Hilkka Soininen

3-Year Study of Donepezil Therapy in Alzheimer’s Disease: Effects of Early and Continuous Therapy

Delays in the diagnosis of Alzheimer’s disease, and, therefore, delays in treatment, may have a detrimental effect on a patient’s long-term well-being. This studyassessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer’s disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer’s disease. These data support the long-term efficacy and safety of donepezil.

Alcohol drinking and cognitive functions: findings from the Cardiovascular Risk Factors Aging and Dementia (CAIDE) Study.

Background: Moderate alcohol drinking is suggested to be beneficial for cognitive functions, but the results of previous studies have varied greatly. Little is known about the effects of midlife alcohol drinking on the cognitive functions later in life. Methods: Participants were derived from random, population-based samples studied in Eastern Finland in 1972, 1977, 1982, or 1987. A total of 1,341 participants were reexamined in 1998, after an average follow-up period of 21 years, at ages 65–79 years. Results: The participants who did not drink alcohol at midlife had a poorer performance in episodic memory, psychomotor speed, and executive function in late life as compared with infrequent and frequent drinkers, adjusted for sociodemographic and vascular factors. Also late-life nondrinkers had poorer psychomotor speed and executive function. These findings were evident especially among nonsmokers. Further, no interactions between apolipoprotein E4 and alcohol or sex and alcohol were found. Conclusions: Alcohol drinking both at midlife and later is favorably related to the function in several cognitive domains, including episodic memory, psychomotor speed, and executive function, in late life. However, it is not clear whether the association is causal, what is the possible mechanism, and what would be a safe limit of drinking for the best cognitive function.

Tetrahydroaminoacridine modulates technetium-99m labelled ethylene dicysteinate retention in Alzheimer's disease measured with single photon emission computed tomography imaging

The present study investigated if acute treatment with tetrahydroaminoacridine (THA) (25 or 75 mg, p.o.) affects technetium-99m labelled ethylene dicysteinate (ECD) retention abnormalities in patients with mild to moderate Alzheimers disease (AD; mean age 69 years). THA (75 mg) increased temporal, prefrontal and occipital ECD retention (normalized to cerebellum) in mildly demented AD patients, but 25 mg of THA had no effect on ECD retention. After 75 mg THA, prefrontal and temporal ECD retention correlated with improved executive and memory functioning, respectively. THA (25 or 75 mg) had no measurable effect on ECD retention of moderately demented patients.

Midlife Work-Related Stress is Associated with Late-Life Gray Matter Volume Atrophy

Background: Work-related stress has been associated with an increased dementia risk. However, less is known about the mechanisms that underlie these associations. Objective: The goal is to examine associations between midlife work-related stress and late-life structural brain alterations. Methods: The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study participants were randomly selected from independent population-based surveys (mean age 50) in Finland. MRI measurements included gray matter (GM) volume, white matter lesions (WML) and medial temporal atrophy (MTA) (1st re-examination, n = 102); and GM volume, hippocampal volume, WML volume, cortical thickness, and MTA (2nd re-examination, n = 64). Work-related stress comprised a score from two questions administered in midlife. Results: Higher levels of midlife work-related stress were associated with lower GM volume (β= –0.077, p = 0.033) at the first re-examination, even after adjusting for several confounders. No significant associations were found with MTA, WML, or MRI measurements at the second re-examination. Conclusion: Previously shown associations of midlife work-related stress with dementia risk may be at least partly explained by associations with lower GM volume in late-life. The lack of associations at the second re-examination may indicate a critical time window for the effects of midlife work-related stress, and/or selective survival/participation.

Prevention of Alzheimer's Disease: Backward through the Lifespan

This is a brief summary of experiences from Finland related to Alzheimers disease (AD) prevention research. The first signals that AD may have vascular modifiable risk factors came from studies on cardiovascular conditions and diabetes. Cardiovascular prevention projects such as North Karelia Project and WHO-MONICA in the 1970-1980 s were focused on younger populations, which led to the idea of looking for risk factors as far back as middle age. Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) is one of the few studies in the world focusing on late-life cognition with a large and representative population-based cohort, baseline examination at midlife, and follow-up time up to three decades. Since 1998, it has identified several modifiable risk factors for cognitive impairment/dementia, and produced the first risk score for estimating dementia risk based on midlife profiles. The CAIDE Dementia Risk Score has been used to select participants in the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER). FINGER is an ongoing multicenter RCT involving 1,200 participants aged 60-77 years, and testing the effects of a two-year multi-domain intervention targeting several risk factors simultaneously. It started in September 2009 and will be completed at the end of 2013. The FINGER study is at the forefront of international collaborative efforts to solve the clinical and public health problems of early identification of individuals at increased risk of late-life cognitive impairment, and of developing intervention strategies to prevent or delay the onset of cognitive impairment and dementia.