Citations

AbstractIntroductionAlzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18F‐flortaucipir‐positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA‐binding protein 43 (TDP‐43) was contributing to this volume‐uptake mismatch.MethodsSeventy‐seven participants with flortaucipir‐PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP‐43 pathology assessments. Bivariate‐response linear regression estimated the effect of age and TDP‐43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices.ResultsOlder participants had lower hippocampal volumes and overall flortaucipir uptake. TDP‐43‐immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP‐43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP‐43‐positives, reflecting the increasing TDP‐43 pathology frequency with age.DiscussionTDP‐43 pathology is a relevant contributor driving the volume‐uptake mismatch in older AD participants.Highlights TDP‐43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP‐43 pathology effect is seen in old age due to its increasing frequency. TDP‐43 pathology is a relevant driver of the volume‐uptake mismatch in old AD patients.

Abstract Diffuse hemispheric glioma, H3 G34-mutant (DHG_H3G34) is a novel tumor type in the 2021 WHO CNS classification. We describe a comprehensive sequencing and high-resolution genome-wide copy number analysis of a series of cases clinically tested by a single laboratory (2018-2022). Cases included tumors from 47 unique patients (1 reportedly recurrent) that had an H3-3A G34 mutation detected using an 187-gene mutation and fusion targeted neuro-oncology NGS panel (n=47). A subset (n=18) of cases was also tested Oncoscan chromosomal microarray. Median age at testing was 20 years (range, 12-50). H3-3A G34 mutations included G34R (n=44; 94%), G34V (n=2) and a novel G34E variant considered to be likely clinically relevant (n=1). All DHG_H3G34 were hemispheric tumors, and one tumor was multifocal with midline involvement. Concurrent mutations recurrently involved ATRX (n=38), TERT promoter (n=3; mutually exclusive with ATRX mutations), TP53 (n=43), PDGFRA (n=26), PTEN (n=5), NF1 (n=4, all patients over 20 years), PIK3CA (n=4) and CDKN2A (n=3). The single recurrent tumor also had an MSH6 mutation, and in addition to 3 other cases, had increased number of sequence variants suggestive of a high tumor mutational burden. A single case also showed an FGFR3::FAM184B (exon 17::exon 2) fusion. All cases with available chromosomal microarray data had unbalanced genomes with multiple chromosomal gains/losses, and regions of copy-neutral loss of heterozygosity. The most frequent recurrent (at least 50% of cases) abnormalities were losses involving 3q, 4q, 10q, 13q and 18q, and 17p copy-neutral loss of heterozygosity encompassing TP53 (all but one case had concomitant TP53 mutation), a pattern reminiscent of IDH-mutant astrocytomas. Oncogene amplifications (PDGFRA and PIK3CA) were detected in 3 (of 18) cases. CDKN2A/B deletion was observed in 8 cases (2 homozygous). In conclusion, we describe additional sequence and copy-number abnormalities in DHG_H3G34, expanding the spectrum of genetic changes associated with this novel tumor type.

AbstractBackgroundGlobular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non‐globular glial 4‐repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD).MethodsFor this case–control study the Mayo Clinic brain banks were queried for all cases with an autopsy‐confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR‐parkinsonism index, midbrain volume, and white matter hyperintensities.18F‐Fluorodeoxyglucose‐, 11C Pittsburg compound‐, and 18F‐flortaucipir‐positron emission tomography scans were reviewed.ResultsTwelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson‐plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR‐parkinsonism index, and larger midbrain volumes.ConclusionsFemale sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

Background: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population. Objective: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer’s disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA). Methods: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years). Results: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n = 33) and without RA (n = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p = 0.02). Conclusion: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA.

AbstractBackground and purposeAutoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt–Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE.MethodsPatients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total‐tau, phosphorylated181 tau and amyloid‐β42 levels were compared.ResultsOf 11 CJD cases, four were autopsy proven; the rest had positive real‐time quaking‐induced conversion testing. Disease‐associated autoantibodies were detected in 8/15 cases of AE: leucine‐rich glioma‐inactivated 1 and neuronal intermediate filaments (two cases each), and N‐methyl‐d‐aspartate receptor, contactin‐associated protein‐like 2, dipeptidyl‐peptidase‐like protein 6 and immunoglobulin‐like cell adhesion molecule IgLON family member 5. Total‐tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pg/ml, 95% confidence interval 1.17–2.11, p < 0.05, c = 0.93). Total‐tau was elevated in 91% of CJD cases (median > 1300, range 236–>1300 pg/ml), of which 55% were above the limit of assay measurement (>1300 pg/ml). Total‐tau was elevated in 20% of AE cases (median 158, range 80–>1300 pg/ml).ConclusionTotal‐tau was greater in CJD than AE. Given that amyloid‐β42 and phosphorylated181 tau were comparable, the ratio differences were probably driven by elevated total‐tau in CJD. This study supports the role for AD biomarker testing in patients with rapidly progressive dementia.

AbstractAmyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of nonmotor neuraxis emphasizes the contribution of glial cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment.