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Cerebral microbleeds (MBs) have been found in patients with cognitive decline. We aimed to examine whether MBs are associated with motor or cognitive decline in patients with Parkinson’s disease (PD). We enrolled 135 PD patients and 34 healthy controls. All participants underwent brain MRI and plasma biomarker assays, including tau, Aβ42, Aβ40, and α-synuclein. PD with dementia (PDD) was operationally defined as Mini-Mental State Examination (MMSE) score < 26 and advanced motor stage was defined as Hoehn-Yahr stage ≥ 3 during “on” status. The association between MBs and disease severity was examined using multivariate logistic regression models. More lobar MBs were observed in PD patients than controls (20.7% vs. 3.3%, p  = 0.031). PDD patients had more lobar MBs (33.3% vs. 15.6%, p  = 0.034), more white matter hyperintensity ( p  = 0.021) and reduced hippocampal volume ( p  = 0.001) than PD with normal cognition. The presence of lobar MB (odds ratio = 2.83 [95% confidence interval 1.04–7.70], p  = 0.042) and severe white matter hyperintensity (3.29 [1.21–8.96], p  = 0.020) was independently associated with PDD after adjusting for vascular risk factors and other confounders. Furthermore, plasma Aβ40 levels were associated the MMSE score ( p  = 0.004) after adjusting for age and sex. Our findings demonstrated that lobar MBs, reduced hippocampal volume, and elevated plasma Aβ40 levels are associated with PDD.

IntroductionWe performed a meta-analysis to synthesise current evidence on amyloid-positron emission tomography (PET) burden and presumed preferential occipital distribution in sporadic cerebral amyloid angiopathy (CAA).MethodsIn a PubMed systematic search, we identified case–control studies with extractable data on global and occipital-to-global amyloid-PET uptake in symptomatic patients with CAA (per Boston criteria) versus control groups (healthy participants or patients with non-CAA deep intracerebral haemorrhage) and patients with Alzheimer’s disease. To circumvent PET studies’ methodological variation, we generated and used ‘fold change’, that is, ratio of mean amyloid uptake (global and occipital-to-global) of CAA relative to comparison groups. Amyloid-PET uptake biomarker performance was then quantified by random-effects meta-analysis on the ratios of the means. A ratio >1 indicates that amyloid-PET uptake (global or occipital/global) is higher in CAA than comparison groups, and a ratio <1 indicates the reverse.ResultsSeven studies, including 106 patients with CAA (>90% with probable CAA) and 138 controls (96 healthy elderly, 42 deep intracerebral haemorrhage controls) and 72 patients with Alzheimer’s disease, were included. Global amyloid-PET ratio between patients with CAA and controls was above 1, with an average effect size of 1.18 (95% CI 1.08 to 1.28; p<0.0001). Occipital-to-global amyloid-PET uptake ratio did not differ between patients with CAA versus patients with deep intracerebral haemorrhage or healthy controls. By contrast, occipital-to-global amyloid-PET uptake ratio was above 1 in patients with CAA versus those with Alzheimer’s disease, with an average ratio of 1.10 (95% CI 1.03 to 1.19; p=0.009) and high statistical heterogeneity.ConclusionsOur analysis provides exploratory actionable data on the overall effect sizes and strength of amyloid-PET burden and distribution in patients with CAA, useful for future larger studies.

