Search

Cerebellar amyloid-β (Aβ) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change. However, Aβ deposits in this anatomic compartment are unique and under-characterized; and their relationship with other pathological findings are largely undefined. In 73 cases of pure or mixed AD with an A3 score in the ABC criteria, parenchymal (plaques) and vascular (cerebral amyloid angiopathy [CAA]) cerebellar Aβ-42 deposits were characterized with respect to localization, morphology, density, and intensity. Over 85% of cases demonstrated cerebellar Aβ-42 parenchymal staining that correlated with a Braak stage V-VI/B3 score (p

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

The integration of positron emission tomography/computed tomography (PET/CT) has revolutionized the landscape of Alzheimer's disease (AD) research and therapeutic interventions. By combining structural and functional imaging, PET/CT provides a comprehensive understanding of disease pathology and response to treatment assessment. PET/CT, particularly with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG), facilitates the visualization of glucose metabolism in the brain, enabling early diagnosis, staging, and monitoring of neurodegenerative disease progression. The advent of amyloid and tau PET imaging has further propelled the field forward, offering invaluable tools for tracking pathological hallmarks, assessing treatment response, and predicting clinical outcomes. While some therapeutic interventions targeting amyloid plaque load showed promising results with the reduction of cerebral amyloid accumulation over time, others failed to demonstrate a significant impact of anti-amyloid agents for reducing the amyloid plaques burden in AD brains. Tau PET imaging has conversely fueled the advent of disease-modifying therapeutic strategies in AD by supporting the assessment of neurofibrillary tangles of tau pathology deposition over time. Looking ahead, PET imaging holds immense promise for studying additional targets such as neuroinflammation, cholinergic deficit, and synaptic dysfunction. Advances in radiotracer development, dedicated brain PET/CT scanners, and Artificial Intelligence-powered software are poised to enhance the quality, sensitivity, and diagnostic power of molecular neuroimaging. Consequently, PET/CT remains at the forefront of AD research, offering unparalleled opportunities for unravelling the complexities of the disease and advancing therapeutic interventions, although it is not yet enough alone to allow patients' recruitment in therapeutic clinical trials. [ABSTRACT FROM AUTHOR]

The article published in Brain Pathology discusses the decreased levels of claudin-5 in the microvasculature of patients with cerebral amyloid angiopathy (CAA) associated with intracerebral hemorrhage (ICH). The study aimed to investigate the role of claudin-5 in CAA-related ICH and found that claudin-5 expression was lower in CAA-ICH cases compared to CAA non-hemorrhagic cases and controls. The findings suggest that decreased claudin-5 levels may be linked to an increased risk of vessel rupture in patients with CAA. Further research is needed to explore the molecular mechanisms underlying this association. [Extracted from the article]

