November 27, 2013, added a new section 503B to the FDCA. Under section 503B, a compounder can elect to become an outsourcing facility.

Outsourcing facilities must comply with current good manufacturing practice requirements, will be subject to inspection by the FDA according to a risk-based schedule, and must meet certain other requirements, such as reporting adverse events and providing the FDA with certain information about the products they compound.

Drugs in vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) is alerting healthcare professionals not to use sterile drugs produced by Unique Pharmaceuticals Ltd., as they may be contaminated.

Healthcare professionals should immediately check their medical supplies and quarantine any sterile drug products from Unique Pharmaceuticals, a compounding outsourcing facility in Temple, Texas.

Administration of a non-sterile product may result in serious infection or death.

Unique Pharmaceuticals’ products were distributed nationwide. Most of the product labels include: “Unique Pharmaceuticals, Temple TX USA 76502.”

FDA investigators conducted 2 recent inspections of the Unique Pharmaceuticals facility and observed unsanitary conditions that resulted in a lack of sterility assurance.

The inspections revealed sterility failures in several lots of products intended to be sterile, recurring environmental contamination problems, and poor sterile production practices.

The FDA previously asked the company to recall all non-expired lots of sterile drug products, but the company refused to do so. The FDA has now issued a formal request for Unique Pharmaceuticals to recall all non-expired lots of its sterile products currently on the market.

The FDA has also asked the company to cease sterile compounding operations until sufficient corrections are made at its facility. Unique Pharmaceuticals has refused this request as well.

To date, the FDA is not aware of reports of illness associated with the use of Unique Pharmaceuticals’ products.

Patients who have received any drug product produced by Unique Pharmaceuticals and have concerns should contact their healthcare professional.

Professionals and consumers may report adverse events or quality problems associated with the use of Unique Pharmaceuticals’ products to the FDA’s MedWatch Adverse Event Reporting Program.

Unique Pharmaceuticals is registered under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) as an outsourcing facility. The Drug Quality and Security Act, signed into law on November 27, 2013, added a new section 503B to the FDCA. Under section 503B, a compounder can elect to become an outsourcing facility.

Outsourcing facilities must comply with current good manufacturing practice requirements, will be subject to inspection by the FDA according to a risk-based schedule, and must meet certain other requirements, such as reporting adverse events and providing the FDA with certain information about the products they compound.

Adipose tissue

Preclinical research raises the prospect of more effective treatments for cachexia, a profound wasting of fat and muscle that can increase the risk of death in cancer patients.

In mouse models, an antibody effectively improved or prevented symptoms of cachexia.

The antibody inhibited the effects of parathyroid hormone-related protein (PTHrP), which is released from many types of cancer cells.

The researchers said their findings, published in Nature, are the first to explain in detail how PTHrP from tumors switches on a thermogenic process in fatty tissues, resulting in unhealthy weight loss.

The team carried out 2 experiments using mice that developed lung tumors and cachexia. In the first, a polyclonal antibody that specifically neutralizes PTHrP prevented cachexia almost completely, while untreated animals became mildly cachexic.

Anti-PTHrP treatment prevented the shrinkage of fat droplets. It blocked thermogenic gene expression in epididymal white adipose tissue, interscapular brown adipose tissue, and inguinal white adipose tissue, which suggests thermogenesis has a causal role in fat wasting.

Treatment with the anti-PTHrP antibody also lowered oxygen consumption in the mice, increased their physical activity, and reduced their heat production.

In the second experiment, the researchers treated mice with the anti-PTHrP antibody until they observed severe cachexia in control animals. The antibody significantly preserved muscle mass, which was evident by improved grip strength and in situ muscle contraction.

“You would have expected, based on our first experiments in cell culture, that blocking PTHrP in the mice would reduce browning of the fat,” said study author Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston.

“But we were surprised that it also affected the loss of muscle mass and improved health.”

Additional experiments, in which the researchers injected PTHrP into healthy and tumor-bearing mice, suggested that PTHrP alone doesn’t directly cause muscle wasting. But blocking the protein’s activity still prevents cachexia.

