Subcortical Small Vessel Disease Research Articles

Baseline levels of soluble amyloid precursor proteins predict conversion to subcortical small-vessel disease

Baseline levels of soluble amyloid precursor proteins predict conversion to subcortical small-vessel disease

Potential of brain age in identifying early cognitive impairment in subcortical small-vessel disease patients.

BackgroundReliable and individualized biomarkers are crucial for identifying early cognitive impairment in subcortical small-vessel disease (SSVD) patients. Personalized brain age prediction can effectively reflect cognitive impairment. Thus, the present study aimed to investigate the association of brain age with cognitive function in SSVD patients and assess the potential value of brain age in clinical assessment of SSVD.Materials and methodsA prediction model for brain age using the relevance vector regression algorithm was developed using 35 healthy controls. Subsequently, the prediction model was tested using 51 SSVD patients [24 subjective cognitive impairment (SCI) patients and 27 mild cognitive impairment (MCI) patients] to identify brain age-related imaging features. A support vector machine (SVM)-based classification model was constructed to differentiate MCI from SCI patients. The neurobiological basis of brain age-related imaging features was also investigated based on cognitive assessments and oxidative stress biomarkers.ResultsThe gray matter volume (GMV) imaging features accurately predicted brain age in individual patients with SSVD (R2 = 0.535, p < 0.001). The GMV features were primarily distributed across the subcortical system (e.g., thalamus) and dorsal attention network. SSVD patients with age acceleration showed significantly poorer Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) scores. The classification model based on GMV features could accurately distinguish MCI patients from SCI patients (area under the curve = 0.883). The classification outputs of the classification model exhibited significant associations with MoCA scores, Trail Making Tests A and B scores, Stroop Color and Word Test C scores, information processing speed total scores, and plasma levels of total antioxidant capacity in SSVD patients.ConclusionBrain age can be accurately quantified using GMV imaging data and shows potential clinical value for identifying early cognitive impairment in SSVD patients.

Shared CSF Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus and Subcortical Small Vessel Disease.

IntroductionIn this study, we examine similarities and differences between 52 patients with idiopathic normal pressure hydrocephalus (iNPH) and 17 patients with subcortical small vessel disease (SSVD), in comparison to 28 healthy controls (HCs) by a panel of cerebrospinal fluid (CSF) biomarkers.MethodsWe analyzed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ isoforms −38, −40, and −42, neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), matrix metalloproteinases (MMP −1, −2, −3, −9, and −10), and tissue inhibitors of metalloproteinase 1 (TIMP1). Radiological signs of white matter damage were scored using the age-related white matter changes (ARWMC) scale.ResultsAll amyloid fragments were reduced in iNPH and SSVD (p < 0.05), although more in iNPH than in SSVD in comparison to HC. iNPH and SSVD showed comparable elevations of NFL, MBP, and GFAP (p < 0.05). MMPs were similar in all three groups except for MMP-10, which was increased in iNPH and SSVD. Patients with iNPH had larger ventricles and fewer WMCs than patients with SSVD.ConclusionThe results indicate that patients with iNPH and SSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response. The reduction in all APP-derived proteins characterizing iNPH patients is also present, indicating that SSVD encompasses similar pathophysiological phenomena as iNPH.

Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease.

IntroductionSubcortical small‐vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease‐specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers.MethodsWe included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid‐β (Aβ)x‐38, Aβx‐40, Aβx‐42, as well as soluble amyloid precursor protein (sAPP)‐α and sAPP‐β.ResultssAPP‐β was lower in SSVD patients than in AD patients and controls. Receiver‐operating characteristic (ROC) analyses showed that sAPP‐β moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses.DiscussionSSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood‐brain barrier (BBB) dysfunction and sAPP‐β could be additional tools to diagnose SSVD.Highlights Patients with subcortical small‐vessel disease (SSVD) exhibited reduced levels of sAPP‐β and disturbances of the blood‐brain barrier (BBB).This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD.Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.

Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in the Era of Disease-Modifying Treatments.

Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction in CSF β-amyloid (marker of amyloid plaque burden), although compatible with Alzheimer’s pathological change, may also be observed in other dementing disorders, including vascular cognitive disorders due to subcortical small-vessel disease, dementia with Lewy bodies and normal-pressure hydrocephalus. Thus, for the diagnosis of AD, an abnormal result of CSF β-amyloid may not be sufficient, and an increase in phospho-tau (marker of tangle pathology) is also required in order to confirm AD diagnosis in patients with a typical amnestic presentation and reveal underlying AD in patients with atypical or mixed and diagnostically confusing clinical presentations.

Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, before the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. We aimed to examine the biological cascade of microstructural and macrostructural white matter (WM) abnormalities underlying cognitive deficits in CADASIL. Methods: We examined 20 nondemented CADASIL mutation carriers and 23 noncarriers who underwent neuropsychological evaluation and magnetic resonance imaging. Using probabilistic tractography of key WM tracts, we examined group differences in diffusivity measures and WM hyperintensity volume. Successive mediation models examined whether tract-specific WM abnormalities mediated subtle cognitive differences between CADASIL mutation carriers and noncarriers. Results: The largest effect size differentiating the two groups was observed for left superior longitudinal fasciculus-temporal (SLFt) diffusivity (Cohen's f = 0.49). No group differences were observed with a global diffusion measure. These specific microstructural differences in the SLFt were associated with higher WM hyperintensities burden, and subtle executive deficits in CADASIL mutation carriers. Discussion: Worse diffusivity in the left SLFt is related to greater severity of small vessel disease and worse executive functioning in the asymptomatic stage of the disease. Worse diffusivity of the left SLFt may potentially hold promise as an indicator of disease progression. Impact statement Diffusion tensor imaging outperforms conventional imaging of subcortical small vessel disease as a potential marker of future disease progression. Here we identified the left superior longitudinal temporal fasciculus as a critical white matter fiber bundle, of which worse diffusivity can link presence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy mutations to greater severity of small vessel disease and worse executive functioning in asymptomatic stages of the disease. This tract may hold promise and deserves further examination as an early indicator of disease progression.

Abstract WP496: Optogenetic Neuronal Stimulation Promotes Myelination After Subcortical Ischemic Vascular Dementia

Introduction: Subcortical ischemic small vessel disease (SIVD) causing hypoxic-ischemic white matter lesions is one of the major subtypes of Vascular dementia. White matter damage is associated with short-term working memory deficits in which medial prefrontal cortex (mPFC) plays a central role. Recent studies have reported that active neurons may produce white matter changes and enhance connectivity. However, little is known about how white matter damage impairs short-term working memory and whether neuronal activity promotes white matter restore in SIVD. In the present study, we used optogenetics in bilateral common carotid artery stenosis (BCAS) model mice to find the damaged circuit and explore whether neuronal activity could ameliorate white matter damage. Methods: Fiber photometry system monitoring in vivo calcium (Ca 2+ ) transients was performed to explore the damaged circuit of BCAS model mice. The damaged circuit were labelled using AAV expressing channel-rhodopsin 2 (CHR2). Optogenetics were used to selectively activate neurons expressing CHR2. The thymidine analog 5-ethynyl-2 ’ -deoxyuridine (EDU) was administered at the time of optogenetic stimulation to mark dividing cells and immunofluorescence was performed to identify the proliferating cell types. Transmission electron microscope (TEM) was used to evaluate myelin thickness. Y-mazes were performed to evaluated short-term working memory. Results and Conclusions: The structure and function of glutamatergic neurons in the circuit from mPFC to corpus callosum (CC) were damaged in BCAS model mice. And optogenetics stimulation of mPFC projecting glutamatergic neurons resulted in proliferation of oligodendrocyte in CC. Besides, an increase of myelin thickness and improved short-term working memory were found after three weeks of optogenetics stimulation. These results suggest that SIVD affected short-term working memory through damaging neuron projections from mPFC to CC, and optogenetic neuronal activity could regulate myelination and restore white matter damage.

Brain White Matter: A Substrate for Resilience and a Substance for Subcortical Small Vessel Disease.

Age-related brain white matter disease is a form of small vessel disease (SVD) that may be associated with lacunar and other small subcortical infarcts, cerebral microbleeds, and perivascular spaces. This common form of cerebrovascular disease may manifest clinically as cognitive impairment of varying degrees and difficulty with mobility. Whereas some persons show cognitive decline and mobility failure when there are brain white matter hyperintensities (WMH) and acute stroke, others recover, and not everyone with brain white matter disease is disabled. Thus, repair or compensation of brain white matter may be possible, and furthermore, certain vascular risks, such as raised blood pressure, are targets for prevention of white matter disease or are administered to reduce the burden of such disease. Vascular risk modification may be useful, but alone may not be sufficient to prevent white matter disease progression. In this chapter, we specifically focus on WMH of vascular origin and explore white matter development, plasticity, and enduring processes of myelination across the health span in the context of experimental and human data, and compare and contrast resilient brain white matter propensity to a diseased white matter state. We conclude with thoughts on novel ways one might study white matter resilience, and predict future healthy cognitive and functional outcomes.

Hereditary forms of subcortical small vessel disease. The need for registries

Hereditary forms of subcortical small vessel disease. The need for registries

Relationships among clinic, home, and ambulatory blood pressures with small vessel disease of the brain and functional status in older people with hypertension

Subcortical small vessel disease, represented as white matter hyperintensity (WMH) on magnetic resonance images (MRI) is associated with functional decline in older people with hypertension. We evaluated the relationships of clinic and out-of-office blood pressures (BP) with WMH and functional status in older persons. Using cross-sectional data from 199 older study participants enrolled in the INFINITY trial, we analyzed the clinic, 24-hour ambulatory, and home BPs and their relationships with WMH burden and mobility and cognitive outcomes. Volume of WMH was associated with clinic and 24-hour ambulatory systolic BP but not home systolic BP. The mobility measure, supine-to-sit time, had a significant association with 24-hour systolic BP and pulse pressure but not with diastolic BP or values obtained by home BP. Cognitive measures of processing speed (Trails Making Test Part A and the Stroop Word Test) were significantly associated with 24-hour systolic BP, but not clinic and home BPs. These data demonstrate that ambulatory BP measurements in older people are more strongly associated with WMH and certain measures of functional status compared to home BP measurements. Hence, home BP may not be a useful substitute for ambulatory BP for assessing subcortical small vessel disease and its consequences. Further longitudinal analyses comparing clinic and various types of out-of-office BP measures with small vessel brain disease are needed. Clinicaltrials.gov identifier: NCT01650402.

Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease.

Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer’s disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.

Peripheral lipid oxidative stress markers are related to vascular risk factors and subcortical small vessel disease

Subcortical white matter hyperintensities (WMH), presumed to indicate small vessel ischemic vascular disease, are found commonly in elderly individuals with and without Alzheimer's disease (AD). Oxidative stress may instigate or accelerate the development of vascular disease, and oxidative stress markers are elevated in AD. Here, we assess independent relationships between three serum lipid peroxidation markers (lipid hydroperoxides [LPH], 8-isoprostane, and 4-hydroxynonenal) and the presence of extensive subcortical WMH and/or AD. Patients were recruited from memory and stroke prevention clinics into four groups: minimal WMH, extensive WMH, AD with minimal WMH, and AD with extensive WMH. Extensive WMH, but not AD, was associated with higher serum concentrations of 8-isoprostane and LPH. Peripheral LPH concentrations mediated the effect of hypertension on deep, but not periventricular, WMH volumes. 4-hydroxynonenal was associated with hyperlipidemia and cerebral microbleeds, but not with extensive WMH or AD. We conclude that lipid peroxidation mediates hypertensive injury to the deep subcortical white matter and that peripheral blood lipid peroxidation markers indicate subcortical small vessel disease regardless of an AD diagnosis.

Pericyte-derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion.

Subcortical small vessel disease (SVD) is characterized by white matter damage resulting from arteriolosclerosis and chronic hypoperfusion. Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). However, very little is known about the role of the largest group in the TGFB superfamily – the bone morphogenetic proteins (BMPs) – in SVD pathogenesis. The aim of this study was to characterize signaling abnormalities of BMPs in sporadic SVD. We examined immunostaining of TGFB1 and BMPs (BMP2/BMP4/BMP6/BMP7/BMP9) in a total of 19 post‐mortem human brain samples as follows: 7 SVD patients (4 males, 76–90 years old); 6 Alzheimer's disease (AD) patients (2 males, 67–93 years old) and 6 age‐matched disease controls (3 males, 68–78 years old). We subsequently investigated the effects of oxygen–glucose deprivation and BMP4 addition on cultured cells. Furthermore, adult mice were subjected to chronic cerebral hypoperfusion using bilateral common carotid artery stenosis, followed by continuous intracerebroventricular infusion of the BMP antagonist, noggin. In the SVD cases, BMP4 was highly expressed in white matter pericytes. Oxygen–glucose deprivation induced BMP4 expression in cultured pericytes in vitro. Recombinant BMP4 increased the number of cultured endothelial cells and pericytes and converted oligodendrocyte precursor cells into astrocytes. Chronic cerebral hypoperfusion in vivo also upregulated BMP4 with concomitant white matter astrogliogenesis and reduced oligodendrocyte lineage cells, both of which were suppressed by intracerebroventricular noggin infusion. Our findings suggest ischemic white matter damage evolves in parallel with BMP4 upregulation in pericytes. BMP4 promotes angiogenesis, but induces astrogliogenesis at the expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage. This may explain white matter vulnerability to chronic hypoperfusion. The regulation of BMP4 signaling is a potential therapeutic strategy for treating SVD.

Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report

BackgroundVascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data.MethodThe group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized.ResultsThis review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer’s disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood–brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau.ConclusionsCombining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

Location of Cerebral Microbleeds May Predict Subsequent Stroke after Transient Ischemic Attack

Location of Cerebral Microbleeds May Predict Subsequent Stroke after Transient Ischemic Attack

Cerebral amyloid angiopathy, subcortical white matter disease and dementia: literature review and study in OPTIMA.

Cerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEε4 carriers and a significant negative relationship in ApoEε2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain.

Cerebral Subcortical Small Vessel Disease in Subjects With Pathologically Confirmed Alzheimer Disease

The understanding of how cerebrovascular disease (CVD) contributes to dementia is hampered by a lack of agreed and validated pathologic methods to accord weight to the contribution of different aspects of CVD to dementia. A previous study from the Oxford Project to Investigate Memory and Ageing (OPTIMA) validated a scheme for assessing the contribution of subcortical small vessel disease (SVD) toward dementia in the elderly by showing a significant inverse relationship between the severity of SVD and cognition in subjects without any other dementia pathology using this method. In the present paper, the method has been used to assess severity of SVD in 161 cases of neuropathologically confirmed Alzheimer disease. The results showed there was no relationship between the SVD score and cognitive scores acquired in the last 2 years of life. SVD scores were significantly related to age (P<0.0017) and were slightly but significantly higher in females than males (P<0.049). SVD scores were not related to blood pressure at entry to OPTIMA and were significantly lower when compared with the cohort of OPTIMA cases with only CVD (mean 5.06 ± 1.85 vs. 5.9 ± 2.67; P<0.0065). We conclude that when Alzheimer disease pathology is present in elderly subjects, it overwhelms the modest contribution that SVD makes to cognitive impairment.

