Faculty Bibliography

OBJECTIVE/UNASSIGNED:Cognitive motor dissociation (CMD) is associated with long-term recovery in acute brain injury, but CMD testing is only available in few centers. Our objective was to identify surface EEG patterns with high sensitivity or positive predictive value (PPV) for CMD in patients with acute disorders of consciousness to refine allocation of this resource-intensive test. METHODS/UNASSIGNED:In this observational cohort study, we enrolled clinically unresponsive, acutely brain injured patients who underwent continuous surface EEG and CMD assessments. CMD was detected by applying a machine learning algorithm to EEG acquired during a motor command paradigm presentation.Electroencephalographers blinded to CMD test results applied standardized ACNS criteria to the EEGs acquired during CMD assessments. We calculated accuracy measures of surface EEG findings for CMD test results using generalized estimating equations, with an exchangeable matrix and accounting for repeated measures per patient. RESULTS/UNASSIGNED:We included 185 patients (mean age: 62 ± 17; 85 [46%] female) and 282 CMD assessments. CMD testing was positive in 39 (14%) assessments. Sensitivity and PPV of normal background voltage, symmetry and continuity were respectively 77% (95%-CI: 60-88%) and 19% (95%-CI: 13-26%), 74% (95%-CI: 58-86%) and 14% (95%-CI: 10-20%), and 74% (95%-CI: 58-86%) and 14% (95%-CI: 9-19%). All EEGs with burst suppression, suppression, sporadic epileptiform discharges, lateralized periodic discharges, bilateral independent periodic discharges, electrographic seizures and brief potentially ictal rhythmic discharges had negative CMD tests. INTERPRETATION/UNASSIGNED:Surface EEG findings are not reliable to screen for CMD or to identify patterns conferring higher CMD pretest probability.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Cerebral amyloid angiopathy (CAA) is a common cause of intracerebral hemorrhage (ICH) in older patients. Whether CAA is associated with isolated subdural hemorrhage (SDH), without an accompanying ICH, remains unclear. We, therefore, tested this relationship in a large, heterogeneous sample of patients across the United States. METHODS:We performed a retrospective cohort study using administrative claims data from all admissions to nonfederal acute care hospitals in 11 states in the United States between 2016 and 2021. Among hospitalized patients, we included only those aged 50 years or older, a threshold necessary to meet Boston criteria v2.0 for CAA. We divided this population into 3 groups: those with a diagnosis of CAA, those with other cerebrovascular diseases (CVDs) but without CAA, and those with neither CAA nor other CVDs. The main outcome was a first-documented, isolated, nontraumatic SDH; we did not count SDH cases with a concurrent traumatic brain injury. The exposures and outcome were identified using previously validated ICD-10-CM diagnosis codes. Using Cox regression analyses, we compared the risk of incident SDH among the 3 groups after adjustment for demographics and comorbidities. In prespecified sensitivity analyses, patients with a baseline diagnosis of dementia were excluded. RESULTS:Among 8.5 million hospitalized patients aged 50 years or older, 2,335 had CAA and 600,646 had other CVDs. During a median follow-up of 2.0 years (interquartile range 1.0-3.9), incident SDH occurred in 34 patients with CAA (1.5%), 3,552 patients with other CVDs (0.6%), and 35,425 patients without CAA or other CVDs (0.4%). In adjusted Cox regression analysis, there was an increased risk of incident SDH seen with CAA (hazard ratio [HR] 3.1; 95% CI 2.2-4.4) and with prevalent CVD (HR 1.4; 95% CI 1.3-1.5). Findings were similar in sensitivity analyses excluding patients with dementia. DISCUSSION/CONCLUSIONS:In a large, heterogeneous cohort, we found that CAA was associated with a 3-fold heightened risk of SDH, higher than the increased risk seen in patients with other CVDs. These findings support the emerging hypothesis that CAA is a risk factor of isolated nontraumatic SDH.

Cerebrovascular dysfunction is associated with risk and progression of Alzheimer's disease, but the extent to which it promotes Alzheimer's pathophysiology is unclear. Understanding the relationship between cerebrovascular dysfunction and Alzheimer's disease markers in midlife is critical to inform our understanding of the earliest manifestations of the disease and prevention strategies. We examined the association of cerebral blood flow with two biomarkers of tau pathophysiology, plasma phosphorylated tau 181 (p-tau181) concentrations and tau PET MK6240 standard uptake value ratio. This was a cross-sectional study of participants in the Offspring Study in upper Manhattan. Analyses included arterial spin labelling MRI, plasma p-tau181 concentration and 18F-MK-6240 tau PET data in the entorhinal cortex. Four hundred and fifty-nine participants (54.8 ± 10.8 years old, 63.3% women) had available MRI and plasma p-tau181 data, and 98 (60.4 ± 5.8 years old, 61.2% women) had additional tau PET data. Lower cerebral blood flow was associated with both higher plasma p-tau181 concentration and entorhinal cortex tau standard uptake value ratio. Higher plasma p-tau181 levels were associated with small clusters of lower regional cerebral blood flow, primarily in regions that correspond to sites of early Alzheimer's disease pathology. Higher tau PET levels were associated with lower cerebral blood flow throughout the brain. These findings suggest that there is relationship between cerebral blood flow and indicators of tau pathophysiology in middle age that is likely bidirectional.

Pantothenate-kinase-associated neurodegeneration (PKAN) is a rare, autosomal recessive neurological disorder characterized by the progressive degeneration of specific regions in the brain and is invariably fatal. Several individuals in families affected by PKAN were known to live in an isolated region in a southwestern province of the Dominican Republic and had been previously studied. Forty-six individuals with PKAN in 34 families were evaluated for disease manifestations using the PKAN-Disease Rating Scale and the Leiter-3 Cognitive and Neuropsychological assessment. We completed whole genome sequencing in the 46 affected individuals and their 80 unaffected relatives. Haplotype analysis was used to identify shared genetic patterns among individuals with the mutation to identify common ancestral and founder effects. The classic form of PKAN was observed in 22 individuals with moderate-to-severe oromandibular dystonia and limb dystonia and onset in early childhood. The atypical form was observed in 24 individuals with Parkinsonism, dystonia, cognitive deficits, and later onset of disease. A PANK2 variant, chr20:3907977: A:G (c.680A  >  G, p.Y227C), was homozygous among 42 affected individuals equally divided by disease form. There were 59 heterozygous carriers of this variant among parents and relatives of the affected individuals. Four individuals from two families were compound heterozygotes for c.680A  >  G and chr20:3918728: C:T (c.1594C  >  T). Haplotype analyses revealed shared patterns across families and of African origin consistent with founder effects for c.680A  >  G and c.1594C  >  T, likely introduced to the island 25-35 generations earlier. The frequency of heterozygous carriers of c.680A  >  G allele among individuals of Dominican ancestry living in New York was 0.18% but was 0.8% among individuals living in the Dominican Republic, significantly higher than the reported frequency for all causal PANK2 mutations worldwide. This investigation confirmed likely founder mutations in PANK2 associated with the classic and atypical forms of PKAN in 34 families in an isolated region of the Dominican Republic. Compound heterozygosity was observed in four individuals from two families. The heterozygous frequency of c.680A  >  G was exceptionally high in the Dominican population compared with worldwide data. Founder mutations in such communities offer a unique opportunity to set up relevant, affordable and accessible genetic counselling and screening.

Over 2 [...].

INTRODUCTION/UNASSIGNED:Downbeat nystagmus (DBN) is classically attributed to cerebellar pathology. Far less often, DBN arises from brainstem disease, with midbrain etiologies being exceptionally rare and poorly characterized. In particular, DBN with the dorsal midbrain syndrome has been sporadically reported and its mechanism is unclear. METHODS/RESULTS/UNASSIGNED:We analyzed non-human primate and human literature on vertical gaze and brainstem-related DBN in the context of three patients with DBN and dorsal midbrain syndrome. Upgaze paresis was universal, skew deviation present in two, and parkinsonism developed in two after shunt-related complications. We reviewed the literature using strict criteria requiring DBN in central gaze and at least two definitive features of the dorsal midbrain syndrome, identifying two additional patients. DISCUSSION/UNASSIGNED:In five patients with DBN and dorsal midbrain syndrome, aqueductal stenosis or compression with upgaze paresis were unifying features. Potential mechanisms for DBN include involvement of the interstitial nucleus of Cajal, disruption of descending midbrain projections to paramedian tracts, or unstable cerebellar outflow, but clinical and experimental evidence makes these explanations less compelling. Converging evidence from our series, prior reports, and non-human primate studies suggests bilateral posterior commissural dysfunction related to aqueductal pathology as the most plausible mechanism for DBN with the dorsal midbrain syndrome.

The heterogeneity among the amyotrophic lateral sclerosis (ALS)/MND patient population is well recognized but not well understood. Such heterogeneity may represent a significant confound in our current and prior clinical trials as certain subgroups of patients might have a selective response (or resistance) to a novel therapeutic. The basis on which to segregate the patient population is, however, unclear. The ALS/MND Committee of the World Federation of Neurology (WFN) convened a symposium to discuss various strategies that might be considered for separating (stratifying) the population to further study. The results of that conference are presented here as a white paper, reflecting current understanding of several of the various criteria that could be implemented to divide the patient population as presented and discussed at that meeting. Consideration of grouping patients based on phenotype, cognitive involvement, imaging, or electrophysiology is presented here.

INTRODUCTION/AIMS/OBJECTIVE:Muscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ-68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ-68 in ALS. METHODS:This study was a double-blind, randomized, placebo-controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years. RESULTS:The enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ-68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance. DISCUSSION/CONCLUSIONS:The study revealed that N-of-1 trial design can detect changes in a small sample size, and TJ-68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ-68.