Background: Anti-amyloid-β (Aβ) immunotherapy trials have revealed amyloid-related imaging abnormalities (ARIA) as the most prevalent and serious adverse events linked to pathological changes in cerebral vasculature. Recent studies underscore the critical involvement of perivascular macrophages and the infiltration of peripheral immune cells in regulating cerebrovascular damage. Specifically, Aβ antibodies engaged at cerebral amyloid angiopathy (CAA) deposits trigger perivascular macrophage activation and the upregulation of genes associated with vascular permeability. Nevertheless, further research is needed to understand the immediate downstream consequences of macrophage activation, potentially exacerbating CAA-related vascular permeability and microhemorrhages linked to Aβ immunotherapy. Methods: This study investigates immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer's disease (AD) mouse model of microhemorrhage. Results: In the present study, we have demonstrated that bapineuzumab murine surrogate (3D6) induces profound vascular damage, leading to smooth muscle cell loss and blood–brain barrier (BBB) breakdown. In addition, digital spatial profiling (DSP) reveals that distinct immune responses contribute to vascular damage with peripheral immune responses and perivascular macrophage activation linked to smooth muscle cell loss and vascular fibrosis, respectively. Finally, RNA in situ hybridization identifies two distinct subsets of Trem2+ macrophages representing tissue-resident and monocyte-derived macrophages around vascular amyloid deposits. Overall, these findings highlight multifaceted roles of immune activation and vascular damage in driving the development of microhemorrhage. Conclusions: In summary, our study has established a significant link between CAA-Aβ antibody immune complex formation, immune activation and vascular damage leading to smooth muscle cell loss. However, the full implications of this cascade on the development of microhemorrhages requires further exploration. Additional investigations are warranted to unravel the precise molecular mechanisms leading to microhemorrhage, the interplay of diverse immune populations and the functional roles played by various Trem2+ macrophage populations in response to Aβ immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The accumulation of amyloid-β (Aβ) peptide in the brain is a hallmark of Alzheimer's disease (AD), occurring years before symptom onset. Current methods for quantifying in vivo amyloid load involve invasive or costly procedures, limiting accessibility. Early detection of amyloid positivity in non-demented individuals is crucial for aiding early AD diagnosis and for initiating anti-amyloid immunotherapies at early stages. This study aimed to develop and validate predictive models to identify brain amyloid positivity in non-demented patients, using routinely collected clinical data. Methods: Predictive models for amyloid positivity were developed using data from 853 non-demented participants in the MEMENTO cohort. Amyloid levels were measured potentially repeatedly during study course through Positron Emision Tomography or CerebroSpinal Fluid analysis. The probability of amyloid positivity was modelled using mixed-effects logistic regression. Predictors included demographic information, cognitive assessments, visual brain MRI evaluations of hippocampal atrophy and lobar microbleeds, AD-related blood biomarkers (Aβ42/40 and P-tau181), and ApoE4 status. Models were subjected to internal cross-validation and external validation using data from the Amsterdam Dementia Cohort. Performance also was evaluated in a subsample that met the main criteria of the Appropriate Use Recommendations (AUR) for lecanemab. Results: The most effective model incorporated demographic data, cognitive assessments, ApoE status, and AD-related blood biomarkers, achieving AUCs of 0.82 [95%CI 0.81-0.82] in MEMENTO sample and 0.90 [95%CI 0.86-0.94] in the external validation sample. This model significantly outperformed a reference model based solely on demographic and cognitive data, with an AUC difference in MEMENTO of 0.10 [95%CI 0.10-0.11]. A similar model without ApoE genotype achieved comparable discriminatory performance. MRI markers did not improve model performance. Performances in AUR of lecanemab subsample were comparable. Conclusion: A predictive model integrating demographic, cognitive, and blood biomarker data offers a promising method to help identify amyloid status in non-demented patients. ApoE genotype and brain MRI data were not necessary for strong discriminatory ability, suggesting that ApoE genotyping may be deferred when assessing the risk-benefit ratio of immunotherapies in amyloid-positive patients who desire treatment. The integration of this model into clinical practice could reduce the need for lumbar puncture or PET examinations to confirm amyloid status. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions The role of asymptomatic diffusion‐weighted imaging‐positive (aDWI+) lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients remains unclear, and their radiographic features may differ from those of symptomatic diffusion‐weighted imaging‐positive (sDWI+) lesions. We aimed to investigate the clinicoradiographic characteristics of aDWI+ lesions in CADASIL patients.We conducted a retrospective analysis using data from the Taiwan CADASIL Registry. aDWI+ lesions were defined as incidentally detected DWI+ lesions without corresponding acute neurological deficits. We compared the baseline clinical characteristics of patients with and without aDWI+ lesions and analyzed their radiological features and evolution in relation to sDWI+ lesions.Among 154 enrolled patients (mean age 62 ± 10 years), 17 (11%) had aDWI+ lesions. Baseline clinical characteristics were similar in the two groups, but those with aDWI+ lesions had more lacunes (median 8 vs. 2), multiple cerebral microbleeds (CMBs; 85% vs. 40%), and anterior temporal white matter hyperintensity (WMH; 47% vs. 14%). Multivariable analysis showed that aDWI+ lesions were associated with anterior temporal WMH (odds ratio 5.7, 95% confidence interval 1.5–21.0) after adjusting for multiple lacunes, multiple CMBs, and total WMH score. Compared to sDWI+ lesions, aDWI+ lesions were more often small infarcts (<1 cm; 89% vs. 23%) and less likely to involve the corticospinal tract (11% vs. 96%). Among the 11 aDWI+ lesions with follow‐up magnetic resonance imaging, seven became microinfarcts, three became lacunes, and one disappeared.aDWI+ lesions in CADASIL are not uncommon and are associated with higher burdens of small vessel disease and anterior temporal WMH. Further research is needed to assess their long‐term impact on CADASIL. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is a common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a novel transgenic rat model (rTg-D) that produces human familial CAA Dutch E22Q mutant amyloid β-protein (Aβ) in brain and develops arteriolar CAA type-2. Here, we show that deposition of fibrillar Aβ promotes arteriolar smooth muscle cell loss and cerebral microhemorrhages that can be detected by magnetic resonance imaging and confirmed by histopathology. Aged rTg-D rats also present with cognitive deficits. Cerebral proteomic analyses revealed 241 proteins that were significantly elevated with an increase of >50% in rTg-D rats presenting with CAA compared to wild-type rats. Fewer proteins were significantly decreased in rTg-D rats. Of note, high temperature requirement peptidase A (HTRA1), a proteinase linked to transforming growth factor beta 1 (TGF-β1) signaling, was elevated and found to accumulate in cerebral vessels harboring amyloid deposits. Pathway analysis indicated elevation of the TGF-β1 pathway and increased TGF-β1 levels were detected in rTg-D rats. In conclusion, the present findings provide new molecular insights into the pathogenesis of CAA and suggest a role for interactions between HTRA1 and TGF-β1 in the disease process. [ABSTRACT FROM AUTHOR]

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level. [ABSTRACT FROM AUTHOR]

Introduction: Cerebral amyloid angiopathy–related inflammation (CAA-ri) derives from inflammatory response to β-amyloid (Aβ) protein deposition within the cerebral blood vessel walls. We report a case that accentuates those clinical and imaging features that can contribute to raise suspicion for the condition and lead to early treatment initiation. Case presentation: A 72-year-old man was referred with one-month history of cognitive decline along with behavioral alterations. Brain MRI showed fluid attenuated inversion recovery (FLAIR) asymmetrical multifocal white matter hyperintensities (WMHs) along with multiple cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS) on T2*-weighted gradient-recalled echo (T2*-GRE) images. Metabolic, infectious, and neoplastic causes were excluded, and subsequently corticosteroids were administered to the patient resulting in clinical recovery. Imaging on follow-up disclosed remission of WMHs, while CMBs load increased significantly. Discussion: Clinical neurologists' acquaintance with the clinical and imaging features of CAA-ri allows prompt diagnosis and medication initiation, that is essential for a conceivably treatable condition. [ABSTRACT FROM AUTHOR]

Introduction: Intracerebral hemorrhage (ICH) is attributable to cerebral small vessel disease (cSVD), which includes cerebral amyloid angiopathy (CAA) and hypertensive-cSVD (HTN-cSVD). HTN-cSVD includes patients with strictly deep ICH/microbleeds and mixed location ICH/microbleeds, the latter representing a more severe form of HTN-cSVD. We test the hypothesis that more severe forms of HTN-cSVD are related to worse hypertension control in long-term follow-up after ICH. Methods: From consecutive non-traumatic ICH patients admitted to a tertiary care center, we classified the ICH as CAA, strictly deep ICH/microbleeds, and mixed-location ICH/microbleeds. CSVD burden was quantified using a validated MRI-based score (range: 0–6 points). We created a multivariable (linear mixed effects) model adjusting for age, sex, race, year of inclusion, hypertension, and antihypertensive medication usage to investigate the association of average systolic blood pressure (SBP) during follow-up with cSVD etiology/severity. Results: 796 ICH survivors were followed for a median of 48.8 months (IQR 41.5–60.4). CAA-related ICH survivors (n = 373) displayed a lower median SBP (138 mmHg, IQR 133–142 mmHg) compared to those of strictly deep ICH (n = 222, 141 mmHg, IQR 136–143 mmHg, p = 0.04), and mixed location ICH/microbleeds (n = 201, 142 mmHg, IQR 135–144 mmHg, p = 0.02). In the multivariable analysis, mixed location ICH/microbleeds (effect: + 3.8 mmHg, SE: 1.3 mmHg, p = 0.01) and increasing cSVD severity (+ 1.8 mmHg per score point, SE: 0.8 mmHg, p = 0.03) were associated with higher SBP in follow-up. Conclusion: CSVD severity and subtype predicts long-term hypertension control in ICH patients. [ABSTRACT FROM AUTHOR]

Background: The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Method: Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1. Results: The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Conclusion: Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors. [ABSTRACT FROM AUTHOR]

Background and purpose: Although the Boston criteria version 2.0 facilitates the sensitivity of cerebral amyloid angiopathy (CAA) diagnosis, there are only limited data about precursor symptoms. This study aimed to determine the impact of neurological and imaging features in relation to the time of CAA diagnosis. Methods: Patients diagnosed with probable CAA according to the Boston criteria version 1.5, treated between 2010 and 2020 in our neurocentre, were identified through a keyword search in our medical database. Neuroimaging was assessed using Boston criteria versions 1.5 and 2.0. Medical records with primary focus on the clinical course and the occurrence of transient focal neurological episodes were prospectively evaluated. Results: Thirty‐eight out of 81 patients (46.9%) exhibited transient focal neurological episodes, most often sensory (13.2%) or aphasic disorders (13.2%), or permanent deficits at a mean time interval of 31.1 months (SD ±26.3; range 1–108 months) before diagnosis of probable CAA (Boston criteria version 1.5). If using Boston criteria version 2.0, all patients receiving magnetic resonance imaging (MRI) met the criteria for probable CAA, and diagnosis could have been made on average 44 months earlier. Four patients were younger than 50 years, three of them with supporting pathology. Cognitive deficits were most common (34.6%) at the time of diagnosis. Conclusions: Non‐haemorrhagic MRI markers enhance the sensitivity of diagnosing probable CAA; however, further prospective studies are proposed to establish a minimum age for inclusion. As the neurological overture of CAA may occur several years before clinical diagnosis, early clarification by MRI including haemosensitive sequences are suggested. [ABSTRACT FROM AUTHOR]

Background: Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage and a more hemorrhagic disease course compared to women. In this cohort study, we investigated sex differences in histopathological markers associated with amyloid-β burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. Methods: First, we investigated presence of parenchymal (Thal score) and vascular amyloid-β (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo magnetic resonance imaging (MRI) markers and local cortical iron burden and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodeling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. Results: In 6120 individuals from the NACC database (45% women, mean age 80 years), the presence of parenchymal amyloid-β (odds ratio (OR) (95% confidence interval (CI)) =0.68 (0.53–0.88)) but not vascular amyloid-β was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75 years), a lower microbleed count (p < 0.001) but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p < 0.001) compared to women. CAA percentage area was comparable in men and women (p = 0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p = 0.03). Conclusion: Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodeling, may contribute, but future studies are necessary to replicate our findings in larger data sets and to further investigate the underlying mechanisms behind these complex sex differences. [ABSTRACT FROM AUTHOR]

Background and aim: The revised Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) add two radiological markers to the existing criteria: severe visible perivascular spaces in the centrum semiovale and white matter hyperintensities (WMHs) in a multispot pattern. This study aims to determine the sensitivity of the updated criteria in mutation carriers with Dutch-type hereditary CAA (D-CAA) in an early and later disease stage. Methods: In this cross-sectional study, we included presymptomatic and symptomatic D-CAA mutation carriers from our prospective natural history study (AURORA) at the Leiden University Medical Center between 2018 and 2021. 3-Tesla scans were assessed for CAA-related magnetic resonance imaging (MRI) markers. We compared the sensitivity of the Boston criteria v2.0 to the previously used modified Boston criteria v1.5. Results: We included 64 D-CAA mutation carriers (mean age 49 years, 55% women, 55% presymptomatic). At least one white matter (WM) feature was seen in 55/64 mutation carriers (86%: 74% presymptomatic, 100% symptomatic). Fifteen (23%) mutation carriers, all presymptomatic, showed only WM features and no hemorrhagic markers. The sensitivity for probable CAA was similar between the new and the previous criteria: 11/35 (31%) in presymptomatic mutation carriers and 29/29 (100%) in symptomatic mutation carriers. The sensitivity for possible CAA in presymptomatic mutation carriers increased from 0/35 (0%) to 15/35 (43%) with the new criteria. Conclusion: The Boston criteria v2.0 increase the sensitivity for detecting possible CAA in presymptomatic D-CAA mutation carriers and, therefore, improve the detection of the early phase of CAA. [ABSTRACT FROM AUTHOR]

A Nature Medicine paper published in January 2024 describes eight cases of iatrogenic Alzheimer's disease in individuals who received cadaveric pituitary‐derived human growth hormone. The paper's conclusions argue for the transmissibility of Alzheimer's disease, which, if true, would create a significant public health crisis. For example, neurosurgical practices would require substantial revision, and many individuals who have undergone neurosurgical procedures would now be at considerable risk of Alzheimer's disease. A detailed review of the presented cases reveals that they do not have Alzheimer's disease, and there are alternative explanations for the cognitive decline described. In people with progressive cognitive decline, the diagnosis of Alzheimer's disease requires a demonstration of amyloid and tau pathology or amyloid and tau biomarkers. Extensive tau pathology is not demonstrated, and some also lack amyloid beta pathology. The cases described in this paper do not meet the criteria for dementia due to Alzheimer's disease by clinical and pathological standards. Highlights: Creutzfeldt‐Jakob disease has been transmitted by cadaveric growth hormone.There is no evidence for the transmission of Alzheimer's disease by cadaveric growth hormone.There is no evidence that Alzheimer's disease is transmissible. [ABSTRACT FROM AUTHOR]

Objective: Epileptic seizures occurring in late adulthood often remain of unknown origin. Sporadic cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease characterized by intracerebral hemorrhage, microhemorrhage and superficial siderosis, occurring mostly in elderly. This observational case–control study aimed to assess the occurrence of CAA in patients experiencing their first seizure in late adulthood. Methods: We enrolled consecutive patients aged ≥55 years presenting with late‐onset seizures (LOS) to the emergency departments or outpatient clinics of two Italian centers, from April 2021 to October 2022. Two age‐matched control subjects with neurological symptoms other than epileptic seizure were recruited for each enrolled case. All participants underwent brain MRI (1.5 Tesla) including blood‐sensitive sequences and were assessed for probable CAA diagnosis according to Boston criteria 2.0. Chi‐squared test was performed to evaluate group differences. Univariate logistic regression analysis tested the association between clinical variables and CAA. Results: We included 65 patients with LOS (27 females; mean age 72.2 ± 8.9 years) and 130 controls (49 females; mean age 70.3 ± 8.9 years). Diagnosis of probable CAA was achieved in 10.8% (7/65) of LOS patients and 2.3% (3/130) controls, with a statistically significant difference (p = 0.011). The OR for CAA in the LOS group was 5.2 as compared to the control group (95% CI = 1.3–20.6, p = 0.02). Significance: The frequency of CAA is significatively higher in patients with LOS as compared to other neurological diseases, suggesting that a portion of LOS of unknown or vascular origin are associated with CAA. Plain Language Summary: Late‐onset seizures (LOS) are very frequent in the elderly and often have no clear cause. Cerebral amyloid angiopathy (CAA) is a condition where amyloid proteins build up in the blood vessels of the brain, causing them to become weak and prone to bleeding. In this study, we explored the occurrence of CAA in people with LOS. We found that people with LOS were more likely to have a diagnosis of CAA than controls (i.e., people with other neurological diseases). [ABSTRACT FROM AUTHOR]

Background: Patients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated. Methods: To explore this, we generated pericyte-like cells from human induced pluripotent stem cells (iPSCs) harboring the Swedish mutation in the amyloid precursor protein (APPswe) along with cells from healthy controls. We initially verified the expression of classic pericyte markers in these cells. Subsequent functional assessments, including permeability, tube formation, and contraction assays, were conducted to evaluate the functionality of both the APPswe and control cells. Additionally, bulk RNA sequencing was utilized to compare the transcriptional profiles between the two groups. Results: Our study reveals that iPSC-derived pericyte-like cells (iPLCs) can produce Aβ peptides. Notably, cells with the APPswe mutation secreted Aβ1-42 at levels ten-fold higher than those of control cells. The APPswe iPLCs also demonstrated a reduced ability to support angiogenesis and maintain barrier integrity, exhibited a prolonged contractile response, and produced elevated levels of pro-inflammatory cytokines following inflammatory stimulation. These functional changes in APPswe iPLCs correspond with transcriptional upregulation in genes related to actin cytoskeleton and extracellular matrix organization. Conclusions: Our findings indicate that the APPswe mutation in iPLCs mimics several aspects of CAA pathology in vitro, suggesting that our iPSC-based vascular cell model could serve as an effective platform for drug discovery aimed to ameliorate vascular dysfunction in AD. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions Data on health‐related quality of life (HRQoL) and mood in cerebral amyloid angiopathy (CAA), a disease characterized by stroke and cognitive decline, are limited. We aimed to investigate the impacted domains of life, value‐based HRQoL and the prevalence of depression and anxiety in patients with CAA.We conducted a cross‐sectional study of patients with sporadic (s)CAA, lobar dominant mixed CAA and hypertensive arteriopathy (mixed CAA‐HTA), or Dutch‐type hereditary (D‐)CAA, from prospective outpatient clinic cohorts. Participants completed four questionnaires: the EuroQoL 5 dimensions 5‐level questionnaire (EQ‐5D‐5L; EQ‐VAS for visual analogue scale; EQ‐Index for index rating), the Short‐Form 36 questionnaire (SF‐36), the Center for Epidemiologic Studies—Depression scale (CES‐D), and the Hospital Anxiety and Depression Scale (HADS; ‐D for depression and ‐A for anxiety subscales). The EQ‐5D‐5L assesses the domains mobility, self‐care, usual activities, pain/discomfort and anxiety/depression. The SF‐36 domains are physical functioning, social functioning, physical role limitations, emotional role limitations, mental health, vitality, bodily pain, and general health perceptions. We compared age‐ and sex‐ adjusted HRQoL (SF‐36 domain scores; EQ‐VAS; EQ‐Index) to the Dutch normative population, and estimated the prevalences of current depression (either: history of depression or current use of antidepressants, with high score on CES‐D [≥16] and/or HADS‐D [≥8]; or high score on both depression questionnaires) and anxiety (HADS‐A ≥ 8).We included 179 patients: 77 with sCAA (mean age: 72 years, women: 36%), 31 with mixed CAA‐HTA (68 years, women: 29%), and 71 with D‐CAA (56 years, women: 52%, symptomatic: 35 [49%]). The SF‐36 profiles of all patient groups were similar, negatively differing from the norm in emotional role functioning, social functioning and vitality. The EQ‐VAS score of patients (mean [SD] sCAA: 76 [16], D‐CAA: 77 [15]) was similar to the norm, as was the EQ‐Index score. Fifteen patients with sCAA (23%; 95% confidence interval [CI] 13%–33%), seven with mixed CAA‐HTA (27%; 95% CI 10%–44%) and eight with D‐CAA (14%; 95% CI 5%–22%) were noted as having depression. The prevalences of anxiety and depression were equivalent.We found that CAA influenced emotional role functioning and aspects linked to social engagement consistently across its subtypes. One quarter of patients exhibited depressive or anxiety symptoms. Recognizing these impacted domains could enhance overall well‐being. [ABSTRACT FROM AUTHOR]

The given text discusses primary central nervous system vasculitis (CNS), a rare condition characterized by inflammation of blood vessels in the brain and spinal cord. It provides information on the clinical manifestations and diagnostic challenges of primary CNS vasculitis, emphasizing the importance of accurate diagnosis and ruling out other potential causes of neurologic symptoms. The text also mentions treatment options and highlights the need for further research in understanding the underlying causes and improving diagnostic criteria and treatment for primary CNS vasculitis. Additionally, there is a document listing references and citations related to primary CNS vasculitis, providing a comprehensive overview of current research and knowledge on the condition. [Extracted from the article]

Background: Dementia can be caused by numerous different diseases that present variable clinical courses and reveal multiple patterns of brain atrophy, making its accurate early diagnosis by conventional examinative means challenging. Although highly accurate and powerful, magnetic resonance imaging (MRI) currently plays only a supportive role in dementia diagnosis, largely due to the enormous volume and diversity of data it generates. AI-based software solutions/algorithms that can perform automated segmentation and volumetry analyses of MRI data are being increasingly used to address this issue. Numerous commercial and non-commercial software solutions for automated brain segmentation and volumetry exist, with FreeSurfer being the most frequently used. Objectives: This Review is an account of the current situation regarding the application of automated brain segmentation and volumetry to dementia diagnosis. Methods: We performed a PubMed search for "FreeSurfer AND Dementia" and obtained 493 results. Based on these search results, we conducted an in-depth source analysis to identify additional publications, software tools, and methods. Studies were analyzed for design, patient collective, and for statistical evaluation (mathematical methods, correlations). Results: In the studies identified, the main diseases and cohorts represented were Alzheimer's disease (n = 276), mild cognitive impairment (n = 157), frontotemporal dementia (n = 34), Parkinson's disease (n = 29), dementia with Lewy bodies (n = 20), and healthy controls (n = 356). The findings and methods of a selection of the studies identified were summarized and discussed. Conclusion: Our evaluation showed that, while a large number of studies and software solutions are available, many diseases are underrepresented in terms of their incidence. There is therefore plenty of scope for targeted research. [ABSTRACT FROM AUTHOR]

essential in cases of suspected neurosyphilis, including a detailed sexual history and appropriate laboratory testing.The fourth article explores the use of virtual reality (VR) therapy in the rehabilitation of patients with stroke-related upper limb motor impairment. The study found that VR therapy was effective in improving upper limb motor function and activities of daily living in stroke patients. The use of VR technology provides an immersive and engaging rehabilitation experience, which may enhance motivation and adherence to therapy. Further research is needed to determine the optimal parameters and protocols for VR therapy in stroke rehabilitation.The fifth article discusses the potential role of neurofeedback training in the treatment of attention-deficit/hyperactivity disorder (ADHD). Neurofeedback training involves teaching individuals to self-regulate their brain activity through real-time feedback. The study found that neurofeedback training was effective in reducing ADHD symptoms and improving cognitive function in children and adolescents. However, more research is needed to determine the long-term effects of neurofeedback training and its efficacy compared to other treatment options for ADHD.Overall, these articles provide valuable insights into various neurological disorders and potential treatment approaches. Further research is needed to validate and expand upon these findings, but they offer promising avenues for improving the diagnosis, treatment, and rehabilitation of individuals with neurological conditions. [Extracted from the article]

A study published in Translational Neurodegeneration introduces a new blood-based biomarker, the plasma p-tau181 assay, which accurately reflects tau pathology in Alzheimer's disease (AD). Unlike current assays, this new biomarker is not affected by amyloid accumulation and shows higher specificity for tau pathology. It has the potential to detect and stage AD tau pathologies in the brain, offering a more accessible and functional alternative to PET scans. The assay may also help predict therapeutic response to current treatments and identify suitable patients for anti-amyloid therapies. However, more research with larger sample sizes is needed to confirm these findings. [Extracted from the article]

Background: While several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted. Methods: We prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer's Disease (AD) Assessment Scale's (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS. Results: Patients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94–5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19–0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05–1.39) and 0.63 units (95% CI 0.19–1.08) more severe NPS. NPS number (MMSE mean difference − 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26–2.56) and severity (MMSE − 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57–1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect − 0.08, 95% CI -0.22 to -0.002). Discussion: This study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA. [ABSTRACT FROM AUTHOR]

