CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders

Irwin, David J.; Xie, Sharon X.; Coughlin, David G.; Nevler, Naomi; Akhtar, Rizwan; McMillan, Corey T.; Lee, Edward B.; Wolk, David A.; Weintraub, Daniel; Chen‐Plotkin, Alice S.; Duda, John E.; Spindler, Meredith; Siderowf, Andrew; Hurtig, Howard I.; Shaw, Leslie M.; Grossman, Murray; Trojanowski, John Q.

doi:10.1212/wnl.0000000000005166

Cited by 73 publications

(70 citation statements)

References 42 publications

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“…An analysis of the DATATOP (Deprenyl And Tocopherol Antioxidant Therapy of Parkinson's) trial found that higher levels of CSF tau may be related to faster motor progression . Whereas postmortem validation studies in LBD are rare, CSF measurements of tau and Aβ1‐42 relate to the severity of AD pathology in LBD, as previously observed in AD . Interestingly, low CSF Aβ1‐42 may also relate to neocortical distribution of SYN pathology .…”

Section: In Vivo Biomarker Associations With Patient Subtypesmentioning

confidence: 86%

“…Whereas postmortem validation studies in LBD are rare, CSF measurements of tau and Aβ1‐42 relate to the severity of AD pathology in LBD, as previously observed in AD . Interestingly, low CSF Aβ1‐42 may also relate to neocortical distribution of SYN pathology . Further work is needed to elucidate the relationship between ante mortem AD CSF biomarkers and underlying neuropathology and to continue to collect longitudinal data on CSF measurements in well‐characterized cohorts .…”

Section: In Vivo Biomarker Associations With Patient Subtypesmentioning

confidence: 97%

“…[165][166][167] Interestingly, low CSF Aβ1-42 may also relate to neocortical distribution of SYN pathology. 35 Further work is needed to elucidate the relationship between ante mortem AD CSF biomarkers and underlying neuropathology and to continue to collect longitudinal data on CSF measurements in well-characterized cohorts. 168 Nevertheless, CSF tau and Aβ biomarkers appear to have some prognostic value in LBD, but further data are needed to clarify this association and longitudinal progression of these markers over time.…”

Section: Data-driven Patient Subtypes Using Cluster Analysesmentioning

confidence: 99%

“…Several converging lines of evidence indicate that AD copathology not only contributes to decreased survival and a shortened motor‐dementia interval, but also influences specific motor and cognitive features . Whereas in vivo SYN biomarkers are still being developed, methods to detect Aβ and tau in living LBD patients are improving . Here, we will review previous and ongoing efforts to connect LBD patient subtypes with ante mortem biomarkers and underlying neuropathology to improve understanding of the biological basis of LBD's clinical heterogeneity.…”

mentioning

confidence: 99%

“…21,25,[29][30][31][32] Whereas in vivo SYN biomarkers are still being developed, methods to detect Aβ and tau in living LBD patients are improving. [33][34][35][36][37] Here, we will review previous and ongoing efforts to connect LBD patient subtypes with ante mortem biomarkers and underlying neuropathology to improve understanding of the biological basis of LBD's clinical heterogeneity.…”

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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: In Vivo Biomarker Associations With Patient Subtypesmentioning

confidence: 86%

Section: In Vivo Biomarker Associations With Patient Subtypesmentioning

confidence: 97%

Section: Data-driven Patient Subtypes Using Cluster Analysesmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Dopamine transporter imaging predicts clinically‐defined α‐synucleinopathy in REM sleep behavior disorder

Chahine

Brumm

Caspell‐Garcia

et al. 2020

Ann Clin Transl Neurol

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IntroductionIndividuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α‐synucleinopathy (aSN). They could serve as a key population for disease‐modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically‐defined aSN in iRBD.MethodsThe sample included individuals with iRBD, early Parkinson’s Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow‐up versus those not diagnosed.ResultsThe sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT‐SPECT at baseline. Over 4.7 years of mean follow‐up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79–83.3], P = 0.0003).ConclusionWe demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short‐term risk of an aSN diagnosis.

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CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders

Abstract: Higher antemortem CSF t-tau/Aβ and lower Aβ levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

Cited by 73 publications

References 42 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

Dopamine transporter imaging predicts clinically‐defined α‐synucleinopathy in REM sleep behavior disorder

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