Fixing Hearts and Protecting Minds

Ischemic heart disease is a significant cause of mortality and morbidity in Western populations. Consistent with this, coronary artery bypass graft (CABG) surgery remains one of the most frequently performed major surgeries. Improved survival rates mean that our research focus now extends beyond surgical technique to include quality of postoperative outcome. Postoperative cognitive dysfunction (POCD) has emerged as one of the most challenging and hotly debated issues, with increasing impetus to answer the unresolved question: does fixing the heart come at a cost to the brain? CABG surgery is associated with neurological events including stroke in 1.6%1 and delirium in 5.8%2 of patients. Beyond these severe and marked alterations to neurological function, there has been a widely held belief that CABG surgery is associated with POCD, which may presage a decline toward dementia. Research has been influenced by the 1995 Consensus Statement3 into the study of POCD in patients undergoing CABG surgery. Although the methods of investigation set forth by the Consensus Statement achieved widespread acknowledgment, its specific recommendations have not always been followed.4 Despite significant methodological issues, it seems that the balance of interpretation has historically been in favor of CABG surgery as a cause of significant POCD. More recently, however, a review of a series of publications from a well-controlled longitudinal cohort study conducted at Johns Hopkins5 and a meta-analysis6 suggested that cognition is in fact stable or may even show some improvement after CABG surgery in the majority of patients, at least within the first year (Figures 1 and 2). There is little doubt that POCD affects some patients in the short term, but the pathophysiological mechanisms underlying this and the influence on longer-term cognitive function remain uncertain. For research to progress, we require a paradigmatic shift in our focus from …

Is encroachment of the carotid termination into the substantia innominata associated with its atrophy and cognition in Alzheimer's disease?

The internal carotid artery termination (CAT) ends in a T-shaped bifurcation just below the substantia innominata (SI), which contains cognitively strategic cholinergic neurons and undergoes atrophy in Alzheimer's disease (AD). This study investigated whether an elongated CAT with possible resulting encroachment into the SI would correlate with SI atrophy and with cognitive dysfunction in AD. We rated the degree of CAT encroachment upon the SI and measured SI volume on magnetic resonance imaging in 30 AD patients, 30 AD patients with subcortical small vessel disease, and 30 age-matched controls. CAT encroachment significantly correlated with SI volume after adjusting for age within the overall group and the groups with dementia. AD patients with higher CAT encroachment scores had lower SI volumes and lower attention, memory, and executive test scores. These data suggest that CAT encroachment may mechanically injure the SI, exacerbating cholinergic damage and contributing to cognitive impairment. This process may represent a possible previously underappreciated mechanism for interaction between large-vessel cerebrovascular disease and AD.

Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort

Subcortical small vessel disease (SVD) is known to contribute to vascular cognitive impairment and vascular dementia, but understanding about the extent of its influence is limited because there is a lack of consensus about how this pathology should be assessed. In this study we have made use of a simple, novel, image-matching scoring system to assess the extent of SVD in a group of 70 cases from the prospectively assessed Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. These cases were found at autopsy to have cerebrovascular disease and no other pathology except Braak stage 4 or less tau pathology, and insufficient amyloid plaque pathology to meet Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for the diagnosis of Alzheimer's disease. Pathology scores for SVD were correlated with cognitive scores [Mini-Mental State Examination (MMSE) and cognitive section of the Cambridge Examination for Mental Disorders in the Elderly (CAMDEX) (CAMCOG)] at the last clinical assessment before death. The severity of SVD pathology was inversely related to cognitive score before death (P < 0.008 for MMSE and P < 0.024 for CAMCOG). Thirty-one per cent and 33% of cases were rated as demented by MMSE or CAMCOG respectively. The degree of dementia was generally mild. Age did not influence severity of SVD. An image-based scoring system for SVD in a group of 70 elderly subjects enabled the severity of SVD pathology to be assessed with results that showed a significant correlation between SVD pathology severity and cognitive impairment.