Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.

Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.

α-Enolase reduces cerebrovascular Aß deposits by protecting Aß amyloid formation.

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid ß (Aß) deposits and causes dementia and cerebral hemorrhage. Although α-enolase (ENO1) was shown to possess multifunctional roles, its exact functions in CAA pathogenesis have not been determined. In this study, we focused on ENO1, a well-known glycolytic enzyme, which was previously identified via a proteomic approach as an upregulated protein in brain samples from patients with Alzheimer's disease (AD). We utilized the thioflavin T fluorescence assay and transmission electron microscopy to monitor the effects of ENO1 on amyloid formation by Aß peptides. We also cultured murine primary cerebrovascular smooth muscle cells to determine the effects of ENO1 on Aß cytotoxicity. To investigate the effects of ENO1 in vivo, we infused ENO1 or a vehicle control into the brains of APP23 mice, a transgenic model of AD/CAA, using a continuous infusion system, followed by a cognitive test and pathological and biochemical analyses. We found that novel functions of ENO1 included interacting with Aß and inhibiting its fibril formation, disrupting Aß fibrils, and weakening the cytotoxic effects of these fibrils via proteolytic degradation of Aß peptide. We also demonstrated that infusion of ENO1 into APP23 mouse brains reduced cerebrovascular Aß deposits and improved cognitive impairment. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aß fibril formation and fibril disruption. The proteolytic activity of ENO1 may thus underlie the enzyme's cytoprotective effect and clearance of Aß from the brain, and ENO1 may be a therapeutic target in CAA.

Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid ß (Aß) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aß deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aß cytotoxicity, Aß fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aß deposits and molecules that accumulate with Aß may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81-127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81-127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81-127-based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis.

A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1.

Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A 23-Year-Old Woman with Sudden-Onset Blindness of the Right Eye.

A 23-year-woman was presented for sudden-onset monocular blindness. Branch retinal artery occlusion in the right eye and multiple brain embolism were detected. Trousseau syndrome due to bilateral ovarian cancer was diagnosed; no embolic events were observed after anticoagulant therapy and surgical resection.

Clinical Characteristics and Outcomes of Intracerebral Hemorrhage in Very Elderly.

BACKGROUND: Intracerebral hemorrhage (ICH) incidences increase with age. Patients of advanced age may have limitations during acute care and recovery. We investigated baseline characteristics, hematoma features, and outcomes of very elderly ICH patients (≥80 years old) and compared them with those of younger ICH patients (<80 years old). METHODS: We studied 377 patients (122 women; 69 ± 11 years old) admitted within 24 hours of ICH onset. Outcome measures included hematoma volumes, National Institutes of Health Stroke Scale scores on admission, and vital and functional prognoses at 30 days. RESULTS: After adjustments for sex, very elderly patients had a higher subcortical hematoma prevalence (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.39-4.86]. On multivariate analyses, very elderly patients had larger hematoma volumes (OR, 1.33; 95% CI, 1.01-1.75, per 10-mL increase). After adjustments for risk factors and comorbidities, modified Rankin scale scores of 0-2 in very elderly patients occurred less often (OR, .34; 95% CI, .14-.82), and those with scores of 5-6 occurred more often (OR, 3.01; 95% CI, 1.09-8.54). CONCLUSIONS: Hematomas were relatively large and often found in the subcortex in very elderly ICH patients. Outcomes of very elderly ICH patients were relatively poor.

Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy.

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aß) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular Aß deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (SRPX1), which is specifically expressed in CAA-affected cerebral blood vessels. Because SRPX1, which is known as a tumor suppressor gene, reportedly induced apoptosis in tumor cells, we hypothesized that SRPX1 may play an important role in Aß-induced apoptosis in CAA. Immunohistochemical studies revealed that SRPX1 co-accumulated with Aß deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co-accumulated with Aß deposits in senile plaques. Furthermore, we demonstrated that both Aß40 and Aß42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aß40. Knockdown of SRPX1, in contrast, reduced the formation of Aß40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells. SRPX1 may thus be a novel molecule that is up-regulated in cerebrovascular Aß deposits and that may increase Aß-induced cerebrovascular degeneration in CAA.

