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Mild TBI May Increase Risk of Parkinson’s Disease Among Military Veterans

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The data underscore the importance of TBI prevention and long-term follow-up, according to the authors.

Among military veterans, mild traumatic brain injury (TBI) is associated with a 56% increased risk of developing Parkinson’s disease over 12 years of follow-up, according to data published online ahead of print April 18 in Neurology. Prior TBI also is associated with a diagnosis of Parkinson’s disease two years earlier than among controls.

“Our findings highlight the critical importance of unraveling mechanisms subserving the association between TBI and Parkinson’s disease to inform treatment and prevention of post-TBI Parkinson’s disease,” said Raquel C. Gardner, MD, Assistant Professor of Neurology at the University of California, San Francisco.

A Longitudinal Cohort Study

Every year, mild TBI affects an estimated 42 million people worldwide. It is especially common among athletes and military personnel and is a growing epidemic among the elderly. In 2008, the Institute of Medicine found sufficient evidence to suggest an association between moderate to severe TBI and a clinical diagnosis of Parkinson’s disease, but limited evidence for an association between mild TBI with loss of consciousness and a clinical diagnosis of Parkinson’s disease. One small case–control study assessed the risk of Parkinson’s disease following mild TBI among military veterans, but the results were inconclusive, said the authors.

Dr. Gardner and colleagues conducted a longitudinal cohort study to evaluate the risk of Parkinson’s disease following TBI, including mild TBI, among patients in the Veterans Health Administration (VHA). They analyzed data from three nationwide VHA health care system databases and identified patients with a diagnosis of TBI from October 2002 to September 2014. Participants were age 18 or older without Parkinson’s disease or dementia at baseline and were age-matched 1:1 to a random sample of patients without TBI.

Researchers defined moderate to severe TBI as a loss of consciousness for more than 30 minutes, alteration of consciousness for more than 24 hours, or amnesia for more than 24 hours. They defined mild TBI as loss of consciousness for zero to 30 minutes, alteration of consciousness for a moment to 24 hours, or amnesia for zero to 24 hours.

TBI exposure and severity were determined via detailed clinical assessments or ICD-9 codes using Department of Defense and Defense and Veterans Brain Injury Center criteria. Baseline comorbidities and incident Parkinson’s disease at more than one year post TBI were identified using ICD-9 codes. In addition, investigators used Cox proportional hazard models adjusted for demographics and medical and psychiatric comorbidities to assess risk of Parkinson’s disease after TBI.

Prior TBI Was Associated With Minority Status

A total of 325,870 patients were included in the study with an average age of 47.9 and an average follow-up of 4.6 years. In all, 1,462 patients were diagnosed with Parkinson’s disease during follow-up. After adjusting for age, sex, race, education, and other health conditions, the researchers found that patients with any severity of TBI had a 71% increased risk of Parkinson’s disease; participants with moderate to severe TBI had an 83% increased risk.

Overall, patients with prior TBI were diagnosed with Parkinson’s disease at a significantly younger age, had significantly higher prevalence of non-Hispanic black and Hispanic race or ethnicity, and had significantly higher prevalence of all medical and psychiatric comorbidities, compared with those without prior TBI.

“Given the growing evidence for several potentially modifiable risk factors for Parkinson’s disease, an important area for future research will be to determine whether improved management of specific highly prevalent comorbidities among TBI-exposed veterans may reduce risk of subsequent Parkinson’s disease,” said the researchers.

Strengths of this study include the use of physicians’ diagnosis of TBI and Parkinson’s disease, a longitudinal cohort design, and a large sample size. One of the study’s limitations was the use of ICD-9 codes for the diagnosis of TBI and Parkinson’s disease, which may have overlooked some cases, such as TBI with polytrauma or mild TBI sustained in combat, said the authors. NR

—Erica Tricarico

Patients Who Die of SUDEP Largely Live Alone and Die Unwitnessed at Home

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The data suggest that more than half of SUDEP cases occur at night.

Patients whose fatality is attributed to sudden unexpected death in epilepsy (SUDEP) largely live alone; die unwitnessed at home at night, usually in the prone position; and have an indication of a preceding seizure, according to research published in the May issue of Epilepsia.

“Our results … highlight the difficulties in implementing preventive efforts that require immediate availability of another person to identify a seizure, to interact and correct body position, or to give pharmacologic emergency treatment,” said Olafur Sveinsson, a graduate student at the Karolinska Institute in Stockholm, and colleagues. “These obstacles need to be considered when strategies for SUDEP prevention are being developed.”

Previous case–control studies have identified a high frequency of tonic-clonic seizures, nocturnal seizures, and lack of nighttime supervision as risk factors for SUDEP, but mechanisms of SUDEP remain unclear. To analyze the circumstances of SUDEP and its incidence in relation to time of year, week, and day, Mr. Sveinsson and colleagues conducted a nationwide, population-based case series.

For their study, the investigators used the Swedish National Patient Registry to identify all persons that, at some point between 1998 and 2005, had an ICD-10 code for epilepsy and were alive on June 30, 2006. Eligible SUDEP cases were all deaths with epilepsy mentioned on the death certificate together with all individuals who died during 2008, irrespective of whether epilepsy was mentioned on the death certificate. Obvious non-SUDEP deaths such as those resulting from cancer, terminal illness, postmortem confirmed pneumonia, stroke, or myocardial infarction were excluded from further analysis.

SUDEP cases were divided into three subgroups based on the certainty of the diagnosis: definite SUDEP (when all clinical criteria were met and an autopsy revealed no alternate cause of death), probable SUDEP (when all clinical criteria were met, but no autopsy was performed), and possible SUDEP (when SUDEP could not be ruled out, but insufficient evidence was available regarding the circumstances of death, and no autopsy was performed). To identify SUDEP cases and related circumstances, investigators reviewed death certificates, medical charts, autopsy, and police records. Autopsied non-SUDEP deaths from the study population served as a reference. Researchers reviewed 3,166 deaths and identified 329 cases of SUDEP (37% were female). Of these cases, 167 were definite, 89 were probable, and 73 were possible. SUDEP cases were younger at death (50.8 years) than non-SUDEP deaths (73.3 years). Most SUDEP cases occurred at night (58%) and at home (91%), and 65% were found dead in bed. When documented, 70% were found in prone position, which may “facilitate SUDEP by compromising postictal ventilation,” said the authors.

Death was witnessed in 17% of SUDEP cases, and in 88% of these, a seizure was observed. In all, 71% of patients were living alone, and 14% shared a bedroom. Among the witnessed definite SUDEP patients, a tonic-clonic seizure was present in 95% of cases, compared with 21% in the autopsied non-SUDEP reference group, strengthening the notion that SUDEP in most cases is a seizure-related event, the researchers said.

Although sudden infant death syndrome (SIDS) and cardiac death have a higher incidence in the winter, the researchers did not find the same to be true in their SUDEP cohort. Furthermore, they did not find a preponderance for Mondays or morning hours, as reported for sudden cardiac death. The researchers did, however, find a clear diurnal variation, with the majority of cases dying during the night hours. Taken together, these findings prompted the researchers to conclude that the underlying mechanisms of SUDEP are different from those of SIDS and sudden cardiac death.

—Erica Tricarico

Alzheimer’s Disease Biomarkers, Not Cognition, Will Now Define Disorder

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The NIA-AA Research Framework establishes eight biomarker profiles with different combinations of amyloid, tau, and neuropathologic damage.

A new definition of Alzheimer’s disease based solely on biomarkers has the potential to strengthen clinical trials and change the way physicians talk to patients.

The paradigm recasts Alzheimer’s disease from a symptomatic syndrome validated by biomarkers to a strictly biologic construct defined by the presence of amyloid beta, tau, and neuronal damage.

Amyloid beta is the key to this classification paradigm—any patient with it is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain are classified as having Alzheimer’s disease. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile. Cognitive staging adds important details, but remains secondary to the biomarker classification.

Jointly created by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), the system—dubbed the NIA-AA Research Framework—represents a common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses and to optimize epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s disease prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathologic hallmarks of the disease.

This recasting adds Alzheimer’s disease to the list of biomarker-defined disorders such as hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford R. Jack Jr, MD, chair of the 20-member committee that created the paradigm, which was published in the April issue of Alzheimer’s & Dementia.

Refining Research Cohorts

“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating that the disease be defined by its neuropathology [of plaques and tangles], which is specific to Alzheimer’s, and no longer by clinical symptoms which are not specific for any disease.”

One of the primary intents is to refine Alzheimer’s disease research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, as much as 30% of subjects who enroll in Alzheimer’s disease drug trials do not have the target pathologies—a situation that researchers say contributes to the long string of failed Alzheimer’s drug studies.

For now, the system is intended only for research settings, said Dr. Jack, an Alzheimer’s disease investigator at the Mayo Clinic in Rochester, Minnesota. But as biomarker testing comes of age and less expensive tests are discovered, the paradigm will likely be incorporated into clinical practice. The process can begin even now with a simple change in the way doctors talk to patients about Alzheimer’s disease, he said.

“We advocate that people stop using the terms ‘probable’ or ‘possible Alzheimer’s disease,’” Dr. Jack said. “A better term is ‘Alzheimer’s clinical syndrome.’ Without biomarkers, the clinical syndrome is the only thing you can know. What you can’t know is whether they do or do not have Alzheimer’s disease. When I am asked by physicians, ‘What do I tell my patients now?’ my very direct answer is ‘Tell them the truth.’ And the truth is that they have Alzheimer’s clinical syndrome and may or may not have Alzheimer’s disease.”

A Reflection of Evolving Science

The research framework reflects advances in Alzheimer’s disease science that have occurred since the NIA last updated its Alzheimer’s disease diagnostic criteria in 2011. Those criteria divided the disease continuum into three phases—preclinical Alzheimer’s disease, mild cognitive impairment (MCI), and Alzheimer’s dementia—largely based on cognitive symptoms, but were the first to recognize a presymptomatic Alzheimer’s disease phase marked by brain changes, including amyloid buildup, without evidence of significant clinical symptoms. In the MCI stage, which may or may not progress to Alzheimer’s dementia, memory or other thinking problems are greater than normal for a patient’s age and education, but do not interfere with his or her independence. Alzheimer’s dementia is the final stage of the disease in which the symptoms of Alzheimer’s disease, such as memory loss, word-finding difficulties, and visual or spatial problems, are significant enough to impair a person’s ability to function independently.

Since the 2011 diagnostic criteria emergered, advances in understanding the biology and pathology of Alzheimer’s disease, as well as technical advances in biomarker measurements, have made it possible not only to measure amyloid beta and tau in CSF, but also to see these proteins in living brains with specialized PET ligands. It also became obvious that about a third of subjects in any given Alzheimer’s disease study did not have the disease-defining brain plaques and tangles—the therapeutic targets of all the largest drug studies to date. And while it is clear that none of the interventions in those studies have exerted a significant benefit yet, “treating people for a disease they don’t have can’t possibly help the results,” Dr. Jack said.

These research observations and biomarker advances have reshaped the way researchers think about Alzheimer’s disease. To maximize research potential and create a global classification standard to unify studies, the NIA and the Alzheimer’s Association convened several meetings to redefine Alzheimer’s disease biologically by pathologic brain changes, as measured by biomarkers. In this paradigm, cognitive dysfunction is a symptom of Alzheimer’s disease, not its primary classification driver.

“The way Alzheimer’s disease has historically been defined is by clinical symptoms. A progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it was not,” Dr. Jack said. “Well, it turns out that both of those statements are wrong. About 30% of people with progressive amnestic dementia have other things causing it.”

It makes much more sense, he said, to define the disease based on its unique neuropathologic signature: amyloid beta plaques and tau neurofibrillary tangles in the brain.

The Three-Part Key: AT(N)

The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).

“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”

The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”

The biomarker profiles are:

A−T−(N)−: Normal Alzheimer’s disease biomarkers
A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
A−T+(N)−: Non-Alzheimer’s disease pathologic change
A−T−(N)+: Non-Alzheimer’s disease pathologic change
A−T+(N)+: Non-Alzheimer’s disease pathologic change.

A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.

Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.

Biomarker Grouping and Cognitive Status Interactions

“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”

The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.

The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.

“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”

The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.

This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.

“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”

Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.

IDEAS on the Horizon

Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.

An interim analysis of 4,000 scans presented at the 2017 Alzheimer’s Association International Conference found that scan results changed patient management in 68% of cases, including by refining dementia diagnoses; adding, stopping, or switching medications; and altering patient counseling.

IDEAS uses an FDA-approved amyloid imaging agent. Tau PET ligands are in development, but have not been approved. However, other less invasive and less costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.

“In the future, … blood-based biomarker tests—along with genetics, clinical, and demographic information—will likely play an important screening role in selecting individuals for more expensive or more invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted.

In any case, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains academic, Dr. Jack said.

“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it,” Dr. Jack said. “Certainly, many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that until there is a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s disease is not going to enable you to change anything.”

Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International and Allon Therapeutics; and holds stock in Johnson & Johnson.

—Michele G. Sullivan

Valproate Exposure in Utero Significantly Decreases Educational Attainment in Children

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Children of mothers prescribed multiple AEDs during pregnancy appear to be less likely to achieve the national minimum standard test scores.

In utero exposure to antiepileptic drugs (AEDs) in combination, or sodium valproate alone, significantly decreases educational attainment in children age 7, compared with both a matched control group and the all-Wales national average, according to a report published online ahead of print March 27 in the Journal of Neurology, Neurosurgery and Psychiatry. “These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy,” said lead author Arron S. Lacey, Prudent Healthcare Intelligence Unit Research Data Analyst at Swansea University in the UK, and colleagues.

Although valproate is considered the most effective drug for treating genetic generalized epilepsy, recent prospective psychometric studies revealed cognitive impairment and neurodevelopmental disorders in 30% to 40% of children exposed to valproate in utero, as well as a significant decrease in IQ. According to Mr. Lacey and colleagues, to adequately counsel women about the risks of uncontrolled seizures during pregnancy and cognitive outcomes for their children, “it is important to know whether the psychometric differences seen in research conditions translate to children in the community.”

To identify whether children exposed to AEDs in utero have poorer school performance, Mr. Lacey and colleagues used the Secure Anonymous Information Linkage databank to access routinely collected health care records and identify children born to mothers with epilepsy. They then linked the identified children to their national attainment Key Stage 1 (KS1) tests in mathematics, language, and science at age 7, and compared them with matched controls (children born to mothers without epilepsy), and with the national KS1 results. As outcome measures, the investigators used the core subject indicator (CSI), which is the proportion of children achieving a minimum standard in all subjects, and the results in individual subjects.

The researchers identified 440 children born to mothers with epilepsy with available KS1 results. Compared with a matched control group, fewer children with mothers prescribed sodium valproate during pregnancy achieved the national minimum standard in CSI (−12.7% less than the control group), mathematics (−12.1%), language (−10.4%) and science (−12.2%). Even fewer children with mothers prescribed multiple AEDs during pregnancy achieved the national minimum standard in CSI (−20.7% less than the control group), mathematics (−21.9%), language (−19.3%), and science (−19.4%). Researchers did not observe significant differences in children whose mothers were prescribed carbamazepine or women taking an AED, when compared with the control group.

