Subcortical Vascular Dementia Research Articles

Computer-aided evaluation method of white matter hyperintensities related to subcortical vascular dementia based on magnetic resonance imaging

It has been reported that the severity of subcortical vascular dementia (VaD) correlated with an area ratio of white matter hyperintensity (WMH) regions to the brain parenchyma (WMH area ratio). The purpose of this study was to develop a computer-aided evaluation method of WMH regions for diagnosis of subcortical VaD based on magnetic resonance (MR) images. A brain parenchymal region was segmented based on the histogram analysis of a T1-weigthed image. The WMH regions were segmented on the subtraction image between a T1-weighted and fluid-attenuated inversion-recovery (FLAIR) images using two segmentation methods, i.e., a region-growing technique and a level-set method, which were automatically and adaptively selected on each WMH region based on its image features by using a support vector machine. We applied the proposed method to 33 slices of the three types of MR images with 245 lesions, which were acquired from 10 patients (age range: 64–90 years, mean: 78) with a diagnosis of VaD on a 1.5-T MR imaging scanner. The average similarity index between regions determined by a manual method and the proposed method was 93.5 ± 2.0% for brain parenchymal regions and 78.2 ± 11.0% for WMH regions. The WMH area ratio obtained by the proposed method correlated with that determined by two neuroradiologists with a correlation coefficient of 0.992. The results presented in this study suggest that the proposed method could assist neuroradiologists in the evaluation of WMH regions related to the subcortical VaD.

Should CSF Biomarkers Support a Routine Analysis for Early Diagnosis of Alzheimer's Disease?

In view of the availability of drugs that may slow or even halt the progression of Alzheimer's disease (AD), the possibility to routinely discriminate individuals carrying incipient AD is utmost important. The CSF biomarkers beta-amyloid and tau are increasingly used in several countries in Europe for their high diagnostic accuracy in detecting early or even prodromal AD. Up till now, thousands of subjects have been studied either in research or routine setting, giving sensitivity and specificity values invariably above 80%. Despite these clinically relevant results, CSF analysis is still considered only a supportive exam in AD diagnostic work-up. We think there is a great need to improve the medical awareness about the importance to perform lumbar puncture as a routine procedure in the diagnostic assessment of cognitive deterioration. In line with this belief, the first paper of this special issue addresses the usefulness of cerebrospinal fluid analysis for diagnostic definition of cognitive deficits, and the second one further focuses on the ethical issues related to early diagnosis of Alzheimer's disease. As a corollary, the third paper reports some reflections about the actual need in clinical practice of guidelines for diagnosis and management of incipient AD. The fourth paper illustrates what is known about CSF biomarkers for diagnosing AD, and the fifth paper gives a different perspective according to the Canadian guidelines for dementia diagnosis. An up-dated and comprehensive view of crucial issues emerged from large multicentre studies (which have clearly highlighted the inter-centre variability of these determinations) on CSF biomarkers for AD diagnosis is reported in the sixth paper. Accordingly, the seventh paper nicely describes the efforts done for standardization of assay procedures and the eighth paper further goes into details about the many factors inducing variation of amyloid beta concentration, which heavily hampers, at present, a good inter-centre reliability. Besides the state of art about what is known on classical CSF biomarkers for early diagnosis in routine clinical practice, there also are impressive international research initiatives aimed at identifying new biomarkers for neurodegenerative diseases. This issue is thoroughly addressed by the ninth paper, which gives an overview of the EU-funded consortium cNEUPRO. The issue of the role of CSF biomarkers in non-AD dementias is also partly addressed in this special issue. An overview on CSF biomarkers in dementia with Lewy bodies (DLB) is given in the tenth paper, and in the eleventh paper the discriminative power of classical and putative CSF biomarkers for differentiating AD, DLB, and Parkinson's disease with dementia (PDD) is accurately described; finally, the usefulness of classical CSF biomarkers in characterizing CADASIL, a genetic model of subcortical vascular dementia, is also reported. Lucilla Parnetti Jens Wiltfang Kaj Blennow

Microglia transplantation attenuates white matter injury in rat chronic ischemia model via matrix metalloproteinase-2 inhibition

Chronic cerebral ischemia is thought to induce white matter lesions (WMLs), which contribute to subcortical vascular dementia. Although glial activation and protease upregulation are believed to modify WML pathology, effective therapy remains elusive. Here, we compare the efficacy of microglial cell transplantation and mesenchymal stem cell (MSC) transplantation in protecting against WML development in a chronic cerebral hypoperfusion rat model. A microglial cell line (HMO6), MSC cell line (B10) or vehicle (phosphate-buffered saline; PBS) was intravenously injected, and the appearance and severity of WMLs were evaluated. Transplanted HMO6 and B10 cells migrated to sites of WMLs, including the corpus callosum (CC) and caudoputamen (CP), reduced the severity of WMLs, and inhibited the accumulation and activation of microglia and astrocytes. Transplantation of both cell types reduced the level of matrix metalloproteinase (MMP)-2 mRNA in microglia of the CC. MMP-2 protein level and activity were also both greatly reduced in the same region. Our results indicate that transplantation of either microglial cells or mesenchymal stem cells could inhibit chronic cerebral ischemia-induced WML formation by decreasing MMP-2 expression in microglia and decreasing MMP-2 activity in the CC region.

Cortical Thinning in Vascular Mild Cognitive Impairment and Vascular Dementia of Subcortical Type

Amnestic mild cognitive impairment (MCI) is known to be a preclinical stage of Alzheimer's disease (AD). Similarly, MCI associated with small-vessel disease (svMCI), might be a forme froste of subcortical vascular dementia (SVaD). Patterns of cortical thinning in addition to the ischemia rating on MRI may further elucidate the clinical characteristics and pathogenesis of SVaD and svMCI. We tried to determine if svMCI differs from SVaD in the distribution of cortical atrophy, which may help understand the hierarchy between svMCI and SVaD and possibly also how svMCI evolves into SVaD. Twenty patients with SVaD, 34 patients with svMCI, 115 patients with AD, and 96 individuals with normal-cognition (NC) were imaged with magnetic resonance imaging (MRI) including 3-dimensional volumetric images for cortical thickness analysis across the entire brain. Compared to NC, svMCI patients showed cortical thinning in inferior frontal and orbitofrontal gyri, anterior cingulate, insula, superior temporal gyrus, and lingual gyrus, while cortical thinning in SVaD patients involved all these areas plus dorsolateral prefrontal and temporal cortices. Our findings suggest the presence of hierarchy between svMCI and SVaD, and that the cognitive decline from svMCI to SVaD is associated with lesions in dorsolateral prefrontal and temporal cortices.

Ongoing Search for Diagnostic Biomarkers in Idiopathic Normal Pressure Hydrocephalus

Idiopathic normal pressure hydrocephalus is a syndrome, which typically has a clinical presentation of gait/balance disturbance, often accompanied by cognitive decline and/or urinary incontinence. Its diagnosis is based on relevant history and clinical examination, appropriate imaging findings and physiological testing. The clinical picture of idiopathic normal pressure hydrocephalus may occasionally be difficult to distinguish from that of Alzheimer's dementia, subcortical ischemic vascular dementia and Parkinson's disease. The aim of this article is to systematically review the literature from the last 29 years in order to identify cerebrospinal fluid (CSF) or imaging biomarkers that may aid in the diagnosis of the syndrome. The authors concluded that no CSF or imaging biomarker is currently fulfilling the criteria required to aid in the diagnosis of the condition. However, a few studies have revealed promising CSF and imaging markers that need to be verified by independent groups. The reasons that the progress in this field has been slow so far is also commented on, as well as steps required to apply the current evidence in the design of future studies within the field.

Cerebral blood flow in ischemic vascular dementia and Alzheimer's disease, measured by arterial spin-labeling magnetic resonance imaging

Background Our objectives were to compare the effects of subcortical ischemic vascular dementia (SIVD) and Alzheimer's disease (AD) on cerebral blood flow (CBF), and then to analyze the relationship between CBF and subcortical vascular disease, measured as volume of white-matter lesions (WMLs). Methods Eight mildly demented patients with SIVD (mean ± SD; aged 77 ± 8 years; Mini-Mental State Examination score 26 ± 3 years) and 14 patients with AD were compared with 18 cognitively normal elderly subjects. All subjects had CBF measured using arterial spin-labeling magnetic resonance imaging, and brain volumes were assessed using structural magnetic resonance imaging. Results AD and SIVD showed marked CBF reductions in the frontal ( P = 0.001) and parietal ( P = 0.001) cortices. In SIVD, increased subcortical WMLs were associated with reduced CBF in the frontal cortex ( P = 0.04), in addition to cortical atrophy (frontal, P = 0.05; parietal, P = 0.03). Conclusions Subcortical vascular disease is associated with reduced CBF in the cortex, irrespective of brain atrophy.

Subcortical Vascular Dementia Biomarker Pattern in Mild Cognitive Impairment

Background: Mild cognitive impairment (MCI) is an etiologically unclear disorder. Cerebrospinal fluid (CSF) biomarkers are potentially useful for the differentiation between various MCI etiologies. Aim: The aim of the study was to assess whether baseline CSF hyperphosphorylated tau (P-tau), total tau (T-tau), amyloid β 1–42 (Aβ₄₂) and neurofilament light (NF-L) in patients with MCI could predict subcortical vascular dementia (SVD) and Alzheimer’s disease (AD) at follow-up. Methods: Biomarker levels were assessed by Luminex xMAP technology and ELISA. Results: Increased baseline concentrations of NF-L significantly separated MCI-SVD from stable MCI. The MCI-SVD patients were inseparable from stable MCI but separable from patients developing AD (MCI-AD) on the basis of Aβ_42, T-tau and P-tau₁₈₁ levels. Conclusion: A combination of the biomarkers Aβ₄₂, T-tau, P-tau₁₈₁ and NF-L has the potential to improve the clinical separation of MCI-SVD patients from stable MCI and MCI-AD patients.

Choline Acetyltransferase Activity in Vascular Dementia and Stroke

Background/Aim: Alterations in cholinergic activity have not been systematically studied in types of cerebrovascular disease. We examined cholinergic function at postmortem, focussing on stroke and vascular dementia (VaD). Methods: Post-mortem brain tissue was studied from 61 patients with stroke or VaD (13 infarct dementia; 8 stroke/no dementia; 11 sub-cortical ischaemic VaD, SIVD; 29 VaD and concurrent Alzheimer’s disease, AD), 12 patients with AD and 23 controls. Choline acetyltransferase (ChAT) was measured in Brodmann areas (BA) 9 and 20/21. Results: There were significant reductions in ChAT activity in patients with VaD and concurrent AD compared to age-matched controls (BA9: t = 2.7, p = 0.009; BA20/21: t = 4.67, p = 0.000). In patients with infarct dementia, there was a significant 27% increase in ChAT activity in BA9 (t = 2.1, p = 0.047), but not in BA20/21 (t = 1.67, p = 0.106), compared to the age-matched control group. There was no relationship between ChAT activity and cognition in the VaD patients. Conclusions: Loss of cholinergic function is only evident in VaD patients with concurrent AD. A novel increase in cholinergic activity was identified in patients with infarct dementia, which may create important new treatment opportunities.

The role of callosal volume as a MRI marker in subcortical ischaemic vascular dementia: a study in CADASIL

Background and purpose: Several studies demonstrate cortical neurodegeneration as an important factor of corpus callosum (CC) atrophy in Alzheimer's disease (AD) but little is known about the factors underlying CC volume loss in subcortical ischemic vascular dementia (SIVD). The aim of this study was to identify these factors and to determine the impact of CC volume on physical and cognitive impairment in CADASIL as a model of pure SIVD.

