Pathological drivers of neurodegeneration in suspected non-Alzheimer’s disease pathophysiology

Abstract Background Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects. Methods Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume. Results SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. Conclusion SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported.

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Early stages of tau pathology and its associations with functional connectivity, atrophy and memory

Brain ◽

10.1093/brain/awab114 ◽

2021 ◽

Author(s):

David Berron ◽

Jacob W Vogel ◽

Philip S Insel ◽

Joana B Pereira ◽

Long Xie ◽

...

Keyword(s):

Functional Connectivity ◽

Entorhinal Cortex ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Memory Impairment ◽

Memory Performance ◽

Hippocampal Atrophy ◽

Tau Pathology ◽

Β Amyloid ◽

With Memory

Abstract In Alzheimer’s disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 β-amyloid negative cognitively unimpaired, 81 β-amyloid positive cognitively unimpaired and 87 β-amyloid positive individuals with mild cognitive impairment, who each underwent [18]F-RO948 tau and [18]F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease-stage specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.

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Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau

10.21203/rs.3.rs-101153/v2 ◽

2021 ◽

Author(s):

Niklas Mattsson-Carlgren ◽

Shorena Janelidze ◽

Randall Bateman ◽

Ruben Smith ◽

Erik Stomrud ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medial Temporal Lobe ◽

Amyloid Plaques ◽

Amyloid Plaque ◽

Amyloid Pet ◽

Tau Pathology ◽

Β Amyloid ◽

Tau Pet ◽

Disease Stages

Abstract Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N=88), both plaque and tangle density contributed independently to higher P-tau217. Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N=426), where β-amyloid and tau PET were independently associated to P-tau217. P-tau217 correlated with β-amyloid PET (but not tau PET) in early disease stages, and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.

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Hippocampal Volume in Provisional Tic Disorder Predicts Tic Severity at 12-Month Follow-up

Journal of Clinical Medicine ◽

10.3390/jcm9061715 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1715

Author(s):

Soyoung Kim ◽

Deanna J. Greene ◽

Carolina Badke D’Andrea ◽

Emily C. Bihun ◽

Jonathan M. Koller ◽

...

Keyword(s):

Symptom Severity ◽

Structural Mri ◽

Hippocampal Volume ◽

Subcortical Structures ◽

Tic Disorder ◽

Tic Severity ◽

Mri Scans ◽

One Year ◽

Important Marker

Previous studies have investigated differences in the volumes of subcortical structures (e.g., caudate nucleus, putamen, thalamus, amygdala, and hippocampus) between individuals with and without Tourette syndrome (TS), as well as the relationships between these volumes and tic symptom severity. These volumes may also predict clinical outcome in Provisional Tic Disorder (PTD), but that hypothesis has never been tested. This study aimed to examine whether the volumes of subcortical structures measured shortly after tic onset can predict tic symptom severity at one-year post-tic onset, when TS can first be diagnosed. We obtained T1-weighted structural MRI scans from 41 children with PTD (25 with prospective motion correction (vNavs)) whose tics had begun less than 9 months (mean 4.04 months) prior to the first study visit (baseline). We re-examined them at the 12-month anniversary of their first tic (follow-up), assessing tic severity using the Yale Global Tic Severity Scale. We quantified the volumes of subcortical structures using volBrain software. Baseline hippocampal volume was correlated with tic severity at the 12-month follow-up, with a larger hippocampus at baseline predicting worse tic severity at follow-up. The volumes of other subcortical structures did not significantly predict tic severity at follow-up. Hippocampal volume may be an important marker in predicting prognosis in Provisional Tic Disorder.

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Subpial Thorn-shaped Astrocytes Are Prevalent In Guam ALS/PDC

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2021.168 ◽

2021 ◽

Vol 48 (s2) ◽

pp. S9-S10

Author(s):

G.G. Kovacs ◽

J.L. Robinson ◽

D.P. Perl ◽

V.M.Y. Lee ◽

J.Q. Trojanowski

Keyword(s):

Neurodegenerative Disorder ◽

University Of Pennsylvania ◽

List Type ◽

Tau Pathology ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Cortical Regions ◽

The University ◽

Formalin Fixed ◽

Lateral Sclerosis

Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex is a progressive neurodegenerative disorder characterized by neuronal and glial tau pathologies. With the aim to evaluate aging-related tau astrogliopathy (ARTAG) we examined the collection at the University of Pennsylvania, consisting of blocks of the frontal parietal, temporal, and occipital cortices. Formalin fixed, paraffin-embedded tissue blocks were evaluated using anti-tau antibodies PHF-1 and AT8. In addition to neuronal and oligodendroglial tau pathology, granular/fuzzy astrocytes in the gray matter and thorn-shaped astrocytes (TSAs) in subpial location were also observed. Twenty-one out of 33 cases (63%) showed subpial TSAs diffusely along the cortical surface in one or more cortical regions. Accumulation of TSAs in the depth of the sulci were seen in 41% in the temporal, 7% in the frontal and 14% in parietal cortex. This was not associated with perivascular neuronal tau pathology in the depth of the sulci. Accumulation of TSAs in the depth of cortical sulci in this cohort is approximately 20 times more frequent than reported in a European aging cohort. The presence of subpial TSAs in the depth of cortical sulci in CTE and Guam PDC, and less frequently in aging brains, might suggest common mechanisms.Learning ObjectivesDescribe the spectrum of neuropathology in Guam ALS/PDCDescribe the frequency of tau positive cortical subpial thorn-shaped astrocytes

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Ex vivo MRI atlas of the human medial temporal lobe: characterizing neurodegeneration due to tau pathology

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01275-7 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Sadhana Ravikumar ◽

Laura E. M. Wisse ◽

Sydney Lim ◽

Ranjit Ittyerah ◽

Long Xie ◽

...

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Ex Vivo ◽

Neurofibrillary Tangle ◽

Stratum Radiatum ◽

Tau Pathology ◽

Cornu Ammonis ◽

Mri Scans ◽

History Of ◽

Low Levels

AbstractTau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.

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Soluble P-tau217 reflects both amyloid and tau pathology in the human brain and mediates the association of amyloid with neocortical tau

10.21203/rs.3.rs-101153/v1 ◽

2020 ◽

Author(s):

Niklas Mattsson-Carlgren ◽

Shorena Janelidze ◽

Randall Bateman ◽

Ruben Smith ◽

Erik Stomrud ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medial Temporal Lobe ◽

Amyloid Plaques ◽

Amyloid Plaque ◽

Amyloid Pet ◽

Tau Pathology ◽

Β Amyloid ◽

Tau Pet ◽

Disease Stages

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Hippocampal volume in Provisional Tic Disorder predicts tic severity at 12-month follow-up

10.1101/2020.02.05.935908 ◽

2020 ◽

Cited By ~ 1

Author(s):

Soyoung Kim ◽

Deanna J. Greene ◽

Carolina Badke D’Andrea ◽

Emily C. Bihun ◽

Jonathan M. Koller ◽

...

Keyword(s):

Symptom Severity ◽

Motion Correction ◽

Structural Mri ◽

Hippocampal Volume ◽

Subcortical Structures ◽

Tic Disorder ◽

Tic Severity ◽

Mri Scans ◽

One Year

BackgroundPrevious studies have investigated differences in the volumes of subcortical structures (e.g., caudate nucleus, putamen, thalamus, amygdala, hippocampus) between individuals with and without Tourette syndrome (TS), as well as the relationships between these volumes and tic symptom severity. These volumes may also predict clinical outcome in Provisional Tic Disorder (PTD), but that hypothesis has never been tested.ObjectiveThis study aimed to examine whether the volumes of subcortical structures measured shortly after tic onset can predict tic symptom severity at one year post tic onset, when TS can first be diagnosed.MethodsWe obtained T1-weighted structural MRI scans from 41 children with PTD (25 with prospective motion correction [vNavs]) whose tics had begun less than 9 months (median 3.7 months) prior to the first study visit (baseline). We re-examined them at the 12-month anniversary of their first tic (follow-up), assessing tic severity using the Yale Global Tic Severity Scale. We quantified the volumes of subcortical structures using volBrain software.ResultsBaseline hippocampal volume was correlated with tic severity at the 12-month follow-up, with a larger hippocampus at baseline predicting worse tic severity at follow-up. This result was confirmed in the subgroup scanned with prospective motion correction. The volumes of other subcortical structures did not significantly predict tic severity at follow-up.ConclusionThese findings suggest that hippocampal volume may be an important marker in predicting prognosis in Provisional Tic Disorder.

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Production of New and Revised A.A.V.S.O. Charts

International Astronomical Union Colloquium ◽

10.1017/s0252921100073620 ◽

1979 ◽

Vol 46 ◽

pp. 368

Author(s):

Clinton B. Ford

Keyword(s):

Variable Star ◽

Standard Form ◽

Original Data ◽

University Of Pennsylvania ◽

Standard Format ◽

Additional Information ◽

The Gift ◽

The University

A “new charts program” for the Americal Association of Variable Star Observers was instigated in 1966 via the gift to the Association of the complete variable star observing records, charts, photographs, etc. of the late Prof. Charles P. Olivier of the University of Pennsylvania (USA). Adequate material covering about 60 variables, not previously charted by the AAVSO, was included in this original data, and was suitably charted in reproducible standard format.Since 1966, much additional information has been assembled from other sources, three Catalogs have been issued which list the new or revised charts produced, and which specify how copies of same may be obtained. The latest such Catalog is dated June 1978, and lists 670 different charts covering a total of 611 variables none of which was charted in reproducible standard form previous to 1966.

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