According to the researchers, the main strength of the study is the ability to select a large cohort of 440 children with national test results without major recruitment bias and compare it with a large control group. One main study limitation “was not being able to use the maternal IQ, as well as other maternal factors, such as maternal weight or alcohol consumption during pregnancy, as covariates,” said the authors. In addition, researchers were unable to account for how parental style, or ability, may have influenced educational attainment.

“Our results add to the growing evidence that in utero exposure to certain AEDs can cause developmental problems in children. Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” the researchers concluded.

—Erica Tricarico

Brain Stimulation May Enhance Memory

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Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

The two studies were part of a multicenter project designed to assess the effects of electrical stimulation on memory-related brain function and were supported by the Defense Advanced Research Projects Agency’s Restoring Active Memory program.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Deep Gray Matter Volume Loss May Drive Disability Worsening in MS

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Deep gray matter atrophy may be a useful outcome measure in neuroprotective clinical trials.

Deep gray matter volume loss drives disability accumulation in multiple sclerosis (MS), according to a multicenter, longitudinal study published in the February issue of Annals of Neurology.

The results “suggest that the development of deep gray matter atrophy may drive disability accumulation irrespective of clinical phenotypes, thereby becoming a useful outcome measure in neuroprotective clinical trials,” said Arman Eshaghi, MD, of the Queen Square MS Centre at the University College London Institute of Neurology, and colleagues.

Gray matter atrophy occurs in all MS phenotypes. To investigate whether a spatiotemporal pattern of gray matter atrophy is associated with faster disability accumulation in MS, the investigators analyzed 3,604 high-resolution T1-weighted MRI brain scans from 1,417 participants. The investigators retrospectively collected the scans from seven European centers in the MRI in MS (MAGNIMS) network.

The study included 253 patients with clinically isolated syndrome (CIS), 708 patients with relapsing-remitting MS, 128 patients with secondary progressive MS and 125 patients with primary progressive MS with an average follow-up of 2.41 years, as well as 203 healthy controls with an average follow-up of 1.83 years. The researchers assessed disability using the Expanded Disability Status Scale (EDSS). They obtained volumes of deep gray matter; temporal, frontal, parietal, occipital, and cerebellar gray matter; brainstem; and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time to EDSS progression.

Of all baseline regional volumes, only deep gray matter predicted time to EDSS progression. For every standard deviation decrease in baseline deep gray matter volume, the risk of having a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, deep gray matter had the fastest annual rate of atrophy. This rate was faster in secondary progressive MS (–1.45%), primary progressive MS (–1.66%), and relapsing-remitting MS (–1.34%) than in CIS (–0.88%) and controls (–0.94%). The rate of temporal gray matter atrophy in secondary progressive MS (–1.21%) was significantly faster than in relapsing-remitting MS (–0.76%), CIS (–0.75%), and healthy controls (–0.51%). Only the atrophy rate in deep gray matter was significantly associated with disability accumulation, however.

—Jake Remaly

Variants in One Gene May Account for 7% of Juvenile Myoclonic Epilepsy Cases

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Data indicate that pathogenic variants in ICK cause juvenile myoclonic epilepsy by disrupting mitosis, neuroblast migration, and apoptosis.

Rare genetic variants that affect the maturation, migration, and death of neurons appear to be responsible for about 7% of cases of juvenile myoclonic epilepsy.

Variants of the intestinal-cell kinase gene (ICK) occurred in 12 members of a family affected by the disorder and were confirmed in 22 of 310 additional patients, Julia N. Bailey, PhD, of the University of California, Los Angeles (UCLA), and her colleagues reported in the March 15 issue of the New England Journal of Medicine.

But among these 34 patients, the variants manifested as different epileptic phenotypes, suggesting genetic pleiotropism, the investigators said.

Clinical Heterogeneity

“We report striking variation with respect to epilepsy phenotypes both within and among families,” the researchers said. “Of 34 affected nonproband family members, five (15%) had juvenile myoclonic epilepsy, 10 (29%) had myoclonic-tonic-clonic seizures, four (12%) had pyknoleptic petit mal seizures alone or with myoclonic-tonic-clonic seizures, four (12%) had febrile seizures alone or with absence seizures or myoclonias, and 11 (32%) were clinically asymptomatic but had polyspikes or focal spikes on EEG. These results strongly suggest that ICK is pleiotropic ... and that epistatic loci with different genes are present in affected family members and interact with ICK and contribute to pleiotropism and clinical heterogeneity.”

ICK “is expressed in all tissues,” said senior study author Antonio Delgado-Escueta, MD, Professor of Neurology at UCLA. The subtle brain dysplasia, or microdysgenesis, that occurs in patients with juvenile myoclonic epilepsy is “diagnosed mainly microscopically, and has neuronal cells that migrated from periventricular zones to the wrong places in wrong layers of the cortical gray matter and even the white matter of the brain,” he said. “The cells can also be abnormally large and bunch up as a thicker gray matter. On voxel-based brain MRI ... focal thickenings of these abnormally migrated cells can also be partly explained by decreased pruning of cells and circuits (apoptosis).”

The gene encoding for ICK is located close to EFHC1 on chromosome 6p12. EFHC1, which encodes for a calcium-binding protein, has been implicated in juvenile myoclonic epilepsy. Dr. Bailey and her colleagues examined whether several genes in close proximity to EFHC1 also influenced that risk.

An Epilepsy Database

The investigators drew data from the GENESS (Genetic Epilepsies Studies) consortium, which has study sites in the United States, Mexico, Honduras, Brazil, and Japan. The current study analyzed information from 334 families with genetic generalized epilepsies. Among these families, 310 patients had adolescent-onset myoclonic seizures and polyspike waves or had a diagnosis of juvenile myoclonic epilepsy.

The investigators first performed an exome-wide analysis of four affected members of a large family with genetic juvenile myoclonic epilepsy. They observed the same variants in all four patients, then ran the screen in all 37 family members. Next, they screened these candidate genes in all 334 of the GENESS families and calculated risk scores for juvenile myoclonic epilepsy.

A linkage analysis confirmed two candidate genes on chromosome 6p12.2. Further analyses pinpointed a single variant: K305T on the ICK gene. This trait was present in each of the 12 affected members and three unaffected members of the initial family examined. Of those affected, three had juvenile myoclonic epilepsy, two had myoclonic-tonic-clonic convulsions only, two had febrile convulsions plus childhood absence seizures or neonatal myoclonus, one had febrile convulsions only, and four had polyspikes on EEG and were clinically asymptomatic.

“These results genetically implicated K305T as an autosomal dominant, possibly disease-causing trait,” the authors noted.

ICK variants were also present in 24 of the 310 database patients who had juvenile myoclonic epilepsy (8%). Of these, nine belonged to families with other affected members. The researchers tested 24 ICK variants for pathogenicity and determined that 13 exerted significant juvenile myoclonic epilepsy risk, with odds ratios exceeding 5.0.

When the researchers looked for these variants in the Genome Aggregation Database (gnomAD), they found that 12 of the variants were present but extremely rare, and eight were absent. They also found an additional ICK variant in a Mexican patient who was in gnomAD. That variant was a benign polymorphism in Africans.

Dr. Bailey and her colleagues thus concluded that 21 ICK variants in 22 patients with juvenile myoclonic epilepsy accounted for 7% of the juvenile myoclonic epilepsy among the 310 cases examined.

Experiments in Mice

The team also conducted a series of in vitro and in vivo mouse experiments. They determined that ICK variants impaired the migration of neuronal progenitor cells and lowered their mitotic index. ICK transgenic mice during light sleep displayed muscle movements similar to human myoclonic seizures. These mice also displayed diffuse polyspike brain waves on EEG recordings.

“The data we obtained through the use of electroporated slices of mouse brain support the conclusion that pathogenic variants in ICK cause 7% of cases of juvenile myoclonic epilepsy by disrupting mitosis, neuroblast migration, and apoptosis,” they concluded.

The study was funded by private and public grants. Several authors are coholders of patents on EFHC1-based diagnostics and therapeutics that have been licensed to Athena Diagnostics.

—Michele G. Sullivan

MRI May Reveal PML in Patients With Undetectable JCV

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Lesion volume may be greater in patients with PML symptoms or widespread lesion dissemination.

Patients with multiple sclerosis (MS) who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions on MRI, yet have undetectable JC virus (JCV) DNA in their CSF, according to a cross-sectional, retrospective study published online ahead of print March 12 in JAMA Neurology.

The findings show that for some people with MS, PML diagnosis could be delayed if CSF sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to Martijn T. Wijburg, MD, a neurologist at the MS Center at VU University Medical Center in Amsterdam, and colleagues.

The study also described a potential correlation between PML lesion volume and JCV copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV polymerase chain reaction [PCR] results in patients with [natalizumab-associated PML]. This finding may have considerable implications for patient care,” said the authors.

A Retrospective Study

PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, when JCV DNA is detected in CSF by PCR, and when specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab-associated PML between January 2007 and December 2014. Patients were required to meet one of the following criteria:

Definite or probable PML, based on positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), nine patients (16.1%) had undetectable JCV DNA in CSF, and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45, and the median natalizumab treatment duration was 43 months. Patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs 6.7 mL). Logistic regression showed that a smaller PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers. PML lesion volume was greater in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

Results Suggest Need for Pharmacovigilance

The findings suggest that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay diagnosis.

“This [finding] can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (eg, when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” said the authors.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume.... As a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR.”

Strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative PCR results, which hampers a formal diagnosis of [PML] and may complicate patient treatment,” said the authors.

Meticulous clinical and MRI follow-up, in combination with repeated CSF JCV PCR testing, was warranted in these patients, they added. Complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”

MRI Alone Cannot Yet Support Diagnosis

“Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF,” said Eugene O. Major, PhD, a consultant in the Division of Neuroimmunology and Neurovirology at NINDS in Bethesda, Maryland, in an accompanying editorial. “However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.”

Repeat testing may be worthwhile when CSF testing is negative, because some patients test positive weeks after testing negative, he added. “Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is too early to rely on MRI alone for diagnosis.”

Dr. Major has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline.He has patent rights at the NIH as coinventor of the Ultrasensitive Quantitative PCR Multiplex assay for the detection of JCV DNA–distinguishing viral variants.

—Nicola Garrett

Sonified EEG Could Be Useful Triage Tool

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The method allows nurses and students to identify seizures and other abnormalities accurately.

Medical students and nurses who listen to 15 seconds of single-channel sonified EEGs may detect seizures with 95% to 98% sensitivity, thus outperforming neurologists who review traditional visual EEG displays, according to the results of a single-center study published in the April issue of Epilepsia.

“Individuals without EEG training can detect ongoing seizures or seizurelike rhythmic and periodic patterns by merely listening to short clips of sonified EEG,” said Josef Parvizi, MD, PhD, Professor of Neurology at Stanford University Medical Center in California, and his associates. “Ours is also the first study to test the capability of a sonification method to detect a range of significant abnormalities when it is used by clinical staff (eg, physicians, nurses, and students).”

The sonification technique is based on an algorithm that translates low-frequency EEG signals into “speechlike declamations,” the investigators said. Vocal pitch, loudness, and resonance vary depending on input. Unlike prior sonification methods, the new method conserves brain rhythms, rate, and seizure severity.

To test the method, 34 medical students and 30 nurses watched a four-minute training video before listening to 84 sonified EEGs, including seven seizures, 52 slowing or normal patterns, and 25 seizurelike abnormalities (ie, generalized periodic discharges, lateralized periodic discharges, triphasic waves, or burst suppression). For each patient, listeners heard two sonified EEG clips, one from each hemisphere, and designated them as “seizure,” “nonseizure,” or “don’t know.” For comparison, 12 EEG-trained neurologists and 29 EEG-trained medical students reviewed traditional visual displays of the same EEGs.

Using sonified EEGs, nurses identified seizures with a sensitivity of 95%, and medical students identified seizures with a sensitivity of 98%. In contrast, the sensitivity of visual displays was 88% when reviewed by neurologists and 76% when reviewed by EEG-trained medical students. Specificity of sonified EEGs was 85% when heard by the medical students and 82% when heard by the nurses. Specificity of traditional review was 90% for neurologists and 65% for medical students.

The study was based on a representative sample, not a prospectively and consecutively recruited cohort, which limits conclusions about how this technique might perform at the bedside, said the researchers. In addition, the sonification method would not identify focal seizures occurring outside the individual channels selected.

The study was funded by a Stanford University BioX Seed Grant. Dr. Parvizi and one coinvestigator invented the sonification method and cofounded a startup that has licensed the technology from Stanford University. The other two investigators had no conflicts of interest.

—Amy Karon

LRRK2 Mutation Is Associated With Slower Motor Decline in Parkinson’s Disease

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Patients carrying the LRRK2 mutation have lower posture, gait, and balance scores, when compared with patients with nonmutation Parkinson’s disease.

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is associated with slower motor function decline in Parkinson’s disease, according to data published in the March 1 issue of JAMA Neurology.

“Our findings of a slower decrease in motor Unified Parkinson’s Disease Rating Scale [UPDRS] score remained consistent even in sensitivity analyses that included only individuals who had two or more visits,” said Rachel Saunders-Pullman, MD, MPH, Associate Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City. “The slower progression estimates could inform clinical trial design for emerging LRRK2-targeted agents.”

A cross-sectional study suggested that Parkinson’s disease associated with LRRK2 G2019S mutation among patients of Ashkenazi Jewish descent is milder and may progress more slowly, compared with idiopathic Parkinson’s disease. To determine whether the longitudinal course of Parkinson’s disease in patients with the LRRK2 mutation differs from that in patients without the mutation, Dr. Saunders-Pullman and colleagues conducted a prospective, comprehensive assessment of patients from July 21, 2009, to September 30, 2016.

Researchers recruited participants of Ashkenazi Jewish ancestry with LRRK2-associated Parkinson’s disease or with idiopathic Parkinson’s disease from three sites. The investigators evaluated 545 participants who had one to four study visits. Patients with the glucocerebrosidase 1 (GBA1) mutation were excluded from the analysis.

The investigators used linear mixed-effects models for longitudinal motor scores to examine the association of LRRK2 mutation status with the rate of change in UPDRS III scores. They used disease duration as the time scale and adjusted the data for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. The researchers also used mixed-effects models to assess change in cognition, as measured by Montreal Cognitive Assessment scores.

Of the 545 participants, 233 were women. The mean age of patients with the LRRK2 mutation was 68.2, and the mean age of those without the mutation was 67.8. Seventy-two of the 144 participants with the LRRK2 mutation and 161 of the 401 participants with no mutation were women. Among patients with the LRRK2 mutation, the estimated rate of change in the UPDRS III motor score per year was lower (0.689 points/year), compared with those without the mutation (1.056 points/year).

Patients carrying the LRRK2 mutation had lower posture, gait, and balance scores, when compared with patients with nonmutation Parkinson’s disease. The estimated difference in the rate of change in Montreal Cognitive Assessment score between individuals with LRRK2 mutation and those without the mutation was not statistically significant.

“The present study is the first, to our knowledge, to demonstrate this milder progression using prospective analysis,” said Dr. Saunders-Pullman and colleagues. “It is unclear whether the overall milder course represents an average of divergent LRRK2 pathologic findings or less overall synuclein burden.

“Larger and longer-duration longitudinal studies, including those evaluating pathologic findings and nonmotor features, are warranted,” the researchers concluded.

—Erica Tricarico