Timo Erkinjuntti

A New Rating Scale for Age-Related White Matter Changes Applicable to MRI and CT

Background and Purpose— MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Methods— Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using &kgr; statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Results— Interrater reliability was good for MRI (&kgr;=0.67) and moderate for CT (&kgr;=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. Conclusions— We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.

Vascular cognitive impairment

Cerebrovascular disease is increasingly recognized as a common cause of cognitive impairment and dementia in later life either alone or in conjunction with other pathologies, most often Alzheimer disease (AD). Progress in the field has been limited by difficulties in terminology; for example, use of the term dementia necessitates the presence of memory impairment, which is the norm in AD, but not in cognitive disorders associated with cerebrovascular disease. The term vascular cognitive impairment (VCI) has been proposed as an umbrella term to recognize the broad spectrum of cognitive, and indeed behavioral, changes associated with vascular pathology. It is characterized by a specific cognitive profile with predominantly attentional and executive impairments together with particular noncognitive features (especially depression) and a relatively stable course, at least in clinical trial populations. Subtypes of VCI have been proposed based on clinical and pathologic differences, including cortical, subcortical, strategic infarct, hypoperfusion, hemorrhagic, and mixed (with AD) type. Diagnostic criteria are emerging but require refinement and validation, especially for mixed dementias. There remain fundamental gaps in our understanding of pathophysiology, predicting prognosis and outcome, and in therapeutics. Clinical trials to date, mainly in populations selected using currently accepted criteria for vascular dementia, have generally been disappointing. A relatively modest cognitive benefit of agents such as nimodipine, memantine, and cholinesterase inhibitors has been reported, although the clinical significance of these improvements remains to be established. Further studies, focusing on particular subtypes of VCI and involving subjects at earlier stages of the disease, are required. The aim of this article is to review the concept of VCI in terms of the evidence base surrounding diagnosis, clinical features, pathophysiology, and management and to make some recommendations regarding further research in the area. It begins with a discussion on the historical background, which is important to understand the different and somewhat confusing terminology that currently exists in the field.

Subcortical ischaemic vascular dementia

Vascular dementia is the second most common type of dementia. The subcortical ischaemic form (SIVD) frequently causes cognitive impairment and dementia in elderly people. SIVD results from small-vessel disease, which produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter due to critical stenosis of medullary arterioles and hypoperfusion (Binswangers disease). Symptoms include motor and cognitive dysexecutive slowing, forgetfulness, dysarthria, mood changes, urinary symptoms, and short-stepped gait. These manifestations probably result from ischaemic interruption of parallel circuits from the prefrontal cortex to the basal ganglia and corresponding thalamocortical connections. Brain imaging (computed tomography and magnetic resonance imaging) is essential for correct diagnosis. The main risk factors are advanced age, hypertension, diabetes, smoking, hyperhomocysteinaemia, hyperfibrinogenaemia, and other conditions that can cause brain hypoperfusion such as obstructive sleep apnoea, congestive heart failure, cardiac arrhythmias, and orthostatic hypotension. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)and some forms of cerebral amyloid angiopathy have a genetic basis. Treatment is symptomatic and prevention requires control of treatable risk factors.

Serum Total Cholesterol, Apolipoprotein E {FC12}e4 Allele, and Alzheimer’s Disease

The σ4 allele of the apolipoprotein E (apoE) is associated with Alzheimer’s disease (AD) and also with elevated serum total cholesterol and low-density lipoprotein levels. However, the interrelationships between apoE genotype, plasma cholesterol levels and AD risk have been studied very little. We examined the possible role of serum total cholesterol in the pathogenesis of AD in a population-based sample of 444 men, aged 70–89 years, who were survivors of the Finnish cohorts of the Seven Countries Study. Previous high serum cholesterol level (mean level ≥6.5 mmol/l) was a significant predictor of the prevalence of AD (odds ratio = 3.1; 95% confidence interval = 1.2, 8.5) after controlling for age and the presence of apoE σ4 allele. In men who subsequently developed AD the cholesterol level decreased before the clinical manifestations of AD. We conclude that high serum total cholesterol may be an independent risk factor for AD and some of the effect of the apoE σ4 allele on risk of AD might be mediated through high serum cholesterol.

Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial

BACKGROUND Vascular dementia is the second commonest form of dementia, and vascular factors contribute to the development of dementia in many patients with Alzheimers disease. Galantamine amplifies the acetylcholine response by inhibiting acetylcholinesterase and modulating nicotinic receptors. It has shown broad, sustained benefits in patients with Alzheimers disease. We investigated the effects of galantamine in patients with a diagnosis of probable vascular dementia or Alzheimers disease combined with cerebrovascular disease. METHODS Eligible patients were randomly assigned galantamine 24 mg/day (n=396) or placebo (n=196) in a multicentre, double-blind, 6-month trial. Primary endpoints were cognition (Alzheimers disease assessment scale, cognitive subscale [ADAS-cog]) and global functioning (clinicians interview-based impression of change plus caregiver input [CIBIC-plus]). Secondary endpoints included assessments of activities of daily living and behavioural symptoms. Patients were monitored for adverse events. Analyses were on the basis of observed case or last observation carried forward. FINDINGS Galantamine showed greater efficacy than placebo on ADAS-cog (galantamine change -1.7 [SE 0.4] vs placebo 1.0 [0.5]; treatment effect 2.7 points; p<0.0001) and CIBIC-plus (213 [74%] vs 95 [59%] patients remained stable or improved, p=0.0001). Activities of daily living and behavioural symptoms were also significantly improved compared with placebo (p=0.002 and p=0.016, respectively). Galantamine was well tolerated. INTERPRETATION Galantamine showed a therapeutic effect on all key areas of cognitive and non-cognitive abilities in this group of dementia patients.

White Matter Hyperintensities on MRI in the Neurologically Nondiseased Elderly: Analysis of Cohorts of Consecutive Subjects Aged 55 to 85 Years Living at Home

BACKGROUND AND PURPOSE We undertook this study to evaluate the frequency and risk factors of white matter hyperintensities seen on T2-weighted MR imaging. We examined cohorts of neurologically nondiseased elderly subjects participating in a general-community study, the Helsinki (Finland) Aging Brain Study. Cohorts of consecutive subjects aged 55, 60, 65, 70, 75, 80, and 85 years (n = 20, 18, 20, 18, 19, 18, and 15, respectively; total, n = 128) were divided into a young-old (age < 75 years, n = 76) group and an old-old (age > or = 75 years, n = 52) group. METHODS Frequency of hyperintensities seen on T2-weighted axial and coronal MR images (0.02 T) was rated using a four-point scale in periventricular and centrum semiovale areas. RESULTS The majority of the subjects showed only mild white matter hyperintensities, which were more frequent in the periventricular areas. Age was the most important factor to explain the presence of hyperintensities. A logistic regression analysis related periventricular hyperintensities in the entire group to central atrophy (odds ratio [OR], 4.7; 95% confidence interval [CI], 1.7 to 12.9) and silent infarcts (OR, 5.6; 95% CI, 1.0 to 19.8); among the young-old, hyperintensities related to diabetes (OR, 17.0; 95% CI, 1.9 to 154.2) and central atrophy (OR, 14.7; 95% CI, 3.5 to 61.8). Centrum semiovale hyperintensities related in the entire group to cardiac arrhythmia (OR, 4.0; 95% CI, 1.0 to 15.5), central atrophy (OR, 3.9; 95% CI, 1.2 to 12.4), and silent infarcts (OR, 3.6; 95% CI, 1.0 to 12.5). CONCLUSIONS These mild white matter hyperintensities in the neurologically nondiseased elderly related especially to age and also to concomitant silent infarcts, atrophy, and some vascular risk factors. The known factors, however, explained only part of the variation. The young-old and old-old groups showed different associations. In contrast to former assumptions, the presence of white matter hyperintensities among the aged is likely to be linked to other as yet unidentified age-related factors.

Association of gait and balance disorders with age-related white matter changes The LADIS Study

Objective: In the Leukoaraiosis and Disability (LADIS) Study, 11 European centers are evaluating the role of age-related white matter changes (ARWMC) as an independent determinant of the transition to disability in the elderly (65 to 84 years). We aimed at determining the influence of ARWMC on different objective measures of gait and balance. Methods: Six hundred thirty-nine nondisabled individuals were prospectively enrolled and are being followed-up for 3 years. Subjects are graded in three standardized categories of ARWMC (mild, moderate, and severe) according to central MRI reading. Quantitative tests of gait and balance include the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]), a timed 8-m walk, and a timed single leg stance test. Results: In cross-sectional analysis, deficiencies in gait and balance performance were correlated with the severity of ARWMC (SPPB: 10.2 ± 2.1 in the mild, 9.9 ± 2.0 in the moderate, 8.9 ± 2.6 in the severe group; p < 0.001). Walking speed correlated with the severity of ARWMC (1.24 ± 0.28 m/second in the mild, 1.18 ± 0.32 m/second in the moderate, and 1.09 ± 0.31 m/second in the severe group; p < 0.001). Balance was best in individuals with mild ARWMC (single leg stance time: 18.9 ± 10.8 seconds) compared with moderate and severe ARWMC (16.4 ± 10.8 and 13.6 ± 11.2 seconds) (p < 0.001). Physically inactive individuals had a higher risk of a pathologic SPPB score (moderate vs mild ARWMC: odds ratio 1.60, 95% CI 1.02 to 2.52; severe vs mild ARWMC: odds ratio 1.75, 95% CI 1.09 to 2.80). Conclusions: Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.

Impact of age-related cerebral white matter changes on the transition to disability -- the LADIS study: rationale, design and methodology

Age-related white matter changes (ARWMC) on brain MRI have been associated with cognitive, motor, mood and urinary disturbances. These factors are known to contribute to disability in elderly people, but the impact of ARWMC and of their progression on the transition to disability is not determined. The LADIS (Leukoaraiosis and Disability in the Elderly) study aims at assessing the role of ARWMC as an independent predictor of the transition to disability in initially nondisabled elderly (65–84 years). Subjects who are not impaired or impaired on only 1 item of the Instrumental Activity of Daily Living (IADL) scale, presenting with different grades of ARWMC severity, were enrolled. Eleven European centers are involved. All the patients were assessed at baseline using an extensive set of clinical and functional tests including global functioning, cognitive, motor, psychiatric and quality of life measures. MRI studies were performed at baseline and will be repeated at the end of the follow-up period to evaluate changes of ARWMC and other lesions. ARWMC were categorized into mild, moderate or severe using the scale of Fazekas et al. For each ARWMC severity class, the primary study outcome is the transition to disability defined as an impairment on 2 or more IADL scale items. Secondary outcomes are the occurrence of dementia, depression, vascular events or death. Six-hundred and thirty-nine subjects (mean age 74.13 ± 5.0 years, M/F: 288/351) were enrolled in a hospital-based setting and are being followed up for up to 3 years. The large and comprehensive set of measures in LADIS enables a comprehensive description of their functional and clinical features to be examined in relation to different morphological patterns and severity of ARWMC. The longitudinal design will give insight into the possible role of ARWMC and their progression as an independent contributor to disability in the elderly, eventually helping to develop preventive strategies to reduce the burden of disability in late life. The study results may also help to standardize, on an international basis, tools and criteria to identify early stages of disability.

Frequency and Clinical Determinants of Poststroke Depression

BACKGROUND AND PURPOSE Previous studies have shown a large variation concerning the frequency of poststroke depression. This variation is caused by differences in patient populations, psychiatric assessment methods, and diagnostic criteria. In this study, we evaluated the frequency and clinical correlates of poststroke depression in a large well-defined stroke cohort. METHODS We studied a consecutive series of 486 patients with ischemic stroke aged from 55 to 85 years. Of these, 277 patients underwent a comprehensive psychiatric evaluation, including the Present State Examination, from 3 to 4 months after ischemic stroke. The criteria of the Diagnostic and Statistical Manual of Mental Disorders, edition 3, revised (DSM-III-R), were used for the diagnosis of depressive disorders. RESULTS The frequency of any depressive disorder was 40.1% (n=111). Major depression was diagnosed in 26.0% (n=72) and minor depression in 14.1% (n=39). Major depression with no other explanatory factor besides stroke was diagnosed in 18.0% (n=49) of the patients. Comparing depressed and nondepressed patients, we found no statistically significant difference in sex, age, education, stroke type, stroke localization, stroke syndrome, history of previous cerebrovascular disease, or frequency of DSM-III-R dementia. According to the multiple logistic regression model, dependency in daily life correlated with the diagnosis of depression (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1 to 3.1) and with the diagnosis of major depression (OR, 2.9; 95% CI, 1.6 to 5.5). A history of previous depressive episodes also correlated with the diagnosis of depression (OR, 2.3; 95% CI, 1.3 to 4.4) and with the diagnosis of major depression (OR, 2.9; 95% CI, 1.6 to 5.5), whereas solely stroke-related major depression correlated only weakly with stroke severity as measured on the Scandinavian Stroke Scale (OR, 1.1; 95% CI, 1.0 to 1.1). CONCLUSIONS Clinically significant depression is frequent after ischemic stroke. We emphasize the importance of the psychiatric examination of poststroke patients, especially those with a significant disability and with a history of prior depressive episodes.

Clinical Determinants of Poststroke Dementia

BACKGROUND AND PURPOSE Frequency of poststroke dementia is high, and stroke considerably increases the risk of dementia. The risk factors for dementia related to stroke are still incompletely understood. We sought to examine clinical determinants of poststroke dementia in a large well-defined stroke cohort. METHODS The study group comprised 337 of 486 consecutive patients aged 55 to 85 years who 3 months after ischemic stroke completed a comprehensive neuropsychological test battery and MRI, including structured medical, neurological, and laboratory evaluations; clinical mental status examination; interview of a knowledgeable informant; detailed history of risk factors; and evaluation of stroke type, localization, and syndrome. The DSM-III definition for dementia was used. RESULTS Frequency of any poststroke dementia was 31.8% (107/337), that of stroke-related dementia (mixed Alzheimers disease plus vascular dementia excluded) was 28.4% (87/306), and that of dementia after first-ever stroke was 28.9% (79/273). The patients with poststroke dementia were older and more often had a low level of education, history of prior cerebrovascular disease and stroke, left hemispheric stroke (reflecting laterality), major dominant stroke syndrome (reflecting laterality and size), dysphasia, gait impairment, and urinary incontinence. The demented patients were also more frequently current smokers, had lower arterial blood pressure values, and more frequently had an orthostatic reaction compared with the nondemented stroke patients. The correlates of dementia in logistic regression analysis were dysphasia (odds ratio [OR], 5.6), major dominant stroke syndrome (OR, 5.0), history of prior cerebrovascular disease (OR, 2.0), and low educational level (OR, 1.1). When we excluded those with cerebrovascular disease plus Alzheimers disease or those with recurrent stroke, the order of correlates remained the same. When the patients with dysphasia (n=30) were excluded, the correlates were major dominant syndrome (OR, 4.6) and low educational level (OR, 1.1). CONCLUSIONS Our data suggest that a single explanation for poststroke dementia is not adequate; rather, multiple factors including stroke features (dysphasia, major dominant stroke syndrome), host characteristics (educational level), and prior cerebrovascular disease each independently contribute to the risk.