Collateral circulation via the circle of Willis in patients with carotid artery steno-occlusive disease: evaluation on 3-T 4D MRA using arterial spin labelling.

AIM: To evaluate whether 3-T four-dimensional (4D) arterial spin-labelling (ASL) -based magnetic resonance angiography (MRA) is useful for assessing the collateral circulation via the circle of Willis in patients with carotid artery steno-occlusive disease. MATERIALS AND METHODS: Institutional review board approval and prior written informed consent from all patients were obtained. The inclusion criteria were fulfilled by 13 patients with carotid artery steno-occlusive disease. All underwent 4D-ASL MRA at 3 T and digital subtraction angiography (DSA). The flow-sensitive alternating inversion recovery (FAIR) preparation scheme with look-locker sampling was used for spin labeling. At 300-ms intervals seven dynamic scans were obtained with a spatial resolution of 0.5×0.5×0.6 mm(3). The collateral flow via the circle of Willis was read on 4D-ASL MRA and DSA images by two sets of two independent readers each. κ statistics were used to assess interobserver and intermodality agreement. RESULTS: On DSA, collateral flow via the anterior communicating artery (AcomA) was observed in six patients, via the posterior communicating artery (PcomA) in four patients, and via both the AcomA and PcomA in three patients. With respect to the qualitative evaluation of 4D-ASL MRA images, interobserver agreement was excellent for all items (κ=1). 4D-ASL MRA and DSA consensus readings agreed on the type of collateral flow pattern in 10 of the 13 patients (77%). Intermodality agreement was good (κ=0.606; 95% confidence interval (CI): 0.215-0.997). CONCLUSION: 3 T 4D-ASL MRA may be a useful tool for the evaluation of the collateral circulation in patients with carotid artery steno-occlusive disease.

Educational campaigns at point of purchase in rural supermarkets improve stroke knowledge.

BACKGROUND: The number of elderly people is dramatically increasing, and this trend is especially pronounced in rural populations. The aim of the present study was to verify the effectiveness of stroke education in a rural area. METHODS: The stroke educational flyers were distributed for 3 weeks at the point of purchase within supermarkets. Questionnaires were used to determine knowledge about stroke and appropriate emergent action on identifying stroke. RESULTS: A total of 882 people responded to the questionnaires before (n = 409) and 3 months after (n = 473) the campaign. Of these, 686 (77.8%) were aged 65 years or older. The percentages of correct answers for hemiplegia and one-sided numbness (P < .05 for both) and calling emergency medical services (EMS) on identifying stroke occurrence (P < .001) were higher after the campaign compared with those before the campaign. Of the respondents aged 65 years or older, the percentages of correct answers for numbness on one side and calling for EMS on identifying stroke were higher after the campaign (P < .05 and P < .001, respectively). CONCLUSIONS: A simple point-of-purchase stroke campaign using educational flyers could meaningfully affect stroke knowledge among elderly persons in a rural community.

Effective Education Materials to Advance Stroke Awareness Without Teacher Participation in Junior High School Students.

BACKGROUND: Youth stroke education is promising for the spread of stroke awareness. The aim of this study was to examine whether our stroke awareness teaching materials without teacher's participation can increase student awareness to act fast on suspected stroke signs. METHODS: We used the face, arm, speech, and time (FAST) mnemonic derived from the Cincinnati Prehospital Stroke Scale. Seventy-three students of the second grade and 72 students of the third grade (age range, 13-15 years) in a junior high school were enrolled in the study. The students were divided into 2 groups: students who received a teacher's lesson (group I) and those who did not receive a teacher's lesson (group II). Students in group II watched an animated cartoon and read a Manga comic in class. All students took the educational aids home, including the Manga comic and magnetic posters printed with the FAST message. Questionnaires on stroke knowledge were examined at baseline and immediately and 3 months after receiving the intervention. RESULTS: At 3 months after the intervention, a significant improvement in understanding the FAST message was confirmed in both the groups (group I, 85%; group II, 94%). Significant increases in the knowledge of risk factors were not observed in each group. CONCLUSIONS: Our education materials include a Manga comic, an animated cartoon, and a magnetic poster, without an accompanying teacher's lesson can increase stroke awareness, including the FAST message, in junior high school students.

Brain infarction with a predilection for cerebellum in a patient with double-outlet left ventricle and vascular malformations.

Double-outlet left ventricle (DOLV) is a rare congenital heart disease characterized by the origin of the great arteries arising predominantly or completely from the left ventricle. In this report, we describe a case with brain infarction with a predilection for cerebellum in a patient with DOLV and vascular malformations. The cerebellar predilection of ischemic lesions appeared to have been caused by hemodynamic effects related to the specific anatomy of the brachiocephalic trunk. This is further supported by our observation that the mean flow velocity was significantly higher in the vertebral arteries than in the common carotid arteries.

Panmedullary edema with inferior olivary hypertrophy in bilateral medial medullary infarction.

Bilateral medial medullary infarction (MMI) is a rare type of stroke with poor outcomes. Inferior olivary nucleus hypertrophy results from a pathologic lesion in the Guillain-Mollaret triangle. The relationship between inferior olivary nucleus hypertrophy and the medullary lesion is obscure. To the best of our knowledge, only 1 autopsy case with unilateral medial medullary infarction that was associated with ipsilateral inferior olivary nucleus hypertrophy has been reported. We describe a rare case with acute infarction in the bilateral medial medulla oblongata accompanied by subacute bilateral inferior olivary nucleus hypertrophy and panmedullary edema. The hypertrophy appeared to have been caused by local ischemic damage to the termination of the central tegmental tract at the bilateral inferior olivary nucleus.

Stroke education using an animated cartoon and a manga for junior high school students.

BACKGROUND: We investigated whether junior high school students could be educated regarding stroke with an animated cartoon and a Manga that we produced for the purpose of dissemination of this knowledge. METHODS: We produced a 10-minute animated cartoon and a Manga that provided information regarding stroke risk factors, stroke signs and symptoms, and awareness to immediately contact emergent medical service (EMS) on identification of stroke signs and symptoms. From December 2011 to March 2012, 493 students in 15 classes of the first grade (age 12-13 years) of 3 junior high schools were enrolled in the study. Each subject watched the animated cartoon and read the Manga; this was referred to as "training." Lessons about stroke were not given. Questionnaires on stroke knowledge were evaluated at baseline, immediately after the training, and 3 months after the training. RESULTS: The proportion of correct answers given immediately after the training was higher for all questions, except those related to arrhythmia, compared with baseline. Percentage of correct answers given at 3 months was higher than that at baseline in questions related to facial palsy (75% versus 33%), speech disturbance (91% versus 60%), hemiplegia (79% versus 52%), numbness of 1 side (58% versus 51%), calling for EMS (90% versus 85%), alcohol intake (96% versus 72%), and smoking (69% versus 54%). At 3 months after the training, 56% of students answered the FAST (facial droop, arm weakness, speech disturbance, time to call for EMS) mnemonic correctly. CONCLUSIONS: Stroke education using these teaching aids of the animated cartoon and the Manga improved stroke knowledge in junior high school students.

Stroke education program of act FAST for junior high school students and their parents.

BACKGROUND: We produced a stroke education program using the FAST (facial droop, arm weakness, speech disturbance, time to call an ambulance) mnemonic. AIMS: The aim of this study is to examine efficacy of our education program for junior high school students and their parents. METHODS: One hundred ninety students of 3 junior high schools (aged 12-13 years) and their parents were enrolled. Students received a 45-minute lesson of stroke enlightenment using the FAST mnemonic. Enlightenment items, such as a magnet poster, were distributed. Parents were educated indirectly from their child. Surveys of stroke knowledge were examined at baseline, immediately after the lesson, and at 3 months after the lesson. RESULTS: For the students, correct answers at 3 months were significantly higher than those at baseline in questions of facial palsy (98% versus 33%), speech disturbance (98% versus 54%), numbness on one side (64% versus 42%), weakness on one side (80% versus 51%), calling an ambulance (88% versus 60%), alcohol drinking (85% versus 65%), smoking (70% versus 43%), dyslipidemia (58% versus 46%), hyperglycemia (59% versus 48%), and obesity (47% versus 23%). At 3 months, the parents answered more correctly questions of facial palsy (93% versus 66%), calling an ambulance (95% versus 88%), and alcohol drinking (65% versus 51%) than at baseline. At 3 months, 96% of students and 78% of parents answered the FAST mnemonic correctly. CONCLUSIONS: Our stroke education program improved stroke knowledge, especially the FAST message, for junior high school students and their parents.

