Clinical and radiological determinants of prestroke cognitive decline in a stroke cohort

OBJECTIVES: Stroke seems to be related to dementia more often than previously assumed and vascular factors are also related to Alzheimer's disease. The pathophysiology of poststroke dementia includes ischaemic changes in the brain, a combination of degenerative and vascular changes, and changes only related to Alzheimer's disease. Some cognitive decline recognised after a stroke may be due to pre-existing cognitive decline. The aim of this study was to determine the clinical and radiological determinants of prestroke cognitive decline. METHODS: The study group comprised 337 of 486 consecutive patients aged 55 to 85 years who 3 months after ischaemic stroke completed a comprehensive neuropsychological test battery; structured medical, neurological, and mental status examination; interview of a knowledgeable informant containing structured questions on abnormality in the cognitive functions; assessment of social functions before the index stroke; and MRI. RESULTS: Frequency of prestroke cognitive decline including that of dementia was 9.2% (31/337). The patients with prestroke cognitive decline were older, more often had less than 6 years of education, and had history of previous stroke. Vascular risk factors did not differ significantly between these two groups. White matter changes (p=0.004), cortical entorhinal, hippocampal, and medial temporal atrophy (p<0.001), cortical frontal atrophy (p=0.008); and any central atrophy (p<0.01), but not the frequencies or volumes of old, silent, or all infarcts on MRI differentiated those with and without prestroke cognitive decline. The correlates of prestroke cognitive decline in logistic regression analysis were medial temporal cortical atrophy (odds ratio (OR) 7.5, 95% confidence interval (95%CI) 3.2-18.2), history of previous ischaemic stroke (OR 4.4, 95% CI 1.8-10.6), and education (OR 0.9, 95% CI 0.8-0.9). CONCLUSIONS: History of previous stroke, but not volumes or frequencies was found to correlate with prestroke cognitive decline. Other associating factors were rather those usually associated with degenerative dementia: white matter changes and cerebral atrophy; and in multiple models medial temporal cortical atrophy and education. The possible overlap between two or more underlying diseases must be remembered in diagnosis and treatment of patients with vascular cognitive impairment.     

Hippocampal volume and white matter disease in the prediction of dementia in Parkinson's disease

BackgroundLongitudinal neuroimaging studies could provide insights into pathophysiology of cognitive impairment in PD. We examined the role of hippocampal atrophy and cerebral white matter disease as risk factors for mild cognitive impairment and dementia in PD.MethodsProspective longitudinal study of patients with mild PD in a tertiary neurology center. All subjects underwent baseline MRI brain and had baseline and 6 monthly cognitive evaluations. Cognitive impairment was diagnosed based on the Movement Disorder Society Criteria. The predictive role of hippocampal volume and white matter hyperintensity at baseline on progression of cognitive impairment was studied.Results97 subjects with mean age 65.3 years, mean education of 10.3 years and mean Hoehn & Yahr of 1.9 were studied. Over 2 years, 16 subjects developed mild cognitive impairment and 8 subjects with mild cognitive impairment progressed to dementia. After adjusting for age and vascular risk factors, hippocampal volume was a significant predictor for mild cognitive impairment (OR 7.05, CI 1.5–34.1; p = 0.015) and dementia (OR 7.03, CI 2.39–25.2; p = 0.001). With Cox regression, hippocampal volume was a significant predictor for “time to cognitive impairment” (HR 7.67; CI 3.47–16.95, p < 0.001). Difference between survival curves based on volume of white matter hyperintensity in predicting “time to mild cognitive impairment” was significant (p = 0.0295).ConclusionsHippocampal volume is a major factor predicting the development of mild cognitive impairment and dementia in PD. White matter hyperintensity also contributes to the longitudinal cognitive status in PD.     

Diabetes and cognitive impairment

BACKGROUND: Diabetes is a risk factor for dementia,but the issue whether this concerns only vascular dementia or also Alzheimer's disease is debated. We compared the clinical diagnoses and abnormalities on brain MRI in patients with or without diabetes who received standardised, detailed diagnostic studies at a memory clinic, in order to establish whether one specific type of dementia or specific MRI abnormalities were more common in diabetes. PATIENTS AND METHODS: Patients who visited our memory clinic between January 2002 and June 2004 were divided into a group with (n = 42) or without diabetes (n = 389). The diagnoses were recorded, and MRI scans were rated for (sub)cortical atrophy, medial temporal lobe atrophy, infarctions, and white matter changes. RESULTS: The proportion of Alzheimer's disease (36% versus 28%; OR 1.1 (95% CI 0.5-2.2), adjusted for age and sex), vascular dementia (5% versus 2%; OR 2.4 (0.5-12.1)), and so called "cognitive impairment no dementia" (24% versus 17%; 1.3 (0.6-2.9)) was similar in patients with or without diabetes. On MRI lacunar and cortical infarctions were more common and cortical atrophy more pronounced among diabetic patients. By contrast, the severity of white matter changes was similar in the two groups. CONCLUSION: The relative frequency of different diagnoses among diabetic and non-diabetic patients attending a memory clinic was similar, indicating that diabetes does not predispose to one particular subtype of dementia. The imaging findings support the notion that the increased risk of cognitive decline and dementia in elderly subjects with diabetes is due to dual pathology, involving both cerebrovascular disease and cortical atrophy.     

Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study: the Rotterdam Scan Study

OBJECTIVE: White matter lesions are often seen on MR scans of elderly non-demented and demented people. They are attributed to degenerative changes of small vessels and are implicated in the pathogenesis of cognitive decline and dementia. There is evidence that especially periventricular white matter lesions are related to cognitive decline, whereas subcortical white matter lesions may be related to late onset depression. The frequency distribution of subcortical and periventricular white matter lesions according to age and sex reported. METHODS: A total of 1077 subjects aged between 60-90 years were randomly sampled from the general population. All subjects underwent 1.5T MR scanning; white matter lesions were rated separately for the subcortical region and the periventricular region. RESULTS: Of all subjects 8% were completely free of subcortical white matter lesions, 20% had no periventricular white matter lesions, and 5% had no white matter lesions in either of these locations. The proportion with white matter lesions increased with age, similarly for men and women. Women tended to have more subcortical white matter lesions than men (total volume 1.45 ml v 1. 29 ml; p=0.33), mainly caused by marked differences in the frontal white matter lesion volume (0.89 ml v 0.70 ml; p=0.08). Periventricular white matter lesions were also more frequent among women than men (mean grade 2.5 v 2.3; p=0.07). Also severe degrees of subcortical white matter lesions were more common in women than in men (OR 1.1; 95% confidence interval (95% CI) 0.8-1.5) and periventricular white matter lesions (OR 1.2; 95% CI 0.9-1.7), albeit that none of these findings were statistically significant. CONCLUSIONS: The prevalence and the degree of cerebral white matter lesions increased with age. Women tended to have a higher degree of white matter lesions than men. This may underlie the finding of a higher incidence of dementia in women than in men, particularly at later age.     

Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy

BACKGROUND AND PURPOSE: Cerebral microangiopathy, indicated on MRI by lacunar infarctions (LI) and deep white matter lesions (DWML), is said to lead to vascular dementia. METHODS: Fifty-seven patients with proven cerebral microangiopathy were assessed for changes in regional cerebral blood flow (rCBF) and glucose metabolism (rMRGlu) and compared with 19 age-matched controls. The findings were correlated with results of extensive neuropsychological testing, as well as with MRI findings. A special head holder ensured reproducibility of positioning during rCBF (single-photon emission CT [SPECT]), rMRGlu (positron emission tomography [PET]), and MR imaging. White matter and cortex were quantified with regions of interest defined on MRI and superimposed to corresponding PET/SPECT slices. LI and DWML were graded by number and extent. RESULTS: Even with severe DWML and multiple LI, rCBF and rMRGlu values were not reduced. ANOVAs identified brain atrophy and neuropsychological deficits as the main determinants for reduced rCBF and rMRGlu values in both cortex and white matter. Neuropsychological deficits correlated well with decreased rCBF and rMRGlu, whereas MRI patterns such as LI and DWML did not. Factor analysis revealed no correlation of LI and DWML with rCBF, rMRGlu, atrophy, and neuropsychological deficits, showing instead positive correlations between rCBF, rMRGlu, and neuropsychological performance and negative correlations of the latter 3 with brain atrophy. CONCLUSIONS: From these data, we conclude that LI and DWML are epiphenomena that may morphologically characterize cerebral microangiopathy but do not in themselves indicate cognitive impairment. Dementia or neuropsychological deficits, by contrast, are reflected exclusively by functional imaging parameters (rCBF, rMRGlu) and cerebral atrophy.     

Aortic atherosclerosis at middle age predicts cerebral white matter lesions in the elderly

BACKGROUND AND PURPOSE: MRI scans of the brains of elderly people frequently show white matter lesions. Clinically, these lesions are associated with cognitive impairment and dementia. A relation between atherosclerosis and white matter lesions was found in some small cross-sectional studies. However, atherosclerosis is a gradual process that starts early in life. We investigated the longitudinal association between aortic atherosclerosis assessed during midlife and late life and cerebral white matter lesions. METHODS: We randomly sampled subjects between 60 and 90 years old from 2 population-based follow-up studies in which subjects had their baseline examinations in 1975 to 1978 (midlife) and in 1990 to 1993 (late life). In 1995 to 1996, subjects underwent 1.5-T MRI scanning; white matter lesions were rated in the deep subcortical and periventricular regions separately. Aortic atherosclerosis was assessed on abdominal radiographs that were obtained from 276 subjects in midlife and 531 subjects in late life. RESULTS: The presence of aortic atherosclerosis during midlife was significantly associated with the presence of periventricular white matter lesions approximately 20 years later (adjusted relative risk, 2.4; 95% CI, 1.2 to 5.0); the relative risks increased linearly with the severity of aortic atherosclerosis. No association was found between midlife aortic atherosclerosis and subcortical white matter lesions (adjusted relative risk, 1.1; 95% CI, 0.5 to 2.3) or between late-life aortic atherosclerosis and white matter lesions. CONCLUSIONS: The pathogenetic process that leads to cerebral periventricular white matter lesions starts already in or before midlife. The critical period for intervention directed at prevention of white matter lesions and its cognitive consequences may be long before these lesions become clinically detectable.     

White matter lesions on magnetic resonance imaging and their relationship with vascular risk factors in memory clinic attenders

BACKGROUND: The association between white matter lesions on magnetic resonance imaging (MRI) and the presence of vascular risk factors has been investigated in different populations, and results have varied widely. However, this relationship has not been adequately addressed in memory clinic attenders who have relatively early cognitive impairment. OBJECTIVES: This study was undertaken to determine the relationship between the severity of white matter lesions and vascular risk factors in elderly subjects referred to a Memory Clinic, irrespective of their diagnoses. Patients attending the Memory Clinic had relatively early, mild cognitive impairment and differed, in this respect, from typical unselected community-based samples and from patients with established dementia. The study also investigated whether periventricular and deep white matter lesions differed in their relationship with vascular risk factors. METHODS: All patients assessed in the Memory Clinic at Leicester General Hospital between April 1998 and October 2000 who had undergone an MRI scan were included in the study. They received a comprehensive clinical and cognitive assessment, a standard dementia laboratory screen and evaluation of vascular risk factors. MRI scans were reviewed by two independent raters and semi-quantitative ratings of the severity of white matter lesions were made using standardised protocols. The relationship between cerebral white matter lesions and vascular risk factor variables was examined by multiple linear regression. RESULTS: One hundred and seventy-seven subjects were included in the study. The mean age was 69.8 and the mean MMSE score was 23.2. Of the risk factors investigated, only age and prior cerebrovascular disease were significantly associated with severe periventricular white matter lesions; age, hypertension and diabetes were significantly associated with severe deep white matter lesions. CONCLUSIONS: Periventricular and deep white matter lesions are differentially influenced by vascular risk factors.     

A voxel based morphometry study on mild cognitive impairment

BACKGROUND: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to confer an increased risk of progressing to dementia and most often Alzheimer's disease (AD). Various approaches such as imaging of the brain have been applied to predict the conversion of MCI to dementia. A number of volumetric magnetic resonance imaging (MRI) studies have detected atrophy of the medial temporal lobe in subjects with MCI, but for the other cerebral regions the results have been inconsistent. OBJECTIVE: To study the pattern of brain atrophy in MCI. METHODS: Thirty two controls and 51 individuals with MCI deriving from population based cohorts were studied by MRI using voxel based morphometry. The threshold of t maps was set at p < 0.001. RESULTS: Individuals with MCI had significant unilateral atrophy in the medial temporal lobe on the right side. Less extensive atrophy was found elsewhere-for example, in the temporal lobe, left superior parietal lobule, left anterior cingulate gyrus, and bilaterally in the thalami. CONCLUSIONS: The MRI findings in MCI resemble those seen in early AD.     

Use of hippocampal and amygdalar volumes on magnetic resonance imaging to predict dementia in cognitively intact elderly people

CONTEXT: The recent focus on the development of preventive interventions for Alzheimer disease has fueled the search for biomarkers of presymptomatic disease. Patients with Alzheimer disease and mild cognitive impairment have marked atrophy of the hippocampus and amygdala compared with healthy elderly people. Whether atrophy of these structures is also present in persons without cognitive impairment who later develop dementia is unknown. OBJECTIVE: To assess whether volumetric assessment of the hippocampus and amygdala using magnetic resonance imaging (MRI) predicts dementia in elderly people without cognitive impairment. DESIGN: Longitudinal cohort study. SETTING: A general community in the Netherlands. PARTICIPANTS: Five hundred eleven persons, aged 60 to 90 years, free of dementia at baseline were followed up during 3043 person-years (mean per person, 6.0 years). We performed volumetric assessment of the hippocampus and amygdala, obtained information about daily memory problems, and performed extensive neuropsychological testing in all study participants. MAIN OUTCOME MEASURE: Dementia, as assessed by repeated neuropsychological screening and monitoring of medical records. RESULTS: Thirty-five persons developed dementia (26 with Alzheimer disease). Hippocampal and amygdalar volumes were strongly associated with the risk of dementia; the age-, sex-, and education-adjusted hazard ratio per 1-SD decrease in volume was 3.0 (95% confidence interval, 2.0-4.6) for the hippocampus and 2.1 (95% confidence interval, 1.5-2.9) for the amygdala. The hazard ratios associated with atrophy were similar in persons without memory complaints or low cognitive function at baseline. Compared with those remaining free of dementia, baseline brain volumes were 17% smaller in persons who received a clinical diagnosis of dementia within 2 to 3 years after MRI and still 5% smaller in those whose conditions were diagnosed 6 years after MRI. CONCLUSION: Atrophy of the hippocampus and amygdala on MRI in cognitively intact elderly people predicts dementia during a 6-year follow-up.     

Community based measures for managing mild cognitive impairment and dementia: the Osaki-Tajiri Project]

A cross-sectional study of aged patients with mild cognitive impairment in a local community was undertaken to investigate the clinical features of the condition, in addition to a longitudinal study to research its progression to cognitive deficit. Impairment of the basic functions of attention and executive function was confirmed, as opposed to impairment in the cognitive domain itself. Magnetic resonance imaging (MRI) findings showed a pattern close to that of healthy persons in their 80s, rather than that of patients with cognitive deficit. The results of the longitudinal study showed more progression to cognitive deficit when the clinical dementia rating was 0.5 in domains other than memory. No effects of lifestyle, internal diseases or psychosocial intervention were confirmed. In progression to Alzheimer's disease, generally low cognitive function and general atrophy were involved, whereas frontal lobe function, atrophy of the frontal and temporal lobes, white matter changes and cerebral infarction were related to progression to vascular dementia. Excessive dependence on primary prevention should be avoided for aged patients with mild cognitive impairment; rather, secondary prevention, using clinical dementia rating, psychological testing and MRI are desirable.     

Community based measures for managing mild cognitive impairment: The Osaki–Tajiri Project

A cross‐sectional study of aged patients with mild cognitive impairment in a local community was undertaken to investigate the clinical features of the condition, in addition to a longitudinal study to research its progression to cognitive deficit. Impairment of the basic functions of attention and executive function was confirmed, as opposed to impairment in the cognitive domain itself. Magnetic resonance imaging (MRI) findings showed a pattern close to that of healthy persons in their 80s, rather than that of patients with cognitive deficit. The results of the longitudinal study showed more progression to cognitive deficit when the clinical dementia rating was 0.5 in domains other than memory. No effects of lifestyle, internal diseases or psychosocial intervention were confirmed. In progression to Alzheimer's disease, generally low cognitive function and general atrophy were involved, whereas frontal lobe function, atrophy of the frontal and temporal lobes, white matter changes and cerebral infarction were related to progression to vascular dementia. Excessive dependence on primary prevention should be avoided for aged patients with mild cognitive impairment; rather, secondary prevention, using clinical dementia rating, psychological testing and MRI are desirable.     

Do white matter changes contribute to the subsequent development of dementia in patients with mild cognitive impairment? A longitudinal study

OBJECTIVE: White matter lesions on brain CT or MRI are a frequent finding in patients with Alzheimer's disease. However, little is known about the prognostic significance of these changes in cognitively impaired individuals who are at risk for subsequent development of dementia. This study aims at investigating the potential impact of white matter lucencies (WML) on brain CT on the course of mild cognitive impairment. PATIENTS AND METHODS: Twenty-seven patients (mean age 72, SD 4.03) with mild cognitive impairment (MCI) and no signs of cerebrovascular disease were prospectively examined. At their initial presentation, all patients underwent a structured interview for the diagnosis of dementia (SIDAM) and a brain CT. Linear measures of atrophy and visual ratings of white matter changes were performed. At follow-up (mean interval 29 months), these patients were re-examined with the SIDAM. Eight patients had developed dementia and met clinical criteria for Alzheimer's disease (crossover group). RESULTS: Evaluation of the initial CT scans revealed significantly more frequent and extended white matter abnormalities and a higher degree of temporal lobe atrophy in the crossover group as compared to the cognitively stable group. In the crossover group, high WML severity initially was associated with a lesser degree of temporal lobe atrophy and higher global cognitive performance. CONCLUSION: We conclude that WML play a role in the dementia process and that they might accelerate cognitive decline in individuals with mild cognitive impairment. WML should be included in prospective studies of MCI as potential predictor variables.     

基于中国社区成年人群超敏C反应蛋白及无症状性颈动脉狭窄与认知障碍的关系研究

目的 拟在一项中国社区研究基础上探索hs-CRP、无症状性颈动脉狭窄（asymptomatic carotid stenosis，ACS）与认知障碍的关系。方法 本研究对2012年无症状性多血管床狭窄的社区（asymptomatic polyvascular abnormalities community，APAC）研究的随访数据进行了横断面分析，MMSE评分<24分被认为存在认知障碍。校正性别、年龄、BMI、受教育程度、吸烟、饮酒、体力活动、高血压病史、高脂血症病史、糖尿病病史、卒中病史等混杂因素后，采用logistic回归模型分析hs-CRP水平、ACS与认知障碍的关系。 结果 共有3925名受试者（其中女性1688名，占43.01%）纳入该研究。logistic回归分析结果显示，在未校正相关因素情况下，hs-CRP水平≥3 mg/L在有无ACS患者中均对认知障碍无影响（无ACS：OR 0.67，95%CI 0.30～1.45；有ACS：OR 0.86，95%CI 0.58～1.28）；在校正混杂因素后，hs-CRP水平≥3 mg/L在有无ACS患者中亦对认知障碍无影响（无ACS：OR 0.65，95%CI 0.24～1.75；有ACS：OR 0.97，95%CI 0.59～1.60）。结论 hs-CRP水平在有无ACS患者中均对认知障碍没有明显影响，因此，无论患者有无ACS，hs-CRP水平可能都与早期认知功能下降无明显相关。     

How complex interactions of ischemic brain infarcts, white matter lesions, and atrophy relate to poststroke dementia

BACKGROUND: Cerebrovascular disease is a major factor related to cognitive impairment. However, behavioral correlates of ischemic brain lesions are insufficiently characterized. OBJECTIVE: To examine magnetic resonance imaging correlates of dementia in a large, well-defined series of patients with ischemic stroke. METHODS: Detailed medical, neurological, and neuropsychological examinations were conducted 3 months after ischemic stroke for 337 of 486 consecutive patients aged 55 to 85 years. Infarcts (type, site, side, number, and volume), extent of white matter lesions (WMLs), and degree of atrophy were categorized according to magnetic resonance images of the head. The definition for dementia of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) was used. RESULTS: Dementia was diagnosed in 107 (31.8%) of the patients and stroke-related dementia in 87 (25.8%). Volumes, numbers, distinct sites of infarcts, extent of WMLs, and degree of atrophy were different for the demented and nondemented subjects. Particularly, volumes of infarcts in any (right- or left-sided) superior middle cerebral artery territory (27.3 vs 13.7 cm(3), P =. 002) and left thalamocortical connection (14.8 vs 4.0 cm(3), P =. 002) differentiated the 2 groups. Logistic regression analysis showed that the correlates of any dementia included the combination of infarct features (volume of infarcts in any superior middle cerebral artery: odds ratio [OR], 1.11; frequency of left-sided infarcts: OR, 1.21), extent of WMLs (OR, 1.3), medial temporal lobe atrophy (OR, 2.1), and host factors (education; OR, 0.91). In the patients with stroke-related dementia, the main correlate was volume of infarcts in the left anterior corona radiata (OR, 1.68). CONCLUSION: Correlates of poststroke dementia do not include merely 1 feature but a combination of infarct features, extent of WMLs, medial temporal lobe atrophy, and host features.     

Brain lesions on MRI in elderly patients with type 2 diabetes mellitus

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) type 2 has been associated with poor cognitive performance and dementia, particularly in elderly patients. The exact mechanisms underlying the cognitive dysfunction in DM remain unclear. Imaging studies of the brain could be helpful to give more insight into possible structural brain lesions underlying these cognitive dysfunctions. Therefore, we performed a study in independently living patients with DM type 2 in order to investigate the association between DM and brain imaging abnormalities. METHODS: The study population consisted of 45 patients with DM type 2 without hypertension (mean age 73.4 +/- 5.1 years, mean duration 16.5 +/- 11.5 years), 45 patients with DM type 2 and hypertension (mean age 73.5 +/- 6.1 years, mean duration 11.9 +/- 9.2 years) and 44 control subjects (mean age 73.1 +/- 5.4 years). All patients and control subjects underwent an MRI of the brain. White matter lesions (WML), cerebral atrophy and medial temporal lobe atrophy were rated by a standardized visual rating scale. Lacunar infarcts were defined as focal hypo-intensities on fluid-attenuated inversion recovery sequences with a hyperintense rim around it. RESULTS: WML occurred more frequently in diabetic patients with hypertension as well as without hypertension. Significantly more deep WML were found in DM patients with and without hypertension when compared to control subjects, whereas no difference was found in the occurrence of periventricular hyperintensities. In all 3 groups, lacunar infarcts occurred sporadically. A trend towards higher atrophy scores was seen in patients with DM compared to control subjects. CONCLUSIONS: The data of this cross-sectional study suggest that type 2 DM is an independent risk factor for deep WML in the independently living elderly patients.     

Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia

OBJECTIVE: To determine whether magnetic resonance imaging (MRI) white matter hyperintensities (WMH), whole-brain atrophy, and cardiovascular risk factors predict the development of cognitive decline and dementia. DESIGN: Subjects were recruited into this prospective cohort study and followed for incident cognitive decline for mean (SD) 6.0 (4.1) years. Magnetic resonance imaging dual-echo sequences, obtained at baseline, were used to determine the volume of WMH and the brain parenchymal fraction (BPF), the proportion of the intracranial cavity occupied by brain. White matter hyperintensity volume was analyzed as the percentage of intracranial volume (WMHr); "high WMH" was defined as a WMHr more than 1 SD above the mean. SETTING: General community. PATIENTS: Volunteer sample consisting of 67 subjects with normal cognition and 156 subjects with mild cognitive impairment (MCI). MAIN OUTCOME MEASURES: Time to diagnosis of MCI (among those with normal cognition at baseline) or time to diagnosis of dementia, either all-cause or probable Alzheimer disease (AD) (among those with MCI at baseline). Cox proportional hazards models were used for multivariable analysis. RESULTS: High WMH was a predictor of progression from normal to MCI (adjusted hazard ratio [HR], 3.30; 95% confidence interval [CI], 1.33-8.17; P= .01) but not conversion from MCI to all-cause dementia. Conversely, BPF did not predict progression from normal to MCI but did predict conversion to dementia (adjusted HR, 1.10 for each 1% decrease in BPF; 95% CI, 1.02-1.19; P= .02). When conversion to AD dementia was considered as the outcome, BPF was likewise a predictor (adjusted HR, 1.16 for each 1% decrease in BPF; 95% CI, 1.08-1.24; P< .001), but high WMH was not. Past tobacco smoking was associated with both progression from normal to MCI (adjusted HR, 2.71; 95% CI, 1.12-6.55; P= .03) and conversion to all-cause dementia (adjusted HR, 2.08; 95% CI, 1.13-3.82; P= .02), but not AD dementia. CONCLUSIONS: These findings suggest that WMH are associated with the risk of progressing from normal to MCI. In persons whose cognitive abilities are already impaired, BPF predicts the conversion to dementia.     

Ischemic white matter damage and cognitive impairment

White matter damage may play an important role in the pathogenesis of vascular dementia. White matter abnormalities are easily visualized as white matter high‐intensity lesions (WML) on T2‐weighted magnetic resonance images. The extent of WML may be an indicator of cognitive impairment, in particular, impairment related to frontal lobe dysfunction. However, it is unclear whether the extent of WML is an independent predictor of cognitive impairment. In patients with extensive WML, atrophy of the corpus callosum may be an important predictor of global cognitive impairment. We investigated the relationship between the extent of WML and callosal size with cognitive function in patients who had been diagnosed with lacunar stroke or no specific neurological disease. Multivariate analysis showed that only callosal size and age were significant independent predictors of mini‐mental state examination scores (a measure of global cognitive function), whereas only the extent of WML was an independent predictor of the score on the verbal fluency task (a measure of frontal lobe function). Callosal atrophy may be an important predictor of global cognitive impairment in patients with WML, whereas the extent of WML per se may be related to impairment of frontal lobe function independent of callosal atrophy. White matter high‐intensity lesions with callosal atrophy may indicate a severe form of white matter damage with axonal loss, the degree of which may determine the severity of global cognitive impairment. Our longitudinal study revealed an association between progression of WML and vascular risk factor status during follow up in patients with initially mild WML. Early detection of WML without callosal atrophy at a stage of subtle cognitive impairment and slowing the progression of WML to a severe form with callosal atrophy might prevent the development of dementia.     

White matter lesion progression: a surrogate endpoint for trials in cerebral small-vessel disease

There is neuropathologic evidence that confluent MRI white matter lesions in the elderly reflect ischemic brain damage due to microangiopathy. The authors hypothesize that measuring changes in the progression of white matter lesions as shown by MRI may provide a surrogate marker in clinical trials on cerebral small-vessel disease in which the currently used primary outcomes are cognitive impairment and dementia. This hypothesis is based on evidence that confluent white matter lesions progress rapidly as shown in a recent follow-up study in community-dwelling subjects. The mean increase in lesion volume was 5.2 cm(3) after 3 years. Based on these data in a clinical trial, 195 subjects with confluent lesions would be required per treatment arm to demonstrate a 20% reduction in the rate of disease progression over a 3-year period. Like any other MRI metric, the change in white matter lesion volume cannot be considered preferable to clinical outcomes unless it has been demonstrated that it matters to the patient in terms of function.     

The role of MRI in dementia

Neuroimaging techniques aimed at studying structural changes of the brain may provide useful information for the diagnosis and the clinical management of patients with dementia. Magnetic resonance imaging (MRI) may show abnormalities amenable to surgical treatment in a significant percentage of patients with cognitive impairment. MRI may also assist the differential diagnosis in dementia associated with metabolic or inflammatory diseases.MRI has the potential to detect focal signal abnormalities which may assist the clinical differentiation between Alzheimer's disease (AD) and vascular dementia (VaD). Severe temporal atrophy, hyperintensities involving the hippocampal or insular cortex, and gyral hypointense bands are more frequently noted in AD. Basal ganglionic/thalamic hyperintense foci, thromboembolic infarctions, confluent white matter and irregular periventricular hyperintensities are more common in VaD.The high sensitivity of MRI in detecting T2 hyperintense lesions and the low specificity off white matter lesions have resulted in a poor correlation between MRI findings and both neuropathological and clinical manifestations. In particular, MRI has disclosed a series of white matter focal changes in the elderly population, which are not necessarily associated with cognitive dysfunction.The recent advent of a new MRI method sensitive to the microstructural changes of white matter, the so-called diffusion tensor imaging, may be helpful in correlating clinical manifestations with white matter abnormalities.     

Blood pressure, white matter lesions and medial temporal lobe atrophy: closing the gap between vascular pathology and Alzheimer's disease?

BACKGROUND: Vascular factors are recognized as important risk factors for Alzheimer's disease, although it is unknown whether these factors directly lead to the typical degenerative pathology such as medial temporal lobe atrophy. We set out to investigate the relation between blood pressure and medial temporal lobe atrophy in patients with senile and presenile Alzheimer's disease with or without white matter lesions. METHODS: We determined the relation between blood pressure and pulse pressure and medial temporal lobe atrophy on MRI in 159 patients with Alzheimer's disease, stratified on white matter lesions and age at onset of dementia. RESULTS: There was a linear relation between systolic blood pressure and pulse pressure (both in tertiles) and the severity of medial temporal lobe atrophy (p(trend) = 0.05 and p(trend) 0.03, respectively). A significant relation was found between pulse pressure [beta = 0.08 (95% CI: 0.00-0.15; p = 0.05) per 10 mm Hg] and (borderline significant) systolic blood pressure [beta = 0.05 (95% CI: -0.01 to 0.11; p = 0.1) per 10 mm Hg] and medial temporal lobe atrophy. White matter lesions and age-stratified analysis revealed a significant association between systolic blood pressure and pulse pressure and medial temporal lobe atrophy, only in the subsample with white matter lesions and in the subsample with a senile onset of dementia. The relations were independent of severity of dementia and diabetes mellitus. CONCLUSIONS: Systolic blood pressure and pulse pressure are associated with medial temporal lobe atrophy in Alzheimer's disease, especially in the presence of white matter lesions and in patients with a late onset of dementia. Our finding may be another step in providing a rationale on how vascular factors could ultimately result in Alzheimer's disease.