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by amyloid β (Aβ) deposition in brain vessels, leading to hemorrhagic phenomena and cognitive impairment. Magnetic resonance imaging (MRI)-based criteria allow a diagnosis of probable CAA in vivo, but such a diagnosis cannot predict the eventual development of CAA. Methods: We conducted a retrospective cohort study of 464 patients with cognitive disorders whose data were included in a brain health biobank. De-identified parameters including sex, age, cognitive score, APOE status, and cerebrospinal fluid (CSF) levels of Aβ 1–40, Aβ 1–42, phosphorylated tau, and total tau were assessed in those with and without CAA. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined. Results: CAA was present in 53 of 464 (11.5%) patients. P-tau level was significantly higher in those with CAA (115 vs. 84.3 pg/mL p = 0.038). In univariate analyses, the risk of developing CAA was higher with increased age (OR, 1.036; 95% CI: 1.008, 1.064; p = 0.011) and decreased CSF level of Aβ 1–40 (OR, 0.685; 95% CI: 0.534, 0.878; p = 0.003). In multivariate analyses, the risk of CAA remained higher with a decreased CSF level of Aβ 1–40 (OR, 0.681; 95% CI: 0.531, 0.874; p = 0.003). Conclusion: These findings suggest that Aβ 1–40 levels in the CSF might be a useful molecular biomarker of CAA in patients with dementia. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) deposition throughout the neuroaxis is a classical hallmark of several neurodegenerative diseases, most notably Alzheimer's disease (AD). Aβ peptides of varied length and diverse structural conformations are deposited within the parenchyma and vasculature in the brains of individuals with AD. Neuropathologically, Aβ pathology can be assessed using antibodies to label and characterize their features, which in turn leads to a more extensive understanding of the pathological process. In the present study, we generated a novel monoclonal antibody, which we found to be specific for the N-terminal region of Aβ. This antibody reacted to amyloid precursor protein expressed in cultured cells and labels Aβ plaques and cerebral amyloid angiopathy in brain tissue from a mouse model of amyloidosis as well as post-mortem brain tissue from patients diagnosed with AD. This highly specific novel antibody will serve as a unique tool for future studies investigating Aβ deposition in novel mouse models and cross-sectional studies using post-mortem human tissue. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is associated with white matter damage and neurodegeneration. Gait is impaired in CAA; however, the neural basis of this impairment is unclear. Are gait impairments in patients with CAA associated with altered cerebral white matter diffusivity and/or atrophy of cortical and subcortical grey matter. Participants with CAA (n=29), Alzheimer's disease (AD; n=16), and normal controls (n=47) were included. Gait was assessed using a 6 m walkway with parameters categorized into rhythm, pace, postural control, and variability domains. The dual-task cost (DTC) of gait speed was calculated for counting backwards, animal fluency, and serial sevens tasks. Whole-brain white matter disruption was quantified using the peak width of skeletonized mean diffusivity (PSMD), and thickness and volume of select cortical, subcortical, and cerebellar regions were quantified using FreeSurfer. In CAA participants, associations were found between PSMD and pace (standardized parameter estimate (β), 95 % confidence interval (CI): 0.17, 0.03–0.32), and medial orbital frontal cortical thickness and counting backwards DTC (parameter estimate (PE), 95 % CI: −5.7 %/SD, −0.24 to −11.23). Across all groups, including CAA, associations were found between PSMD and pace, variability, counting backwards DTC, and animal fluency DTC; between frontal cortical thickness and pace, counting backwards DTC, and animal fluency DTC; between cortical regions affected by AD (inferior parietal cortex, inferior and middle temporal gyrus) and counting backwards DTC; and between thalamus volume and postural control. Reduced white matter structural integrity and grey matter loss is associated with poor overall gait performance in CAA, AD, and normal controls. • Cerebral amyloid angiopathy (CAA) is associated with gait impairments. • Impairments may be linked to white matter (WM) damage and grey matter loss. • Worse gait pace and dual task cost (DTC) of walking were related to WM disruption. • DTC of walking was associated with grey matter atrophy in multiple brain regions. [ABSTRACT FROM AUTHOR]

Background Dementia results from multiple neuropathologies causing cognitive impairment sufficiently severe to affect functional status. However, these pathologies and functional impairment are common in persons without dementia. We examined the association of Alzheimer's disease (AD) and multiple other neuropathologies with instrumental and basic activities of daily living in persons with and without dementia. Methods Participants were 1 509 deceased from the Religious Orders Study or Rush Memory and Aging Project. Pathologic AD and 3 other AD indices were examined, in addition to 4 non-AD neurodegenerative pathologies: cerebral amyloid angiopathy (CAA), hippocampal sclerosis, TDP-43, and Lewy bodies, and 4 cerebrovascular pathologies: gross- and microinfarctions, athero- and arteriolosclerosis. Functional assessment included Lawton and Katz Index Instrumental and Basic Activities of Daily Living (IADL and BADL). Ordinal regression models adjusted for age, sex, and education were used to examine the association of neuropathologies with IADL and BADL. Results Alzheimer's disease and the other neuropathologies were associated with impaired IADL (all p s < .001) and with impaired BADL (p s < .01), except for atherosclerosis and CAA, which were not associated with BADL. The effects of most neuropathologies were largely affected by dementia. However, small effects on IADL remained for PHF-tau tangles after adjusting models for dementia. Direct effects of gross infarcts on IADL and BADL and of microinfarcts on BADL remained unchanged after adjusting the models for dementia. Conclusions Alzheimer's disease and all other neuropathologies are strongly associated with functional disability. The association of most neuropathologies with disability was eliminated or attenuated by dementia, except for gross infarcts and microinfarcts. [ABSTRACT FROM AUTHOR]

Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer's disease; this Aβ heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55–90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Conclusions: Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, in which there is a progressive deterioration of intellectual and social functions, memory loss, personality changes and inability for self-care, and has become the fourth leading cause of death in developed countries. Pathogenesis of AD, there is a progressive deposition of β-amyloid (Aβ)- peptide in the hippocampal and cerebral cortical regions. This deposition is associated with the presence of neurofibrillary tangles (NFTs) and senile plaques. The senile plaques deposited between the neurons consist mainly protein β amyloid. Neurofibrillary tangles deposited inside the neurons fabricated from Tau protein. Diagnosing Alzheimer's requires careful medical evaluation thorough medical history, mental status testing, physical and neurological examination tests (such as blood tests and brain imaging), two classes of medications approved to treat AD. Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine, NMDA receptor antagonists: Memantine. The major goal in designing nanoparticles as a delivery system are to control particle size, surface property and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutic optimum rate and dose regimen of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Many strategies have been developed to deliver the drug into brain by crossing the BBB: chemical delivery systems, magnetic drug targeting or drug carrier systems such as antibodies, liposomes or nanoparticles. Among those, nanoparticles have got a great concentration as the potential targeted drug delivery systems in the brain recently. [ABSTRACT FROM AUTHOR]

BACKGROUND: Apolipoprotein E ε4 allele (APOE-ε4) is the main genetic risk factor for late-onset Alzheimers disease (AD) and may impact cognitive function also via other neuropathological lesions. However, there is limited evidence available from diverse populations, as APOE associations with dementia seem to differ by race. Therefore, we aimed to evaluate the pathways linking APOE-ε4 to cognitive abilities through AD and non-AD neuropathology in an autopsy study with an admixed sample. METHODS: Neuropathological lesions were evaluated following international criteria using immunohistochemistry. Participants were classified into APOE-ε4 carriers (at least one ε4 allele) and non-carriers. Cognitive abilities were evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the indirect association of APOE-ε4 with cognition through AD-pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA-binding protein 43 (TDP-43). RESULTS: We included 648 participants (mean age 75 ± 12 years old, mean education 4.4 ± 3.7 years, 52% women, 69% White, and 28% APOE-ε4 carriers). The association between APOE-ε4 and cognitive abilities was mediated by neurofibrillary tangles (β = 0.88, 95% CI = 0.45; 1.38, p

An 87-year-old woman was admitted to our hospital (day 0) because of acute disorientation caused by multiple acute intracerebral hemorrhages. T2*-weighted magnetic resonance imaging (MRI) at admission revealed multiple subcortical old microbleeds indicative of cerebral amyloid angiopathy. Microbleeds in the right cerebellar hemisphere and acute spotty ischemia in the left cerebellum were also identified. The patient had been afebrile, and blood examinations on day 7 were within normal limits of inflammatory findings without antibiotics. On day 11, she developed a high fever and blood culture was performed. Her fever resolved within 2 days of antibiotic administration, although subsequent findings revealed her blood culture was positive for Staphylococcus aureus. Echocardiogram revealed bacterial vegetation in the mitral valve and moderate mitral regurgitation, with a diagnosis of infectious endocarditis (IE). Follow-up MRI demonstrated multiple spotty acute infarctions and an increased number of microbleeds. The patient may have been infected via peripheral infusions administered during the first few days after admission. However, considering the coexistence of acute hemorrhagic and ischemic lesions on MRI, as well as the acute lesions in the cerebellum, it is possible that IE was already latent on admission, and that the multiple brain hemorrhages might have been caused by IE rather than by cerebral amyloid angiopathy.

Abstract Background Patients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated. Methods To explore this, we generated pericyte-like cells from human induced pluripotent stem cells (iPSCs) harboring the Swedish mutation in the amyloid precursor protein (APPswe) along with cells from healthy controls. We initially verified the expression of classic pericyte markers in these cells. Subsequent functional assessments, including permeability, tube formation, and contraction assays, were conducted to evaluate the functionality of both the APPswe and control cells. Additionally, bulk RNA sequencing was utilized to compare the transcriptional profiles between the two groups. Results Our study reveals that iPSC-derived pericyte-like cells (iPLCs) can produce Aβ peptides. Notably, cells with the APPswe mutation secreted Aβ1-42 at levels ten-fold higher than those of control cells. The APPswe iPLCs also demonstrated a reduced ability to support angiogenesis and maintain barrier integrity, exhibited a prolonged contractile response, and produced elevated levels of pro-inflammatory cytokines following inflammatory stimulation. These functional changes in APPswe iPLCs correspond with transcriptional upregulation in genes related to actin cytoskeleton and extracellular matrix organization. Conclusions Our findings indicate that the APPswe mutation in iPLCs mimics several aspects of CAA pathology in vitro, suggesting that our iPSC-based vascular cell model could serve as an effective platform for drug discovery aimed to ameliorate vascular dysfunction in AD.

Abstract Background While several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted. Methods We prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer’s Disease (AD) Assessment Scale’s (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS. Results Patients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94–5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19–0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05–1.39) and 0.63 units (95% CI 0.19–1.08) more severe NPS. NPS number (MMSE mean difference − 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26–2.56) and severity (MMSE − 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57–1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect − 0.08, 95% CI -0.22 to -0.002). Discussion This study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA.

IntroductionThe extent to which the Big Five personality traits and subjective well-being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia-related neuropathology is unclear.MethodsUsing data from eight independent studies (Ntotal = 44,531; Ndementia = 1703; baseline Mage = 49 to 81 years, 26 to 61% female; Mfollow-up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia.ResultsSynthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long-term dementia diagnosis. There were no consistent associations with neuropathology.DiscussionThis multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy.HighlightsN(+), C(-), E(-), PA(-), and NA(+) were associated with incident diagnosis. Results were consistent despite self-report versus clinical diagnosis of dementia. Psychological factors were not associated with neuropathology at autopsy. Individuals with higher conscientiousness and no diagnosis had less neuropathology. High C individuals may withstand neuropathology for longer before death.

High blood pressure (BP) and cerebral amyloid angiopathy (CAA) are two common risk factors for intracranial hemorrhage, potentially leading to cognitive impairment. Less is known about the relationship between BP and CAA, the examination of which was the objective of this study. We analyzed data from 2510 participants in the National Alzheimer’s Coordinating Center (NACC) who had information on longitudinal BP measurements before death and on CAA from autopsy. Using the average of four systolic BPs (SBPs) prior to death, SBP was categorized into three groups: n = 435), 120–139 mmHg (n = 1335), and ≥140 mmHg (n = 740). CAA was diagnosed using immunohistochemistry in 1580 participants and categorized as mild (n = 759), moderate (n = 529), or severe (n = 292). When adjusted for age at death, sex, APOE genotype, Braak, CERAD, antihypertensive medication use, and microinfarcts, the odds ratios (95% CIs) for CAA associated with SBPs of 120–139 and ≥140 mmHg were 0.91 (0.74–1.12) and 1.00 (0.80–1.26), respectively. Findings from predictor effect plots show no variation in the probability of CAA between the three SBP categories. Microbleeds had no association with CAA, but among those with SBP ≥ 130 mmHg, the proportion of those with microbleeds was numerically greater in those with more severe CAA (p for trend, 0.084). In conclusion, we found no evidence of an association between SBP and CAA. Future studies need to develop non-invasive laboratory tests to diagnose CAA and prospectively examine this association and its implication on the pathophysiology and outcome of Alzheimer’s disease.

