Alzheimer Disease: Soininen H

Hiltunen M, Iivonen S, Soininen H. · Department of Neurology, Clinical Research Centre/Mediteknia, University of Kuopio, Kuopio, Finland. · Minerva Endocrinol. · Pubmed #16498364 No free full text.

Abstract: Aromatase enzyme encoded by CYP19 gene is responsible for the formation of estrone and estradiol from C19 androgens, androstenedione and testosterone. Several lines of evidence suggest an important role for the estrogens as well as androgens in the key pathogenic processes of Alzheimer's disease (AD) such as amyloid beta (Abeta) production, hyperphosporylation of tau protein, oxidative stress and apoptosis. Moreover, epidemiological studies suggest a neuroprotective role for estrogen in AD for which reason estrogen replacement therapies have been extensively studied as a way to improve the cognition and to lower the risk of AD. Aromatase enzyme is a key player in this context as it controls estrogen biosynthesis and, therefore, it may exert neuroprotective effects via increasing the local estrogen levels in injured neurons. Consistent with this idea, brain injury in mice and rats rapidly up-regulates aromatase enzyme expression in glial cells at the injury site suggesting that aromatase may be involved in protection of injured neurons through increased estrogen levels. Additional support for the role of aromatase in AD originates from the recent genetic studies, which have shown that single nucleotide polymorphisms in CYP19 gene are independently or in synergy with other AD risk genes increasing the susceptibility for AD. These genetic findings suggest that CYP19 gene encompasses functional alterations, which may affect stability, expression or activity of the aromatase enzyme. Characterization of these novel alternations may ultimately reveal new avenues to understand and design new therapeutic approaches to AD.

Hiltunen M, Helisalmi S, Kivipelto M, Soininen H. · Kuopion yliopisto, neurologian klinikka, Mediteknia. · Duodecim. · Pubmed #15641511 No free full text.

This publication has no abstract.

Kivipelto M, Laakso MP, Tuomilehto J, Nissinen A, Soininen H. · Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. · CNS Drugs. · Pubmed #12056919 No free full text.

Abstract: This paper focuses on hypertension and hypercholesterolaemia as risk factors for Alzheimer's disease and, as such, subjects for prevention. The long-term, prospective, population-based studies regarding the relationship between hypertension or hypercholesterolaemia and Alzheimer's disease, and the clinical studies regarding the association between antihypertensive or lipid-lowering medications and the risk of Alzheimer's disease, are reviewed. These studies provide evidence to suggest that elevated blood pressure and cholesterol levels earlier in life may have an important role in the development and expression of late-life Alzheimer's disease. Based on these data, we propose that proper, early interventions aimed at reducing these cardiovascular risk factors may have an impact on the future incidence and prevalence of Alzheimer's disease.

Partanen K, Laakso M, Erkinjuntti T, Soininen H. · KYS:n Kliinisen radiologian Osasto PL 1777, 70211 Kuopio. · Duodecim. · Pubmed #11989015 No free full text.

This publication has no abstract.

Mikkonen M, Soininen H, Alafuzof I, Miettinen R. · Department of Neuroscience and Neurology, University Hospital and University of Kuopio, Finland. · Rev Neurosci. · Pubmed #11783717 No free full text.

Abstract: During recent years, many reports have indicated that in addition to the progressive neuropathology observed in Alzheimer's disease (AD), there are also plasticity-related changes in the AD brain. It is thought that these plastic events are an attempt by the brain either to try to restore structure and function or to compensate for the damage caused by the disease. Alternatively, it is possible that these changes are a part of the disease's pathologic cascade. Here we discuss our recent findings on highly polysialylated neural cell adhesion molecule (PSA-NCAM) and neuronal-expressed calcium-binding proteins in the hippocampus and entorhinal cortex of controls and patients with AD in relation to the other findings which suggest that structural plasticity is an integral part of the disease process of AD.

Lehtovirta M, Laakso MP, Frisoni GB, Soininen H. · Department of Neurology, Kuopio University Hospital, P.O. Box 1777, 70211, Kuopio, Finland. · Neurobiol Aging. · Pubmed #10867214 No free full text.

Abstract: The epsilon 4 allele of apolipoprotein E is a risk factor for Alzheimer's disease, but also a modulator of its clinical picture. In this paper, recent research in neuroimaging of aging and Alzheimer's disease in relation to apolipoprotein E is reviewed, emphasizing the advances but also the controversies. Further, the possible clinicopathological implications of these findings are discussed.

Julkunen P, Jauhiainen AM, Westerén-Punnonen S, Pirinen E, Soininen H, Könönen M, Pääkkönen A, Määttä S, Karhu J. · Department of Clinical Neurophysiology, Kuopio University Hospital, POB 1777, Kuopio, Finland. · J Neurosci Methods. · Pubmed #18533272 No free full text.

Abstract: Our aim was to assess the potential of navigated transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) responses in studying neuronal reactivity and cortical connectivity in Alzheimer's disease (AD) and in mild cognitive impairment (MCI). We studied 14 right-handed subjects: five patients with AD, five patients with MCI and four healthy controls. Fifty TMS-pulses at an intensity of 110% of individually determined motor threshold were delivered to the hand area of primary motor cortex (M1) with navigated brain stimulation (NBS). Spreading of primary NBS-evoked neuronal activity was monitored with a compatible 60-channel EEG, and analyzed in time, frequency and spatial-domains. We found significantly reduced TMS-evoked P30 (time-locked response 30 ms after the magnetic stimulation) in the AD subjects. This reduction was seen in the temporo-parietal area ipsilateral to stimulation side as well as in the contralateral fronto-central cortex corresponding to the sensorimotor network, which is anatomically interconnected with the stimulated M1. In addition, there was a significant decrease in the N100 amplitude in the MCI subjects when compared with the control subjects. Thus, the combination of NBS and EEG revealed prominent changes in functional cortical connectivity and reactivity in the AD subjects. This pilot study suggests that the method may provide a novel tool for examining the degree and progression of dementia.

Sakka P, Tsolaki M, Hort J, Hager K, Soininen H, López Pousa S, Li C, Schwam E. · HYGEIA Diagnostic & Therapeutic Center of Athens, Athens, Greece. · Curr Med Res Opin. · Pubmed #17988434 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of donepezil in patients with Alzheimer's disease (AD) who discontinue memantine due to a lack of efficacy or not being well tolerated. METHODS: This study enrolled patients with moderate-to-severe AD (Mini-Mental State Examination [MMSE] score 5-17) who had a history of treatment with memantine monotherapy (10 mg/BID) for > or = 3 months prior to screening and maintained until study baseline. For inclusion in this study, the patient's memantine treatment had to have been judged as lacking efficacy or not well tolerated at the screening visit. Information on previous memantine use was also obtained with regard to dose and duration of treatment. At the baseline visit, patients were switched to open-label donepezil 5 mg/day for 4 weeks, and 10 mg/day thereafter. The primary efficacy measure was a change in MMSE at week 12 using a last observation carried forward (LOCF) analysis. Secondary measures included Physician and Caregiver Satisfaction Questionnaires (PSQ, CSQ), the Clinical Global Impression-Improvement (CGI-I), Neuropsychiatric Inventory (NPI), and a Caregiver Diary (CD). RESULTS: At week 12-LOCF, MMSE scores increased by a mean of 1.55 points from baseline (p < 0.0001). At end point, the PSQ and CSQ indicated consistent improvements in satisfaction/ease of use with donepezil; 60.2% of patients improved on the CGI-I; and 44.4-55.6% improved on each of three components of the CD. Improvements on the MMSE, CSQ, and CGI-I were apparent, irrespective of previous cholinesterase (ChE) inhibitor use. No significant effects were seen for the total score on the NPI. Withdrawal rates (8.7% due to adverse events [AEs]) and AEs were consistent with the known donepezil safety profile. CONCLUSION: Donepezil was effective and well tolerated in moderate-to-severe AD patients who discontinued memantine monotherapy, including those with previous exposure to ChE inhibitors.

Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M. · Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, Stockholm, Sweden. · Lancet Neurol. · Pubmed #16239176 No free full text.

Abstract: BACKGROUND: Physical activity may help maintain cognitive function and decrease dementia risk, but epidemiological findings remain controversial. The aim of our study was to investigate the association between leisure-time physical activity at midlife and the subsequent development of dementia and Alzheimer's disease (AD). METHODS: Participants were randomly selected from the survivors of a population-based cohort previously surveyed in 1972, 1977, 1982, or 1987. 1449 persons (72.5%) age 65-79 years participated in the re-examination in 1998 (mean follow-up, 21 years). 117 persons had dementia and 76 had AD. Multiple logistic regression methods were used to analyse the association between leisure-time physical activity and dementia or AD. FINDINGS: Leisure-time physical activity at midlife at least twice a week was associated with a reduced risk of dementia and AD (odds ratio [OR] 0.48 [95% CI 0.25-0.91] and 0.38 [0.17-0.85], respectively), even after adjustments for age, sex, education, follow-up time, locomotor disorders, APOE genotype, vascular disorders, smoking, and alcohol drinking. The associations were more pronounced among the APOE epsilon4 carriers. INTERPRETATION: Leisure-time physical activity at midlife is associated with a decreased risk of dementia and AD later in life. Regular physical activity may reduce the risk or delay the onset of dementia and AD, especially among genetically susceptible individuals.

