Natural speech markers of Alzheimer's disease co-pathology in Lewy body dementias

Shellikeri, Sanjana; Cho, Sunghye; Cousins, Katheryn A.Q.; Liberman, Mark; Howard, Erica; Balganorth, Yvonne; Weintraub, Daniel; Spindler, Meredith; Deik, Andres; Lee, Edward B.; Trojanowski, John Q.; Irwin, David J.; Wolk, David A.; Grossman, Murray; Nevler, Naomi

doi:10.1016/j.parkreldis.2022.07.023

Cited by 12 publications

(11 citation statements)

References 28 publications

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“…We tested the hypothesis that ATN PD incorporating T and N status would improve prediction of clinical outcomes in PD; alternatively A status alone may be sufficient for prognosis in early PD. We also predicted that AD biomarker strategies would specifically associate with declines in cognition, language, and postural stability in PD, but not with other motor and autonomic functioning, in line with previous literature [3][4][5][6] .…”

Section: Introductionsupporting

confidence: 85%

“…Models covaried for education and gender, as these variables are known to influence cognitive performance. [4]…”

Section: Part 2: Prediction Of Clinical Outcomes By Biomarker Strategymentioning

confidence: 99%

“…Clinically-relevant levels of Alzheimer's disease (AD) pathology are common in Lewy body disease (LBD), with roughly 40% having sufficient β-amyloid plaques and tau neurofibrillary tangles for a secondary neuropathological diagnosis of intermediate-to-high AD neuropathologic change (ADNC) 2,3 . Moreover, AD co-pathology in PD may contribute to more severe episodic memory and language impairments, as well as worse postural instability and shorter survival [3][4][5][6] . AD biomarkers may prove important to prognosticate clinical outcomes in PD.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of ATN_PDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Cousins

Irwin

Tropea

et al. 2023

Preprint

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Background and Objectives: In Parkinson's disease (PD), Alzheimer's disease (AD) co-pathology is common and clinically relevant. However, the longitudinal progression of AD cerebrospinal fluid (CSF) biomarkers - β-amyloid 1-42 (Aβ42), phosphorylated tau 181 (p-tau181) and total tau (t-tau) - in PD is poorly understood, and may be distinct from clinical AD. Moreover, it is unclear if CSF p-tau181and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ42. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATNPD) using CSF Aβ42(A), p-tau181(T), and serum NfL (N), and tested ATNPDprediction of longitudinal cognitive decline in PD. Methods: Participants were selected from the Parkinson's Progression Markers Initiative (PPMI) cohort, clinically-diagnosed with sporadic PD or as normal Controls, and followed annually for 5 years. Linear mixed effects models (LMEM) tested the interaction of diagnosis with longitudinal trajectories of analytes (log-transformed, FDR-corrected). In PD, LMEMs tested how baseline ATNPDstatus (AD [A+T+N±] vs. not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank-transformed, FDR-corrected). Results: Participants were 364 PD and 168 Controls, with comparable baseline mean (±SD) age (PD=62 ± 10; Control=61 ± 11]; Mann-Whitney-Wilcoxon: p=0.40) and gender distribution (PD=231 males [63%]; Control=107 males [64%]; chi-square: p=1.0). PD had overall lower CSF p-tau181(β=-0.16, 95%CI=-0.23 - -0.092, p=2.2e-05) and t-tau than Controls (β=-0.13, 95%CI=-0.19 - -0.065, p=4.0e-04), but not Aβ42(p=0.061) or NfL (p=0.32). Over time, PD had greater increases in serum NfL than Controls (β=0.035, 95%CI=0.022 - 0.048, p=9.8e-07); PD slopes did not differ from controls for CSF Aβ42(p=0.18), p-tau181(p=1.0) or t-tau (p=0.96). Using ATNPD, PD classified as A+T+N± (n=32; 9%) had consistently worse cognitive decline, including on global MoCA (β=-73, 95%CI=-110 - -37, p=0.00077), than all other ATNPDstatuses including A+ alone (A+T-N-; n=75; 21%). Discussion: In early PD, CSF p-tau181and t-tau were low compared to Controls and did not increase over 5 year follow-up. Even so, classification using modified ATNPD(incorporating CSF p-tau181with CSF Aβ42and serum NfL) may identify biologically--relevant subgroups of PD to improve prediction of cognitive decline in early PD.