Thus, the role of PTHrP “is definitely not the whole answer” to the riddle of cachexia, Dr Spiegelman noted. Furthermore, it may turn out that the PTHrP mechanism is responsible for cachexia in only a subset of cancer patients.

The researchers analyzed blood samples from 47 cachexic patients with lung or colon cancer. And they found increased levels of PTHrP in 17 of the patients. Those patients had significantly lower lean body mass and were producing more heat energy at rest than the other patients in the group.

Dr Spiegelman noted that, before they test the anti-PTHrP antibody in clinical trials, clinicians would likely want to determine if the protein is elevated in certain cancers and determine which patients would be good candidates for the treatment.

Adipose tissue

Preclinical research raises the prospect of more effective treatments for cachexia, a profound wasting of fat and muscle that can increase the risk of death in cancer patients.

In mouse models, an antibody effectively improved or prevented symptoms of cachexia.

The antibody inhibited the effects of parathyroid hormone-related protein (PTHrP), which is released from many types of cancer cells.

The researchers said their findings, published in Nature, are the first to explain in detail how PTHrP from tumors switches on a thermogenic process in fatty tissues, resulting in unhealthy weight loss.

The team carried out 2 experiments using mice that developed lung tumors and cachexia. In the first, a polyclonal antibody that specifically neutralizes PTHrP prevented cachexia almost completely, while untreated animals became mildly cachexic.

Anti-PTHrP treatment prevented the shrinkage of fat droplets. It blocked thermogenic gene expression in epididymal white adipose tissue, interscapular brown adipose tissue, and inguinal white adipose tissue, which suggests thermogenesis has a causal role in fat wasting.

Treatment with the anti-PTHrP antibody also lowered oxygen consumption in the mice, increased their physical activity, and reduced their heat production.

In the second experiment, the researchers treated mice with the anti-PTHrP antibody until they observed severe cachexia in control animals. The antibody significantly preserved muscle mass, which was evident by improved grip strength and in situ muscle contraction.

“You would have expected, based on our first experiments in cell culture, that blocking PTHrP in the mice would reduce browning of the fat,” said study author Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston.

“But we were surprised that it also affected the loss of muscle mass and improved health.”

Additional experiments, in which the researchers injected PTHrP into healthy and tumor-bearing mice, suggested that PTHrP alone doesn’t directly cause muscle wasting. But blocking the protein’s activity still prevents cachexia.

Thus, the role of PTHrP “is definitely not the whole answer” to the riddle of cachexia, Dr Spiegelman noted. Furthermore, it may turn out that the PTHrP mechanism is responsible for cachexia in only a subset of cancer patients.

The researchers analyzed blood samples from 47 cachexic patients with lung or colon cancer. And they found increased levels of PTHrP in 17 of the patients. Those patients had significantly lower lean body mass and were producing more heat energy at rest than the other patients in the group.

Dr Spiegelman noted that, before they test the anti-PTHrP antibody in clinical trials, clinicians would likely want to determine if the protein is elevated in certain cancers and determine which patients would be good candidates for the treatment.

Adipose tissue

Preclinical research raises the prospect of more effective treatments for cachexia, a profound wasting of fat and muscle that can increase the risk of death in cancer patients.

In mouse models, an antibody effectively improved or prevented symptoms of cachexia.

The antibody inhibited the effects of parathyroid hormone-related protein (PTHrP), which is released from many types of cancer cells.

The researchers said their findings, published in Nature, are the first to explain in detail how PTHrP from tumors switches on a thermogenic process in fatty tissues, resulting in unhealthy weight loss.

The team carried out 2 experiments using mice that developed lung tumors and cachexia. In the first, a polyclonal antibody that specifically neutralizes PTHrP prevented cachexia almost completely, while untreated animals became mildly cachexic.

Anti-PTHrP treatment prevented the shrinkage of fat droplets. It blocked thermogenic gene expression in epididymal white adipose tissue, interscapular brown adipose tissue, and inguinal white adipose tissue, which suggests thermogenesis has a causal role in fat wasting.

Treatment with the anti-PTHrP antibody also lowered oxygen consumption in the mice, increased their physical activity, and reduced their heat production.

In the second experiment, the researchers treated mice with the anti-PTHrP antibody until they observed severe cachexia in control animals. The antibody significantly preserved muscle mass, which was evident by improved grip strength and in situ muscle contraction.

“You would have expected, based on our first experiments in cell culture, that blocking PTHrP in the mice would reduce browning of the fat,” said study author Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston.

“But we were surprised that it also affected the loss of muscle mass and improved health.”

Additional experiments, in which the researchers injected PTHrP into healthy and tumor-bearing mice, suggested that PTHrP alone doesn’t directly cause muscle wasting. But blocking the protein’s activity still prevents cachexia.

Thus, the role of PTHrP “is definitely not the whole answer” to the riddle of cachexia, Dr Spiegelman noted. Furthermore, it may turn out that the PTHrP mechanism is responsible for cachexia in only a subset of cancer patients.

The researchers analyzed blood samples from 47 cachexic patients with lung or colon cancer. And they found increased levels of PTHrP in 17 of the patients. Those patients had significantly lower lean body mass and were producing more heat energy at rest than the other patients in the group.

Dr Spiegelman noted that, before they test the anti-PTHrP antibody in clinical trials, clinicians would likely want to determine if the protein is elevated in certain cancers and determine which patients would be good candidates for the treatment.

Lab mouse

Scientists say they’ve generated a mouse model that supports the transplantation of human hematopoietic stem cells (HSCs), despite the species barrier and without the need for irradiation.

The group used a mutation of the Kit receptor in the mouse stem cells to facilitate the engraftment of human cells.

In this model, human HSCs can expand and differentiate into all blood cell types without any additional treatment.

Even cells of the innate immune system that are not typically found in “humanized” mice were efficiently generated in this mouse.

Furthermore, the stem cells can be maintained in the mouse over a longer period of time.

The researchers reported these results in Cell Stem Cell.

“Our goal was to develop an optimal model for the transplantation and study of human blood stem cells,” said study author Claudia Waskow, PhD, of Technische Universität Dresden in Germany.

To achieve optimal stem cell engraftment, she and her colleagues introduced a naturally occurring mutation of the Kit receptor into mice lacking a functional immune system.

In this way, the team circumvented the 2 major obstacles of HSC transplantation: the rejection by the recipient’s immune system and the absence of free niche space for the incoming donor stem cells in the recipient’s bone marrow.

The Kit mutation in the new mouse model impairs the recipient’s stem cell compartment in such a way that the endogenous HSCs can be easily replaced by human donor stem cells with a functional Kit receptor.

The researchers said this replacement works so efficiently that irradiation can be completely omitted, allowing the study of human blood development in a physiological setting. The model can now be used to study diseases of the human blood and immune system or to test new treatment options.

The results of this research also show that the Kit receptor is important for the function of human HSCs, notably in a transplant setting. The researchers said future studies will focus on using this knowledge to improve conditioning therapy for patients undergoing HSC transplant.

Lab mouse

Scientists say they’ve generated a mouse model that supports the transplantation of human hematopoietic stem cells (HSCs), despite the species barrier and without the need for irradiation.

The group used a mutation of the Kit receptor in the mouse stem cells to facilitate the engraftment of human cells.

In this model, human HSCs can expand and differentiate into all blood cell types without any additional treatment.

Even cells of the innate immune system that are not typically found in “humanized” mice were efficiently generated in this mouse.

Furthermore, the stem cells can be maintained in the mouse over a longer period of time.

The researchers reported these results in Cell Stem Cell.

“Our goal was to develop an optimal model for the transplantation and study of human blood stem cells,” said study author Claudia Waskow, PhD, of Technische Universität Dresden in Germany.

To achieve optimal stem cell engraftment, she and her colleagues introduced a naturally occurring mutation of the Kit receptor into mice lacking a functional immune system.

In this way, the team circumvented the 2 major obstacles of HSC transplantation: the rejection by the recipient’s immune system and the absence of free niche space for the incoming donor stem cells in the recipient’s bone marrow.

