CSF Biomarkers of Alzheimer Disease in Patients With Concomitant α-Synuclein Pathology.

BACKGROUND AND OBJECTIVES: Cerebrospinal fluid (CSF) biomarkers amyloid-ß42 (Aß42), phosphorylated tau (p-tau181), total tau (t-tau) and neurogranin (Ng) can diagnose Alzheimer's disease (AD) in life. However, it is unknown if CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test if biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aß42, p-tau181, t-tau and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD+αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD+αSyn affected diagnostic accuracy of two CSF-based strategies: the ATN framework and the t-tau/Aß42 ratio. METHODS: Inclusion criteria were neuropathologic diagnoses of AD, mixed AD+αSyn, and αSyn. A convenience sample of non-impaired controls were selected with available CSF and a mini mental state exam (MMSE)≥27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aß42, p-tau181, t-tau, and Ng differences across AD and AD+αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic amyloid-ß and tau. Receiver operating characteristic and area under the curve (AUC), including 95% confidence intervals (CI), evaluated diagnostic accuracy. RESULTS: Participants were 61 AD, 39 mixed AD+αSyn, 20 αSyn, and 61 Controls. AD had similar median age (73 [IQR=12]), MMSE (23 [IQR=9]), and sex distribution (Male=49%) compared to AD+αSyn age (70 [IQR=13]; p=0.3), MMSE (25 [IQR=9.5]; p=0.19), and sex distribution (Male=69%; p=0.077). ANCOVAs showed AD+αSyn had lower p-tau181 (F(1,94)=17, p=0), t-tau (F(1,93)=11, p=0.0004), and Ng levels (F(1,50)=12, p=0.0004) than AD; there was no difference in Aß42 (p=0.44). Models showed increasing αSyn related to lower p-tau181 (ß=-0.26, SE=0.092, p=0.0065), t-tau (ß=-0.19, SE=0.092, p=0.041), and Ng levels (ß=-0.2, SE=0.066, p=0.0046); αSyn was not a significant factor for Aß42 (p=1). T-tau/Aß42 had the highest accuracy when detecting AD, including mixed AD+αSyn cases (AUC=0.95; CI=0.92 to 0.98). DISCUSSION: Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau181, t-tau, and Ng levels, and can affect diagnositic accuracy in AD patients.

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES: Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes. METHODS: We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test. RESULTS: We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants. DISCUSSION: We present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders. TRIAL REGISTRATION INFORMATION: NCT02365922, NCT02372773, and NCT04363684.

Lexical and Acoustic Speech Features Relating to Alzheimer Disease Pathology.

BACKGROUND AND OBJECTIVES: We compared digital speech and language features of patients with amnestic Alzheimer's disease (aAD) or logopenic variant primary progressive aphasia (lvPPA) in a biologically confirmed cohort and related these features to neuropsychiatric test scores and CSF analytes. METHODS: We included patients with aAD or lvPPA with cerebrospinal fluid (CSF) (phosphorylated Tau (p-Tau)/Aß≥ 0.09 and total Tau/Aß≥ 0.34) or autopsy confirmation of AD pathology and age-matched healthy controls (HC) recruited at the Frontotemporal Degeneration Center of the University of Pennsylvania for a cross-sectional study. We extracted speech and language variables with automated lexical and acoustic pipelines from participants' oral picture descriptions. We compared the groups and correlated distinct features with clinical ratings and CSF p-Tau levels. RESULTS: We examined patients with aAD (n=44; 62±8 years; 24 females; Mini-Mental State Exam (MMSE)=21.1±4.8) or lvPPA (n=21; 64.1±8.2 years; 11 females; MMSE=23.0±4.2), and healthy controls (HC) (n=28; 65.9±5.9 years, 15 females; MMSE=29±1). Patients with lvPPA produced fewer verbs (10.5±2.3; p=0.001), adjectives (2.7±1.3, p=0.019), and more fillers (7.4±3.9; p=0.022) with lower lexical diversity (0.84±0.1; p=0.05) and higher pause rate (54.2±19.2; p=0.015) than aAD (verbs: 12.5±2; adjectives: 3.8±2; fillers: 4.9±4.5; lexical diversity: 0.87±0.1; pause rate: 45.3±12.8). Both groups showed some shared language impairments compared with HC. Word frequency (MMSE: ß=-1.6, p=0.009, BNT: ß=-4.36, p<0.001), adverbs (MMSE: ß=-1.9, p=0.003, BNT: ß=-2.41, p=0.041), pause rate (MMSE: ß=-1.21, p=0.041, BNT: ß=-2.09, p=0.041), and word length (MMSE: ß=1.75, p=0.001, BNT: ß=2.94, p=0.003) were significantly correlated with both MMSE and BNT, but other measures were not correlated with MMSE and/or BNT. Prepositions (r=-0.36, p=0.019), nouns (r=-0.31, p=0.047), speech segment duration (r=-0.33, p=0.032), word frequency (r=0.33, p=0.036), and pause rate (r=0.34, p=0.026) were correlated with patients' CSF p-Tau levels. DISCUSSION: Our measures captured language and speech differences between the two phenotypes that traditional language-based clinical assessments failed to identify. This work demonstrates the potential of natural speech in reflecting underlying variants with AD pathology.