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Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias.

ABSTRACT: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.

SUBMITTER: Howlett DR

PROVIDER: S-EPMC8029273 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias.

Howlett David R DR Whitfield David D Johnson Mary M Attems Johannes J O'Brien John T JT Aarsland Dag D Lai Mitchell K P MK Lee Jasinda H JH Chen Christopher C Ballard Clive C Hortobágyi Tibor T Francis Paul T PT

Brain pathology (Zurich, Switzerland) 20141030 4

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive de ...[more]

PMID: 25103200

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Project description:BackgroundAlzheimer's disease neuropathologic change (ADNC) and Lewy pathology (LP) often coexist in cognitively impaired individuals. These pathologies' relative distribution and severity may modify these individuals' clinical presentation, cognitive profile, and prognosis. Therefore, we examined the contributions of LP and concomitant ADNC to disease survival and profiles of cognitive decline in preclinical and clinical stages in a large neuropathologically diagnosed group.MethodsWe evaluated 597 participants with LP and 491 participants with intermediate/high ADNC in the absence of LP from the National Alzheimer Coordinating Center (NACC) database. At baseline, 237 participants were cognitively normal (CN), 255 were diagnosed with mild cognitive impairment (MCI), and 596 with dementia. Cognition was assessed using three cognitive domain scores (i.e., Memory, Executive, and Language) from the NACC Uniform Dataset (UDS) neuropsychological test battery, MMSE, and Clinical Dementia Rating (CDR). Multivariate adaptive regression splines were used to evaluate associations between baseline cognitive scores and mean annual rate of change over two years. The likelihood of progression to MCI or dementia was assessed using Cox hazard models.ResultsNeocortical LP, independent of the clinical diagnosis, was associated with lower Executive and higher Language and Memory scores at baseline, whereas Braak V-VI neurofibrillary tangle pathology was associated with lower Memory and Language scores. Similarly, neocortical LP was associated with faster Executive decline, whereas Braak V-VI neurofibrillary tangle pathology was associated with faster Memory and Language decline. A clinical diagnosis of Lewy Body Dementia (i.e., a strong LP phenotype) was associated with the LP cognitive profile and shorter disease duration. Progression to incident MCI or dementia was primarily associated with the degree of tau pathology; neocortical LP or a diagnosis of Lewy Body Dementia only predicted progression when those with intermediate/high ADNC were excluded.ConclusionsLP and ADNC differentially affected cross-sectional and longitudinal cognitive profiles in a large autopsy sample. Concomitant Braak V-VI neurofibrillary tangle pathology had a strong impact on clinical progression in those with LP, regardless of the initial stage. Thus, LB and ADNC co-pathology interact to affect cognitive domains that may be used to track Lewy Body disease longitudinally and as outcome measures in therapeutic trials.

Project description:ObjectiveThe goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories.MethodsParticipants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aβ-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline.ResultsWomen showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). β-amyloid (Aβ)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aβ + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04).InterpretationTau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aβ were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.

Dataset Information

Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias.

Publications

Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias.

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