CTAD

SAN DIEGO – Patients recently diagnosed with Alzheimer’s disease had an increased prevalence of diagnoses for neuropsychiatric conditions that mimic symptoms of mild cognitive impairment in a large retrospective, case-control study.

The findings underscore the need for an instrument designed to help clinicians differentiate mild cognitive impairment (MCI) from other neuropsychiatric conditions, Jiao Yang, Ph.D., said in an interview at the Clinical Trials Conference on Alzheimer’s Disease.

"We need a better guidance for clinical practice," said Dr. Yang, a project statistician with Deerfield, Ill.–based Takeda Pharmaceuticals International. "We do need some type of a diagnostic test to differentiate or to detect MCI."

In an effort to characterize the 3-year period immediately preceding the first diagnosis of Alzheimer’s disease (AD) and the first 6 months after diagnosis, Dr. Yang and her associates used data from the 2010-2011 Truven Health Analytics MarketScan Commercial and Medicare Supplemental Database to identify risk and prognostic factors in 28,879 newly diagnosed AD patients with a mean age of 79 years. The researchers also randomly selected a control cohort of 28,879 patients, excluding those with dementia or taking AD medications, and matched them in a 1:1 fashion with the AD cohort on age, gender, insurance plan type, and geographic region.

The percentage of AD patients, compared with controls, who had a diagnosis of MCI at 36 months before AD diagnosis to 6 months before AD diagnosis to 6 months after AD diagnosis increased from 0.2% to 5.2% to 7.6%, compared with controls (0% at all three time points). The same significant trend occurred for diagnoses of AD-related conditions or dementias or frontotemporal dementia, dementia with Lewy bodies, and memory loss (from 1.9% to 36.2% to 48.2% for AD patients and from 0.2% to 1.1% to 1.4% for controls) and various neurologic disorders (from 5.4% to 26.4% to 31.9% for AD patients and from 1.1% to 4.2% to 4.9% for controls).

"The steeper slope of the increase in prevalence in the 6 months pre-index period seems to suggest that diagnosis of these disorders may lead a physician to test for AD, while the 6 months post-index increase could indicate higher awareness among physicians of the need to test AD patients for other similar diagnoses," Dr. Yang said.

Over time, a higher percentage of AD patients vs. controls also had anxiety disorder (from 2.4% to 6.6% to 6.5% vs. from 1.1% to 1.7% to 1.9%) and depression (from 4.6% to 11.1% to 11.6% vs. from 1.4% to 2.0% to 2.3%). The percentage of patients with cerebrovascular disease also increased with time (from 8.3% to 41.8% to 47.5% for AD patients and from 5.1% to 19.9% to 22.4% for controls), as did the percentage of patients with congestive heart failure (from 3.7% to 16.5% to 19.4% for AD patients and from 2.9% to 11.4% to 13.0% for controls).

The researchers also noted that, at each subsequent interval, a higher proportion of AD patients were using antidepressants, tranquilizers/antipsychotics, and benzodiazepines, compared with controls. In addition, 37.2% of MCI patients were primarily first diagnosed by neurologists, "possibly highlighting the difficulty of making the diagnosis," she noted in the poster presentation. "This could be due to the lack of tests or procedures to demonstrate conclusively the presence of MCI."

Takeda Pharmaceuticals International sponsored the study.

[email protected]

SAN DIEGO – Patients recently diagnosed with Alzheimer’s disease had an increased prevalence of diagnoses for neuropsychiatric conditions that mimic symptoms of mild cognitive impairment in a large retrospective, case-control study.

The findings underscore the need for an instrument designed to help clinicians differentiate mild cognitive impairment (MCI) from other neuropsychiatric conditions, Jiao Yang, Ph.D., said in an interview at the Clinical Trials Conference on Alzheimer’s Disease.

"We need a better guidance for clinical practice," said Dr. Yang, a project statistician with Deerfield, Ill.–based Takeda Pharmaceuticals International. "We do need some type of a diagnostic test to differentiate or to detect MCI."

In an effort to characterize the 3-year period immediately preceding the first diagnosis of Alzheimer’s disease (AD) and the first 6 months after diagnosis, Dr. Yang and her associates used data from the 2010-2011 Truven Health Analytics MarketScan Commercial and Medicare Supplemental Database to identify risk and prognostic factors in 28,879 newly diagnosed AD patients with a mean age of 79 years. The researchers also randomly selected a control cohort of 28,879 patients, excluding those with dementia or taking AD medications, and matched them in a 1:1 fashion with the AD cohort on age, gender, insurance plan type, and geographic region.

The percentage of AD patients, compared with controls, who had a diagnosis of MCI at 36 months before AD diagnosis to 6 months before AD diagnosis to 6 months after AD diagnosis increased from 0.2% to 5.2% to 7.6%, compared with controls (0% at all three time points). The same significant trend occurred for diagnoses of AD-related conditions or dementias or frontotemporal dementia, dementia with Lewy bodies, and memory loss (from 1.9% to 36.2% to 48.2% for AD patients and from 0.2% to 1.1% to 1.4% for controls) and various neurologic disorders (from 5.4% to 26.4% to 31.9% for AD patients and from 1.1% to 4.2% to 4.9% for controls).

"The steeper slope of the increase in prevalence in the 6 months pre-index period seems to suggest that diagnosis of these disorders may lead a physician to test for AD, while the 6 months post-index increase could indicate higher awareness among physicians of the need to test AD patients for other similar diagnoses," Dr. Yang said.

Over time, a higher percentage of AD patients vs. controls also had anxiety disorder (from 2.4% to 6.6% to 6.5% vs. from 1.1% to 1.7% to 1.9%) and depression (from 4.6% to 11.1% to 11.6% vs. from 1.4% to 2.0% to 2.3%). The percentage of patients with cerebrovascular disease also increased with time (from 8.3% to 41.8% to 47.5% for AD patients and from 5.1% to 19.9% to 22.4% for controls), as did the percentage of patients with congestive heart failure (from 3.7% to 16.5% to 19.4% for AD patients and from 2.9% to 11.4% to 13.0% for controls).

The researchers also noted that, at each subsequent interval, a higher proportion of AD patients were using antidepressants, tranquilizers/antipsychotics, and benzodiazepines, compared with controls. In addition, 37.2% of MCI patients were primarily first diagnosed by neurologists, "possibly highlighting the difficulty of making the diagnosis," she noted in the poster presentation. "This could be due to the lack of tests or procedures to demonstrate conclusively the presence of MCI."

Takeda Pharmaceuticals International sponsored the study.

[email protected]

SAN DIEGO – Patients recently diagnosed with Alzheimer’s disease had an increased prevalence of diagnoses for neuropsychiatric conditions that mimic symptoms of mild cognitive impairment in a large retrospective, case-control study.

The findings underscore the need for an instrument designed to help clinicians differentiate mild cognitive impairment (MCI) from other neuropsychiatric conditions, Jiao Yang, Ph.D., said in an interview at the Clinical Trials Conference on Alzheimer’s Disease.

"We need a better guidance for clinical practice," said Dr. Yang, a project statistician with Deerfield, Ill.–based Takeda Pharmaceuticals International. "We do need some type of a diagnostic test to differentiate or to detect MCI."

In an effort to characterize the 3-year period immediately preceding the first diagnosis of Alzheimer’s disease (AD) and the first 6 months after diagnosis, Dr. Yang and her associates used data from the 2010-2011 Truven Health Analytics MarketScan Commercial and Medicare Supplemental Database to identify risk and prognostic factors in 28,879 newly diagnosed AD patients with a mean age of 79 years. The researchers also randomly selected a control cohort of 28,879 patients, excluding those with dementia or taking AD medications, and matched them in a 1:1 fashion with the AD cohort on age, gender, insurance plan type, and geographic region.

The percentage of AD patients, compared with controls, who had a diagnosis of MCI at 36 months before AD diagnosis to 6 months before AD diagnosis to 6 months after AD diagnosis increased from 0.2% to 5.2% to 7.6%, compared with controls (0% at all three time points). The same significant trend occurred for diagnoses of AD-related conditions or dementias or frontotemporal dementia, dementia with Lewy bodies, and memory loss (from 1.9% to 36.2% to 48.2% for AD patients and from 0.2% to 1.1% to 1.4% for controls) and various neurologic disorders (from 5.4% to 26.4% to 31.9% for AD patients and from 1.1% to 4.2% to 4.9% for controls).

"The steeper slope of the increase in prevalence in the 6 months pre-index period seems to suggest that diagnosis of these disorders may lead a physician to test for AD, while the 6 months post-index increase could indicate higher awareness among physicians of the need to test AD patients for other similar diagnoses," Dr. Yang said.

Over time, a higher percentage of AD patients vs. controls also had anxiety disorder (from 2.4% to 6.6% to 6.5% vs. from 1.1% to 1.7% to 1.9%) and depression (from 4.6% to 11.1% to 11.6% vs. from 1.4% to 2.0% to 2.3%). The percentage of patients with cerebrovascular disease also increased with time (from 8.3% to 41.8% to 47.5% for AD patients and from 5.1% to 19.9% to 22.4% for controls), as did the percentage of patients with congestive heart failure (from 3.7% to 16.5% to 19.4% for AD patients and from 2.9% to 11.4% to 13.0% for controls).

The researchers also noted that, at each subsequent interval, a higher proportion of AD patients were using antidepressants, tranquilizers/antipsychotics, and benzodiazepines, compared with controls. In addition, 37.2% of MCI patients were primarily first diagnosed by neurologists, "possibly highlighting the difficulty of making the diagnosis," she noted in the poster presentation. "This could be due to the lack of tests or procedures to demonstrate conclusively the presence of MCI."

Takeda Pharmaceuticals International sponsored the study.

[email protected]

SAN DIEGO – Subjective memory complaints at study enrollment predicted clinical memory impairment 8 years later in healthy men aged 60 years and older, findings from a large ongoing study showed.

"This suggests the utility of subjective memory complaints for future prevention trials," Erin L. Abner, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

She and her associates also found that hypertension, diabetes, black race, and education level emerged as significant risk factors for clinical impairment, while the use of antihypertensive agents and statins emerged as protective factors.

The findings come from centralized follow-up of men enrolled in the PREADVISE (Prevention of Alzheimer’s Disease by Vitamin E and Selenium) trial, which was launched in 2002 as an ancillary to the SELECT (Selenium and Vitamin E in Preventing Prostate Cancer) trial. PREADVISE was designed to assess the effect of vitamin E and selenium on reducing the incidence of Alzheimer’s disease and other neurodegenerative disorders.

The PREADVISE study had four arms: Participants received 400 IU vitamin E per day, 200 mcg of selenium per day, both, or matching placebos. Recruitment began in 2002, and a total of 7,553 nondemented men aged 60 and older participated. In 2008, SELECT was suspended because of an interim futility analysis, and study sites began closing. Two years later, 4,246 PREADVISE participants consented to centralized follow-up by telephone. Of these, 3,701 have been screened to date, said Dr. Abner of the Sanders-Brown Center on Aging and the department of epidemiology at the University of Kentucky, Lexington.

Men were eligible for PREADVISE if they scored at least a 5 on the Memory Impairment Screen (MIS) at baseline. "They received alternating versions of the MIS in subsequent years to minimize learning effects," she said. "If they failed the MIS, they were given the Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] neuropsychological test battery. If their age-adjusted CERAD score was 35 or less, they were referred to a physician for a medical work-up and had their medical records forwarded to us." If they failed the MIS over the phone, they were administered the Modified Telephone Interview for Cognitive Status [TICS-M] test. "If they scored 31 or less on TICS-M, they were advised to seek a medical work-up." Dr. Abner explained. "Although the records were forwarded to us, we were still blinded to treatment status."

The main outcome of interest was clinical impairment, which was defined as impaired cognition indicated by failing scores on the CERAD or the TICS-M. Confirmed impairment was verified by a medical work-up, while suspected impairment was defined as that not yet confirmed. Subjective memory complaints were defined as self-perceived changes in memory that may not be reflected by cognitive testing. "Subjective memory complaints are common in older adults and have been previously reported to predict future cognitive decline," Dr. Abner noted. "All PREADVISE participants were asked at baseline if they had noticed any changes in their memory. Positive responders were also asked if they thought they had more problems with their memory than most people." Thus, participants were classified as having no memory complaint, memory changes, or memory problems at baseline.

The researchers used a stepwise Cox proportional hazards model to identify risk factors associated with the time from baseline to clinical impairment. The predictive variables in the model were both fixed and time dependent. Fixed variables (self-reported) were baseline age, education, black race, Hispanic ethnicity, mother’s age at childbirth, a family history of dementia, and comorbidities. Time-dependent variables were depression, anxiety, alcohol abuse, a high cholesterol level, antihypertensive use, hyperglycemia, thyroid disorder, and sleep apnea.

The mean age of the 3,701 participants was 68 years old, and most (77%) had no memory complaints at baseline. Participants underwent an average of eight annual assessments. Hypertension emerged as the most common comorbidity (34%), with 22% reporting the use of a statin. High cholesterol was the most common time-dependent comorbidity (68%), followed by antihypertensive use (64%), sleep apnea (18%), and depression (11%).

