Atypical astroglial pTDP-43 pathology in astroglial predominant tauopathy.

We observed atypical astrocytic pTDP-43 pathology in astroglial predominant tauopathy.

Regional Overlap of Pathologies in Lewy Body Disorders.

Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, ß-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, ß-amyloid (Aß), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease [PD], 28 with dementia, and 19 with dementia with Lewy bodies). APOE and MAPT genetic variants were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology. Pathological stages of tau, ß-amyloid and α-synuclein pathologies were increased in cases with dementia. Aß score was the best correlate of the time to dementia in PD. In addition, ß-amyloid deposition correlated with α-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD that may have an impact on the clinical expression of the diseases.

Cerebrospinal fluid ß-amyloid and phospho-tau biomarker interactions affecting brain structure in preclinical Alzheimer disease.

OBJECTIVE: To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD). METHODS: In this cross-sectional study, normal controls (n = 145) from the Alzheimer's Disease Neuroimaging Initiative underwent structural 3T magnetic resonance imaging (MRI) and lumbar puncture. CSF ß-amyloid1-42 (Aß) and phospho-tau181p (p-tau) levels were measured by Luminex assays. Samples were dichotomized using published cutoffs (Aß(+) /Aß(-) and p-tau(+) /ptau(-)). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction by analysis of covariance. RESULTS: We found a significant biomarker interaction between CSF Aß and CSF p-tau levels affecting brain structure. Cortical atrophy only occurs in subjects with both Aß(+) and p-tau(+). The stratified correlation analyses showed that the relationship between p-tau and CTh is modified by Aß status and the relationship between Aß and CTh is modified by p-tau status. p-Tau-dependent thinning was found in different cortical regions in Aß(+) subjects but not in Aß(-) subjects. Cortical thickening was related to decreasing CSF Aß values in the absence of abnormal p-tau, but no correlations were found in p-tau(+) subjects. INTERPRETATION: Our data suggest that interactions between biomarkers in AD result in a 2-phase phenomenon of pathological cortical thickening associated with low CSF Aß, followed by atrophy once CSF p-tau becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy.