Brain Small Vessel Research Articles

Hidden ills May Underlie Parkinson's Signs

Parkinsonian signs such as motor slowing, gait disturbance, and tremor in old age may be caused by underlying cerebrovascular pathologies that cannot be detected by conventional brain imaging, according to findings from a clinical-autopsy study involving 418 cases. “Together these data suggest that a substantial portion of older people have brain tissue damage and small vessel disease that are unlikely to be detected before death and suggest that cerebrovascular disease may be an even larger public health challenge than currently estimated,” wrote Dr. Aron S. Buchman and his colleagues in Stroke: Journal of the American Heart Association. Macroscopic infarcts were found in 150 (36%) of the 418 brains that were autopsied for the study, and 110 of those also had evidence of pathologies that can’t be detected by conventional imaging, including microinfarcts, arteriolosclerosis, or both. Furthermore, those pathologies were detected in almost 30% of cases without macroscopic infarcts, according to Dr. Buchman, associate professor of neurological sciences at Rush University Medical Center, Chicago, and his coauthors. Of the 268 patients without macroinfarcts, 33 (7.9%) had microinfarcts, 62 (14.8%) had arteriolosclerosis, and 24 (5.7%) had both microinfarcts and arteriolosclerosis (Stroke doi:10.1161/ STROKEAHA.111.623462). Multiple cortical infarcts, or a single subcortical macroscopic infarct, was related to a higher global parkinsonian score, the investigators said. After the researchers controlled for macroscopic infarcts, they found an association between multiple microscopic infarcts and higher global parkinsonism. Cortical microinfarcts, but not subcortical microinfarcts, also were associated with a higher global parkinsonian score. Each type of pathology (arteriolosclerosis, microinfarcts, and macroinfarcts — particularly subcortical microinfarcts and macroinfarcts) was found to be independently and significantly associated with gait disturbance. This association was present for both single and multiple subcortical macroscopic infarcts, and for multiple subcortical microinfarcts. The brain autopsies used for this study were from deceased participants from the Religious Order Study, a longitudinal clinical-pathological study of aging in community-dwelling nuns and priests who had no known dementia at enrollment, and who were evaluated for parkinsonian signs with the 26-item modified version of the motor portion of the Unified Parkinson’s Disease Rating Scale prior to death. The study involved more women (61%) than men, and participants had a mean global parkinsonian score of 18.6 and a mean age of 88.5 years at death. The findings are important because mild parkinsonian signs affect up to 50% of people aged 85 and older without known neurological disease and are the source of significant morbidity and mortality, the investigators said. They also noted that the findings raise the question of whether improved public health strategies to increase prevention and treatment of vascular disease could decrease the burden of mild age-related parkinsonian signs. The researchers also suggested that the contribution of cerebrovascular disease to loss of motor function in old age is underestimated. “Further clinical-pathological-imaging studies will be needed to delineate antemortem imaging markers as well as the pathophysiology of both microinfarcts and small vessel disease in the development of motor impairment in old age,” they wrote. The study was funded by National Institutes of Health grants and the Illinois Department of Public Health. The authors disclosed no conflict of interest. CfA

Advances in our Understanding of the Pathophysiology, Detection and Management of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is pathologically defined as the deposition of amyloid protein, most commonly the amyloid β peptide (Aβ), primarily within the media and adventitia of small and medium-sized arteries of the leptomeninges, cerebral and cerebellar cortex. This deposition likely reflects an imbalance between Aβ production and clearance within the brain and leads to weakening of the overall structure of brain small vessels, predisposing patients tolobar intracerebral haemorrhage (ICH), brain ischaemia and cognitive decline. CAA is associated with markers of small vessel disease, like lobar microbleeds and white matter hyperintensities on magnetic resonance imaging. Therefore, it can be now be diagnosed during life with reasonable accuracy by clinical and neuroimaging criteria. Despite the lack of a specific treatment for this condition, the detection of CAA may help in the management of patients, regarding the prevention of major haemorrhagic complications and genetic counselling. This review discusses recent advances in our understanding of the pathophysiology, detection and management of CAA.

African ancestry protects against Alzheimer's disease-related neuropathology.

Previous studies in dementia epidemiology have reported higher Alzheimer's disease rates in African-Americans when compared with White Americans. To determine whether genetically determined African ancestry is associated with neuropathological changes commonly associated with dementia, we analyzed a population-based brain bank in the highly admixed city of São Paulo, Brazil. African ancestry was estimated through the use of previously described ancestry-informative markers. Risk of presence of neuritic plaques, neurofibrillary tangles, small vessel disease, brain infarcts and Lewy bodies in subjects with significant African ancestry versus those without was determined. Results were adjusted for multiple environmental risk factors, demographic variables and apolipoprotein E genotype. African ancestry was inversely correlated with neuritic plaques (P=0.03). Subjects with significant African ancestry (n=112, 55.4%) showed lower prevalence of neuritic plaques in the univariate analysis (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.55–0.95, P=0.01) and when adjusted for age, sex, APOE genotype and environmental risk factors (OR 0.43, 95% CI 0.21–0.89, P=0.02). There were no significant differences for the presence of other neuropathological alterations. We show for the first time, using genetically determined ancestry, that African ancestry may be highly protective of Alzheimer's disease neuropathology, functioning through either genetic variants or unknown environmental factors. Epidemiological studies correlating African-American race/ethnicity with increased Alzheimer's disease rates should not be interpreted as surrogates of genetic ancestry or considered to represent African-derived populations from the developing nations such as Brazil.

COL4A1 Mutation: Expansion of the Phenotype

Background: COL4A1 is a major basement membrane component, providing basement membrane stability. Mutations in COL4A1 lead to a small-vessel brain disease, sometimes associated with renal disorders, cataract and tortuosity of the retinal vessels. COL4A1-related cerebral stroke is considered to result from thrombosis preferring deep venous structures in the brain.Results: Mutations in COL4A1 were diagnosed in seven infants, antenatally in one, who presented at 20 weeks of gestation with an intraventricular and a cerebellar haemorrhage; postnatally in the other six, either in the perinatal period (n=3) or in infancy (n=3). Unilateral porencephaly (PC) was present in four and was recognised at birth in three and at seven months in one. Two were preterm born sibs, showing a PC with resolving clots in the lateral ventricles. The third one with PC, presented at seven months with familiar hemiplegia. More severe cerebral stroke of antenatal onset was seen in two infants, with ventriculomegaly at 26 and 37 weeks gestation respectively. They had severe supratentorial as well as infratentorial lesions with severe cerebellar atrophy. Outcome was poor, with early death in two, severe cerebral palsy in three and moderate hemiplegia in one. The pregnancy with the affected child was still ongoing. In two infants the mutation in COL4A1 was inherited, in one the mother had a somatic mosaicism, the others had a de novo mutation of the COL4A1-gene, affecting different exons.Conclusion: COL4A1 mutation should be considered in the fetus with antenatal haemorrhage, newborns with PC and children presenting with (familiar) hemiplegia.

Clinical Interaction between Brain and Kidney in Small Vessel Disease

Patients with chronic kidney disease (CKD) are well known to have a higher prevalence of cardiovascular disease from epidemiological studies. Recently, CKD has also been shown to be related to neurological disorders, not only ischemic brain injury but also cognitive impairment. This cerebrorenal connection is considered to involve small vessel disease in both the kidney and brain, based on their hemodynamic similarities. Clinical studies suggest that markers for CKD such as estimated glomerular filtration rate (eGFR), proteinuria, and albuminuria may be helpful to predict brain small vessel disease, white matter lesions (WMLs), silent brain ischemia (SBI), and microhemorrhages. Recently, changes in the vascular system of the brain have been shown to contribute to the onset and progression of cognitive impairment, not only vascular dementia but also Alzheimer's disease. Patients with CKD are also reported to have higher risk of impaired cognitive function in the future compared with non-CKD subjects. These results indicate that CKD markers may be helpful to predict the future risk of neuronal disease.

Severity of Dilated Virchow-Robin Spaces Is Associated With Age, Blood Pressure, and MRI Markers of Small Vessel Disease

Little is known about the risk factors of dilated Virchow-Robin spaces (dVRS) and their relation with other markers of brain small vessel disease. We investigated both issues in a large population-based sample of elderly individuals. Severity of dVRS was semiquantitatively graded in both white matter and basal ganglia using high-resolution 3-dimensional MRI images taken from 1818 stroke- and dementia-free subjects enrolled in the Three-City Dijon MRI study. Multinomial logistic regression models were used to model the association of cardiovascular risk factors, APOE genotype, brain atrophy, and MRI markers of small vessel disease with the degree of dVRS. Severity of dVRS was found to be strongly associated with age in both basal ganglia (degree 4 versus 1: OR, 2.1; 95% CI, 1.4 to 3.2) and white matter (OR, 1.5; 95% CI, 1.2 to 1.9). The proportion of hypertensive subjects increased with the degrees of dVRS in both basal ganglia (P = 0.02) and white matter (P = 0.048). Men presented a higher risk of severe dVRS in basal ganglia than women, particularly degree 4 (OR, 6.0; 95% CI, 1.8 to 19.8). The degree of dVRS was associated with the volume of white matter hyperintensities and the prevalence of lacunes, but not with brain atrophy. In this large cohort study of elderly subjects, the degree of dVRS appears independently associated with age, hypertension, volume of white matter hyperintensities, and lacunar infarctions. dVRS should be considered as another MRI marker of cerebral small vessel disease in the elderly with regional variations in their severity.

Novel COL4A1 mutations associated with HANAC syndrome: A role for the triple helical CB3[IV] domain

The COL4A1 gene encodes the α1-chain of type IV collagen, which is ubiquitously expressed in basement membranes. Mutations in COL4A1 have been reported in autosomal-dominant porencephaly and in patients with symptomatic small vessel brain disease, inconstantly associated with eye defects. We have previously reported three COL4A1 mutations associated with a systemic phenotype that we called HANAC (Hereditary Angiopathy, Nephropathy, Aneurysms, and Cramps). We carried out a clinical and genetic study of three families presenting with characteristic features of HANAC syndrome. Common systemic signs included arterial retinal tortuosity and muscle cramps, with a variable combination of small vessel brain disease, Raynaud phenomena, and kidney defects. Three novel COL4A1 missense substitutions are described, which affect highly conserved glycine residues within the collagenous domain of the protein. All six known mutations associated with the HANAC phenotype are localized within the CB3[IV] fragment of COL4A1, which encompasses major integrin-binding sites. Our results confirm that HANAC syndrome is a distinct clinical entity within the COL4A1-related disorders, which is characterized by systemic involvement and usually asymptomatic brain disease. The restricted distribution of COL4A1 mutations within the CB3[IV] region is a characteristic of the reports of patients with HANAC, which suggests that abnormal cell-type IV collagen interactions may underlie the systemic defects observed in this syndrome.

Association of Central Systolic Blood Pressure With Intracerebral Small Vessel Disease in Japanese

Recent studies have reported the association between advanced arterial stiffness and brain small vessel diseases (SVDs). Two possible hemodynamic mechanisms, increases in central blood pressure (BP) and pulsatile flow load to the brain, have been speculated to link arterial stiffness and SVD. The carotid flow augmentation index (AI) has been proposed as an index of pulsatile flow to the brain. We compared its association with brain SVD with that of central BP in a general population. Subjects were 500 individuals free from symptomatic cardiovascular diseases with a mean age of 66.9 +/- 8.4 years. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Carotid flow AI was obtained by Doppler ultrasonography. The presence of silent cerebral lacunar infarcts (SCI) was determined as a manifestation of SVD by 3-tesla magnetic resonance imaging (MRI). Second peak radial systolic BP (SBP2) and pulse pressure (PP2) were used as estimates of central BP. baPWV was significantly associated with radial BP2 (r = 0.55, P < 0.0001) but not with carotid flow AI (r = 0.03, P = 0.51). Radial BPs and baPWV, but not flow AI, were significantly higher in subjects with SCI. Radial SBP2 had higher odds ratio for the presence of SCI than brachial SBP, PP, and radial PP2. Logistic regression analysis showed that radial SBP2, but not flow AI, was independently related to the presence of SCI. These findings indicate that the SBP2, an estimate of central SBP, is significantly associated with the presence of SVD in an apparently healthy general population.

Cerebral microbleeds: a guide to detection and interpretation.

Cerebral microbleeds (CMBs) are increasingly recognised neuroimaging findings in individuals with cerebrovascular disease and dementia, and in normal ageing. There has been substantial progress in the understanding of CMBs in recent years, particularly in the development of newer MRI methods for the detection of CMBs and the application of these techniques to population-based samples of elderly people. In this Review, we focus on these recent developments and their effects on two main questions: how CMBs are detected, and how CMBs should be interpreted. The number of CMBs detected depends on MRI characteristics, such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength, and image post-processing, emphasising the importance of taking into account MRI technique in the interpretation of study results. Recent investigations with sensitive MRI techniques have indicated a high prevalence of CMBs in community-dwelling elderly people. We propose a procedural guide for identification of CMBs and suggest possible future approaches for elucidating the role of these common lesions as markers for, and contributors to, small-vessel brain disease.

Decrease in the Volume of White Matter Lesions with Improvement of Hepatic Encephalopathy

MR imaging has found abnormalities compatible with low-grade edema in the brain of patients with cirrhosis that have been related to hepatic encephalopathy. We present 3 patients with hepatic encephalopathy who exhibit supratentorial focal or diffuse white matter lesions compatible with small-vessel brain disease. The volume and number of white matter lesions reduced with the improvement of hepatic encephalopathy, suggesting the participation of the blood-brain barrier in the pathogenesis of brain edema in hepatic encephalopathy.

Small Vessels, Big Problems

Dr. Steven Greenberg writes that like many neurologic conditions, small-vessel brain disease is a common and potentially devastating disorder crying out for improved treatment.

The Need for Animal Models in Small-Vessel Brain Disease

An argument is made that small-vessel stroke, which usually results in lacunar infarction, is a serious medical problem. Therefore, it is surprising that only a few animal models exist that mimic small-vessel stroke and that these models have not been used for a systematic investigation of the genesis of lacunar infarctions. We make a case that the modified pial vessel class II disruption model mimics certain important aspects of lacunar infarctions, namely cavitation caused specifically by ischemia of smaller vessels. We found evidence that upregulation of inflammatory properties within a few days of inducing lesions prevents repopulation of the lesion with reactive astrocytes. We propose that this is the key mechanism by which cavitation occurs weeks later. We also found that treatment with minocycline after induction of lesions but before cavitation prevented the formation of the fluid-filled cavity. Rather than being walled off, the lesion apparently became part of the brain parenchyma and consisted of reactive astrocytes. We conclude that this new model can be used to investigate the mechanism of lacune formation and its prevention.

The Cerebrovascular Model of Depression in Late Life

Depression in older people, especially depression with an older age of onset, may be a manifestation of acquired brain disease. The cerebrovascular model of depression, often referred to as "vascular depression," hypothesizes that otherwise clinically occult small vessel brain disease contributes to the pathogeneses of some late-life depressive conditions. This paper reviews several lines of evidence supporting the cerebrovascular model and addresses the limitations of the existing literature. Several directions for future research are noted, including empirical testing of the notion that cerebrovascular disease might underlie the pathogeneses of depression with prominent executive dysfunction or other cognitive impairments. At this time, there are no specific therapeutic options for patients with suspected vascular depression beyond standard approaches to depression treatments, although education about the possibly greater risks of chronicity should be included in treatment planning. Therapy of cerebrovascular risk factors and stroke-risk reduction are important as consistent with general practice guidelines, although it is not known whether this will reduce the incidence or improve the outcome of late-life depression.

Cerebrovascular Risk Factors and Depression in Older Primary Care Patients: Testing a Vascular Brain Disease Model of Depression

The authors examined whether cerebrovascular risk factors (CVRFs) are associated with depressive diagnoses and symptoms in 303 primary-care patients age >/=60 years, as would be consistent with a small-vessel brain disease model of later-life depression. CVRFs were not significantly independently associated with major, minor, or subsyndromal depression, late-onset major depression, or overall depressive symptom severity. These data did not support the notion that a small-vessel brain disease model of depression might apply to the majority of older persons with depressive symptoms and syndromes in primary-care settings. Future work should include longitudinal study with larger sample sizes.

Cerebrovascular Risk Factors and Later-Life Major Depression: Testing a Small-Vessel Brain Disease Model

The topic of vascular depression has received increasing prominence as a putative etiology of depression in later life. The authors examined one aspect of this model by comparing the burden of systemic cerebrovascular risk factors (CVRFs) in 130 psychiatric inpatients with major depression and 64 normal control (NC) subjects, all age > or = 50 years. Depressed subjects did not differ statistically from NCs on cumulative CVRF scores. Diabetes mellitus and atrial fibrillation were both associated with depression, but only atrial fibrillation retained an independent association after medical disability was statistically controlled. Among the depressed subjects, CVRF scores were not significantly associated with overall symptom severity, psychiatric disability, age at onset of depression, melancholic subtype, or psychotic depression. These data did not support the notion that a linear model of small-vessel disease might apply to the great majority of older inpatients with major depression.

Continuous recordings of brain regional circulation during sleep/wake state transitions in rats.

Continuous measurement of regional blood flow (RBF) in the brain of a freely behaving rat was attained by a combination of laser-Doppler (LD) flowmetry and our originally devised apparatus, which had been developed for the automatic releasing of the twisting of lines connected between experimental apparatus and the freely behaving animal. RBF changes were studied in a ventral region of the rostral basal forebrain along with sleep-wake states. When compared with the RBF level during slow-wave sleep (SWS), levels of RBF during paradoxical sleep (PS) and wakefulness were higher by 24 (P = 0.0001) and 9% (P < 0.05), respectively. The LD signals suggested that the RBF elevation during PS was produced by dilation of both the large brain arteries and small vessels, whereas the elevation during wakefulness was caused by dilation of small vessels that was counteracted by contraction of large arteries. It was noticed that the original circulation tended to begin changing before the onset of SWS. A circadian rhythm was also demonstrated for the RBF, which largely decreased around the onset of the light period and returned to the high level before the beginning of the dark period. Thus continuous and real-time recordings of regional circulation were performed with satisfactorily precision in freely behaving rats.

CD4 expression in neurons of the central nervous system.

CD4 is a member of the Ig gene super family expressed on the surface of many thymocytes and of a subset of T lymphocytes. Human CD4 is the receptor for HIV envelope glycoprotein gp120. Human and mouse CD4 transcripts are expressed in human and mouse central nervous system (CNS), but no corresponding proteins have been reported yet. We have analyzed mRNA expression and carried out immunological experiments on adult mouse brain with probes specific for the long and short CD4 transcripts and with antibodies monospecific for mouse CD4. The main result of these experiments is that the full length CD4 transcript and the CD4 protein are expressed coordinately in neurons throughout the adult mouse brain. CD4 immunoreactivity is also present in brain small vessel walls, ependymal cells, and choroid plexus. The brain mouse CD4 protein is indistinguishable from the thymus protein. In addition, we show that neuronal cells in primary cultures from human fetal CNS are immunoreactive to human CD4 mAbs.

Angiography and Cisternography in Acute Meningitis due toHemophilus influenzae

Two cases of Hemophilus injluenzae meningitis in infants are presented. In both cases, narrowing of vessels at the base of the brain and mUltiple small vessel occlusions of the middle and callosal systems were demonstrated at angiography, and acute communicating hydrocephalus was demonstrated by cisternography. Cisternography is a safe diagnostic technique that will demonstrate bulk movement of cerebrospinal fluid and changes associated with acute meningitis, thereby aiding in the selection of patients who may benefit from diversionary shunts.