Dr. Abner reported that of the 3,701 men screened to date, 436 (12%) have clinical impairments with 332 having suspected mild cognitive impairment (MCI), 85 confirmed MCI, 4 suspected dementia, and 15 confirmed dementia. The risk of a clinical impairment was significantly increased by an older age at baseline (HR, 1.12 for every 1-year increment); baseline hypertension (HR, 1.96); African American race (HR, 3.24); a high school education or less (HR, 1.66); a history of diabetes (HR, 1.37); and, in the absence of apolipoprotein E4 (apo E4), baseline memory complaint (HR, 1.66 for changes vs. no complaint and HR, 4.48 for problems vs. no complaint). "It turns out that in the absence of apo E4, subjective memory complaints are predictive of clinical impairment," she said. "When apo E4 is present, the hazard ratios are not significant."

The risk of an observed impairment was significantly reduced by the use of antihypertensives (HR, 0.34) and a report of high cholesterol (HR, 0.75).

Dr. Abner acknowledged certain limitations of the study, including the fact that most clinical impairments are not yet confirmed by medical review. In addition, "relevant early to midlife socioeconomic status exposures were not measured, which may mitigate the effect observed for black race," she said. "Also, many of our black participants were recruited from Veterans Affairs sites, so their exposures may be qualitatively different in terms of their risk of head trauma and PTSD [posttraumatic stress disorder]. Overall, the sample was highly educated and healthy."

Screening of the full PREADVISE cohort is expected to be completed in early 2014.

The study is funded by the National Institute on Aging. Dr. Abner said she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Subjective memory complaints at study enrollment predicted clinical memory impairment 8 years later in healthy men aged 60 years and older, findings from a large ongoing study showed.

"This suggests the utility of subjective memory complaints for future prevention trials," Erin L. Abner, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

She and her associates also found that hypertension, diabetes, black race, and education level emerged as significant risk factors for clinical impairment, while the use of antihypertensive agents and statins emerged as protective factors.

The findings come from centralized follow-up of men enrolled in the PREADVISE (Prevention of Alzheimer’s Disease by Vitamin E and Selenium) trial, which was launched in 2002 as an ancillary to the SELECT (Selenium and Vitamin E in Preventing Prostate Cancer) trial. PREADVISE was designed to assess the effect of vitamin E and selenium on reducing the incidence of Alzheimer’s disease and other neurodegenerative disorders.

The PREADVISE study had four arms: Participants received 400 IU vitamin E per day, 200 mcg of selenium per day, both, or matching placebos. Recruitment began in 2002, and a total of 7,553 nondemented men aged 60 and older participated. In 2008, SELECT was suspended because of an interim futility analysis, and study sites began closing. Two years later, 4,246 PREADVISE participants consented to centralized follow-up by telephone. Of these, 3,701 have been screened to date, said Dr. Abner of the Sanders-Brown Center on Aging and the department of epidemiology at the University of Kentucky, Lexington.

Men were eligible for PREADVISE if they scored at least a 5 on the Memory Impairment Screen (MIS) at baseline. "They received alternating versions of the MIS in subsequent years to minimize learning effects," she said. "If they failed the MIS, they were given the Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] neuropsychological test battery. If their age-adjusted CERAD score was 35 or less, they were referred to a physician for a medical work-up and had their medical records forwarded to us." If they failed the MIS over the phone, they were administered the Modified Telephone Interview for Cognitive Status [TICS-M] test. "If they scored 31 or less on TICS-M, they were advised to seek a medical work-up." Dr. Abner explained. "Although the records were forwarded to us, we were still blinded to treatment status."

The main outcome of interest was clinical impairment, which was defined as impaired cognition indicated by failing scores on the CERAD or the TICS-M. Confirmed impairment was verified by a medical work-up, while suspected impairment was defined as that not yet confirmed. Subjective memory complaints were defined as self-perceived changes in memory that may not be reflected by cognitive testing. "Subjective memory complaints are common in older adults and have been previously reported to predict future cognitive decline," Dr. Abner noted. "All PREADVISE participants were asked at baseline if they had noticed any changes in their memory. Positive responders were also asked if they thought they had more problems with their memory than most people." Thus, participants were classified as having no memory complaint, memory changes, or memory problems at baseline.

The researchers used a stepwise Cox proportional hazards model to identify risk factors associated with the time from baseline to clinical impairment. The predictive variables in the model were both fixed and time dependent. Fixed variables (self-reported) were baseline age, education, black race, Hispanic ethnicity, mother’s age at childbirth, a family history of dementia, and comorbidities. Time-dependent variables were depression, anxiety, alcohol abuse, a high cholesterol level, antihypertensive use, hyperglycemia, thyroid disorder, and sleep apnea.

The mean age of the 3,701 participants was 68 years old, and most (77%) had no memory complaints at baseline. Participants underwent an average of eight annual assessments. Hypertension emerged as the most common comorbidity (34%), with 22% reporting the use of a statin. High cholesterol was the most common time-dependent comorbidity (68%), followed by antihypertensive use (64%), sleep apnea (18%), and depression (11%).

Dr. Abner reported that of the 3,701 men screened to date, 436 (12%) have clinical impairments with 332 having suspected mild cognitive impairment (MCI), 85 confirmed MCI, 4 suspected dementia, and 15 confirmed dementia. The risk of a clinical impairment was significantly increased by an older age at baseline (HR, 1.12 for every 1-year increment); baseline hypertension (HR, 1.96); African American race (HR, 3.24); a high school education or less (HR, 1.66); a history of diabetes (HR, 1.37); and, in the absence of apolipoprotein E4 (apo E4), baseline memory complaint (HR, 1.66 for changes vs. no complaint and HR, 4.48 for problems vs. no complaint). "It turns out that in the absence of apo E4, subjective memory complaints are predictive of clinical impairment," she said. "When apo E4 is present, the hazard ratios are not significant."

The risk of an observed impairment was significantly reduced by the use of antihypertensives (HR, 0.34) and a report of high cholesterol (HR, 0.75).

Dr. Abner acknowledged certain limitations of the study, including the fact that most clinical impairments are not yet confirmed by medical review. In addition, "relevant early to midlife socioeconomic status exposures were not measured, which may mitigate the effect observed for black race," she said. "Also, many of our black participants were recruited from Veterans Affairs sites, so their exposures may be qualitatively different in terms of their risk of head trauma and PTSD [posttraumatic stress disorder]. Overall, the sample was highly educated and healthy."

Screening of the full PREADVISE cohort is expected to be completed in early 2014.

The study is funded by the National Institute on Aging. Dr. Abner said she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Subjective memory complaints at study enrollment predicted clinical memory impairment 8 years later in healthy men aged 60 years and older, findings from a large ongoing study showed.

"This suggests the utility of subjective memory complaints for future prevention trials," Erin L. Abner, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

She and her associates also found that hypertension, diabetes, black race, and education level emerged as significant risk factors for clinical impairment, while the use of antihypertensive agents and statins emerged as protective factors.

The findings come from centralized follow-up of men enrolled in the PREADVISE (Prevention of Alzheimer’s Disease by Vitamin E and Selenium) trial, which was launched in 2002 as an ancillary to the SELECT (Selenium and Vitamin E in Preventing Prostate Cancer) trial. PREADVISE was designed to assess the effect of vitamin E and selenium on reducing the incidence of Alzheimer’s disease and other neurodegenerative disorders.

The PREADVISE study had four arms: Participants received 400 IU vitamin E per day, 200 mcg of selenium per day, both, or matching placebos. Recruitment began in 2002, and a total of 7,553 nondemented men aged 60 and older participated. In 2008, SELECT was suspended because of an interim futility analysis, and study sites began closing. Two years later, 4,246 PREADVISE participants consented to centralized follow-up by telephone. Of these, 3,701 have been screened to date, said Dr. Abner of the Sanders-Brown Center on Aging and the department of epidemiology at the University of Kentucky, Lexington.

Men were eligible for PREADVISE if they scored at least a 5 on the Memory Impairment Screen (MIS) at baseline. "They received alternating versions of the MIS in subsequent years to minimize learning effects," she said. "If they failed the MIS, they were given the Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] neuropsychological test battery. If their age-adjusted CERAD score was 35 or less, they were referred to a physician for a medical work-up and had their medical records forwarded to us." If they failed the MIS over the phone, they were administered the Modified Telephone Interview for Cognitive Status [TICS-M] test. "If they scored 31 or less on TICS-M, they were advised to seek a medical work-up." Dr. Abner explained. "Although the records were forwarded to us, we were still blinded to treatment status."

The main outcome of interest was clinical impairment, which was defined as impaired cognition indicated by failing scores on the CERAD or the TICS-M. Confirmed impairment was verified by a medical work-up, while suspected impairment was defined as that not yet confirmed. Subjective memory complaints were defined as self-perceived changes in memory that may not be reflected by cognitive testing. "Subjective memory complaints are common in older adults and have been previously reported to predict future cognitive decline," Dr. Abner noted. "All PREADVISE participants were asked at baseline if they had noticed any changes in their memory. Positive responders were also asked if they thought they had more problems with their memory than most people." Thus, participants were classified as having no memory complaint, memory changes, or memory problems at baseline.

The researchers used a stepwise Cox proportional hazards model to identify risk factors associated with the time from baseline to clinical impairment. The predictive variables in the model were both fixed and time dependent. Fixed variables (self-reported) were baseline age, education, black race, Hispanic ethnicity, mother’s age at childbirth, a family history of dementia, and comorbidities. Time-dependent variables were depression, anxiety, alcohol abuse, a high cholesterol level, antihypertensive use, hyperglycemia, thyroid disorder, and sleep apnea.

The mean age of the 3,701 participants was 68 years old, and most (77%) had no memory complaints at baseline. Participants underwent an average of eight annual assessments. Hypertension emerged as the most common comorbidity (34%), with 22% reporting the use of a statin. High cholesterol was the most common time-dependent comorbidity (68%), followed by antihypertensive use (64%), sleep apnea (18%), and depression (11%).

Dr. Abner reported that of the 3,701 men screened to date, 436 (12%) have clinical impairments with 332 having suspected mild cognitive impairment (MCI), 85 confirmed MCI, 4 suspected dementia, and 15 confirmed dementia. The risk of a clinical impairment was significantly increased by an older age at baseline (HR, 1.12 for every 1-year increment); baseline hypertension (HR, 1.96); African American race (HR, 3.24); a high school education or less (HR, 1.66); a history of diabetes (HR, 1.37); and, in the absence of apolipoprotein E4 (apo E4), baseline memory complaint (HR, 1.66 for changes vs. no complaint and HR, 4.48 for problems vs. no complaint). "It turns out that in the absence of apo E4, subjective memory complaints are predictive of clinical impairment," she said. "When apo E4 is present, the hazard ratios are not significant."

The risk of an observed impairment was significantly reduced by the use of antihypertensives (HR, 0.34) and a report of high cholesterol (HR, 0.75).

Dr. Abner acknowledged certain limitations of the study, including the fact that most clinical impairments are not yet confirmed by medical review. In addition, "relevant early to midlife socioeconomic status exposures were not measured, which may mitigate the effect observed for black race," she said. "Also, many of our black participants were recruited from Veterans Affairs sites, so their exposures may be qualitatively different in terms of their risk of head trauma and PTSD [posttraumatic stress disorder]. Overall, the sample was highly educated and healthy."

Screening of the full PREADVISE cohort is expected to be completed in early 2014.

The study is funded by the National Institute on Aging. Dr. Abner said she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – In a 3-year Swedish study of patients with mild or moderate forms of Alzheimer’s disease who were taking cholinesterase inhibitors, varying outcomes were demonstrated in the different domains of the disease and in the scales used.

The findings show the clinical importance of functional evaluations, even in the mild stages of Alzheimer’s disease (AD), Carina Wattmo, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Some randomized trials, such as that of the anti-beta-amyloid antibody solanezumab and the medical food souvenaid, "have shown small but significant positive cognitive effects in mild AD exclusively," said Dr. Wattmo of the clinical memory research unit in the department of clinical sciences at Lund University, Malmö, Sweden.

"Placebo-controlled trials longer than 6 months in untreated AD patients are not allowed for ethical reasons. New, longer studies are most often performed on patients who are on active treatment with cholinesterase inhibitors and/or memantine. Therapies expected to modify disease progression need to be thoroughly evaluated over many years. Knowledge on the expected longitudinal outcome in different stages of AD is scarce."

Dr. Wattmo and her associates analyzed data from the Swedish Alzheimer Treatment Study (SATS), a 3-year, prospective, open-label, nonrandomized multicenter study launched to evaluate the long-term effectiveness of cholinesterase inhibitor treatment in a routine clinical setting. Patients were diagnosed with possible or probable AD; the population included 734 patients with mild AD and 287 with moderate disease.

The patients were assessed after 2 months of therapy and every 6 months over the 3-year period, with the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog), the Clinician’s Interview-Based Impression of Change (CIBIC), and functional capacity based on the Instrumental Activities of Daily Living scale (IADL).

The mean age of patients was 75 years, and 64% were female. At baseline, patients in the mild AD group showed an illness duration of 2.9 years vs. 3.4 years in the moderate AD group, a difference that was statistically significant (P = .005). They also had more years of education (9.6 vs. 9.0 years; P less than .001), and a better functional capacity based on the IADL score (14.7 points vs. 19.1 points; P less than .001).

Dr. Wattmo reported 3-year results from 306 patients in the mild AD group and 79 patients in the moderate AD group. The mean change in MMSE was 3.1 points in the mild AD group vs. 4 points in the moderate AD group, a difference that did not reach statistical significance (P = .148). The mean decline in the ADAS-cog was 6.1 points in the mild AD group vs. 13.2 points in the moderate AD group, a difference that reached statistical significance (P less than .001).

In addition, 33% of patients in the mild AD group showed global CIBIC improvement or no change after 3 years of therapy, compared with 15% in the moderate AD group, a difference that was statistically significant (P = .002).

On the IADL, the mean decline was 6.3 points in the mild AD group vs. 7.5 points in the moderate AD group, a difference that was not statistically significant (P = .063).

"Varying outcomes were demonstrated in the different domains and stages of AD in this study from routine clinical practice," Dr. Wattmo concluded. "The outcome could be dependent on the scales used."

Dr. Wattmo said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – In a 3-year Swedish study of patients with mild or moderate forms of Alzheimer’s disease who were taking cholinesterase inhibitors, varying outcomes were demonstrated in the different domains of the disease and in the scales used.

The findings show the clinical importance of functional evaluations, even in the mild stages of Alzheimer’s disease (AD), Carina Wattmo, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Some randomized trials, such as that of the anti-beta-amyloid antibody solanezumab and the medical food souvenaid, "have shown small but significant positive cognitive effects in mild AD exclusively," said Dr. Wattmo of the clinical memory research unit in the department of clinical sciences at Lund University, Malmö, Sweden.

"Placebo-controlled trials longer than 6 months in untreated AD patients are not allowed for ethical reasons. New, longer studies are most often performed on patients who are on active treatment with cholinesterase inhibitors and/or memantine. Therapies expected to modify disease progression need to be thoroughly evaluated over many years. Knowledge on the expected longitudinal outcome in different stages of AD is scarce."

Dr. Wattmo and her associates analyzed data from the Swedish Alzheimer Treatment Study (SATS), a 3-year, prospective, open-label, nonrandomized multicenter study launched to evaluate the long-term effectiveness of cholinesterase inhibitor treatment in a routine clinical setting. Patients were diagnosed with possible or probable AD; the population included 734 patients with mild AD and 287 with moderate disease.

The patients were assessed after 2 months of therapy and every 6 months over the 3-year period, with the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog), the Clinician’s Interview-Based Impression of Change (CIBIC), and functional capacity based on the Instrumental Activities of Daily Living scale (IADL).

The mean age of patients was 75 years, and 64% were female. At baseline, patients in the mild AD group showed an illness duration of 2.9 years vs. 3.4 years in the moderate AD group, a difference that was statistically significant (P = .005). They also had more years of education (9.6 vs. 9.0 years; P less than .001), and a better functional capacity based on the IADL score (14.7 points vs. 19.1 points; P less than .001).

Dr. Wattmo reported 3-year results from 306 patients in the mild AD group and 79 patients in the moderate AD group. The mean change in MMSE was 3.1 points in the mild AD group vs. 4 points in the moderate AD group, a difference that did not reach statistical significance (P = .148). The mean decline in the ADAS-cog was 6.1 points in the mild AD group vs. 13.2 points in the moderate AD group, a difference that reached statistical significance (P less than .001).

In addition, 33% of patients in the mild AD group showed global CIBIC improvement or no change after 3 years of therapy, compared with 15% in the moderate AD group, a difference that was statistically significant (P = .002).

On the IADL, the mean decline was 6.3 points in the mild AD group vs. 7.5 points in the moderate AD group, a difference that was not statistically significant (P = .063).

"Varying outcomes were demonstrated in the different domains and stages of AD in this study from routine clinical practice," Dr. Wattmo concluded. "The outcome could be dependent on the scales used."

Dr. Wattmo said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – In a 3-year Swedish study of patients with mild or moderate forms of Alzheimer’s disease who were taking cholinesterase inhibitors, varying outcomes were demonstrated in the different domains of the disease and in the scales used.

The findings show the clinical importance of functional evaluations, even in the mild stages of Alzheimer’s disease (AD), Carina Wattmo, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Some randomized trials, such as that of the anti-beta-amyloid antibody solanezumab and the medical food souvenaid, "have shown small but significant positive cognitive effects in mild AD exclusively," said Dr. Wattmo of the clinical memory research unit in the department of clinical sciences at Lund University, Malmö, Sweden.

"Placebo-controlled trials longer than 6 months in untreated AD patients are not allowed for ethical reasons. New, longer studies are most often performed on patients who are on active treatment with cholinesterase inhibitors and/or memantine. Therapies expected to modify disease progression need to be thoroughly evaluated over many years. Knowledge on the expected longitudinal outcome in different stages of AD is scarce."

Dr. Wattmo and her associates analyzed data from the Swedish Alzheimer Treatment Study (SATS), a 3-year, prospective, open-label, nonrandomized multicenter study launched to evaluate the long-term effectiveness of cholinesterase inhibitor treatment in a routine clinical setting. Patients were diagnosed with possible or probable AD; the population included 734 patients with mild AD and 287 with moderate disease.

The patients were assessed after 2 months of therapy and every 6 months over the 3-year period, with the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog), the Clinician’s Interview-Based Impression of Change (CIBIC), and functional capacity based on the Instrumental Activities of Daily Living scale (IADL).

The mean age of patients was 75 years, and 64% were female. At baseline, patients in the mild AD group showed an illness duration of 2.9 years vs. 3.4 years in the moderate AD group, a difference that was statistically significant (P = .005). They also had more years of education (9.6 vs. 9.0 years; P less than .001), and a better functional capacity based on the IADL score (14.7 points vs. 19.1 points; P less than .001).

Dr. Wattmo reported 3-year results from 306 patients in the mild AD group and 79 patients in the moderate AD group. The mean change in MMSE was 3.1 points in the mild AD group vs. 4 points in the moderate AD group, a difference that did not reach statistical significance (P = .148). The mean decline in the ADAS-cog was 6.1 points in the mild AD group vs. 13.2 points in the moderate AD group, a difference that reached statistical significance (P less than .001).

In addition, 33% of patients in the mild AD group showed global CIBIC improvement or no change after 3 years of therapy, compared with 15% in the moderate AD group, a difference that was statistically significant (P = .002).

On the IADL, the mean decline was 6.3 points in the mild AD group vs. 7.5 points in the moderate AD group, a difference that was not statistically significant (P = .063).

"Varying outcomes were demonstrated in the different domains and stages of AD in this study from routine clinical practice," Dr. Wattmo concluded. "The outcome could be dependent on the scales used."

Dr. Wattmo said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Patients with mild Alzheimer’s disease who took 20 mg/day of memantine for 1 year remained the same or improved their driving ability, compared with placebo-treated patients in a small pilot trial.

Memantine is currently approved for moderate and severe Alzheimer’s disease (AD), but the findings suggest that the agent may have some neuroprotective qualities for people in the early stages of the disease, Anna Lisa Curtis said in an interview at the Clinical Trials Conference on Alzheimer’s Disease.

