ABSTRACT
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.
ABSTRACT
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.