Lobar cerebral microbleeds are a characteristic neuroimaging finding in cerebral amyloid angiopathy (CAA) but can also be found in hypertensive arteriolosclerosis. We aimed to investigate whether CAA is more associated with intracortical lobar microbleeds than hypertensive arteriosclerosis. Ninety-one survivors of spontaneous intracerebral hemorrhage with at least one lobar microbleed were included and underwent brain MRI and amyloid PET. We categorized lobar microbleeds as intracortical, juxtacortical, or subcortical. We assessed the associations between the lobar microbleed categories and microangiopathy subtypes or cerebral amyloid load based on the Pittsburgh Compound-B PET standardized uptake value ratio (SUVR). Patients with CAA had a higher prevalence of intracortical lobar microbleeds (80.0% vs. 50.8%, P  = 0.011) and lower prevalence of subcortical lobar microbleeds (13.3% vs. 60.1%, P  < 0.001) than patients with hypertensive arteriolosclerosis. Strictly intracortical/juxtacortical lobar microbleeds were associated with CAA (OR 18.9 [1.9–191.4], P  = 0.013), while the presence of subcortical lobar microbleeds was associated with hypertensive arteriolosclerosis (OR 10.9 [1.8–68.1], P  = 0.010). Amyloid retention was higher in patients with strictly intracortical/juxtacortical CMBs than those without (SUVR = 1.15 [1.05–1.52] vs. 1.08 [1.02–1.19], P  = 0.039). Amyloid retention positively correlated with the number of intracortical lobar microbleeds ( P  < 0.001) and negatively correlated with the number of subcortical lobar microbleeds ( P  = 0.018). CAA and cortical amyloid deposition are more strongly associated with strictly intracortical/juxtacortical microbleeds than subcortical lobar microbleeds. Categorization of lobar microbleeds based on anatomical location may help differentiate the underlying microangiopathy and potentially improve the accuracy of current neuroimaging criteria for cerebral small vessel disease.

Background Blood‐based biomarkers may offer a non‐invasive approach to diagnose cerebral amyloid angiopathy (CAA), especially in early‐stage. We evaluated the ability of plasma phosphorylated tau‐217 (p‐tau 217) to differentiate CAA from Alzheimer's disease (AD) and deep perforator arteriopathy (DPA). Methods Patients with AD (age 73.7 ± 8.1 years), probable CAA (74.8 ± 6.9 years), or DPA (66.1 ± 10.4 years) were enrolled from memory and stroke clinics at a medical center in Taiwan. All participants received amyloid and tau PET scans. Plasma biomarkers were measured via a SIMOA immunoassay platform. The diagnostic utility of p‐tau 217 was assessed using ROC analyses and the Youden cutoff. Associations between plasma p‐tau 217 and neuroimaging variables in CAA were explored. Results Patients with CAA had lower plasma p‐tau 217 (0.69 ± 0.76 vs. 1.28 ± 0.97 pg/mL, p < 0.001) and a lower p‐tau 217/Aβ40 ratio (0.003 ± 0.002 vs. 0.006 ± 0.003, p < 0.001) than the AD group but higher levels than the DPA group (p‐tau 217, 0.27 ± 0.13 pg/mL, p = 0.001; p‐tau 217/Aβ40, 0.001 ± 0.0005, p < 0.001), although adjustment attenuated the difference in p‐tau 217 between CAA and DPA. Plasma Aβ40, Aβ42, and Aβ40/Aβ42 were not significantly different between groups. Plasma p‐tau 217 had moderate to good diagnostic utility to differentiate CAA vs. AD (sensitivity, 64.4%; specificity, 89.5%; AUC, 0.809) and CAA vs. DPA (sensitivity, 67.8%; specificity, 100%; AUC, 0.855). In CAA, p‐tau 217 significantly correlated with the severity of CAA, amyloid PET signal intensity, and lobar microbleed count (p < 0.001). Conclusions Plasma p‐tau 217 may represent a non‐invasive biomarker for distinguishing cerebral amyloid angiopathy (CAA) from other conditions, including AD and DPA.

To determine whether acute kidney injury (AKI) is a risk factor for dementia. This nationwide population-based cohort study was based on data from the Taiwan National Health Insurance Research Database for 2000-2011. The incidence and relative risk of dementia were assessed in 207788 patients hospitalized for AKI. The comparison control was selected using the propensity score based on age, sex, index year and comorbidities. During the 12-year follow-up, patients with AKI had a significantly higher incidence for developing dementia than did the controls (8.84 vs 5.75 per 1000 person-y). A 1.88-fold increased risk of dementia (95% confidence interval, 1.76-2.01) was observed after adjustment for age, sex, and several comorbidities (diabetes, hypertension, hyperlipidemia, head injury, depression, stroke, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atrial fibrillation, cancer, liver disease, chronic infection/inflammation, autoimmune disease, malnutrition). We found that patients with AKI exhibited a significantly increased risk of developing dementia. This study provides evidence on the association between AKI and long-term adverse outcomes. Additional clinical studies investigating the related pathways are warranted.

Enlarged perivascular spaces (EPVS) are MRI markers of impaired glymphatic clearance and have been associated with neurodegenerative diseases. However, their clinical significance in amyotrophic lateral sclerosis (ALS) and underlying mechanisms remain poorly understood. This study investigated the prevalence, clinical relevance, and pathophysiological basis of EPVS in ALS. MRI data from 114 ALS patients and 119 matched controls were analyzed, with high-degree EPVS defined as more than 20 visible spaces. High-degree EPVS in the centrum semiovale (CSO) was more prevalent in ALS patients (49.1%) than in controls (15.1%, p < 0.001). Age, male sex, and ALS diagnosis were independent predictors, while disease severity and aggressiveness were not associated. ALS patients with high-degree CSO-EPVS were older at disease onset and MRI but showed similar clinical progression. In SOD1/G93A ALS mice, cerebral perivascular spaces were significantly enlarged at 5 months compared to wild-type and younger ALS mice. Cervical lymphatic ligation promoted misfolded SOD1 accumulation in motor neurons and cerebral vessels, further increasing perivascular space width without altering motor function. These findings suggest that about half of ALS patients exhibit high-degree CSO-EPVS, reflecting impaired protein clearance rather than disease aggressiveness.

Objectives Radiological diagnosis of subtypes of cerebral small vessel diseases remains challenging. This study aimed to explore the spatial distribution of cerebral microbleeds (CMBs) in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) in contrast to cerebral amyloid angiopathy (CAA) in the lobar regions. Methods Thirty-two patients with CADASIL and 33 patients with probable CAA were prospectively and consecutively included. On 3-Tesla susceptibility-weighted magnetic resonance images, CMBs were analyzed for incidence and volume within atlas-based regions of interest, followed by voxel-wise analysis using risk mapping. The distribution of CMBs was correlated with the status of hypertension. Correlation and group differences with a p -value less than 0.05 were considered to be significant. Results As compared with the CAA group, the CADASIL group presents a larger CMB volume in hippocampus/amygdala and white matter (nonparametric analysis of covariance, p  = 0.014 and 0.037, respectively), a smaller CMB volume in parietal lobe ( p  = 0.038), and a higher incidence in hippocampus/amygdala, white matter, and insula (logistic regression, p  = 0.019, 0.024, and 0.30, respectively). As part of the exclusion criteria of probable CAA, thalamus, basal ganglia, and pons exhibit greater CMB volume/incidence in the CADASIL group. In CADASIL patients, hot spots of CMBs are identified in the putamen and posteromedial thalamus; hypertension is associated with larger CMB volumes in insula, basal ganglia, and pons. Conclusions The spatial distribution of CMBs is differentiable between CADASIL and CAA in lobar regions. In CADASIL patients, hypertension has a region-dependent mediating effect on the CMB volume. Key Points • The topological distribution of lobar CMBs is differentiable between CADASIL and CAA. • In CADASIL patients, hypertension mediates CMB volume and the mediation is region dependent. • CMB risk mapping allows for voxel-wise exploration of CMB distribution and reveals hot spots in the putamen and posteromedial thalamus in CADASIL.