"In Florida, we have a large population of elderly that are still on the road, including those with early AD," said Ms. Curtis, a research coordinator at Florida Atlantic University (FAU), Boca Raton. "Being able to help maintain an imperative skill like driving for one’s sense of self and [the] ability to have a broader life is important, as is the safety of pedestrians and other motorists, and caregiver burden."

In a study led by Dr. Peter J. Holland, a psychiatrist at FAU, the researchers set out to evaluate the effects of 20 mg/day of memantine on delaying the progression of driving impairment in 60 men and women with mild AD as measured by actual driving and by a battery of neuropsychological tests focused on the cognitive skills necessary for driving, including executive functioning, visuospatial abilities, attention, and orientation. At baseline, 6 months, and 12 months, driving ability was measured with the DriveABLE-On-Road Test. They tested cognition with ADAS-Cog mazes, Fuld Object-Memory Evaluation, Clinical Dementia Rating scale, Trail-Making Tests A and B, the Rey-Osterrieth Complex Figure Test, the Useful Field of View test, and the Motor Free Visual Perception TestVisual Closure Subtest. The primary outcome was the number of subjects in each group who were able to pass the DriveABLE test at month 12. The secondary outcome measures were the changes from baseline to month 12 on the driving-related neuropsychological battery.

The researchers reported findings from 22 patients in the memantine group and 21 patients in the placebo group. Their mean age was 79 years and 62% were male. In terms of driving ability, 100% of patients in the memantine group remained the same or improved, compared with 75% of those in the placebo group, a difference that reached statistical significance (P = .04). In addition, after controlling for baseline ability, patients in the memantine group performed significantly better on the Rey-Osterrieth Complex Figure Test (P = .05) and on the Trails A and B tests (P = .05 and .02, respectively). Outcomes on the other tests were similar between the two groups.

"We did not anticipate that the treatment group would perform as well as it did," Ms. Curtis said. "In a 12-month period with AD, we can see quite a bit of decline, and we were surprised to see people in the memantine group maintaining skills or actually improving in their capacity."

She concluded that the findings warrant further study on the role of memantine in delaying driving impairment in patients with mild AD.

Forest Laboratories funded the study. Ms. Curtis said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Patients with mild Alzheimer’s disease who took 20 mg/day of memantine for 1 year remained the same or improved their driving ability, compared with placebo-treated patients in a small pilot trial.

Memantine is currently approved for moderate and severe Alzheimer’s disease (AD), but the findings suggest that the agent may have some neuroprotective qualities for people in the early stages of the disease, Anna Lisa Curtis said in an interview at the Clinical Trials Conference on Alzheimer’s Disease.

"In Florida, we have a large population of elderly that are still on the road, including those with early AD," said Ms. Curtis, a research coordinator at Florida Atlantic University (FAU), Boca Raton. "Being able to help maintain an imperative skill like driving for one’s sense of self and [the] ability to have a broader life is important, as is the safety of pedestrians and other motorists, and caregiver burden."

In a study led by Dr. Peter J. Holland, a psychiatrist at FAU, the researchers set out to evaluate the effects of 20 mg/day of memantine on delaying the progression of driving impairment in 60 men and women with mild AD as measured by actual driving and by a battery of neuropsychological tests focused on the cognitive skills necessary for driving, including executive functioning, visuospatial abilities, attention, and orientation. At baseline, 6 months, and 12 months, driving ability was measured with the DriveABLE-On-Road Test. They tested cognition with ADAS-Cog mazes, Fuld Object-Memory Evaluation, Clinical Dementia Rating scale, Trail-Making Tests A and B, the Rey-Osterrieth Complex Figure Test, the Useful Field of View test, and the Motor Free Visual Perception TestVisual Closure Subtest. The primary outcome was the number of subjects in each group who were able to pass the DriveABLE test at month 12. The secondary outcome measures were the changes from baseline to month 12 on the driving-related neuropsychological battery.

The researchers reported findings from 22 patients in the memantine group and 21 patients in the placebo group. Their mean age was 79 years and 62% were male. In terms of driving ability, 100% of patients in the memantine group remained the same or improved, compared with 75% of those in the placebo group, a difference that reached statistical significance (P = .04). In addition, after controlling for baseline ability, patients in the memantine group performed significantly better on the Rey-Osterrieth Complex Figure Test (P = .05) and on the Trails A and B tests (P = .05 and .02, respectively). Outcomes on the other tests were similar between the two groups.

"We did not anticipate that the treatment group would perform as well as it did," Ms. Curtis said. "In a 12-month period with AD, we can see quite a bit of decline, and we were surprised to see people in the memantine group maintaining skills or actually improving in their capacity."

She concluded that the findings warrant further study on the role of memantine in delaying driving impairment in patients with mild AD.

Forest Laboratories funded the study. Ms. Curtis said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Patients with mild Alzheimer’s disease who took 20 mg/day of memantine for 1 year remained the same or improved their driving ability, compared with placebo-treated patients in a small pilot trial.

Memantine is currently approved for moderate and severe Alzheimer’s disease (AD), but the findings suggest that the agent may have some neuroprotective qualities for people in the early stages of the disease, Anna Lisa Curtis said in an interview at the Clinical Trials Conference on Alzheimer’s Disease.

"In Florida, we have a large population of elderly that are still on the road, including those with early AD," said Ms. Curtis, a research coordinator at Florida Atlantic University (FAU), Boca Raton. "Being able to help maintain an imperative skill like driving for one’s sense of self and [the] ability to have a broader life is important, as is the safety of pedestrians and other motorists, and caregiver burden."

In a study led by Dr. Peter J. Holland, a psychiatrist at FAU, the researchers set out to evaluate the effects of 20 mg/day of memantine on delaying the progression of driving impairment in 60 men and women with mild AD as measured by actual driving and by a battery of neuropsychological tests focused on the cognitive skills necessary for driving, including executive functioning, visuospatial abilities, attention, and orientation. At baseline, 6 months, and 12 months, driving ability was measured with the DriveABLE-On-Road Test. They tested cognition with ADAS-Cog mazes, Fuld Object-Memory Evaluation, Clinical Dementia Rating scale, Trail-Making Tests A and B, the Rey-Osterrieth Complex Figure Test, the Useful Field of View test, and the Motor Free Visual Perception TestVisual Closure Subtest. The primary outcome was the number of subjects in each group who were able to pass the DriveABLE test at month 12. The secondary outcome measures were the changes from baseline to month 12 on the driving-related neuropsychological battery.

The researchers reported findings from 22 patients in the memantine group and 21 patients in the placebo group. Their mean age was 79 years and 62% were male. In terms of driving ability, 100% of patients in the memantine group remained the same or improved, compared with 75% of those in the placebo group, a difference that reached statistical significance (P = .04). In addition, after controlling for baseline ability, patients in the memantine group performed significantly better on the Rey-Osterrieth Complex Figure Test (P = .05) and on the Trails A and B tests (P = .05 and .02, respectively). Outcomes on the other tests were similar between the two groups.

"We did not anticipate that the treatment group would perform as well as it did," Ms. Curtis said. "In a 12-month period with AD, we can see quite a bit of decline, and we were surprised to see people in the memantine group maintaining skills or actually improving in their capacity."

She concluded that the findings warrant further study on the role of memantine in delaying driving impairment in patients with mild AD.

Forest Laboratories funded the study. Ms. Curtis said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Delivery of a gene therapy viral vector designed to express only the gene for human growth factor to the nucleus basalis of Meynert in patients with mild to moderate Alzheimer’s disease appears to be safe and feasible, results from a first-in-human trial demonstrated.

"There are significant deficiencies with the therapies that exist for treating the memory and cognitive impairments of Alzheimer’s disease," Raymond T. Bartus, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Currently available cholinesterase inhibitors "are nonselective and suffer from serious dose-limiting side effects," said Dr. Bartus, president of San Diego–based RTBioconsultants. "Their mechanism of action for cholinergic enhancement is suboptimal, and they do not repair neurons, protect against death, or truly restore lost neuronal function. While they work to some extent, they are modest in their level of efficacy and do not improve symptoms in all patients. Moreover, they do nothing to affect the disease progression."

Nerve growth factor neurotrophic therapy, he continued, "should overcome all of these deficiencies and therefore provide a more effective therapy, applying a variation of the cholinergic approach that has shown proof of concept." Decades of research in animal models suggest that nerve growth factor "has remarkable antiapoptotic (i.e., antideath) and reparative properties for certain neurons in the degenerative brain," Dr. Bartus said. "There are at least two major obstacles to apply this technology to Alzheimer’s disease. The first is, Alzheimer’s is an extremely complicated disease, so determining where to target the treatment is especially important. Targeting the cholinergic neurons is compelling because their degeneration is known to contribute significantly to the memory loss."

The second key challenge, he said, is the need for constant exposure to cholinergic neurons that comprise the nucleus basalis of Meynert (NBM) while avoiding exposure to untargeted neuronal populations. This has proven very difficult in past efforts extending back 20 years. In the past decade, gene therapy combined with stereotactic surgery has emerged as a practical enabling technology to accomplish this. On this basis, Dr. Bartus and his associates at Ceregene (where he served as chief scientific officer for more than 10 years) developed a viral gene therapy vector bioengineered to express only the gene for human nerve growth factor (AAV2-NGF, or CERE-110).

"You can think of it as an off-the-shelf biopharmaceutical that when injected into the human brain will induce the target neurons to produce or express and secrete only nerve growth factor and therefore provide support to NBM cholinergic neurons," he explained. "Preclinical studies have demonstrated an orderly dose-response relationship with NGF restricted to targeted basal forebrain cholinergic neurons, and no side effects or toxicity, even after testing very high doses in animals. That was quite surprising and certainly welcome."

Dr. Bartus presented phase I clinical data from 10 patients aged 50-79 years with mild to moderate Alzheimer’s disease who received one of three ascending doses of AAV2-NGF via bilateral stereotactic injection into the nucleus basalis of Meynert: dose A (1.2 x 10¹⁰ viral genomes), dose B (5.8 x 10¹⁰ viral genomes; five times more than dose A), and dose C (1.2 x 10¹¹ viral genomes; two times more than dose B). Patients were followed at 24 months for safety and feasibility and preliminary efficacy as measured by 18-fluorodeoxyglucose PET scans at baseline, 6, 12, and 24 months; autopsy tissue; and validated neuropsychological tests that included the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-Cog). Computer graphic software was used to provide a 3-D model of the nucleus basalis of Meynert in an effort to "determine where to distribute CERE-110 in the NBM and how much should be given to achieve optimal NGF exposure."

Dr. Bartus reported that AAV2-NGF was safe and well tolerated through 24 months. Adverse events and serious adverse events "were uneventful," he said. "What you see is a profile that reflects either incidental or unrelated events, or those related to a surgical procedure (e.g., temporary headache)."

PET imaging showed no evidence of accelerated decline, and brain autopsy tissue from three patients who died of unrelated causes confirmed long-term, therapeutically active, gene-mediated NGF expression accurately targeted to the nucleus basalis of Meynert.

The researchers observed some deterioration over time based on the ADAS-Cog and other neuropsychological measures. "There is no clinical evidence that cognitive decline is accelerated, but we can’t speak to whether or not we actually improved rate of decline," Dr. Bartus said.

These findings formed the basis of a phase II trial currently underway that is funded by the National Institutes of Health under the auspices of the Alzheimer’s Disease Collaborative Study. Outcomes from that 24-month trial are expected in 2015.

The phase 1 study was funded by Ceregene, which was acquired in October 2013 by Sangamo BioSciences.

Dr. Bartus disclosed that he is a consultant for Sangamo BioSciences.

[email protected]

SAN DIEGO – Delivery of a gene therapy viral vector designed to express only the gene for human growth factor to the nucleus basalis of Meynert in patients with mild to moderate Alzheimer’s disease appears to be safe and feasible, results from a first-in-human trial demonstrated.

"There are significant deficiencies with the therapies that exist for treating the memory and cognitive impairments of Alzheimer’s disease," Raymond T. Bartus, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Currently available cholinesterase inhibitors "are nonselective and suffer from serious dose-limiting side effects," said Dr. Bartus, president of San Diego–based RTBioconsultants. "Their mechanism of action for cholinergic enhancement is suboptimal, and they do not repair neurons, protect against death, or truly restore lost neuronal function. While they work to some extent, they are modest in their level of efficacy and do not improve symptoms in all patients. Moreover, they do nothing to affect the disease progression."

Nerve growth factor neurotrophic therapy, he continued, "should overcome all of these deficiencies and therefore provide a more effective therapy, applying a variation of the cholinergic approach that has shown proof of concept." Decades of research in animal models suggest that nerve growth factor "has remarkable antiapoptotic (i.e., antideath) and reparative properties for certain neurons in the degenerative brain," Dr. Bartus said. "There are at least two major obstacles to apply this technology to Alzheimer’s disease. The first is, Alzheimer’s is an extremely complicated disease, so determining where to target the treatment is especially important. Targeting the cholinergic neurons is compelling because their degeneration is known to contribute significantly to the memory loss."

The second key challenge, he said, is the need for constant exposure to cholinergic neurons that comprise the nucleus basalis of Meynert (NBM) while avoiding exposure to untargeted neuronal populations. This has proven very difficult in past efforts extending back 20 years. In the past decade, gene therapy combined with stereotactic surgery has emerged as a practical enabling technology to accomplish this. On this basis, Dr. Bartus and his associates at Ceregene (where he served as chief scientific officer for more than 10 years) developed a viral gene therapy vector bioengineered to express only the gene for human nerve growth factor (AAV2-NGF, or CERE-110).