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Section: Introductionsupporting

confidence: 85%

“…Models covaried for education and gender, as these variables are known to influence cognitive performance. [4]…”

Section: Part 2: Prediction Of Clinical Outcomes By Biomarker Strategymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of ATN_PDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Cousins

Irwin

Tropea

et al. 2023

Preprint

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“…In addition, it remains unknown whether the conversion to dementia versus parkinsonism first is related to a different top‐down synuclein spread reaching the cortex before the substantia nigra or to the effects of co‐morbid pathology 44,45 . For instance, Alzheimer's disease co‐pathology and mutations in the glucocerebrosidase gene are more common in DLB, 46 which might influence resulting linguistic abnormalities 47 …”

Section: Discussionmentioning

confidence: 99%

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study

Šubert,

Novotný,

Tykalová

et al. 2023

Annals of Neurology

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ObjectiveThis study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD).MethodsPatients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story‐tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow‐up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow‐up period of 5 years.ResultsOf 180 patients free of parkinsonism or dementia, 156 provided follow‐up information. After a mean follow‐up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia‐first (n = 16) and parkinsonism‐first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism‐first with normal cognition converters (n = 17).InterpretationAutomated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2023

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“…Nearly 50% of cases have significant accumulations of β-amyloid plaques and tau neurofibrillary tangles (intermediate or high AD neuropathologic change [ADNC]), justifying a secondary diagnosis of AD at autopsy 1,2 . Concomitant AD may describe much of the clinical heterogenity across LBSD 3 , and is associated with memory and linguistic impairments [4][5][6] , postural instability and gait 7 , and reduced survival 2,6 . Thus, the in vivo detection of concomitant AD is important for prognosis and disease management of LBSD 8 and may inform clinical trial design 9 .…”

Section: Introductionmentioning

confidence: 99%

Plasma GFAP associates with secondary Alzheimer’s pathology in Lewy body disease

Cousins

Irwin

Chen‐Plotkin

et al. 2022

Preprint

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Objective: Within Lewy body spectrum disorders (LBSD) with α-synuclein pathology (αSyn), concomitant Alzheimer's disease (AD) pathology is common and is predictive of clinical outcomes, including cognitive impairment and decline. Plasma phosphorylated tau 181 (p-tau181) is sensitive to AD neuropathologic change (ADNC) in clinical AD, and plasma glial fibrillary acidic protein (GFAP) is associated with the presence of β-amyloid plaques. While these plasma biomarkers are well tested in clinical and pathological AD, their diagnostic and prognostic performance for concomitant AD in LBSD is unknown. Methods: In autopsy-confirmed αSyn-positive LBSD, we tested how plasma p-tau181 and GFAP differed across αSyn with concomitant ADNC (αSyn+AD, n=19) and αSyn without AD (αSyn, n=30). Severity of burden was scored on a semi-quantitative scale for several pathologies (e.g., β-amyloid and tau), and scores were averaged across sampled brainstem, limbic, and neocortical regions. Results: Linear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β=0.31, 95%CI=0.065 - 0.56, p=0.015), after covarying for age at plasma, plasma-to-death interval and sex; plasma p-tau181 was not (p=0.37). Next, linear models tested associations of AD pathological features with both plasma analytes, covarying for plasma-to-death, age at plasma, and sex. GFAP was significantly associated with brain β-amyloid (β=15, 95%CI=6.1 - 25, p=0.0018) and tau burden (β=12, 95%CI=2.5 - 22, p=0.015); plasma p-tau181 was not associated with either (both p>0.34). Interpretation: Findings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β-amyloid plaques.

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Natural speech markers of Alzheimer's disease co-pathology in Lewy body dementias

Cited by 12 publications

References 28 publications

Evaluation of ATN_PDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Evaluation of ATN_PDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study

Plasma GFAP associates with secondary Alzheimer’s pathology in Lewy body disease

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Natural speech markers of Alzheimer's disease co-pathology in Lewy body dementias

Cited by 12 publications

References 28 publications

Evaluation of ATNPDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Evaluation of ATNPDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study

Plasma GFAP associates with secondary Alzheimer’s pathology in Lewy body disease

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Product

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Evaluation of ATN_PDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease

Evaluation of ATN_PDframework and biofluid markers to predict cognitive decline in early Parkinson’s disease