Tarja Järvenpää

Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease

Donepezil and rivastigmine are acetylcholinesterase (AChE) inhibitors used to improve cholinergic neurotransmission and cognitive function in Alzheimer’s disease (AD). This study examined direct effects of these drugs on AChE activity in the frontal, temporal, and parietal cortices in AD. Six AD patients were scanned with positron emission tomography before and after 3 months of treatment with donepezil (10 mg/day), and five AD patients were scanned before and after 3 to 5 months of treatment with rivastigmine (9 mg/day). Healthy unmedicated controls were imaged twice to evaluate the reproducibility of the method. A specific AChE tracer, [methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission tomography system with MRI coregistration were used for imaging. Treatment with donepezil reduced the AChE activity (k3 values) in the AD brain by 39% in the frontal (p < 0.001, Bonferroni corrected), 29% in the temporal (p = 0.02, corrected) and 28% in the parietal cortex (p = 0.05, corrected). The corresponding levels of inhibition for rivastigmine were 37% (p = 0.003, corrected), 28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When the treatment groups were combined, the level of AChE inhibition was significantly greater in the frontal cortex compared to the temporal cortex (p = 0.03, corrected). The test-retest analysis with healthy subjects indicated good reproducibility for the method, with a nonsignificant 0% to 7% intrasubject variability between scans. The present study provides first evidence for the effect of rivastigmine on cortical AChE activity. Our results indicate that the pooled effects of donepezil and rivastigmine on brain AChE are greater in the frontal cortex compared to the temporal cortex in AD. This regional difference is probably related to the prominent temporoparietal reduction of AChE in AD. We hypothesize that the clinical improvement in behavioral and attentional symptoms of AD due to AChE inhibitors is associated with the frontal AChE inhibition.

Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease

Objective: Brain acetylcholinesterase activity was determined in healthy controls and in patients with mild cognitive impairment and early Alzheimer’s disease. Methods: A specific acetylcholinesterase tracer, [methyl-11C]N-methyl-piperidyl-4-acetate ([11C]MP4A), and a three dimensional PET system with magnetic resonance coregistration were used for imaging. Results: There was a significant difference in the acetylcholinesterase activity in the hippocampus between the groups (p = 0.03), the mean (SD) acetylcholinesterase activity (k3 values, min−1) being 0.114 (0.036) in controls, 0.098 (0.023) in mild cognitive impairment, and 0.085 (0.022) in Alzheimer’s disease. The mini-mental state examination score showed no significant relation with acetylcholinesterase activity in any brain area in the combined mild cognitive impairment/Alzheimer group. Conclusions: Hippocampal acetylcholinesterase activity is only slightly reduced in mild cognitive impairment and early Alzheimer’s disease and so the value of in vivo acetylcholinesterase measurements in detecting the early Alzheimer process is limited.

Characteristics of two telephone screens for cognitive impairment

We studied 56 subjects, 30 patients with a clinical diagnosis of Alzheimer’s disease (AD) and 26 healthy controls, using two telephone screens for cognitive impairment, a self-report interview referred to as the TELE and the Telephone Interview for Cognitive Status (TICS). The sensitivity and specificity of the TELE to differentiate AD patients from healthy controls was 90.0 and 88.5% and those of the TICS were 86.7 and 88.5%, respectively. When receiver operator characteristic curves were constructed, the area under the curve for the TELE was 96.0% (SE 2.4%) and for the TICS 90.3% (SE 4.2%). Pearson’s correlation between the TELE and the Mini-Mental State Examination (MMSE) was 0.87 (p < 0.0001) and between the TICS and the MMSE 0.86 (p < 0.0001). The correlation between the TELE and the sum of the boxes of the Clinical Dementia Rating scale (CDR-SB) was –0.71 (p < 0.0001) and –0.75 between the TICS and the CDR-SB (p < 0.0001). These results indicate that both screens are sensitive and specific instruments for differentiating AD patients from healthy controls and have a strong correlation with face-to-face measures of cognitive function.

Binge Drinking in Midlife and Dementia Risk

Background: Studies examining the long-term effects of alcohol consumption on cognitive functioning have produced conflicting results. Our goal was to determine whether a long follow-up period combined with information about drinking patterns, in addition to total alcohol consumption, would provide new insights about the relationship of alcohol use with dementia risk. Methods: A population-based cohort of 554 Finnish twins, who had provided data on alcohol consumption in questionnaires in 1975 and 1981, was followed for 25 years. Subjects were age 65 years or older at the time of dementia assessment in 1999–2001. Dementia risk was analyzed with respect to varying patterns of alcohol use by log-linear modeling, adjusted for age, sex, and education. Results: By the end of follow-up, 103 participants had developed dementia. Binge drinking (ie, alcohol exceeding the amount of 5 bottles of beer or a bottle of wine on 1 occasion at least monthly), as reported in 1975, was associated with a relative risk of 3.2 (95% confidence interval = 1.2–8.6) for dementia. Passing out at least twice as a result of excessive alcohol use during the previous year, as reported in 1981, was associated with a relative risk of 10.5 (2.4–46) for dementia in drinkers. Conclusions: Binge drinking in midlife is associated with an increased risk of dementia.

