Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL.

BACKGROUND: Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimer's disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASIL's early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL. METHODS: 168 patients with CADASIL (mean age 54.8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10-27 or a trail making test (TMT) B time score at least 1.5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948. FINDINGS: 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was -0.81 (SE 0.59) in the placebo group and -0.85 (SE 0.57) in the donepezil group (p=0.956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0.023), TMT A time (p=0.015), and EXIT25 (p=0.022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients. INTERPRETATION: Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment.

Atrial fibrillation, stroke, and cognition: a longitudinal population-based study of people aged 85 and older.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the association between atrial fibrillation (AF), stroke, dementia, and their correlation with brain pathology in subjects aged 85 years or older. METHODS: This is a prospective 9-year follow-up population based study in Vantaa, a town in Southern Finland; 553 subjects (92% of the total population) aged 85 years or older were clinically examined by a neurologist. The presence of AF was collected from the medical records or examined by ECG or ambulatory ECG. Neuropathological examination was conducted in more than half of the clinically examined subjects. RESULTS: AF was significantly associated with stroke at baseline; 32% of patients with AF had clinical evidence of stroke compared with 16.7% of those without such evidence (P<0.001). Dementia at baseline was significantly associated with age, clinical stroke, and the presence of apolipoprotein E epsilon4 allele, but not with sex, education, or vascular risk factors. Multiple regression analysis including neuropathological results showed that dementia was significantly associated with education (OR, 0.89; 95% CI, 0.80 to 0.98; P=0.019), the beta-amyloid load in the brain (OR, 1.26; 95% CI, 1.13 to 1.39; P<0.001) and with the vascular pathology (OR, 2.03; 95% CI, 1.14 to 3.62; P=0.016), but not with sex, age at death, apolipoprotein E epsilon4 allele, or vascular risk factors. CONCLUSIONS: AF is a significant and preventable risk factor for stroke but not for dementia in the very old. The etiology of dementia syndrome in the very old is multifactorial. Both Alzheimer disease pathology and vascular pathology, particularly multiple small infarcts, contribute to cognitive decline.

Association between blood pressure and survival over 9 years in a general population aged 85 and older.

OBJECTIVES: To investigate the association between blood pressure and mortality in people aged 85 and older. DESIGN: Population-based prospective study with 9-year follow-up. SETTING: Department of Neuroscience and Neurology and Department of Public Health and General Practice, University of Kuopio, and Department of Clinical Neurosciences, Helsinki University Hospital. PARTICIPANTS: Of all 601 people living in the city of Vantaa born before April 1, 1906, whether living at home or in institutions and alive on April 1, 1991, 521 were clinically examined and underwent blood pressure measurement. MEASUREMENTS: Blood pressure was measured using a standardized method in the right arm of the subject after resting for at least 5 minutes. Information on medical history for each participant was verified from a computerized database containing all primary care health records. Death certificates were obtained from the National Register; the collection of death certificates was complete. RESULTS: After adjusting for age, sex, functional status, and coexisting diseases (earlier-diagnosed myocardial infarction, congestive heart failure, dementia, cancer, stroke, or hypertension), low systolic blood pressure (BP) was associated with risk of death. CONCLUSION: Low systolic BP may be partially related to poor general health and poor vitality, but the very old may represent a select group of individuals, and the use of BP-lowering medications needs to be evaluated in this group.

Senile systemic amyloidosis, cerebral amyloid angiopathy, and dementia in a very old Finnish population.

Senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) are amyloid disorders, which typically manifest with old age. The aim of our study was to examine the possible association of these disorders in very old Finns. We performed a prospective, population-based post mortem study and used histological and immunohistochemical staining methods to verify the presence of these types of amyloid. All 63 subjects (59% of the 107 individuals 95 years of age or more, who died during the 10-year follow-up study), 53 women and 10 men), had been neurologically examined. The prevalence of SSA and its association with CAA, dementia, and neuropathologically verified AD was analyzed. Overall SSA occurred in 23 (37%) and CAA in 28 (44%) of the 63 subjects. At clinical examination 41 individuals (65%) were demented; 24 (38%) had Alzheimer's disease. SSA showed no association with the presence of CAA (P = 0.45), clinical dementia (P = 0.09), or Alzheimer's disease (P = 0.21), or sex (P = 0.53). Our prospective population based study shows that SSA and CAA are frequent in very old Finns, but they do not associate.

ApoE epsilon3-haplotype modulates Alzheimer beta-amyloid deposition in the brain.

ApoE epsilon4 allele increases the risk of late-onset Alzheimer disease (AD) as well as the amount of beta-amyloid deposition in the brain. Because half of AD patients do not have ApoE epsilon4, it is important to search for other determinants of ApoE that modify AD risk. We tested whether the haplotype background of the most common ApoE allele, epsilon3, influences brain amyloid deposition or the risk of neuropathologically verified AD in a population-based sample of elderly Finns. To exclude the effects of ApoE protein polymorphism we focused these analyses on subjects homozygous for epsilon3. Haplotypes were defined using polymorphisms at positions - 491 and -219 of the ApoE promoter and at position +113 of intron-1. We found that epsilon3-haplotypes containing the promoter allele -219T were associated with reduced amyloid deposition and reduced risk of neuropathologically verified AD as compared to epsilon3-haplotypes containing -219G. The functional polymorphism(s) responsible for the haplotypic difference remains to be identified. These results indicate that there is significant allelic variation in the ApoE gene region, which modulates brain amyloid deposition and AD risk, independent of the ApoE protein polymorphism.

Neuropsychological functions in variant Alzheimer's disease with spastic paraparesis.

Few data exist on the effects of specific Alzheimer's disease (AD)-related mutations on cognitive function. We present neuropsychological test results in eight members of a large kindred with variant Alzheimer's disease (VarAD) due to a deletion of the presenilin 1 (PS-1) gene, encompassing exon 9. The disease was neuropathologically characterized by the presence of large, unusual, "cotton wool" plaques (CWP). Four surviving patients were prospectively tested, and retrospective neuropsychological data were collected from additional four deceased patients. The neuropsychological evaluation was based on tests of verbal and visual memory, abstract thinking, and visuoconstructive and spatial functions. In addition, psychiatric symptoms were evaluated. In four patients, brain glucose metabolism was examined by positron emission tomography (PET). PET showed temporoparietal hypometabolism typical of AD. In addition, variable patterns of hypometabolism (hemispherical asymmetry and occipital accentuation) were related to individual deficits of cognitive performance. However, all these early-onset patients (age range 43-63 years) with a deletion mutation of PS-1 gene showed prominent memory impairment and deficits in visuoconstructive and intellectual functions.

Association of apolipoprotein E genotypes, blood pressure, blood lipids and ECG abnormalities in a general population aged 85+.

BACKGROUND: Several studies have linked apolipoprotein E (ApoE) epsilon4 allele with elevated cholesterol and blood pressure levels. Data on the association of APOE genotypes with blood pressure, lipids, atrial fibrillation and ECG abnormalities in individuals aged 85 years and over is sparse. METHODS: This cross sectional study consisted of all residents of the city of Vantaa (N = 601) aged 85 years or over of whom 505 participated in the study. Blood pressure was measured by using mercury sphygmomanometer. 12-Lead ECG, short ambulatory ECG, or both were taken from all study subjects to diagnose atrial fibrillation (AF). Ambulatory ECG was carried out home or in the institute. APOE genotyping was performed using a combination of the polymerase chain reaction (PCR) and solid-phase minisequencing technique. Statistical analysis was made by using Kruskall-Wallis-test (continuous data) and chi2-test (rates and proportions). RESULTS: In these very elderly individuals, APOE 4 allele was significantly associated with elevated cholesterol and low-density lipoprotein (LDL) levels. Blood pressure or cardiac arrhythmias did not differ between APOE genotypes. CONCLUSIONS: These observations suggest that the important role of APOE genotype still influences cardiovascular risk profile even among the very elderly people.

Vascular risk factors and dementia in the general population aged >85 years: prospective population-based study.

The aim of this study was to evaluate the association between dementia and common vascular risk factors including blood pressure, blood lipids, homocysteine and diabetes mellitus in a population of very old people. This study is a 9-year follow-up prospective population-based study monitoring 339 non-demented subjects aged 85 years or over in the city of Vantaa, Southern Finland. During the follow-up, those individuals with diabetes mellitus at the baseline and new incident stroke had a higher probability for developing dementia. History of hypertension or higher level of education were associated with a lower probability of dementia. It seems that the contribution of vascular risk factors to the risk of dementia may be age-dependent and their role in the very old subjects may be mediated through their influence on cerebrovascular morbidity. Thus, prevention of stroke and diabetes mellitus may reduce the risk of cognitive decline in the very old.

Incidence of dementia in very elderly individuals: a clinical, neuropathological and molecular genetic study.

AIMS: To evaluate the effect of medical record use on figures for the incidence of dementia and the effect of apolipoprotein E (APOE) polymorphism on this incidence and neuropathologically defined Alzheimer's disease (AD) in very elderly individuals. METHODS: Cognitive functions were examined in a cohort of 328 (92% of the very elderly people of a town participated in this study) nondemented Finnish elderly individuals 85 years of age or more in 1991. The examination was repeated in survivors in 1994, 1996, 1999 and 2001. Medical notes and social work records were evaluated. All these individuals were genotyped for APOE. Neuropathological analysis of AD-type pathology was performed on 159 of 303 subjects who died during the follow-up. RESULTS: Age group, gender or APOE did not significantly affect the incidence of dementia, which was over 20% higher (85 vs. 69 per 1,000 person-years) if the cognitive status at death was ascertained by medical and social work records than without this evaluation. The APOE upsilon4 allele was highly significantly (p=0.002) and age almost significantly (p=0.06) associated with neuropathological AD in nondemented individuals. CONCLUSIONS: Medical records should be analyzed in studies on the incidence of dementia in very elderly individuals. APOE polymorphism does not affect the incidence of dementia in this age group. However, clinical dementia diagnosis in very elderly individuals does not necessarily correlate well with the presence of neuropathological AD which, even in this age group, is significantly associated with the APOE upsilon4 allele.