Diffusion Mediates Molecular Transport through the Perivascular Space in the Brain

The perivascular space has been proposed as a clearance pathway for degradation products in the brain, including amyloid β, the accumulation of which may induce Alzheimer’s disease. Live images were acquired using a two-photon microscope through a closed cranial window in mice. In topical application experiments, the dynamics of FITC-dextran were evaluated from 30 to 150 min after the application and closure of the window. In continuous injection experiments, image acquisition began before the continuous injection of FITC-dextran. The transport of dextran molecules of different sizes was evaluated. In topical application experiments, circumferential accumulation around the penetrating arteries, veins, and capillaries was observed, even at the beginning of the observation period. No further increases were detected. In continuous injection experiments, a time-dependent increase in the fluorescence intensity was observed around the penetrating arteries and veins. Lower-molecular-weight dextran was transported more rapidly than higher-molecular-weight dextran, especially around the arteries. The largest dextran molecules were not transported significantly during the observation period. The size-dependent transport of dextran observed in the present study strongly suggests that diffusion is the main mechanism mediating substance transport in the perivascular space

In Vivo Dynamic Movement of Polymerized Amyloid β in the Perivascular Space of the Cerebral Cortex in Mice

Disposition of amyloid β (Aβ) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. Here, we explored the in vivo dynamics of Aβ in the perivascular space of anesthetized mice. Live images were obtained with two-photon microscopy through a closed cranial window. Either fluorescent-dye-labeled Aβ oligomers prepared freshly or Aβ fibrils after 6 days of incubation at 37 °C were placed over the cerebral cortex. Accumulation of Aβ was observed in the localized perivascular space of the penetrating arteries and veins. Transportation of the accumulated Aβ along the vessels was slow and associated with changes in shape. Aβ oligomers were transported smoothly and separately, whereas Aβ fibrils formed a mass and moved slowly. Parenchymal accumulation of Aβ oligomers, as well as Aβ fibrils along capillaries, increased gradually. In conclusion, we confirmed Aβ transportation between the cortical surface and the deeper parenchyma through the perivascular space that may be affected by the peptide polymerization. Facilitation of Aβ excretion through the system can be a key target in treating Alzheimer’s disease

Impact of depression on mental fatigue and attention in patients with multiple sclerosis

Abstract11 AbbreviationsBDI, Beck Depression Inventory; CFS, Chalder Fatigue Scale; EDSS, Expanded Disability Status Scale; HC, Health control subjects; MMSE, Mini-Mental State ExaminationMS, Multiple sclerosis; PASAT, Paced Auditory Serial Addition Test; QoL, Quality-of-lifeSD, Standard deviation; SDMT, Symbol Digit Modalities Test; VC, Visual cancellation;: Background: Depression and fatigue are debilitating symptoms in multiple sclerosis (MS), which affect cognitive function. This study investigated the association between depression and fatigue, and whether depression or fatigue influences cognition in MS patients. Methods: Twenty MS patients were included. The severity of fatigue was assessed using the Chalder Fatigue Scale (CFS), which classified CFS_Physical and CFS_Mental fatigue and MMSE. Depression was assessed using the Beck Depression Inventory (BDI). Attention deficit was evaluated using several tasks. The CFS scores, the BDI scores and performance during the attention tasks were compared between MS patients and healthy control subjects (HCs). Correlations between CFS sub-scores, BDI values, and participants’ attention performance were also investigated. Results: The total CFS, BDI, and MMSE scores were significantly worse in MS patients compared to HCs (p < 0.05). The CFS_Mental sub-score was significantly correlated with performance on attention tasks (p < 0.05). MS patients with severe depression exhibited the worst scores on attention tests and significantly higher CFS_Mental sub-scores than the remaining MS patients and HCs. The BDI scores of MS patients with severe depression correlated with disease duration. In the remaining MS patients, attention tests and BDI scores did not differ significantly from those in HCs. Limitations: This study had a small sample size, which limits generalization. Premobid cognitive functions were not matched. Conclusion: Mental fatigue is closely associated with attention deficit. Depression affects mental fatigue and attention in MS patients

Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer\u27s Disease with APP Osaka Mutation

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer\u27s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer\u27s disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques

Staging of tau distribution by positron emission tomography may be useful in clinical staging of Alzheimer disease

BackgroundClinical staging of Alzheimer disease (AD) may help develop novel treatment in the early stage.AimWe measured the accumulation of amyloid beta (Aβ) and tau with positron emission tomography (PET) in patients with AD to explore its utility for clinical staging.MethodsSix patients with AD, two patients with mild cognitive impairment (MCI), and 12 healthy controls (HC) were studied. Aβ and tau accumulation was evaluated with [11C]PiB and [11C]PBB3, respectively. ResultsPBB3‐PET showed that two cases were in stage I‐II (Braak stage), one case was in stage III‐IV, and three cases were in stage V‐VI. PiB‐PET showed that all cases were in stage C. The duration of the disease correlated positively with PBB3 staging but not with PiB staging. The performance on the Mini‐Mental State Examination (MMSE) tended to decrease with advancing of PBB3 stage but not with PiB stage. PBB3 SUVR and PiB SUVR in all AD signature areas including the parahippocampal gyrus were significantly higher in AD than in HC. A decrease in MMSE is correlated with increases in PBB3 and PiB. Increase in PBB3 started with decrease in MMSE whereas increase in PiB was already observed in the point of highest MMSE, indicating amyloid is already accumulated in the earliest stage.ConclusionsThe expansion of tau distribution from the parahippocampal gyrus to the cerebral cortex was observed with advancing AD, whereas Aβ distribution was already advanced in the earliest stage. PBB3 may be useful in determining stages in AD based on tau distribution

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. Exposures: Alzheimer disease biomarkers detected on PET or in CSF. Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. Results: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies