This comprehensive review synthesizes the latest advancements in understanding inflammatory disorders affecting cerebral small vessels, a distinct yet understudied category within cerebral small vessel diseases (SVD). Unlike classical SVD, these inflammatory conditions exhibit unique clinical presentations, imaging patterns, and pathophysiological mechanisms, posing significant diagnostic and therapeutic challenges. Highlighting their heterogeneity, this review spans primary angiitis of the central nervous system, cerebral amyloid angiopathy-related inflammation, systemic vasculitis, secondary vasculitis, and vasculitis in autoinflammatory diseases. Key discussions focus on emerging insights into immune-mediated processes, neuroimaging characteristics, and histopathological distinctions. Furthermore, this review underscores the importance of standardized diagnostic frameworks, individualized immunomodulation approaches, and novel targeted therapies to address unmet clinical demands.
Humans ; Cerebral Small Vessel Diseases/pathology* ; Inflammation/pathology* ; Cerebral Amyloid Angiopathy/pathology* ; Vasculitis, Central Nervous System/pathology* ; Vasculitis/pathology*

Intracerebral hemorrhage (ICH) and lacunar infarction (LI) are the major acute clinical manifestations of cerebral small vessel diseases (cSVDs). Hypertensive small vessel disease, cerebral amyloid angiopathy, and hereditary causes, such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), constitute the three common cSVD categories. Diagnosing the underlying vascular pathology in these patients is important because the risk and types of recurrent strokes show significant differences. Recent advances in our understanding of the cSVD-related radiological markers have improved our ability to stratify ICH risk in individual patients, which helps guide antithrombotic decisions. There are general good-practice measures for stroke prevention in patients with cSVD, such as optimal blood pressure and glycemic control, while individualized measures tailored for particular patients are often needed. Antithrombotic combinations and anticoagulants should be avoided in cSVD treatment, as they increase the risk of potentially fatal ICH without necessarily lowering LI risk in these patients. Even when indicated for a concurrent pathology, such as nonvalvular atrial fibrillation, nonpharmacological approaches should be considered in the presence of cSVD. More data are emerging regarding the presentation, clinical course, and diagnostic markers of hereditary cSVD, allowing accurate diagnosis, and therefore, guiding management of symptomatic patients. When suspicion for asymptomatic hereditary cSVD exists, the pros and cons of prescribing genetic testing should be discussed in detail in the absence of any curative treatment. Recent data regarding diagnosis, risk stratification, and specific preventive approaches for both sporadic and hereditary cSVDs are discussed in this review article.
Anticoagulants ; Atrial Fibrillation ; Blood Pressure ; CADASIL ; Cerebral Amyloid Angiopathy ; Cerebral Hemorrhage ; Cerebral Small Vessel Diseases ; Diagnosis ; Genetic Testing ; Humans ; Pathology ; Stroke ; Stroke, Lacunar*

Cerebral amyloid angiopathy (CAA) is associated with perivascular disruption, which is caused by progressive amyloid-beta (Aβ) deposition in vessels. Previous autopsy studies have shown that the prevalence of CAA in Alzheimer's disease (AD) is 70% to 90%. CAA is principally characterized by restricted lobar microbleeds (MBs), which can be detected by gradient-echo T2* (GRE) and susceptibility-weighted imaging (SWI). We herein report on a 62-year-old man who presented with 8 years of memory impairment. The apolipoprotein E (APOE) genotype was ε4/ε4, and a brain GRE performed 28 months before death revealed mild atrophy and no MBs. At autopsy, the patient scored “A3, B3, C3” according to the National Institute on Aging-Alzheimer's Association guidelines; the patient thus exhibited a high level of AD neuropathological changes. Furthermore, immunohistochemical staining for Aβ showed antibody accumulation and severe cerebral amyloid angiopathic changes in numerous vessels with amyloid deposits. Our case suggests that radiological CAA markers, such as cerebral microbleed (CMB) or cerebral superficial siderosis, may not suffice to detect amyloid angiopathy in cerebral vessels. CAA should therefore be considered as a combined pathology in APOE ε4 homozygotes with AD, even if such patients do not exhibit CMB on MRI.
Alzheimer Disease* ; Amyloid ; Apolipoproteins ; Apolipoproteins E ; Atrophy ; Autopsy ; Brain ; Cerebral Amyloid Angiopathy* ; Genotype ; Homozygote ; Humans ; Magnetic Resonance Imaging ; Memory ; Middle Aged ; Pathology ; Plaque, Amyloid ; Prevalence ; Siderosis

Intracranial hemorrhage is common and is caused by diverse pathology, including trauma, hypertension, cerebral amyloid angiopathy, hemorrhagic conversion of ischemic infarction, cerebral aneurysms, cerebral arteriovenous malformations, dural arteriovenous fistula, vasculitis, and venous sinus thrombosis, among other causes. Neuroimaging is essential for the treating physician to identify the cause of hemorrhage and to understand the location and severity of hemorrhage, the risk of impending cerebral injury, and to guide often emergent patient treatment. We review CT and MRI evaluation of intracranial hemorrhage with the goal of providing a broad overview of the diverse causes and varied appearances of intracranial hemorrhage.
Arteriovenous Malformations ; Central Nervous System Vascular Malformations ; Cerebral Amyloid Angiopathy ; Cerebral Infarction ; Craniocerebral Trauma ; Hematoma, Subdural ; Hemorrhage ; Humans ; Hypertension ; Intracranial Aneurysm ; Intracranial Hemorrhages* ; Magnetic Resonance Imaging ; Neuroimaging ; Pathology ; Sinus Thrombosis, Intracranial ; Subarachnoid Hemorrhage ; Vasculitis

Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid beta-protein (Abeta)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Abeta deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2* imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Abeta40 for CAA and anti-Abeta antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Abeta immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.
Alzheimer Disease ; Amyloid ; Amyloid beta-Peptides ; Biomarkers ; Biopsy ; Blood Vessels ; Brain ; Cerebral Amyloid Angiopathy* ; Cerebrospinal Fluid ; Cerebrovascular Disorders ; Dementia ; Diagnosis ; Epidemiology ; Humans ; Immunotherapy ; Infarction ; Inflammation ; Leukoencephalopathies ; Ligands ; Magnetic Resonance Imaging ; Neuroimaging ; Pathology ; Plaque, Amyloid ; Positron-Emission Tomography ; Risk Factors ; Siderosis ; Stroke ; Subarachnoid Hemorrhage

Two major vascular pathologies underlie brain damage in patients with disease of small size penetrating brain arteries and arterioles; 1) thickening of the arterial media and 2) obstruction of the origins of penetrating arteries by parent artery intimal plaques. The media of these small vessels may be thickened by fibrinoid deposition and hypertrophy of smooth muscle and other connective tissue elements that accompanies degenerative changes in patients with hypertension and or diabetes or can contain foreign deposits as in amyloid angiopathy and genetically mediated conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These pathological changes lead to 2 different pathophysiologies: 1) brain ischemia in regions supplied by the affected arteries. The resultant lesions are deep small infarcts, most often involving the basal ganglia, pons, thalami and cerebral white matter. And 2) leakage of fluid causing edema and later gliosis in white matter tracts. The changes in the media and adventitia effect metalloproteinases and other substances within the matrix of the vessels and lead to abnormal blood/brain barriers in these small vessels. and chronic gliosis and atrophy of cerebral white matter.
Adventitia ; Amyloid ; Arteries ; Arterioles ; Atrophy ; Basal Ganglia ; Brain ; Brain Ischemia ; CADASIL ; Cerebral Amyloid Angiopathy ; Cerebral Small Vessel Diseases ; Connective Tissue ; Edema ; Gliosis ; Humans ; Hypertension ; Hypertrophy ; Metalloproteases ; Muscle, Smooth ; Parents ; Pathology* ; Pons ; Stroke, Lacunar* ; Tunica Media

OBJECTIVETo examine cerebral pathologies in cerebral amyloid angiopathy in a rat model of Alzheimer's disease.

METHODSRat models of Alzheimer's disease was established by stereotactic Aβ1-42 fiber injection in the bilateral hippocampus. The cognitive function of the rats was evaluated with water maze test. HE staining, Congo red staining and double-labeling indirect immunofluorescence were used to examine the dynamic distribution of Aβ fiber deposit in the brain.

RESULTSThe model rats showed significant differences from the control rats in the escape latency and the times of crossing platform in waster maze test. HE staining revealed a decreased number and degeneration of the granular cells with increased glial cells in the model rats. Congo Red staining showed that the Aβ fiber was deposited gradually in the small vessels in the brain parenchyma to cause thickening, stenosis or occlusion of the small vessels. Immunofluorescence staining detected Aβ fiber migration from the parenchyma to the walls of the small arteries in the rat models.

CONCLUSIONCerebral amyloid angiopathy is a major pathological feature in Alzheimer's disease.

Alzheimer Disease ; pathology ; Amyloid beta-Peptides ; chemistry ; Animals ; Brain ; pathology ; Cerebral Amyloid Angiopathy ; pathology ; Disease Models, Animal ; Rats ; Staining and Labeling

OBJECTIVETo recognize relationship of protein related neurodegeneration abnormal aggregation in the aged brains with their cognitive and motor functions.