The effectiveness of a stroke educational activity performed by a schoolteacher for junior high school students.

BACKGROUND: The purpose of this study was to determine whether our stroke education system can help junior high school students acquire stroke knowledge when performed by a schoolteacher. METHODS: A stroke neurologist gave a stroke lesson to 25 students (S group) and a schoolteacher through our stroke education system. After instruction, the schoolteacher performed the same lesson using the same education system to another 75 students (T group). Questionnaires on stroke knowledge were examined at baseline, immediately after the lesson (IL), and at 3 months after the lesson (3M). We analyzed the results of stroke knowledge assessment by linear mixed effects models adjusted for gender and class difference using the student number. RESULTS: We assessed 24 students in the S group and 72 students in the T group. There were no significant differences in the changes of predicted scores of symptoms and risk factors adjusted for gender, class difference, and each student knowledge level until 3M between the 2 groups. Correct answer rates for the meaning of the FAST (facial droop, arm weakness, speech disturbance, time to call 119) at IL were 92% in the S group and 72% in the T group, respectively. At 3M, they were 83% in the S group and 84% in the T group. The correct answer rates of FAST at 3M were not significantly different adjusted for group, gender, class difference, and correct answer rate at IL. CONCLUSIONS: A schoolteacher can conduct the FAST message lesson to junior high school students with a similar outcome as a stroke neurologist using our stroke education system.

Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer's disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer's disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer's disease.

Low serum calcium levels contribute to larger hematoma volume in acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: We investigate whether admission serum calcium levels are associated with hematoma volume, stroke severity, and outcomes in patients with acute intracerebral hemorrhage. METHODS: A total of 273 patients admitted within 24 hours after intracerebral hemorrhage onset was divided into quartiles based on admission serum calcium levels (Q1 [≤9.0], Q2 [9.1-9.3], Q3 [9.4-9.7], Q4 [≥9.8] mg/dL). RESULTS: Median hematoma volumes for each quartile (Q1 to Q4) were 18, 9, 10, and 9 mL (P=0.005), and median National Institutes of Health Stroke Scale scores were 16, 11, 11, and 9 (P=0.010), respectively. On multivariate analysis, Q1 had larger hematoma volume (P=0.025) and higher National Institutes of Health Stroke Scale score (P=0.020) than Q4. There were fewer patients with modified Rankin Scale scores 0 to 2 in Q1 than Q4 after adjustment for risk factors and comorbidities (odds ratio, 0.31; 95% confidence interval, 0.11-0.84) but not after additional adjustment for hematoma volume and National Institutes of Health Stroke Scale score. There were more patients with modified Rankin Scale scores 5 to 6 (P=0.016) and with fatal outcomes (P=0.048) in Q1 than Q4 as crude values, but not after adjustment. CONCLUSIONS: Low admission serum calcium levels were associated with larger hematoma volume and higher National Institutes of Health Stroke Scale score among patients with acute intracerebral hemorrhage.

Hepatic soluble epoxide hydrolase: A promising target for unveiling the liver-brain axis in Alzheimer's disease.

Wu and Dong et al.1 report that hepatic soluble epoxide hydrolase (sEH) manipulation impacts amyloid-ß (Aß) deposits and cognitive impairment in mouse models for Alzheimer's disease (AD), suggesting that hepatic sEH activity is a promising therapeutic target to treat AD.

Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer's disease.

Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer's disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood-brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD.