Vascular cognitive impairment: epidemiology, subtypes, diagnosis and management.

Dementia occurs after stroke in 25% of patients but also can arise from covert cerebrovascular disease (CVD). 'Silent' lacunes occur in 25% of the elderly, often associated with focal or confluent hyperintensities on T2-weighted magnetic resonance imaging, which are detected in 95% of seniors. These covert infarcts predict future stroke and faster cognitive decline. Best practice guidelines advocate screening for cognitive impairment in all phases of overt stroke, when covert CVD is uncovered, when vascular risk factors are present and if patients present with cognitive complaints. Standardised testing is recommended, emphasising executive function and speed of processing. Cholinesterase inhibitors have cognitive enhancing effects in vascular dementia, but the major thrust is still aggressive management of vascular risk factors and healthy lifestyle choices. Given that mixed Alzheimer's dementia and CVD is likely the most common substrate for dementia and that they share common vascular risk factors, a major goal for vascular medicine is cerebrovascular protection, not just to prevent heart attack and stroke, but also to maintain brain health and delay dementia.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel disease with an identified gene, along with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The exact prevalence of CARASIL is currently unknown, and to date approximately 50 patients have been reported, most of them from Japan and two from China. Genetically, no founder haplotype has been identified, and thus the disease is expected to be found more widely. The main clinical manifestations of CARASIL are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic findings on brain magnetic resonance imaging are diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1 exhibited decreased protease activity and failed to repress transforming growth factor-ß family signaling, indicating that the increased signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.

[Gender-specific predictors of institutionalisation in the elderly--results of the Leipzig longitudinal study of the aged (LEILA 75+)]. / Geschlechtsspezifische Prädiktoren von Institutionalisierung im Alter - Ergebnisse der Leipziger Längsschnittstudie in der Altenbevölkerung (LEILA 75+).

OBJECTIVE: Especially given the different socialization and life conditions of men and women, it could not be assumed that factors leading to nursing home admission (NHA) can be equally applied to both genders. We aimed to determine gender-specific predictors of NHA. METHODS: Data were derived from the Leipzig Longitudinal Study of the Aged, a population-based study of individuals aged 75 years and older. 1,058 older adults were interviewed six times on average every 1.4 years. Sociodemographic, clinical, and psychometric variables were obtained. Cox proportional hazards regression was used to determine predictors of NHA. RESULTS: 10.3 % of men and 19.5 % of women (p < 0.001) were admitted to nursing home during the study period. The mean time to nursing home was 7.2 years for men and 6.8 years for women. Characteristics associated with a shorter time to NHA were increased age for men and women; cognitive impairment, poor self-rated health status, and less than two specialist's visits in the preceding 12 months for women, and being unmarried, moderate educational status, and hospitalization in the preceding 12 months were predictors of NHA for men. CONCLUSIONS: Gender differences in prediction of NHA do actually exist. The inclusion of gender-specific factors in design and application of interventions to support individuals at home and delay or prevent NHA appears to be warranted.

[Vascular dementia]. / Vaskuläre Demenz.

Vascular dementia (VaD) constitutes the second most frequent cause of dementia following Alzheimer's disease (AD). In contrast to AD, VaD encompasses a variety of conditions and dementia mechanisms including multiple and strategic infarcts, widespread white matter lesions and hemorrhages. The diagnosis of VaD is based on the patient history, the clinical evaluation and neuroimaging. Treatment of VaD should account for the underlying vascular condition and is directed towards the control of vascular risk factors and stroke prevention. The need for early diagnosis and preventive treatment has promoted the concept of vascular cognitive impairment (VCI). Harmonization standards for the description and study of VCI have recently been published. A common and distinct subtype of VaD is subcortical ischemic vascular dementia (SIVD) which is related to cerebral small vessel disease. SIVD is clinically characterized by impairment of executive functions and processing speed with relatively preserved memory. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of SIVD, represents an important differential diagnosis and may serve as a model of SIVD.

Prevalence and factors associated with urinary tract infections (UTIs) in very old women.

The aim of this study was to describe the prevalence of urinary tract infection (UTI) and associated factors among very old women. In a cross-sectional, population-based study in Sweden and Finland, 532 women were asked to participate and 395 (74.2%) were possible to evaluate for UTI. Data were collected from structured interviews and assessments made during home visits, from medical charts, caregivers and relatives. UTI diagnosis documented in medical records during the preceding 1 and 5 years was registered. About one-third (117/395, 29.6%) were diagnosed as having suffered from at least one UTI in the preceding year and 60% in the preceding 5 years. In a multivariate logistic regression model, UTI in the preceding year, was associated with vertebral fractures (odds ratio (OR) = 3.2; 95% confidence interval (95% CI) = 1.4-7.1), incontinence (OR = 2.8; 95% CI = 1.8-4.5), inflammatory rheumatic disease (OR = 2.8; 95% CI = 1.4-5.7) and multi-infarct dementia (OR = 2.4; 95% CI = 1.3-4.5). UTI is a major public health problem in very old women and were independently associated with vertebral fractures, urinary incontinence, inflammatory rheumatic disease and multi-infarct dementia which might indicate that UTI is not a harmless disease.

Vascular and biochemical risk factors of vascular dementia after lacunar strokes (S-VaD) and after multiinfarcts in strategic areas (M-VaD).

Vascular cognitive impairment is an important cause of cognitive decline in the elderly. Ischemic lesions in the brain have an influence on the natural history of dementia. Vascular dementia can be caused by small-vessels disease (S-VaD) or by large-artery atherosclerosis with vascular lesions in strategic areas of the brain (M-VaD). In both cases changes in white matter are observed. In 60 patients with S-VaD and in 34 with M-VaD the presence of vascular and biochemical risk factors was evaluated and compared to age and sex matched 126 controls without dementia. Coronary artery disease, atrial fibrillation, hypertension and strokes were observed more frequently in both investigated groups. Of biochemical risk factors, hyperhomocysteinemia (associated with low levels of folic acid and vitamin B 12) and low HDL cholesterol levels were found in both forms of VaD.

The pathology of "vascular dementia": a critical update.

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive disorder (VCD), are a matter of discussion.VaD is suggested in 8-15% of cognitively impaired aged subjects. Its prevalence in autopsy series ranges from 0.03 to 58% (mean 8-15% in Western series, 22-35% in Japan). Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system), white matter lesions and hippocampal sclerosis to multi-infarct encephalopathy and diffuse post-ischemic lesions. They result from systemic, cardiac and local large and small vessel disease. Pathogenesis is multifactorial and pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer's disease (AD) and other pathologies. Minor vascular lesions hardly contribute to cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease interact synergistically. AD pathology is less severe in the presence of vascular lesions. The lesion pattern in "pure" VaD/VCD) related to microangiopathies differs from that in "mixed dementia" (AD + vascular encephalopathy), often associated with large infarcts, suggesting different pathogenesis. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Further prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognitive impairment.

Ischemic stroke incidence in Santa Coloma de Gramenet (ISISCOG), Spain. A community-based study.

BACKGROUND: In Spain, stroke is one of the major causes of death and the main cause of severe disability in people over 65 years. We analyzed the incidence of ischemic stroke, stroke subtypes, case fatality and disability at 90 days after the event in a Spanish population. METHODS: A prospective community-based register of ischemic strokes was established in Santa Coloma de Gramenet (Barcelona) [116,220 inhabitants of all ages, according to the municipal census of December 31,2001], from January 1 to December 31, 2003. Standard definitions and case finding methods were used to identify all cases in all age groups. Every patient underwent a complete clinical evaluation and systematic tests including neuroimaging (CT/MRI) and vascular studies (carotid duplex ultrasound intra and extracranial and MR angiography). RESULTS: Over a one year period, 196 ischemic strokes were registered [107 men; median age = 76 years (range 39-98)], being the first event in 159 patients (81.1%) and a recurrent stroke in 37 (18.9%). After age-adjustment to the European population, the incidence of ischemic stroke per 100,000 inhabitants was 172 (95% CI, 148-196); 219 (176-261) in men and 133 (105-160) in women, with an annual incidence for first ischemic stroke of 139 (118-161); 165 (128-201) in men and 115 (89-140) in women. The incidence of stroke increased with age. Stroke subtypes (TOAST classification criteria) were lacunar in 28.8%, atherothrombotic in 18.6%, cardioembolic in 26.6% and undetermined in 26.0% of patients. At 90 days, the case-fatality was 12%, and among survivors, moderate-to-severe disability was present in 45 % at 3 months. CONCLUSION: This prospective community-based study shows one of the lowest incidences of stroke in Europe, as well as one of the lowest case fatality and disability rates at 90 days after stroke.

Neuroimaging predictors of cognitive impairment in confluent white matter lesion: volumetric analyses of 99 brain regions.

BACKGROUND: Although confluent white matter lesion (WML) is associated with cognitive impairment, the mechanism explaining this association is controversial. We aimed to investigate comprehensively the MRI predictors of cognitive impairment in confluent WML. METHODS: Among 45 lacunar stroke patients who had confluent WML, we evaluated the association of executive function [Mattis Dementia Rating Scale - Initiation/Perseveration subscale (MDRS I/P)] and global cognition [Mini-Mental State Examination (MMSE)] with the volume of WML, measures of lacunes and microbleeds, and the volumes of 99 other specific brain regions. RESULTS: Regression analyses showed that WML volume predicted performance on the MDRS I/P (beta = -0.34, p = 0.016) independent of age. Volumes of cortical gray matter (cGM; beta = 0.41, p = 0.003), the lateral fronto-orbital gyrus (beta = 0.38, p = 0.01), superior frontal gyrus (beta = 0.29, p = 0.04), lateral ventricle (beta = -0.30, p = 0.04), and posterior limb of the internal capsule (beta = 0.43, p = 0.002) predicted MDRS I/P performance independent of WML volume. Volumes of cGM, and the lateral fronto-orbital gyrus predicted MMSE performance as well. CONCLUSION: Atrophy along the frontosubcortical pathways and cGM predict cognition in confluent WML independent of WML volume.

Health-related quality-of-life of care-givers as a predictor of nursing-home placement of patients with dementia.

Care-giver health-related quality-of-life (QoL) as a predictor of nursing-home placement of family-member patients with dementia was evaluated (using the SF-36 questionnaire) in 181 care providers (78% females; mean age 63 years) at the start and at the end of 12 months of follow-up. The patients and their carers were evaluated at home or at the local Primary Health-care Centers (n = 37) in the area of Barcelona (Catalunya, Spain). Data were evaluated using logistic regression analysis with nursing-home placement of patients as the main outcome measure, and the care-givers' QoL, demographic, medical, social and cognitive variables as covariates. The incidence rate of nursing-home placement was 10.5% (95%CI: 6.4-15.9). Carers of patients who had not been placed in a nursing home had better QoL scores, even after controlling for potential confounding factors. The adjusted odds ratio of being admitted to a nursing home was 6.4 (95%CI: 2.1-19.0) for patients cared-for by relatives who rated their health as being much worse compared with the previous year. The care-giver's poor health-related QoL significantly influenced rates of nursing-home admission of patients in their care.

Predictive accuracy of MCI subtypes for Alzheimer's disease and vascular dementia in subjects with mild cognitive impairment: a 2-year follow-up study.

AIM: The aim of this study was to investigate the prognostic accuracy of different subtypes of mild cognitive impairment (MCI): amnestic MCI, multiple domain MCI, and single non-memory domain MCI, for the development of Alzheimer's dementia (AD) and vascular dementia (VaD). PATIENTS: Nondemented patients from a memory clinic cohort (n = 118), and a stroke cohort (n = 80, older than 55 years and with a cognitive impairment). RESULTS: 'Multiple domain MCI' had the highest sensitivity for both AD (80.8%) and VaD (100%), and 'amnestic MCI' had the highest specificity (85.9% for AD, 100% for VaD). The positive predictive value was low for all subtypes (0.0-32.7%), whereas the negative predictive value was high (72.8-100%). DISCUSSION: The subtype 'multiple domain MCI' has high sensitivity in identifying people at risk for developing AD or VaD. The predictive accuracy of the MCI subtypes was similar for both AD and VaD.

Some observations on the spectrum of dementia.

A study was designed to generate epidemiological and clinical data on dementia, in a teaching hospital in India. It was conducted on 124 (94 male and 30 female) elderly patients (aged more than 60 years) presenting with clinical syndrome of dementia (DSM-3). Their age range was 64-78 (mean 65.7 4.1) years. Detailed clinical, biochemical, radiological and electrophysiological evaluation was done to establish etiology. Patients with psychiatric ailments, cranial trauma and tumors were excluded. The study period was 4.2 years. Multi-infarct dementia (MID) was observed to be commonest cause of dementia and was present in 59 (47.6%) cases. There were 10 (8%) patients each of tuberculosis (TB) and neurocysticercosis (NCC). Alcohol-related dementia was present in 13 (10.5%), while malnutrition (Vitamin B12 deficiency) was present in 9 (7.2%). Alzheimer's Disease (AD) was present (NINCDS-ADRDA criteria) in 6 patients (4.8%). There were 3 (2.4%) cases 1 each of Huntington's disease, Parkinson's and Normal Pressure Hydrocephalus and 2 each of diabetes, hypothyroidism, hyperthyroidism and Creutzfeldt' Jakob Disease. We conclude that AD, which is irreversible and common in the west, is relatively uncommon in India as compared to MID, infections and malnutrition, which are potentially treatable.

Frequency of subclinical lacunar infarcts in ischemic leukoaraiosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: Small vessel cerebrovascular disease is an important cause of vascular cognitive impairment. It is usually sporadic but also occurs secondary to the genetic disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recurrent lacunar stroke is a characteristic feature, although symptomatic events are relatively rare, making large numbers necessary for evaluation of potential therapies. Diffusion-weighted imaging is sensitive to acute ischemic lesions and differentiates them from chronic infarcts. Detection of asymptomatic lacunar infarcts with diffusion-weighted imaging is a potential surrogate marker for treatment trials. In this study, the frequency of asymptomatic new lesions in ischemic leukoaraiosis and CADASIL was determined as a step toward assessing the potential of this technique as a surrogate marker of disease activity. METHODS: Fifty patients with sporadic small vessel disease and 19 patients with CADASIL underwent diffusion-weighted imaging. All had been asymptomatic for 3 months before imaging. Diffusion-weighted images were screened by two raters for new lesions; lesions were confirmed as recent by a visible reduction of diffusivity on the corresponding apparent diffusion coefficient maps. RESULTS: Recent ischemic lesions were identified in four patients with sporadic small vessel disease (8.0%) and two patients with CADASIL (10.5%). CONCLUSION: Asymptomatic new lesions are found in cases of sporadic small vessel disease and CADASIL. The frequency of new lesions suggests that this approach has a potential role as a surrogate marker in therapeutic trials that warrants further investigation.

Incipient CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited. OBJECTIVE: To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years. DESIGN: Clinical characterization and blinded survey comparing MCs with non-MCs. SETTING: Referral center. PARTICIPANTS: Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria. METHODS: Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale. RESULTS: Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps. CONCLUSIONS: Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and CADASIL-like disorders in Japan.

We reviewed 12 patients from 11 Japanese families diagnosed as having CADASIL from 1998 to 2001. The age of onset of focal neurologic deficits ranged from 38 to 71 years (mean: 50.4 +/- 9.8 years). Japanese CADASIL patients rarely had migraine and frequently presented with symptoms of dementia at diagnosis. Notch3 mutations were concentrated in exons 3, 4, and 5. Cysteine was replaced by another amino acid or vice versa in the majority of Japanese CADASIL patients. However, in 2 families, the mutations were not related to cysteine. In the prospective study, 2030 patients with stroke were hospitalized in 6 hospitals with stroke units in the Kumamoto district from 1999 to 2001. Among them, 14 patients fulfilled the criteria of being less than 60 years of age, showing lacunar strokes and/or TIA, presence of a family history, and no risk factors of stroke. One of these 14 patients was diagnosed as having CADASIL by DNA analysis. However, if hyperlipidemia was excluded from the list, 16 patients fulfilled the criteria and 2 patients were diagnosed as having CADASIL by DNA analysis. It was suspected that the incidence of CADASIL is not so rare in Japan. There were some families with CADASIL-like features, but without Notch3 mutations or GOM, suggesting the need for genetic analysis in the future.

Frequency of white matter lesions and silent lacunar infarcts.

White matter lesions and silent lacunar infarcts are related to and may result from cerebral small vessel disease. Reported frequencies of these lesions vary largely among studies. Differences in imaging techniques, rating scales, cut-off points in lesion severity grading and study populations contribute to the variation, in addition to differences in risk factor profiles across studies. In this paper, we will firstly discuss general methodological issues that may influence reported frequencies of white matter lesions and silent lacunar infarctions, and then review published data. We will focus on the results from population-based studies and only briefly comment on patient series of stroke and dementia.

[Prevalence and incidence of dementia among nursing home residents and residents in homes for the aged in comparison to private homes]. / Prävalenz und Inzidenz von Demenzerkrankungen in Alten- und Altenpflegeheimen im Vergleich mit Privathaushalten.

Based on a representative epidemiological study on dementia, prevalence and incidence rates of institutionalized individuals aged 75 years and older in comparison to those living in private homes are presented. The study was conducted between 1997 and 1999. Core component assessing cognitive function was the SIDAM (Structured Interview for the diagnosis of Dementia of the Alzheimer type, Multi-infarct dementia and dementias of other etiology according to ICD-10 and DSM-III-R, DSM-IV). If cognitive testing with study participants was not possible (e.g., due to fragility, death before examination) proxy interviews were performed with relatives or staff using the CDR (Clinical Dementia Rating). Prevalence and incidence rates in institutions were four times higher than in private homes. A prevalence rate of dementia for institutionalized individuals 75+ according to DSM-III-R of 47.6% was found; the annual incidence rate was 17.2%. This high proportion of people with dementia in institutions requires the development of new concepts of care to meet the demands of this changing situation in residential and nursing homes.