Young onset dementias present significant diagnostic challenges. We present the case of a 35-year-old Kuwaiti man with social withdrawal, drowsiness, irritability, anxiety, aphasia, memory loss, hypereflexia, and Parkinsonism. Brain MRI showed bilateral symmetric gradient echo hypointensities in the globi pallidi and substantiae nigrae. Left cortical hypometabolism was seen on brain fluorodeoxyglucose positron emission tomography. A cortical brain biopsy revealed a high Lewy body burden. Genetic testing revealed a homozygous p.T11M mutation in the C19orf12 gene consistent with mitochondrial membrane protein-associated neurodegeneration. This is the oldest onset age of MPAN reported.

Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have recently reported early clinical results of a novel PHF-tau targeting PET imaging agent, [F18]-T807. Since then, we have investigated a second novel PHF-tau targeting PET imaging agent, [F18]-T808, with different pharmacokinetic characteristics, which may be favorable for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F18]-T808.

Objective

To evaluate the evidence basis of single-domain cognitive tests frequently used by behavioral neurologists in an effort to improve the quality of clinical cognitive assessment.

Methods

Behavioral Neurology Section members of the American Academy of Neurology were surveyed about how they conduct clinical cognitive testing, with a particular focus on the Neurobehavioral Status Exam (NBSE). In contrast to general screening cognitive tests, an NBSE consists of tests of individual cognitive domains (e.g., memory or language) that provide a more comprehensive diagnostic assessment. Workgroups for each of 5 cognitive domains (attention, executive function, memory, language, and spatial cognition) conducted evidence-based reviews of frequently used tests. Reviews focused on suitability for office-based clinical practice, including test administration time, accessibility of normative data, disease populations studied, and availability in the public domain.

Results

Demographic and clinical practice data were obtained from 200 respondents who reported using a wide range of cognitive tests. Based on survey data and ancillary information, between 5 and 15 tests in each cognitive domain were reviewed. Within each domain, several tests are highlighted as being well-suited for an NBSE.

Conclusions

We identified frequently used single-domain cognitive tests that are suitable for an NBSE to help make informed choices about clinical cognitive assessment. Some frequently used tests have limited normative data or have not been well-studied in common neurologic disorders. Utilizing standardized cognitive tests, particularly those with normative data based on the individual's age and educational level, can enhance the rigor and utility of clinical cognitive assessment.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Introduction

Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.

Methods

We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.

Results

We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10^-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.

Discussion

MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.

Highlights

Long-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.