Background Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive dysfunction in the elderly, and frequently coexists with Alzheimer's disease and tau pathology. Dual‐phase 11C‐PiB PET detects amyloid deposition and cerebral perfusion changes and may have diagnostic value for identifying tau in CAA. Methods We prospectively enrolled patients with probable CAA for dynamic PiB and AV1451 scans. We compared early‐phase (0–6 min after tracer injection) and late‐phase (40–70 min) PiB PET between the tau(+) and tau(−) groups (based on AV1451 PET) and investigated their diagnostic values for detecting tau. Results CAA/tau(+) had lower early‐phase temporal PiB uptake than CAA/tau(−) (p = 0.014) and higher late‐phase uptake in the whole cortex and temporal and parietal lobes (all p < 0.05). Early‐phase temporal PiB SUVR correlated with tau burden (r = −0.34, p = 0.038). Using Youden's cut‐off, early‐phase and late‐phase PET had sensitivities of 55% and 80% and specificities of 85% and 65% for detecting tau, respectively. Combining early‐ and late‐phase scans provided a rule‐out sensitivity of 90% and rule‐in specificity of 100% for tau pathology in CAA. Conclusions Dual‐phase 11C‐PiB PET represents a reliable approach for assessing tau and could potentially identify CAA patients for tau biomarker testing.

To investigate the association between cerebral amyloid deposition and long-term cognitive outcomes in patients with hemorrhagic small vessel disease (SVD) and survivors of intracerebral hemorrhage (ICH). Patients experiencing an ICH without overt dementia were prospectively recruited (n = 68) for brain MRI and Pittsburgh compound B (PiB) positron emission tomography scans at baseline. Cognitive function was assessed using the mini-mental status examination (MMSE) and clinical dementia rating after an overall median follow-up of 3.8 years. A positive amyloid scan was defined as a global PiB standardized uptake value ratio >1.2. Associations between follow-up cognitive outcomes and neuroimaging markers were explored using multivariable Cox regression models. PiB(+) patients were older (72.1 ± 7.8 vs. 59.9 ± 11.7, p = .002) and more frequently had cerebral amyloid angiopathy (CAA) (63.6% vs. 15.8%, p = .002) than PiB(-) patients. PiB(+) was associated with a higher risk of dementia conversion (32.9 vs. 4.0 per 100-person-years, hazard ratio [HR] = 15.7 [3.0-80.7], p = .001) and MMSE score decline (58.8 vs. 9.9 per 100-person-years, HR = 6.2 [1.9-20.0], p = .002). In the non-CAA subgroup (n = 52), PiB(+) remained an independent predictor of dementia conversion, p = .04). In the Cox models, PiB(+) was an independent predictor of dementia conversion (HR = 15.8 [2.6-95.4], p = .003) and MMSE score decline (HR = 5.7 [1.6-20.3], p = .008) after adjusting for confounders. Cerebral amyloid deposition potentially contributes to long-term cognitive decline in SVD-related ICH.

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease caused by β -amyloid (Aβ) deposition at the leptomeningeal vessel walls. It is a common cause of spontaneous intracerebral hemorrhage and a frequent comorbidity in Alzheimer’s disease. The high recurrent hemorrhage rate in CAA makes it very important to recognize this disease to avoid potential harmful medication. Imaging studies play an important role in diagnosis and research of CAA. Conventional computed tomography and magnetic resonance imaging (MRI) methods reveal anatomical alterations, and remains as the most reliable tool in identifying CAA according to modified Boston criteria. The vascular injuries of CAA result in both hemorrhagic and ischemic manifestations and related structural changes on MRI, including cerebral microbleeds, cortical superficial siderosis, white matter hyperintensity, MRI-visible perivascular spaces, and cortical microinfarcts. As imaging techniques advance, not only does the resolution of conventional imaging improve, but novel skills in functional and molecular imaging studies also enable in vivo analysis of vessel physiological changes and underlying pathology. These modern tools help in early detection of CAA and may potentially serve as sensitive outcome markers in future clinical trials. In this article, we reviewed past studies of CAA focusing on utilization of various conventional and novel imaging techniques in both research and clinical aspects.