Background Deposition and spreading of misfolded proteins (α‐synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep‐dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function. Objective The objective of this current study was to determine if the decoupling of brain activity–CSF flow is linked to Parkinson's disease cognitive dysfunction. Methods Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting‐state global blood‐oxygen‐level‐dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. Results Global blood‐oxygen‐level‐dependent signal–CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood‐oxygen‐level‐dependent signal–CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood‐oxygen‐level‐dependent signal–CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, −0.36; P = 0.012), an early structural change often seen in Alzheimer's disease. Conclusions The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society

BackgroundDeposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson’s cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow that may reflect glymphatic function.ObjectiveTo determine if the decoupling of brain activity-CSF flow is linked to Parkinson’s cognitive dysfunction.MethodsFunctional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment, MoCA) scores were collected from 60 Parkinson’s and 58 control subjects. Parkinson’s patients were subgrouped into those with (MoCA < 26; N = 29) and without (MoCA ≥ 26; N = 31) mild cognitive impairment (MCI).The coupling strength between the resting-state global blood-oxygen-level-dependent signal (gBOLD) and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements.ResultsgBOLD-CSF coupling decreased significantly (p < 0.006) in Parkinson’s patients showing MCI, compared to those without MCI and controls. Reduced gBOLD-CSF coupling was associated with decreased MoCA scores that was present in Parkinson’s patients (p = 0.005) but not in controls (p = 0.65). Weaker gBOLD-CSF coupling in Parkinson’s patients also was associated with a thinner right entorhinal cortex (Spearman’s correlation = − 0.36; p = 0.012), an early structural change often seen in Alzheimer’s.ConclusionsThe decoupling between global brain activity and associated CSF flow is related to Parkinson’s cognitive impairment.

Background To better assist with the design of future clinical trials for Alzheimer’s disease (AD) and aid in our understanding of the disease’s symptomatology, it is essential to clarify what roles β-amyloid (Aβ) plaques and tau tangles play in longitudinal tau accumulation inside and outside the medial temporal lobe (MTL) as well as how age, sex, apolipoprotein E (APOE) ε4 (APOE-ε4), and Klotho-VS heterozygosity (KL-VShet) modulate these relationships. Methods We divided the 325 Aβ PET-positive (A+) participants into two groups, A+/T− (N = 143) and A+/T+ (N = 182), based on the threshold (1.25) of the temporal meta-ROI 18F-flortaucipir (FTP) standardized uptake value ratio (SUVR). We then compared the baseline and slopes of A+/T− and A+/T+ individuals’ Aβ plaques and temporal meta-ROI tau tangles with those of A−/T− cognitively unimpaired individuals (N = 162) without neurodegeneration. In addition, we looked into how baseline Aβ and tau may predict longitudinal tau increases and how age, sex, APOE-ε4, and KL-VShet affect these associations. Results In entorhinal, amygdala, and parahippocampal (early tau-deposited regions of temporal meta-ROI), we found that baseline Aβ and tau deposition were positively linked to more rapid tau increases in A+/T− participants. However, in A+/T+ individuals, the longitudinal tau accumulation in fusiform, inferior temporal, and middle temporal cortices (late tau-deposited regions of temporal meta-ROI) was primarily predicted by the level of tau tangles. Furthermore, compared to older participants (age ≥ 65), younger individuals (age < 65) exhibited faster Aβ-dependent but slower tau-related tau accumulations. Additionally, compared to the KL-VShet− group, KL-VShet+ individuals showed a significantly lower rate of tau accumulation associated with baseline entorhinal tau in fusiform and inferior temporal regions. Conclusion These findings offer novel perspectives to the design of AD clinical trials and aid in understanding the tau accumulation inside and outside MTL in AD. In particular, decreasing Aβ plaques might be adequate for A+/T− persons but may not be sufficient for A+/T+ individuals in preventing tau propagation and subsequent downstream pathological changes associated with tau.

INTRODUCTION Alzheimer’s disease (AD) affects approximately 100 million aged 60 or above older adults in China. However, a community-based longitudinal neuroimaging AD cohort is rarely available in China, particularly in the Guangdong-Hong Kong-Macao Great-Bay-Area of South China. METHODS Following the standard protocols of the Alzheimer’s Disease Neuroimaging Initiative, the Greater-Bay-Area Healthy Aging Brain Study (GHABS) was initiated in Shenzhen in May 2021. The GHABS cohort focuses on the pathophysiology characterization and early detection of AD in the Guangdong-Hong Kong-Macao Greater Bay Area, one of the largest population regions in China. RESULTS The aims, study design, data collection, and potential applications of GHABS are summarized. Currently, 565 participants have completed cognitive assessments and blood sample collection in the GHABS cohort by June 23, 2023, and 68% of the cohort were cognitively unimpaired or had a subjective cognitive decline. Additionally, 276 and 65 participants completed stool and CSF sample collection. So far, 396, 346, and 70 participants had MRI, Aβ PET, and tau PET imaging scans, respectively. DISCUSSION The GHABS cohort aims to: 1) summarize the characteristic and evolution of AD pathologies across the clinical and biological stages of AD in the Guangdong-Hong Kong-Macao Greater Bay Area; 2) determine the earliest abnormal signs of AD using biofluid markers and neuroimaging; 3) identify and validate novel blood biomarkers and imaging techniques for the early detection and prevention trials of AD.

Background Clarifying the relative roles of β-amyloid (Aβ) plaques and tau tangles in longitudinal tau replication and propagation inside and outside the medial temporal lobe (MTL) as well as how age, sex, APOE-4, and Klotho-VS heterozygosity (KL-VShet) modulate their relationships in Alzheimer’s disease (AD) may help with designing therapeutic clinical trials for AD and aid in our understanding of the disease’s symptoms. Methods We divided the 325 Aβ PET positive (A+) participants in this study into two groups, A+/T- (143) and A+/T+ (182), based on the threshold (1.25) of the Temporal-metaROI 18F-flortaucipir (FTP) standardized uptake value ratio (SUVR). We compared the baseline and slopes of A+/T- and A+/T + individuals’ Aβ plaques and Temporal-metaROI tau tangles with those of 162 A-/T- cognitively normal individuals without neurodegeneration. We also looked into how baseline Aβ and tau predict longitudinal tau increases and how age, sex, APOE-4, and KL-VShet affect these associations. Results In entorhinal, amygdala, and parahippocampal (early tau-affected regions of Temporal-metaROI), we found baseline Aβ and tau deposition were positively linked with more rapid tau increases in A+/T- participants. However, in A+/T + individuals, the longitudinal tau propagation of the fusiform, inferior temporal, and middle temporal cortices (late tau-affected regions of Temporal-metaROI) was primarily fueled by the presence of tau tangles rather than Aβ plaques. Furthermore, compared to older people (age≥65), younger individuals (age≤65) had faster Aβ-dependent but slower tau-related tau accumulation. Additionally, compared to the KL-VShet− group, KL-VShet+ carriers showed significantly less longitudinal tau accumulation associated with baseline entorhinal tau in the fusiform and inferior temporal regions. Conclusion These findings offer novel perspectives on developing AD treatment plans and aid in understanding tau replication and propagation inside and outside MTL in AD. In particular, decreasing Aβ plaques might be adequate for A+/T- persons but may not be sufficient for A+/T + individuals in preventing tau propagation and subsequent downstream effects connected to tau.