The Kit mutation in the new mouse model impairs the recipient’s stem cell compartment in such a way that the endogenous HSCs can be easily replaced by human donor stem cells with a functional Kit receptor.

The researchers said this replacement works so efficiently that irradiation can be completely omitted, allowing the study of human blood development in a physiological setting. The model can now be used to study diseases of the human blood and immune system or to test new treatment options.

The results of this research also show that the Kit receptor is important for the function of human HSCs, notably in a transplant setting. The researchers said future studies will focus on using this knowledge to improve conditioning therapy for patients undergoing HSC transplant.

Lab mouse

Scientists say they’ve generated a mouse model that supports the transplantation of human hematopoietic stem cells (HSCs), despite the species barrier and without the need for irradiation.

The group used a mutation of the Kit receptor in the mouse stem cells to facilitate the engraftment of human cells.

In this model, human HSCs can expand and differentiate into all blood cell types without any additional treatment.

Even cells of the innate immune system that are not typically found in “humanized” mice were efficiently generated in this mouse.

Furthermore, the stem cells can be maintained in the mouse over a longer period of time.

The researchers reported these results in Cell Stem Cell.

“Our goal was to develop an optimal model for the transplantation and study of human blood stem cells,” said study author Claudia Waskow, PhD, of Technische Universität Dresden in Germany.

To achieve optimal stem cell engraftment, she and her colleagues introduced a naturally occurring mutation of the Kit receptor into mice lacking a functional immune system.

In this way, the team circumvented the 2 major obstacles of HSC transplantation: the rejection by the recipient’s immune system and the absence of free niche space for the incoming donor stem cells in the recipient’s bone marrow.

The Kit mutation in the new mouse model impairs the recipient’s stem cell compartment in such a way that the endogenous HSCs can be easily replaced by human donor stem cells with a functional Kit receptor.

The researchers said this replacement works so efficiently that irradiation can be completely omitted, allowing the study of human blood development in a physiological setting. The model can now be used to study diseases of the human blood and immune system or to test new treatment options.

The results of this research also show that the Kit receptor is important for the function of human HSCs, notably in a transplant setting. The researchers said future studies will focus on using this knowledge to improve conditioning therapy for patients undergoing HSC transplant.

COPENHAGEN – The location of cerebral microbleeds appears to be strongly associated with dementia subtypes, perhaps reflecting the disorders’ underlying pathologies.

"This regional association with dementia subtypes is consistent with the hypothesis that lobar cerebral microbleeds reflect cerebral amyloid angiopathy, which is consistent with Alzheimer’s disease, while those in deep areas reflect hypertensive arteriopathy, which is important in vascular dementia," Lenore Launer, Ph.D., said at the Alzheimer’s Association International Conference 2014.

Dr. Launer, chief of the neuroepidemiology section in the laboratory of epidemiology and population science at the National Institute on Aging, and her colleagues examined the relationship between incident microbleeds and dementia in the AGES (Age, Gene/Environment Susceptibility) Reykjavik Study.

The population-based study is a project of the Icelandic Heart Association. It was established in 1967 and has followed more than 9,000 people, all of whom were born between 1907 and 1935. In 2000, the group partnered with the National Institute on Aging to further study diseases of old age, with an emphasis on imaging.

Since then, participants have undergone extensive phenotyping and repeat brain imaging to look specifically at cerebral microbleeds, infarcts, white-matter hyperintensities, and whole-brain volume.

Dr. Launer’s study comprised 2,482 people who were without stroke or dementia at baseline and who had complete brain MRI data during two 5-year periods: 2002-2006 and 2007-2011.

At baseline, patients’ mean age was 75 years. About 25% were carriers of the apolipoprotein E epsilon 4 allele. Hypertension was common (77% of patients). Almost a third of patients (29%) had brain infarct–like lesions, 11% had white-matter hyperintensities, and 16% had cerebral microbleeds.

Over the study period, 458 (18%) of the cohort’s patients developed new microbleeds, with 30% of those developing multiple bleeds. Of those new microbleeds, 64% were strictly lobar, with 1-15 bleeds per person. The remainder were deep lesions, numbering 1-19 per person.

There were 111 new dementia cases; of those, 83 were diagnosed as Alzheimer’s and 17 as vascular dementia. The rest were designated as "other dementia."

Two multivariate regression analyses examined the relationship between microbleed location and dementia subtype. Both controlled for a number of clinical and demographic factors. The first analysis included age, gender, and baseline cerebral microbleeds. The second analysis included all of those factors, plus education, depression, baseline vascular risk factors (hypertension, smoking, diabetes, body mass index, and total cholesterol), and baseline MRI markers (infarcts, total brain volume, and hyperintense lesions).

In the fully adjusted model, microbleed location showed a significant relationship with dementia subtypes. Lobar microbleeds were associated with a doubling in the risk of Alzheimer’s disease, while deep bleeds increased the risk of vascular dementia sixfold.

"It’s difficult to disentangle the temporal relationship here," Dr. Launer said. "But incident cerebral microbleeds may indicate more severe small-vessel disease, and be the thing that pushes a person off the cliff into the clinical presentation of dementia."

The Icelandic Heart Association and the National Institute on Aging sponsored the study. As a government employee, Dr. Launer has no financial disclosures.

[email protected]

On Twitter @alz_gal

COPENHAGEN – The location of cerebral microbleeds appears to be strongly associated with dementia subtypes, perhaps reflecting the disorders’ underlying pathologies.

"This regional association with dementia subtypes is consistent with the hypothesis that lobar cerebral microbleeds reflect cerebral amyloid angiopathy, which is consistent with Alzheimer’s disease, while those in deep areas reflect hypertensive arteriopathy, which is important in vascular dementia," Lenore Launer, Ph.D., said at the Alzheimer’s Association International Conference 2014.

Dr. Launer, chief of the neuroepidemiology section in the laboratory of epidemiology and population science at the National Institute on Aging, and her colleagues examined the relationship between incident microbleeds and dementia in the AGES (Age, Gene/Environment Susceptibility) Reykjavik Study.

The population-based study is a project of the Icelandic Heart Association. It was established in 1967 and has followed more than 9,000 people, all of whom were born between 1907 and 1935. In 2000, the group partnered with the National Institute on Aging to further study diseases of old age, with an emphasis on imaging.

Since then, participants have undergone extensive phenotyping and repeat brain imaging to look specifically at cerebral microbleeds, infarcts, white-matter hyperintensities, and whole-brain volume.

Dr. Launer’s study comprised 2,482 people who were without stroke or dementia at baseline and who had complete brain MRI data during two 5-year periods: 2002-2006 and 2007-2011.

At baseline, patients’ mean age was 75 years. About 25% were carriers of the apolipoprotein E epsilon 4 allele. Hypertension was common (77% of patients). Almost a third of patients (29%) had brain infarct–like lesions, 11% had white-matter hyperintensities, and 16% had cerebral microbleeds.

Over the study period, 458 (18%) of the cohort’s patients developed new microbleeds, with 30% of those developing multiple bleeds. Of those new microbleeds, 64% were strictly lobar, with 1-15 bleeds per person. The remainder were deep lesions, numbering 1-19 per person.

There were 111 new dementia cases; of those, 83 were diagnosed as Alzheimer’s and 17 as vascular dementia. The rest were designated as "other dementia."

Two multivariate regression analyses examined the relationship between microbleed location and dementia subtype. Both controlled for a number of clinical and demographic factors. The first analysis included age, gender, and baseline cerebral microbleeds. The second analysis included all of those factors, plus education, depression, baseline vascular risk factors (hypertension, smoking, diabetes, body mass index, and total cholesterol), and baseline MRI markers (infarcts, total brain volume, and hyperintense lesions).

In the fully adjusted model, microbleed location showed a significant relationship with dementia subtypes. Lobar microbleeds were associated with a doubling in the risk of Alzheimer’s disease, while deep bleeds increased the risk of vascular dementia sixfold.

"It’s difficult to disentangle the temporal relationship here," Dr. Launer said. "But incident cerebral microbleeds may indicate more severe small-vessel disease, and be the thing that pushes a person off the cliff into the clinical presentation of dementia."