Midlife Alcohol Consumption and Later Risk of Cognitive Impairment: A Twin Follow-up Study

In this prospective follow-up study, we monitored the effects of midlife alcohol consumption and drinking patterns on cognitive impairment risks in late life. 1,486 subjects recruited from the Finnish Twin Cohort were included in the analyses. Alcohol consumption data was obtained with structured questionnaires in 1975 and 1981, and subjects were contacted between 1999 and 2007 to conduct a telephone interview evaluating cognitive function. The mean follow-up period was 22.8 years (standard deviation 2.1 years). Both abstainers and heavy drinkers were found to have an increased risk of cognitive impairment in comparison to light drinkers (relative risk ratios 1.44; 95% confidence interval: 1.02-2.10 and 1.94, 1.10-3.44, respectively. Also, binge drinking at least monthly in 1975 and 1981, as well as more than two pass-outs due to excess drinking in 1981 were associated with an increased risk of cognitive impairment (1.98, 1.08-3.64 and 3.85, 1.51-9.83, respectively), even when excluding abstainers and controlling for total alcohol consumption. Subgroup analyses based on apolipoprotein E ε4 status suggest that the increased risk of cognitive impairment associated with being an abstainer is limited to subjects without an ε4 allele. Our results add to the evidence that light to moderate alcohol use is associated with a lower risk of cognitive impairment compared with higher levels of consumption. In addition, binge drinking was found to be an independent risk factor for cognitive impairment.

Regional cerebral glucose metabolism in monozygotic twins discordant for Alzheimer's disease.

We investigated regional cerebral glucose metabolic rates (rCMRgluc) with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in 7 monozygotic twin pairs discordant for Alzheimer’s disease (AD). Ten healthy volunteers with comparable mean age and educational level served as controls. In the hippocampus, the mean ± SD rCMRgluc were 0.20 ± 0.03 µmol/ml/min for the demented twins, 0.21 ± 0.03 µmol/ml/min for their non-demented co-twins, and 0.23 ± 0.02 µmol/ml/min for the controls. The mean hippocampal rCMRgluc was reduced in the demented twins (p = 0.006), compared with the controls. In the lateral temporal cortex, the mean ± SD rCMRgluc were 0.27 ± 0.05, 0.28 ± 0.04, and 0.32 ± 0.02 µmol/ml/min, respectively. These mean rates were reduced both in the demented (p = 0.02) and the non-demented (p = 0.01) twins, compared with the controls. In conclusion, in the demented twins, the reduction of rCMRgluc was detected in the hippocampus and lateral temporal cortex, i.e. the 2 brain areas which show early changes in pathological and imaging studies in AD. Their non-demented co-twins showed milder reductions, which may be an indication of genetic susceptibility for dementia, and an early sign of a dementing illness in them.

Voxel-based analysis of cerebral glucose metabolism in mono- and dizygotic twins discordant for Alzheimer disease

Background: Sporadic Alzheimer disease (AD) is a multifactorial disease to which both genetic and environmental factors contribute. Therefore, twin pairs are useful in studying its pathogenesis and aetiology. Cerebral glucose metabolism has been found to be reduced in AD patients. Methods: Cerebral glucose metabolism was studied in seven monozygotic (MZ) and nine same-sexed dizygotic (DZ) twin pairs discordant for AD using positron emission tomography. To obtain objective and explorative results concerning differences in glucose metabolism, the analysis was performed utilising modern voxel-based analysis methodology statistical parametric mapping and automated region-of-interest analysis. Results: In the demented MZ and DZ co-twins, cerebral glucose metabolism was extensively reduced compared with controls. The non-demented MZ co-twins showed reduced metabolism in inferior frontal, lateral temporal, parietal and medial temporal cortices as well as in the thalamus, putamen and right amygdala. In contrast, no reductions were found in the non-demented DZ co-twins. The reduction found in the non-demented MZ co-twins may be an indicator of genetic susceptibility to AD.

Voxel-based morphometry study on monozygotic twins discordant for Alzheimer's disease

We set to investigate the possible role of genes and environment in developing Alzheimers disease (AD) in monozygotic twin pairs discordant for AD.