METHODSBrain tissues from the consecutive autopsy cases of the aged from January 2005 to December 2006 in PLA General Hospital were carried out for immunohistochemical staining with beta amyloid, tau, α-synuclein and ubiquitin antibodies. The consortium to establish a registry for Alzheimer's disease (CERAD) was used to semi-quantitatively analyze Aβ positive core plaques density and Braak staging for tau positive neurofibrillary tangles (NFTs) and α-synuclein positive Lewy bodies. In addition, Aβ positive cerebral amyloid angiopathy (CAA), neuritic plaques and various ubiquitin positive structures were also observed. The relationship of these protein abnormal depositions in the aged brains with cognitive and motor functions were analyzed.

RESULTSIn brain tissues of 16 consecutive autopsy cases of the aged from 78 to 95 years, there were 13 cases with Aβ positive core plaques, their density was 2 cases with sparse, 2 cases with moderate and 9 cases with frequent, respectively, according to CREAD.Eight cases with Aβ positive CAA were found, including 6 cases of mild CAA and 2 cases of severe CAA. There were 12 cases with tau positive NFTs, including 6 cases with Braak stageI-II, 4 cases with stage III-IV and 2 cases with stage V-VI. There were 5 cases with frequent Aβ core plaques, meanwhile existing numerous tau/ubiquitin positive neuritic plaques and Braak stage IV-VI of tau positive NFTs, all of them presented cognitive dysfunction. Among 4 other cases with frequent Aβ core plaques, only one case coexisted α-synuclein positive Lewy bodies showed moderate cognitive impairment, remaining 3 cases did not present cognitive dysfunction. There were 4 cases with α-synuclein positive Lewy bodies in the brainstem, and all of these cases presented parkinsonian motor dysfunction. 13 cases with ubiquitin positive structures were found.

CONCLUSIONSBeta amyloid protein positive deposit in the aged brain is an important marker of normal brain aging and cognitive impairment; frequent Aβ core plaques in the neocortex plus Braak IV and above tau positive NFTs are closely related to cognitive dysfunction of Alzheimer's disease; α-synuclein positive Lewy bodies in the brainstem is one of the important pathological markers of parkinsonian motor disorders; ubiquitin deposition involves the development of some characteristic structures of several neurodegenerative diseases.

Aged ; Alzheimer Disease ; metabolism ; pathology ; Amyloid beta-Peptides ; analysis ; Autopsy ; Brain ; pathology ; Brain Chemistry ; Cerebral Amyloid Angiopathy ; Humans ; Neurofibrillary Tangles ; chemistry ; pathology ; Plaque, Amyloid ; Ubiquitin ; analysis ; alpha-Synuclein ; analysis ; tau Proteins ; analysis

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are associated with various pathologies of the cerebral small vessels according to their distribution (i.e., cerebral amyloid angiopathy or hypertensive angiopathy). We investigated the association between CMB location and kidney function in acute ischemic stroke patients. METHODS: We enrolled 1669 consecutive patients with acute ischemic stroke who underwent gradient-recalled echo brain magnetic resonance imaging. Kidney function was determined using the estimated glomerular filtration rate (eGFR). CMBs were classified into strictly lobar, strictly nonlobar (i.e., only deep or infratentorial), and a combination of both lobar and nonlobar. Multinomial logistic regression analyses were used to determine the factors associated with the existence of CMBs according to their location. RESULTS: The patients were aged 66+/-12 years (mean+/-standard deviation), and 61.9% (1033/1669) of them were male. CMBs were found in 27.0% (452/1669) of the patients. The stroke subtypes of small-artery occlusion and cardioembolism occurred more frequently in those with strictly nonlobar CMBs (10.8%) and strictly lobar CMBs (48.8%), respectively. The mean eGFR was lower in the strictly nonlobar CMBs group (72+/-28 mL/min/1.73 m2) and the both lobar and nonlobar CMBs group (72+/-25 mL/min/1.73 m2) than in the no-CMBs group (86+/-29 mL/min/1.73 m2). Multivariate multinomial logistic regression revealed that eGFR <60 mL/min/1.73 m2 was independently related to strictly nonlobar CMBs (odds ratio=2.63, p=0.001). CONCLUSIONS: Impaired kidney function is associated with strictly nonlobar CMBs. Our findings indicate that the distribution of CMBs should be considered when evaluating their relationships or prognoses.
Brain ; Cerebral Amyloid Angiopathy ; Glomerular Filtration Rate ; Humans ; Kidney Failure, Chronic ; Kidney* ; Logistic Models ; Magnetic Resonance Imaging ; Male ; Pathology ; Prognosis ; Stroke

Alzheimer Disease ; metabolism ; pathology ; Amyloid beta-Peptides ; metabolism ; Animals ; Brain ; metabolism ; pathology ; Cerebral Amyloid Angiopathy ; metabolism ; pathology ; Fluorescent Dyes ; chemistry ; Humans ; Mice ; Peptide Fragments ; metabolism ; Staining and Labeling ; Thiazoles ; chemistry