The Icelandic Heart Association and the National Institute on Aging sponsored the study. As a government employee, Dr. Launer has no financial disclosures.

[email protected]

On Twitter @alz_gal

COPENHAGEN – The location of cerebral microbleeds appears to be strongly associated with dementia subtypes, perhaps reflecting the disorders’ underlying pathologies.

"This regional association with dementia subtypes is consistent with the hypothesis that lobar cerebral microbleeds reflect cerebral amyloid angiopathy, which is consistent with Alzheimer’s disease, while those in deep areas reflect hypertensive arteriopathy, which is important in vascular dementia," Lenore Launer, Ph.D., said at the Alzheimer’s Association International Conference 2014.

Dr. Launer, chief of the neuroepidemiology section in the laboratory of epidemiology and population science at the National Institute on Aging, and her colleagues examined the relationship between incident microbleeds and dementia in the AGES (Age, Gene/Environment Susceptibility) Reykjavik Study.

The population-based study is a project of the Icelandic Heart Association. It was established in 1967 and has followed more than 9,000 people, all of whom were born between 1907 and 1935. In 2000, the group partnered with the National Institute on Aging to further study diseases of old age, with an emphasis on imaging.

Since then, participants have undergone extensive phenotyping and repeat brain imaging to look specifically at cerebral microbleeds, infarcts, white-matter hyperintensities, and whole-brain volume.

Dr. Launer’s study comprised 2,482 people who were without stroke or dementia at baseline and who had complete brain MRI data during two 5-year periods: 2002-2006 and 2007-2011.

At baseline, patients’ mean age was 75 years. About 25% were carriers of the apolipoprotein E epsilon 4 allele. Hypertension was common (77% of patients). Almost a third of patients (29%) had brain infarct–like lesions, 11% had white-matter hyperintensities, and 16% had cerebral microbleeds.

Over the study period, 458 (18%) of the cohort’s patients developed new microbleeds, with 30% of those developing multiple bleeds. Of those new microbleeds, 64% were strictly lobar, with 1-15 bleeds per person. The remainder were deep lesions, numbering 1-19 per person.

There were 111 new dementia cases; of those, 83 were diagnosed as Alzheimer’s and 17 as vascular dementia. The rest were designated as "other dementia."

Two multivariate regression analyses examined the relationship between microbleed location and dementia subtype. Both controlled for a number of clinical and demographic factors. The first analysis included age, gender, and baseline cerebral microbleeds. The second analysis included all of those factors, plus education, depression, baseline vascular risk factors (hypertension, smoking, diabetes, body mass index, and total cholesterol), and baseline MRI markers (infarcts, total brain volume, and hyperintense lesions).

In the fully adjusted model, microbleed location showed a significant relationship with dementia subtypes. Lobar microbleeds were associated with a doubling in the risk of Alzheimer’s disease, while deep bleeds increased the risk of vascular dementia sixfold.

"It’s difficult to disentangle the temporal relationship here," Dr. Launer said. "But incident cerebral microbleeds may indicate more severe small-vessel disease, and be the thing that pushes a person off the cliff into the clinical presentation of dementia."

The Icelandic Heart Association and the National Institute on Aging sponsored the study. As a government employee, Dr. Launer has no financial disclosures.

[email protected]

On Twitter @alz_gal

Adults who consumed high levels of omega-3 polyunsaturated fatty acids showed a markedly reduced risk of developing amyotrophic lateral sclerosis in a pooled analysis of five large prospective cohort studies that assessed diet.

Diet-derived omega-3 polyunsaturated fatty acids (PUFAs) are known to have neuroprotective effects, and those present in neural plasma membranes can modulate oxidative stress, excitotoxicity, and inflammation. But no prospective studies have explored a possible relationship between omega-3 PUFA intake and amyotrophic lateral sclerosis (ALS) risk, according to Kathryn C. Fitzgerald of the department of nutrition, Harvard School of Public Health, Boston, and her associates.

© Suprijono Suharjoto - Fotolia.com

In a study published July 14 in JAMA Neurology, Ms. Fitzgerald and her colleagues pooled data from the Health Professionals Follow-up Study, the Nurses’ Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study. A total of 995 ALS patients were identified among 1,002,082 participants in these studies. The five studies included detailed dietary information and tracked the occurrence of ALS in the study participants through the National Death Index.

Omega-3 PUFA intake in the highest quintile of consumption at a median of 2.11 g/day was associated with a 34% reduced risk of developing ALS, compared with the lowest quintile of consumption at a median of 0.94 g/day. This finding was consistent across all five studies. This means that adding 0.5% of energy from omega-3 PUFAs and maintaining a constant intake of omega-6 fatty acids while reducing the intake of other types of fat would reduce ALS risk by 34%. Consumption of alpha-linolenic acid, another PUFA, also was associated with significantly reduced risk of developing ALS. In contrast, consumption of omega-6 PUFAs, consumption of linolenic acid, total energy intake, and percentage of energy from other types of fat showed no association with ALS risk, the investigators said (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1214]).

Foods that are rich in omega-3 PUFAs include fatty fish (salmon, sardines, tuna, herring) and fish oils; vegetable oils (corn, safflower, canola, soy, and flaxseed oils); and nuts and seeds (walnuts, chia seeds, butternuts, and sunflower seeds). Further studies are needed to confirm this protective effect in ALS and to determine whether patients who already have the disease would benefit from the addition of omega-3 PUFAs to their diets, Ms. Fitzgerald and her associates added.

The findings from Ms. Fitzgerald and her associates are persuasive and consistent with earlier suggestions that PUFAs may play a role in other neurodegenerative conditions, Dr. Michael Swash said in a related editorial (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1894]).

"Ideas on long-term risk-susceptibility factors are very much welcomed in trying to unravel the mystery that is ALS. Now, in addition to genetic factors, there are the following five risk factors to work on: male sex, smoking status, BMI, physical exercise, and dietary intake of PUFAs," said Dr. Swash of the Royal London Hospital, Queen Mary University of London, and the Institute of Neuroscience at the University of Lisbon.

This study was supported by the National Institute of Neurological Diseases and Stroke, the National Cancer Institute, and the ALS Therapy Alliance Foundation. The study authors and Dr. Swash had no financial disclosures.

Adults who consumed high levels of omega-3 polyunsaturated fatty acids showed a markedly reduced risk of developing amyotrophic lateral sclerosis in a pooled analysis of five large prospective cohort studies that assessed diet.

Diet-derived omega-3 polyunsaturated fatty acids (PUFAs) are known to have neuroprotective effects, and those present in neural plasma membranes can modulate oxidative stress, excitotoxicity, and inflammation. But no prospective studies have explored a possible relationship between omega-3 PUFA intake and amyotrophic lateral sclerosis (ALS) risk, according to Kathryn C. Fitzgerald of the department of nutrition, Harvard School of Public Health, Boston, and her associates.

© Suprijono Suharjoto - Fotolia.com

In a study published July 14 in JAMA Neurology, Ms. Fitzgerald and her colleagues pooled data from the Health Professionals Follow-up Study, the Nurses’ Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study. A total of 995 ALS patients were identified among 1,002,082 participants in these studies. The five studies included detailed dietary information and tracked the occurrence of ALS in the study participants through the National Death Index.

Omega-3 PUFA intake in the highest quintile of consumption at a median of 2.11 g/day was associated with a 34% reduced risk of developing ALS, compared with the lowest quintile of consumption at a median of 0.94 g/day. This finding was consistent across all five studies. This means that adding 0.5% of energy from omega-3 PUFAs and maintaining a constant intake of omega-6 fatty acids while reducing the intake of other types of fat would reduce ALS risk by 34%. Consumption of alpha-linolenic acid, another PUFA, also was associated with significantly reduced risk of developing ALS. In contrast, consumption of omega-6 PUFAs, consumption of linolenic acid, total energy intake, and percentage of energy from other types of fat showed no association with ALS risk, the investigators said (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1214]).

Foods that are rich in omega-3 PUFAs include fatty fish (salmon, sardines, tuna, herring) and fish oils; vegetable oils (corn, safflower, canola, soy, and flaxseed oils); and nuts and seeds (walnuts, chia seeds, butternuts, and sunflower seeds). Further studies are needed to confirm this protective effect in ALS and to determine whether patients who already have the disease would benefit from the addition of omega-3 PUFAs to their diets, Ms. Fitzgerald and her associates added.

The findings from Ms. Fitzgerald and her associates are persuasive and consistent with earlier suggestions that PUFAs may play a role in other neurodegenerative conditions, Dr. Michael Swash said in a related editorial (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1894]).

"Ideas on long-term risk-susceptibility factors are very much welcomed in trying to unravel the mystery that is ALS. Now, in addition to genetic factors, there are the following five risk factors to work on: male sex, smoking status, BMI, physical exercise, and dietary intake of PUFAs," said Dr. Swash of the Royal London Hospital, Queen Mary University of London, and the Institute of Neuroscience at the University of Lisbon.

This study was supported by the National Institute of Neurological Diseases and Stroke, the National Cancer Institute, and the ALS Therapy Alliance Foundation. The study authors and Dr. Swash had no financial disclosures.

Adults who consumed high levels of omega-3 polyunsaturated fatty acids showed a markedly reduced risk of developing amyotrophic lateral sclerosis in a pooled analysis of five large prospective cohort studies that assessed diet.

Diet-derived omega-3 polyunsaturated fatty acids (PUFAs) are known to have neuroprotective effects, and those present in neural plasma membranes can modulate oxidative stress, excitotoxicity, and inflammation. But no prospective studies have explored a possible relationship between omega-3 PUFA intake and amyotrophic lateral sclerosis (ALS) risk, according to Kathryn C. Fitzgerald of the department of nutrition, Harvard School of Public Health, Boston, and her associates.

© Suprijono Suharjoto - Fotolia.com

In a study published July 14 in JAMA Neurology, Ms. Fitzgerald and her colleagues pooled data from the Health Professionals Follow-up Study, the Nurses’ Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study. A total of 995 ALS patients were identified among 1,002,082 participants in these studies. The five studies included detailed dietary information and tracked the occurrence of ALS in the study participants through the National Death Index.

Omega-3 PUFA intake in the highest quintile of consumption at a median of 2.11 g/day was associated with a 34% reduced risk of developing ALS, compared with the lowest quintile of consumption at a median of 0.94 g/day. This finding was consistent across all five studies. This means that adding 0.5% of energy from omega-3 PUFAs and maintaining a constant intake of omega-6 fatty acids while reducing the intake of other types of fat would reduce ALS risk by 34%. Consumption of alpha-linolenic acid, another PUFA, also was associated with significantly reduced risk of developing ALS. In contrast, consumption of omega-6 PUFAs, consumption of linolenic acid, total energy intake, and percentage of energy from other types of fat showed no association with ALS risk, the investigators said (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1214]).

Foods that are rich in omega-3 PUFAs include fatty fish (salmon, sardines, tuna, herring) and fish oils; vegetable oils (corn, safflower, canola, soy, and flaxseed oils); and nuts and seeds (walnuts, chia seeds, butternuts, and sunflower seeds). Further studies are needed to confirm this protective effect in ALS and to determine whether patients who already have the disease would benefit from the addition of omega-3 PUFAs to their diets, Ms. Fitzgerald and her associates added.

The findings from Ms. Fitzgerald and her associates are persuasive and consistent with earlier suggestions that PUFAs may play a role in other neurodegenerative conditions, Dr. Michael Swash said in a related editorial (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1894]).

"Ideas on long-term risk-susceptibility factors are very much welcomed in trying to unravel the mystery that is ALS. Now, in addition to genetic factors, there are the following five risk factors to work on: male sex, smoking status, BMI, physical exercise, and dietary intake of PUFAs," said Dr. Swash of the Royal London Hospital, Queen Mary University of London, and the Institute of Neuroscience at the University of Lisbon.

This study was supported by the National Institute of Neurological Diseases and Stroke, the National Cancer Institute, and the ALS Therapy Alliance Foundation. The study authors and Dr. Swash had no financial disclosures.