Impact of educational level and lesion volume on cognitive performance in subcortical ischaemic vascular dementia: a study in CADASIL

Impact of educational level and lesion volume on cognitive performance in subcortical ischaemic vascular dementia: a study in CADASIL

Depression as a confounding factor in subcortical ischaemic vascular dementia: results from a cross-sectional study in CADASIL

Depression as a confounding factor in subcortical ischaemic vascular dementia: results from a cross-sectional study in CADASIL

Mild cognitive impairment in stroke patients with ischemic cerebral small-vessel disease: a forerunner of vascular dementia?

Ischemic cerebral small-vessel disease accounts for a third of acute cerebral ischemic events and contributes to the development of cognitive decline and dementia. Cerebral small-vessel disease can be visualized on MRI studies as lacunar infarcts, white matter lesions and cerebral microbleeds. In general, the short-term prognosis of ischemic cerebral small-vessel disease compared with other stroke subtypes is more favorable, with almost negligible early mortality, absence of neuropsychological impairment and excellent neurological recovery. However, it has been shown recently that the proportion of dementia caused by small-vessel disease ranges from 36 to 67%. On the other hand, patients with a first-ever lacunar infarction present with cognitive impairment (mainly executive dysfunction) in more than half of cases and more than 55% of patients fulfil the criteria of mild cognitive impairment of the vascular type. Moreover, patients with small-vessel disease have an increase in the mid- and long-term risk of death, stroke recurrence and dementia. Neuropsychological abnormalities in small-vessel disease occurred more frequently than previously recognized. Ischemic cerebral small-vessel disease should be regarded as a potentially severe condition prodrome of subcortical vascular dementia rather than a relatively benign disorder.

Midbrain atrophy in subcortical ischemic vascular dementia

Magnetic resonance imaging (MRI) has revealed age-related changes in midbrain volume in normal subjects. Atrophy of the midbrain in patients with progressive supranuclear palsy (PSP) has been demonstrated using conventional brain MRI, and it was recently reported that some patients with vascular dementia also have midbrain atrophy. The aim of the present study was to investigate if the patients with subcortical ischemic vascular dementia (SIVD) have atrophic changes in the midbrain. MRIs of 23 SIVD patients, 18 probable PSP patients, and 96 controls were retrospectively analyzed. Differences in the distances between midbrain structures were compared across the patient groups and controls. We measured the anteroposterior diameter (AP), and the distance between the interpeduncular fossa and the aqueduct (IF–AQ), the aqueduct and posterior margin of the superior colliculi (AQ–SC), and the peduncular prominence and the interpeduncular fossa (PP–IF) of the midbrain. The AP diameter and IF–AQ were negatively correlated with age in normal controls (r = -0.21, p < 0.005 for AP; r = -0.14, p < 0.0001 for IF–AQ). In SIVD patients, the AP diameter and IF–AQ were both significantly smaller than in controls (p < 0.001). Changes in the midbrain found for SIVD patients were similar to those seen in PSP patients. Our results suggest that the midbrain decreases in size with normal aging, especially around the tegmental region. This change is more pronounced in patients with SIVD and in patients with PSP. Prospective functional studies are needed to ascertain the clinical relevance of midbrain atrophy in SIVD.

Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia

Cortical microinfarcts are reported in Alzheimer's disease, but not in subcortical vascular dementia; the disease specificity of cortical microinfarcts therefore remains unclear. The distribution of cortical microinfarcts in Alzheimer's disease (n = 8) and subcortical vascular dementia (n = 6) was analyzed. Cortical microinfarcts were frequently detected in Alzheimer's disease, whereas they were rarely observed in subcortical vascular dementia. In Alzheimer's disease, cortical microinfarcts were present predominantly in the occipital lobe, the area of predilection for amyloid angiopathy, and also in the vascular borderzone. Cortical microinfarcts were invariably located very close to amyloid beta-deposited vessels with intercellular adhesion molecule-1 expression. These results indicate that cortical microinfarcts are caused by the pathomechanism related to Alzheimer's disease, most likely to amyloid angiopathy.

MRI surrogates for vascular dementia trials

There is neuropathological evidence that confluent MRI white matter lesions, lacunes and cerebral microbleeds in the elderly reflect ischemic brain damage due to microangiopathy. It has been suggested that MRI may be used to monitor treatment trials on subcortical vascular dementia. A prerequisite for the use of any small vessel disease-related brain abnormality as surrogate marker is longitudinal change allowing detection of treatment effects within a reasonable time period and correlation with cognitive decline.

The value of quantitative EEG in differential diagnosis of Alzheimer's disease and subcortical vascular dementia

The value of quantitative EEG in differential diagnosis of Alzheimer's disease and subcortical vascular dementia

Differences of TC-99M HMPAO spect imaging in the early stage of subcortical vascular dementia compared with Alzheimer's disease

Differences of TC-99M HMPAO spect imaging in the early stage of subcortical vascular dementia compared with Alzheimer's disease

The demographic and clinical characteristics of subcortical vascular dementia: An analysis of 125 patients

The demographic and clinical characteristics of subcortical vascular dementia: An analysis of 125 patients

Neuropsychological Assessment

See related article, pages 2969–2972. Research on vascular factors in dementia and vascular cognitive impairment has gone through some major developments the past decades. Until 1993, the term multi-infarct dementia was used to distinguish dementia caused by one or more infarctions from Alzheimer disease.1 Research on cognitive functioning aimed at obvious cognitive impairment after a stroke, that was generally quantified with dementia screening methods. In 1993, the first set of diagnostic criteria of vascular dementia was introduced, which led to an expansion in the number of publications on the subject.2 In these criteria, several vascular mechanisms, pathology, and circumscript lesions or localizations were defined that may lead to vascular dementia. As the field evolved, new insights arose, accompanied with the acknowledgment that not all cognitive decline fulfilled the criteria of dementia. The concept of vascular cognitive impairment was formulated as an umbrella term that encompasses all cognitive deficits associated with vascular factors or mechanisms.3 Meanwhile, several attempts have been made to further differentiate specific patterns of cognitive impairment related to distinct vascular pathology. Efforts have been made with regard to poststroke dementia4,5 and subcortical vascular ischemic dementia.6 Still, the number of publications on cognitive deficits related to vascular factors is growing, and presently several studies aim to objectify even more subtle cognitive changes. In this issue of Stroke , …

Subcortical Vascular versus Amnestic Mild Cognitive Impairment: Comparison of Cerebral Glucose Metabolism

Most studies on mild cognitive impairment (MCI) have been focused on amnestic MCI (aMCI) that is the preclinical stage of Alzheimer's disease (AD). In contrast, only a few studies have involved patients in the preclinical stages of subcortical vascular dementia (subcortical vascular MCI, svMCI). We tried to compare the overall glucose metabolism in patients with svMCI with that of patients with aMCI. We compared the regional metabolic patterns shown on 18 F-FDG (fluro deoxy glucose) positron emission tomography (PET) images from 18 patients with svMCI with those from 25 aMCI patients matched for age, sex, education, and mini-mental state examination (MMSE) score and with those from 35 healthy subjects using a voxel-wise analysis. SPM 2 was used for statistical analysis. Relative to normal controls, the hypometabolic regions in the aMCI patients were in the bilateral parahippocampal, bilateral posterior cingulate, left superior temporal gyri, left inferior parietal lobule, and right inferior frontal gyrus while those in the svMCI patients were located in the thalamus, insula, superior temporal gyrus, anterior cingulate gyrus, cingulum, right basal ganglia, cerebellum, and brainstem. A direct comparison of glucose metabolism between svMCI and aMCI showed that the glucose hypometabolism in patients with svMCI was more severe in the thalamus, brainstem, and cerebellum. Our study suggested that svMCI was distinct from aMCI in terms of neuropsychological and PET findings, which may explain their clinical manifestations.