To investigate the independent and interaction effects of Alzheimer disease (AD) and Lewy body disease (LBD) on cognition and brain atrophy.We consecutively recruited 38 controls and 108 patients with AD-related cognitive impairment (ADCI) and/or LBD-related cognitive impairment (LBCI) from university-based dementia and movement clinics. Diagnoses of ADCI and LBCI were supported by 18F-florbetaben PET and 18F-N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane-PET, respectively. There were 38 controls, 26 patients with pure ADCI (18 mild cognitive impairment [MCI] and 8 dementia), 28 patients with pure LBCI (13 MCI and 15 dementia), and 54 patients with mixed ADCI and LBCI (17 MCI and 37 dementia). We performed group-wise comparisons for neuropsychological z scores and regional cortical thickness. We also evaluated the effects of ADCI and LBCI using general linear models.Compared to the controls, patients in the pure ADCI group and pure LBCI group had focused cortical thinning in the bilateral entorhinal/right anterior temporal cortices and bilateral anteromedial temporal/basal frontal cortices, respectively, while the mixed disease group had additional cortical thinning in the widespread association cortices. The independent effects of ADCI and LBCI on regional cortical thinning overlapped in the widespread association cortices, especially at the bilateral temporoparietal junction and parietal cortices. ADCI and LBCI had independent detrimental effects on the copying item of the Rey-Osterrieth Complex Figure Test.Concomitant ADCI and LBCI are associated with the accentuation of neurodegeneration to widespread association cortices, and both diseases contribute to visuospatial dysfunction.
Parkinson disease (PD) shows degeneration of dopaminergic neurons in the substantia nigra and characteristic changes in brain metabolism. However, how they correlated and affect motor and cognitive dysfunction in PD has not yet been well elucidated.
Abstract Objective Although basal forebrain (BF) cholinergic degeneration and white matter hyperintensities (WMHs) are important in neurodegeneration in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), their relationships with dopaminergic degeneration and clinical manifestations remain unclear. Methods A total of 407 patients with cognitive impairment meeting the diagnostic criteria for AD, DLB, or both (AD+DLB) were assessed. All participants underwent 3T MRI, dopamine transporter (DAT) positron emission tomography, neuropsychological tests, and assessments for parkinsonism, cognitive fluctuation, visual hallucination, and rapid eye movement sleep behavior disorder (RBD). General linear and logistic regression models were used to investigate the relationships among BF volume, DAT uptake in the anterior caudate (DAT‐AC), WMH volumes in anterior, posterior, periventricular, and deep regions, and clinical manifestations. Results DAT‐AC was positively associated with BF volume and negatively associated with anterior periventricular WMH volume, but not with deep WMHs. Both deep and periventricular WMHs volumes were associated with hypertension and the number of microbleeds and lacunae. Lower BF volume and DAT‐AC were independently associated with increased risk of cognitive fluctuation and visual hallucination, whereas lower DAT‐AC was additionally associated with increased risk of RBD and greater parkinsonian severity. Both lower BF volume and DAT‐AC were independently associated with widespread cognitive impairment, whereas higher anterior periventricular WMH volume was associated with executive dysfunction. Interpretation BF cholinergic degeneration and anterior periventricular WMHs are closely associated with dopaminergic degeneration. Anterior periventricular WMHs may represent axonal alterations caused by the interplay between Lewy body‐related degeneration and vascular pathologies.
This study aimed to determine the pattern of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) related to postmortem Lewy body disease (LBD) pathology in clinical Alzheimer disease (AD).FDG-PET scans were analyzed in 62 autopsy-confirmed patients and 110 controls in the Alzheimer's Disease Neuroimaging Initiative. Based on neuropathologic evaluations on Braak stage for neurofibrillary tangle, Consortium to Establish a Registry for AD score for neuritic plaque, and Lewy-related pathology, subjects were classified into AD(-)/LBD(-), AD(-)/LBD(+), AD(+)/LBD(-), and AD(+)/LBD(+) groups. The association between postmortem LBD and AD pathologies and antemortem brain metabolism was evaluated.AD and LBD pathologies had significant interaction effects to decrease metabolism in the cerebellar vermis, bilateral caudate, putamen, basal frontal cortex, and anterior cingulate cortex in addition to the left side of the entorhinal cortex and amygdala, and significant interaction effects to increase metabolism in the bilateral parietal and occipital cortices. LBD pathology was associated with hypermetabolism in the cerebellar vermis, bilateral putamen, anterior cingulate cortex, and basal frontal cortex, corresponding to the Lewy body-related hypermetabolic patterns. AD pathology was associated with hypometabolism in the bilateral hippocampus, entorhinal cortex, and posterior cingulate cortex regardless of LBD pathology, whereas LBD pathology was associated with hypermetabolism in the bilateral putamen and anterior cingulate cortex regardless of AD pathology.Postmortem LBD and AD pathologies had significant interaction effects on the antemortem brain metabolism in clinical AD patients. Specific metabolic patterns related to AD and LBD pathologies could be elucidated when simultaneously considering the two pathologies. ANN NEUROL 2022;91:853-863.
Abstract Objective Although chronic exposure to air pollution is associated with an increased risk of dementia in normal elderlies, the effect of chronic exposure to air pollution on the rates of cognitive decline in Alzheimer's disease (AD) has not been elucidated. Methods In this longitudinal study, a total of 269 patients with mild cognitive impairment or early dementia due to AD with the evidence of brain β‐amyloid deposition were followed‐up for a mean period of 4 years. Five‐year normalized hourly cumulative exposure value of each air pollutant, such as carbon monoxide (CO), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), and particulate matter (PM 2.5 and PM 10 ), was computed based on nationwide air pollution database. The effects of chronic exposure to air pollution on longitudinal cognitive decline rate were evaluated using linear mixed models. Results Higher chronic exposure to SO 2 was associated with a faster decline in memory score, whereas chronic exposure to CO, NO 2 , and PM 10 were not associated with the rate of cognitive decline. Higher chronic exposure to PM 2.5 was associated with a faster decline in visuospatial score in apolipoprotein E ε4 carriers. These effects remained significant even after adjusting for potential confounders. Interpretation Our findings suggest that chronic exposure to SO 2 and PM 2.5 is associated with faster clinical progression in AD.
Abstract Background Although mixed pathologies are common in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), effects of β‐amyloid and dopaminergic depletion on brain perfusion and clinical features have not been elucidated. Method In 99 patients with cognitive impairment due to AD and/or DLB and 32 control participants, 18 F‐Florbetaben (FBB) PET, dual‐phase dopamine transporter (DAT) PET, and brain MRI were performed to measure β‐amyloid standardized uptake value ratio (SUVR), dopaminergic depletion in the ventral striatum, caudate, and putamen, and regional brain perfusion. Cognitive score, visual hallucination (VH), cognitive fluctuation (CF), and rapid eye movement sleep behavior disorder (RBD) were evaluated. Relationship among global FBB‐SUVR, striatal DAT uptakes, regional brain perfusion, clinical symptoms, and cognitive scores were evaluated using general linear or logistic regression models as appropriate. Result Global and mean lobar FBB SUVRs negatively correlated with DAT uptakes in the ventral striatum and caudate but not with putamen DAT uptake. Lower ventral striatal DAT uptake was associated with right temporo‐parietal hypoperfusion and hyper‐perfusion in the anterior cingulate cortex, vermis, motor cortex, and hippocampus, while higher FBB SUVR was associated with hypoperfusion in the left entorhinal cortex and temporo‐parietal cortex. Lower ventral striatal DAT uptake increased the risks of VH and RBD directly and indirectly through the mediation of hippocampal hyper‐perfusion, while hippocampal hyper‐perfusion fully mediated the effect of lower ventral striatal DAT uptake on the risk of CF. Higher FBB SUVR and lower DAT uptake were associated with language, memory, and executive dysfunction directly and indirectly through the mediation of regional perfusion, while regional perfusion fully mediated their effects on visuospatial dysfunction. Conclusion β‐amyloid deposition and striatal dopaminergic depletion reflecting AD‐ and DLB‐related neurodegenerations are inter‐correlated but differently contribute to regional perfusion changes and cognitive dysfunction.
Nigrostriatal dopaminergic degeneration is a pathological hallmark of dementia with Lewy bodies (DLB). To identify the subregional dopamine transporter (DAT) uptake patterns that improve the diagnostic accuracy of DLB, we analyzed N-(3-[
Abstract Introduction Lewy body–related pathology is commonly observed at autopsy in individuals with dementia, but in vivo biomarkers for α‐synucleinopathy are lacking. Methods Baseline cerebrospinal fluid (CSF) biomarkers, polygenic risk score (PRS) for Parkinson's disease (PRS‐PD) and Alzheimer's disease (PRS‐AD), longitudinal cognitive scores, and magnetic resonance imaging were measured in 217 participants from the Alzheimer's Disease Neuroimaging Initiative. Linear mixed models were used to find the relationship of CSF biomarkers and the PRS with cognition and cortical atrophy. Results Higher PRS‐PD and PRS‐AD were associated with lower CSF α‐synuclein and amyloid beta (Aβ), respectively. Lower CSF α‐synuclein and the interaction of CSF α‐synuclein and Aβ were associated with lower cognitive scores and global cortical atrophy most prominently in the occipital cortex. Discussion Lower CSF α‐synuclein could be a biomarker for α‐synucleinopathy, and the simultaneous evaluation of CSF biomarkers for AD and CSF α‐synuclein could reveal the independent and interactive effects on cognition and cortical atrophy.
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