"You can think of it as an off-the-shelf biopharmaceutical that when injected into the human brain will induce the target neurons to produce or express and secrete only nerve growth factor and therefore provide support to NBM cholinergic neurons," he explained. "Preclinical studies have demonstrated an orderly dose-response relationship with NGF restricted to targeted basal forebrain cholinergic neurons, and no side effects or toxicity, even after testing very high doses in animals. That was quite surprising and certainly welcome."

Dr. Bartus presented phase I clinical data from 10 patients aged 50-79 years with mild to moderate Alzheimer’s disease who received one of three ascending doses of AAV2-NGF via bilateral stereotactic injection into the nucleus basalis of Meynert: dose A (1.2 x 10¹⁰ viral genomes), dose B (5.8 x 10¹⁰ viral genomes; five times more than dose A), and dose C (1.2 x 10¹¹ viral genomes; two times more than dose B). Patients were followed at 24 months for safety and feasibility and preliminary efficacy as measured by 18-fluorodeoxyglucose PET scans at baseline, 6, 12, and 24 months; autopsy tissue; and validated neuropsychological tests that included the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-Cog). Computer graphic software was used to provide a 3-D model of the nucleus basalis of Meynert in an effort to "determine where to distribute CERE-110 in the NBM and how much should be given to achieve optimal NGF exposure."

Dr. Bartus reported that AAV2-NGF was safe and well tolerated through 24 months. Adverse events and serious adverse events "were uneventful," he said. "What you see is a profile that reflects either incidental or unrelated events, or those related to a surgical procedure (e.g., temporary headache)."

PET imaging showed no evidence of accelerated decline, and brain autopsy tissue from three patients who died of unrelated causes confirmed long-term, therapeutically active, gene-mediated NGF expression accurately targeted to the nucleus basalis of Meynert.

The researchers observed some deterioration over time based on the ADAS-Cog and other neuropsychological measures. "There is no clinical evidence that cognitive decline is accelerated, but we can’t speak to whether or not we actually improved rate of decline," Dr. Bartus said.

These findings formed the basis of a phase II trial currently underway that is funded by the National Institutes of Health under the auspices of the Alzheimer’s Disease Collaborative Study. Outcomes from that 24-month trial are expected in 2015.

The phase 1 study was funded by Ceregene, which was acquired in October 2013 by Sangamo BioSciences.

Dr. Bartus disclosed that he is a consultant for Sangamo BioSciences.

[email protected]

SAN DIEGO – Delivery of a gene therapy viral vector designed to express only the gene for human growth factor to the nucleus basalis of Meynert in patients with mild to moderate Alzheimer’s disease appears to be safe and feasible, results from a first-in-human trial demonstrated.

"There are significant deficiencies with the therapies that exist for treating the memory and cognitive impairments of Alzheimer’s disease," Raymond T. Bartus, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Currently available cholinesterase inhibitors "are nonselective and suffer from serious dose-limiting side effects," said Dr. Bartus, president of San Diego–based RTBioconsultants. "Their mechanism of action for cholinergic enhancement is suboptimal, and they do not repair neurons, protect against death, or truly restore lost neuronal function. While they work to some extent, they are modest in their level of efficacy and do not improve symptoms in all patients. Moreover, they do nothing to affect the disease progression."

Nerve growth factor neurotrophic therapy, he continued, "should overcome all of these deficiencies and therefore provide a more effective therapy, applying a variation of the cholinergic approach that has shown proof of concept." Decades of research in animal models suggest that nerve growth factor "has remarkable antiapoptotic (i.e., antideath) and reparative properties for certain neurons in the degenerative brain," Dr. Bartus said. "There are at least two major obstacles to apply this technology to Alzheimer’s disease. The first is, Alzheimer’s is an extremely complicated disease, so determining where to target the treatment is especially important. Targeting the cholinergic neurons is compelling because their degeneration is known to contribute significantly to the memory loss."

The second key challenge, he said, is the need for constant exposure to cholinergic neurons that comprise the nucleus basalis of Meynert (NBM) while avoiding exposure to untargeted neuronal populations. This has proven very difficult in past efforts extending back 20 years. In the past decade, gene therapy combined with stereotactic surgery has emerged as a practical enabling technology to accomplish this. On this basis, Dr. Bartus and his associates at Ceregene (where he served as chief scientific officer for more than 10 years) developed a viral gene therapy vector bioengineered to express only the gene for human nerve growth factor (AAV2-NGF, or CERE-110).

"You can think of it as an off-the-shelf biopharmaceutical that when injected into the human brain will induce the target neurons to produce or express and secrete only nerve growth factor and therefore provide support to NBM cholinergic neurons," he explained. "Preclinical studies have demonstrated an orderly dose-response relationship with NGF restricted to targeted basal forebrain cholinergic neurons, and no side effects or toxicity, even after testing very high doses in animals. That was quite surprising and certainly welcome."

Dr. Bartus presented phase I clinical data from 10 patients aged 50-79 years with mild to moderate Alzheimer’s disease who received one of three ascending doses of AAV2-NGF via bilateral stereotactic injection into the nucleus basalis of Meynert: dose A (1.2 x 10¹⁰ viral genomes), dose B (5.8 x 10¹⁰ viral genomes; five times more than dose A), and dose C (1.2 x 10¹¹ viral genomes; two times more than dose B). Patients were followed at 24 months for safety and feasibility and preliminary efficacy as measured by 18-fluorodeoxyglucose PET scans at baseline, 6, 12, and 24 months; autopsy tissue; and validated neuropsychological tests that included the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-Cog). Computer graphic software was used to provide a 3-D model of the nucleus basalis of Meynert in an effort to "determine where to distribute CERE-110 in the NBM and how much should be given to achieve optimal NGF exposure."

Dr. Bartus reported that AAV2-NGF was safe and well tolerated through 24 months. Adverse events and serious adverse events "were uneventful," he said. "What you see is a profile that reflects either incidental or unrelated events, or those related to a surgical procedure (e.g., temporary headache)."

PET imaging showed no evidence of accelerated decline, and brain autopsy tissue from three patients who died of unrelated causes confirmed long-term, therapeutically active, gene-mediated NGF expression accurately targeted to the nucleus basalis of Meynert.

The researchers observed some deterioration over time based on the ADAS-Cog and other neuropsychological measures. "There is no clinical evidence that cognitive decline is accelerated, but we can’t speak to whether or not we actually improved rate of decline," Dr. Bartus said.

These findings formed the basis of a phase II trial currently underway that is funded by the National Institutes of Health under the auspices of the Alzheimer’s Disease Collaborative Study. Outcomes from that 24-month trial are expected in 2015.

The phase 1 study was funded by Ceregene, which was acquired in October 2013 by Sangamo BioSciences.

Dr. Bartus disclosed that he is a consultant for Sangamo BioSciences.

[email protected]