Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders

Coughlin, David G.; Xie, Sharon X.; Liang, Mendy; Williams, Andrew; Peterson, Claire; Weintraub, Daniel; McMillan, Corey T.; Wolk, David A.; Akhtar, Rizwan; Hurtig, Howard I.; Coslett, H. Branch; Hamilton, Roy H.; Siderowf, Andrew; Duda, John E.; Rascovsky, Katya; Lee, Edward B.; Lee, Virginia M.‐Y.; Grossman, Murray; Trojanowski, John Q.; Irwin, David J.

doi:10.1002/ana.25392

Cited by 96 publications

(159 citation statements)

References 54 publications

(186 reference statements)

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“…We also found that tau in LBD occurred in a different distribution than in AD, with more relative temporal neocortical pathology. Last, we also found that regional tau burden was consistently related to worse cognitive performance both on measures of global cognition and domain‐specific testing . Another recent digital study of LBD found relative sparing of tau pathology in the hippocampus of LBD patients with AD copathology, compared to patients with clinical AD and mixed AD and SYN pathology .…”

Section: Ad Neuropathologysupporting

confidence: 75%

“…Digital histological measurements, using image analysis techniques, offer a potential improvement over traditional methods by generating objective, finely grained, continuous measurements of pathological burden, which, in contrast to the traditional methodology, may improve the potential to make clinicopathological correlations and relate pathological burden to ante mortem biomarker assessments. However, more work is needed to standardize methodology across labs . In our recent work using digital histology, we found that co‐occurring tau and Aβ pathology was related to a higher burden of neocortical SYN in patients with LBD.…”

Section: Ad Neuropathologymentioning

confidence: 99%

“…Although these group‐wise differences exist between PDD and DLB, there are no neuropathological findings that reliably distinguish these clinical phenotypes on an individual patient level . Tau neurofibrillary tangle pathology is most often shown to have a similar distribution as observed in typical AD using conventional neuropathological staging methods, but more recent digital assessments suggest relative sparing of medial temporal lobe and greater relative distribution in temporal neocortex in LBD versus AD …”

Section: Ad Neuropathologymentioning

confidence: 99%

“…Studies differ on whether tau or Aβ is the most significant contributor to dementia and shortened survival . AD copathology has also been associated with a greater burden of neocortical deposition of SYN . These disparate conclusions may be, in part, attributed to the high correlation between these pathologies and relatively sparse sampling and qualitative ratings used on traditional autopsy studies.…”

Section: Ad Neuropathologymentioning

confidence: 99%

“…These observations have resulted in alterations to the neuropathological assessment of DLB, whereby higher stages of tau are associated with a lower likelihood of patients exhibiting a “classic” DLB phenotype . Other studies have documented alterations in domain‐specific cognitive function in LBD patients with co‐occurring tau and Aβ pathology at autopsy . In PD, patients with tau and Aβ copathology are more likely to have a clinical phenotype of postural instability with little or no tremor (the “postural‐instability‐gait dysfunction” or PIGD phenotype) .…”

Section: Ad Neuropathologymentioning

confidence: 99%

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Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

2019

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PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha‐synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta‐amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease‐modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society

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Section: Ad Neuropathologysupporting

confidence: 75%

Section: Ad Neuropathologymentioning

confidence: 99%

Section: Ad Neuropathologymentioning

confidence: 99%

Section: Ad Neuropathologymentioning

confidence: 99%

Section: Ad Neuropathologymentioning

confidence: 99%

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Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

2019

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Tau pathology associates with in vivo cortical thinning in Lewy body disorders

Spotorno

Coughlin

Olm

et al. 2020

Ann Clin Transl Neurol

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Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Ab 1-42 > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBDÀAD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBDÀAD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Ab, and alpha-synuclein using digital histopathology in five representative neocortical regions. Results: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBDÀAD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Ab or alpha-synuclein pathology. Interpretation: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.

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Quantifying regional α ‐synuclein, amyloid β, and tau accumulation in lewy body dementia

Miller

Dhavale

O'Shea

et al. 2022

Ann Clin Transl Neurol

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Objective Parkinson disease (PD) is defined by the accumulation of misfolded α‐synuclein (α‐syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α‐syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions. Methods We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α‐syn, Aβ, and tau with recently developed sandwich ELISAs. Results We detected a wide range of insoluble α‐syn accumulation in LBD cases. The majority had substantial α‐syn accumulation in most regions, and dementia severity correlated with neocortical α‐syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α‐syn accumulation. Tau accumulation accompanied Aβ in only one LBD case. Interpretation LBD is associated with insoluble α‐syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α‐syn accumulation suggests a pathophysiologic relationship between these two processes.

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Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders

Cited by 96 publications

References 54 publications

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

Tau pathology associates with in vivo cortical thinning in Lewy body disorders

Quantifying regional α ‐synuclein, amyloid β, and tau accumulation in lewy body dementia

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