Abstract Background Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA. Methods Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings. Results rhApoJ-treated APP23 presented fewer cortical CMBs (50–300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036). Conclusions Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.

Abstract Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-β (Aβ) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) is associated with cardiovascular functioning and disease and has been linked to vascular dementia. Using immunohistochemistry, we studied occipital brain tissue samples of 57 patients with CAA (39 without ICH and 18 with ICH) and 42 controls, and semi-quantitatively assessed expression levels of TIMP4. Patients with CAA had increased vascular expression of TIMP4 compared to controls (p

Introduction: MRI rating criteria for small vessel disease markers include definitions for microbleeds and macrobleeds but do not account for small (<10 mm) hemorrhages with a cystic cavity and/or irregular shape. Such hemorrhages, however, are often present in patients with cerebral amyloid angiopathy (CAA). In this study, we aimed to investigate the frequency, diameter, and volume distribution of these hemorrhages (which we called mesobleeds) in patients with CAA. Methods: We selected participants with Dutch-type hereditary CAA (D-CAA) and sporadic CAA (sCAA) and scored microbleeds, mesobleeds, and macrobleeds on 3T susceptibility-weighted images MRI. Hemorrhage diameter and volume were calculated in a subset of participants using a semi-automatic tool; their distribution was evaluated on a logarithmic scale. Results: We included 25 participants with D-CAA (mean age 56 years) and 25 with sCAA (mean age 73 years). In total, 11,007 microbleeds, 602 mesobleeds, and 195 macrobleeds were observed. Eighty-two percent of participants had ≥1 mesobleed. Hemorrhage diameter and volume were calculated in four participants with 272 microbleeds (median diameter 1.52 mm, volume 0.004 mL), 84 mesobleeds (median diameter 5.61 mm, volume 0.06 mL), and 37 macrobleeds (median diameter 19.58 mm, volume 1.33 mL). Mesobleed diameter and volume were larger than microbleeds (optimal cut-off 0.02 mL) but showed overlap with macrobleeds. Conclusion: Hemorrhages <10 mm with an irregular shape and/or cystic cavity are frequently found in participants with CAA and have a distinct diameter and volume distribution. We propose to name these hemorrhage mesobleeds and to rate them separately from micro- and macrobleeds. Future research is necessary to investigate their pathophysiology and prognostic value. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating, age‐associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ‐targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD‐related pathologies, such as NFTs, are not directly targeted. A non‐mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD‐related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusion The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD).Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD.Of the inflammatory cytokines, five were risk factors (e.g., tumour‐necrosis‐factor‐related apoptosis‐inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub‐type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces.Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionsCentral nervous system dysfunction is common in longstanding hereditary transthyretin amyloidosis (ATTRv) caused by the V30M (p.V50M) mutation. Neuropathology studies show leptomeningeal amyloid deposition and cerebral amyloid angiopathy (CAA). Brain MRI is widely used in the assessment of Aβ associated CAA but there are no systematic studies with brain MRI in ATTRv amyloidosis.we performed 3 T brain MRIs in 16 patients with longstanding (>14 years) ATTRV30M. We additionally retrospectively reviewed 48 brain MRIs from patients followed at our clinic. CNS symptoms and signs were systematically accessed, and MRIs were blindly reviewed for ischaemic and haemorrhagic lesions.in the prospective cohort, we found white matter hyperintensities in 8/16 patients (50%, Fazekas score> =1). There were no relevant microbleeds, large ischaemic or haemorrhagic lesions or superficial siderosis. In the retrospective cohort, microbleeds were found in 5/48 patients (10,4%), two of which with > =20 microbleeds. White matter hyperintensities were found in 20/48 cases (41.7%). White matter lesions, microbleeds and cortical atrophy were not associated with disease duration.white matter hyperintensities are common in ATTRV30M, irrespective of disease duration. Haemorrhagic lesions are rare, even in patients with longstanding disease, suggesting the existence of other risk factors. [ABSTRACT FROM AUTHOR]

Background and purpose: Arteriosclerotic cerebral small vessel disease (aCSVD) is a cause of cognitive impairment, dementia, and stroke. Developing a better understanding of the risk factor of aCSVD is key to reducing the incidence of these conditions. This study investigated the association between intracranial arterial calcification (IAC) and total cerebral small vessel disease (CSVD) burden score. Materials and methods: This is a retrospective study, the subjects were transient ischemic attack (TIA) or acute ischemic stroke (AIS) patients. The data of 303 inpatients admitted to our study hospital between December 2018 and July 2020 were analyzed. Four imaging markers of CSVD (lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces) were evaluated by magnetic resonance imaging, and a total CSVD burden score was calculated. The experimental group was divided into four subgroups according to total CSVD burden score (1-4 points). Patients without CSVD (0 points) served as the control group. Head computerized tomography (CT) scans were used to assess ICA, using Babiarz's method. The correlations between IAC and single imaging markers of CSVD were determined using Spearman's rank correlation. Binary logic regression analysis and multivariate ordered logic regression analysis were used to determine the associations between IAC and aCSVD. Results: IAC was positively correlated with total CSVD burden score (r = 0.681), deep white matter hyperintensities (r = 0.539), periventricular white matter hyperintensities (r = 0.570), cerebral microbleeds (r = 0.479), lacunes (r = 0.541), and enlarged perivascular spaces (r = 0.554) (all p<0.001). After adjusting for the confounding factors of age, diabetes, and hypertension, aCSVD was independently associated with IAC grade 1-2 [odds ratio (OR) = 23.747, 95% confidence interval (CI) = 8.376-67.327] and IAC grade 3-4 (OR = 30.166, 95% CI = 8.295-109.701). aCSVD severity was independently associated with IAC grade 3-4 (OR = 4.697, 95% CI = 1.349-16.346). Conclusion: IAC is associated with the total CSVD burden score and single imaging signs. [ABSTRACT FROM AUTHOR]