Pennanen C, Laakso MP, Kivipelto M, Ramberg J, Soininen H. · Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. · J Neuroendocrinol. · Pubmed #14763994 No free full text.

Abstract: This study aimed to investigate whether there are differences in serum testosterone levels between male patients with Alzheimer's disease (AD) and cognitively normal male controls. Testosterone and sex hormone binding globulin (SHBG) levels were measured from 14 patients with mild to moderate AD and 16 age-matched control males. The AD patients had higher levels of serum total (P = 0.02) and free testosterone (P < 0.001), and higher free androgen index (FAI) (P = 0.02) compared to controls. No differences were found for the SHBG levels. These data provide no support for hypotheses of (disproportionally) decreased levels of serum testosterone in AD. These data also show that all cognitively normal controls had an FAI below the normal range.

Jones RW, Soininen H, Hager K, Aarsland D, Passmore P, Murthy A, Zhang R, Bahra R. · Research Institute for the Care of the Elderly, St Martin's Hospital, Bath, UK. · Int J Geriatr Psychiatry. · Pubmed #14716700 No free full text.

Abstract: OBJECTIVES: To compare directly, in the same patient cohort, the ease of use and tolerability of donepezil and galantamine in the treatment of Alzheimer's disease (AD), and investigate the effects of both treatments on cognition and activities of daily living (ADL). METHODS: Patients with mild to moderate AD from 14 European centres were randomised to receive open-label donepezil (up to 10 mg once daily) or galantamine (up to 12 mg twice daily) for 12 weeks, according to the approved product labelling. Physicians and caregivers completed questionnaires rating satisfaction with treatment/ease of use in daily practice. Secondary assessments were the ADAS-cog, the MMSE, and the DAD scale to assess ADL. Tolerability was evaluated by reporting adverse events (AEs). RESULTS: Both physicians and caregivers reported significantly greater overall satisfaction/ease of use for donepezil (n = 64) compared with galantamine (n = 56) at weeks 4, 12, and endpoint (week 12 LOCF; all p-values <0.05). Significantly greater improvements in cognition were also observed for donepezil versus galantamine on the ADAS-cog at Week 12 and endpoint (p-values <0.05). ADL improved significantly in the donepezil group compared with the galantamine group at weeks 4, 12, and endpoint (p-values <0.05). Most AEs were mild to moderate, however, 46% galantamine-treated patients reported gastrointestinal AEs vs 25% donepezil patients. CONCLUSIONS: Physician and caregiver ease of use/satisfaction scores, and assessments of cognition and ADL, showed significant benefits for donepezil compared with galantamine in this direct comparative trial. Both treatments were well tolerated, with more gastrointestinal AEs reported for galantamine vs donepezil.

Wimo A, Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wetterholm AL, Mastey V, Haglund A, Zhang R, Miceli R, Chin W, Subbiah P, Anonymous00005. · Department of Family Medicine, Umeå University, Umeå, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #12457078 No free full text.

Abstract: The costs and consequences of donepezil versus placebo treatment in patients with mild to moderate Alzheimer's disease (AD) were evaluated as part of a 1-year prospective, double-blind, randomized, multinational clinical trial. Patients received either donepezil (n = 142; 5 mg/day for 28 days followed by 10 mg/day according to the clinician's judgement) or placebo (n = 144). Unit costs were assessed in 1999 Swedish kronas (SEK) and converted to US dollars (USD). Donepezil-treated patients gained functional benefits relative to placebo on the Progressive Deterioration Scale (p = 0.042) and Instrumental Activities of Daily Living scale (p = 0.025) at week 52. Caregivers of donepezil-treated patients spent an average of 400 h less annually providing care than caregivers of placebo-treated patients. Mean annual healthcare costs were SEK 137,752 (USD 16,438) per patient for the donepezil group and SEK 135,314 (USD 16,147) in the placebo group. With the average annual cost of donepezil at SEK 10,723 (USD 1,280) per patient, the SEK 2,438 (USD 291) cost difference represented a 77% cost offset. When caregiver time and healthcare costs were included, mean annual costs were SEK 209,244 (USD 24,969) per patient in the donepezil group and SEK 218,434 (USD 26,066) in the placebo group, a total saving associated with donepezil treatment of SEK 9,190 (USD 1,097) per patient [95% CI of SEK -43,959 (USD -5,246), SEK 25,581 (USD 3,053); p = 0.6]. The positive effects on the efficacy outcome measures combined with no additional costs from a societal perspective indicate that donepezil is a cost-effective treatment, representing an improved strategy for the management of patients with AD.

Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P, Anonymous00311. · Karolinska Institutet, Alzheimer's Disease Research Center, Division of Geriatric Medicine, Huddinge Hospital B, Stockholm, Sweden. · Neurology. · Pubmed #11502918 No free full text.

Abstract: OBJECTIVE: To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD. METHODS: Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year. RESULTS: The study was completed by 66.9% of the donepezil- and 67.4% of the placebo-treated patients. The benefit of donepezil over placebo was demonstrated by the Gottfries-Bråne-Steen (a global assessment for rating dementia symptoms) total score at weeks 24, 36, and 52 (p < 0.05) and at the study end point (week 52, last observation carried forward; p = 0.054). Advantages of donepezil over placebo were also observed in cognition and activities of daily living (ADL) assessed by the Mini-Mental State Examination at weeks 24, 36, and 52, and the end point (p < 0.02) and by the Progressive Deterioration Scale at week 52 and the end point (p < 0.05). Adverse events (AE) were recorded for 81.7% of donepezil- and 75.7% of placebo-treated patients, with 7% of donepezil- and 6.3% of placebo-treated patients discontinuing because of AE. Treatment response to donepezil was not predicted by APOE genotype or sex in this population. CONCLUSION: As the first 1-year, multinational, double-blinded, placebo-controlled study of a cholinesterase inhibitor in AD, these data support donepezil as a well tolerated and effective long-term treatment for patients with AD, with benefits over placebo on global assessment, cognition, and ADL.

Laakso MP, Frisoni GB, Könönen M, Mikkonen M, Beltramello A, Geroldi C, Bianchetti A, Trabucchi M, Soininen H, Aronen HJ. · Department of Neurology, Kuopio University Hospital, Finland. · Biol Psychiatry. · Pubmed #10862805 No free full text.

Abstract: BACKGROUND: Magnetic resonance imaging (MRI) of hippocampal atrophy is a sensitive but not specific method to support the clinical diagnosis of early Alzheimer's disease (AD). We recently described our findings that atrophy of the entorhinal cortex (ERC) in frontotemporal dementia (FTD) is equal to that found in AD but that hippocampal atrophy in FTD is less than that found in AD. The MRI volumes of these structures provide a topographic representation of the region of interest. We hypothesized that two different dementias with distinct histopathologic and clinical features might, in addition to quantitative patterns, display topographically different patterns of atrophy. METHODS: We adopted a morphometric approach to monitor the pattern of atrophy of the hippocampus and the ERC by computing two-dimensional profiles from MRI volumes of the structures in control subjects and patients with FTD and AD. RESULTS: Compared with control subjects, atrophy of the hippocampus in patients with AD was diffuse. In patients with FTD, atrophy of the hippocampus was localized predominantly in the anterior hippocampus, suggesting a different pattern of hippocampal atrophy in FTD compared with AD. The amount and pattern of atrophy of the entorhinal cortex was virtually equal in both demented groups. CONCLUSIONS: This study provides novel data on the nature of medial temporal lobe atrophy in FTD. Morphometric MRI may be a useful technique for characterizing different patterns of atrophy in primary degenerative dementias in vivo.

Alafuzoff I, Helisalmi S, Heinonen EH, Reinikainen K, Hallikainen M, Soininen H, Koivisto K. · Department of Neuroscience and Neurology, Kuopio University, Finland. · Eur J Clin Pharmacol. · Pubmed #10805059 No free full text.

Abstract: BACKGROUND: A beneficial effect of selegiline (L-deprenyl) in Alzheimer's disease (AD) has been reported in several clinical studies. METHODS: The brain tissue from 17 deceased patients, members of a double-blind clinical trial to assess the potential benefit of selegiline in AD, were analysed. FINDINGS: In our study, the decrease in the Mini-Mental State Examination (MMSE) scores during the progress of the disease had been significantly influenced by selegiline treatment. Prior to death, the MMSE scores were significantly higher in those patients receiving selegiline than in those receiving placebo. However, according to our results, none of the lesions critical for AD diagnosis, such as counts of senile/neuritic plaques, neurofibrillary tangles or beta-A4 load, were influenced by the selegiline treatment. INTERPRETATION: In conclusion, according to our study, mechanisms other than neuronal degeneration seen as lesions critical for AD diagnosis are influenced by selegiline treatment, leading to the functional benefit found in AD.

Laakso MP, Hallikainen M, Hänninen T, Partanen K, Soininen H. · Department of Neurology, Kuopio University Hospital, Kuopio, Finland. · Neuropsychologia. · Pubmed #10689035 No free full text.

Abstract: Hippocampal volume measurements using magnetic resonance imaging (MRI) and assessment of performance in tests of delayed recall are among the most useful aids for diagnosing early Alzheimer's disease (AD) on an individual level. However, their comparative diagnostic accuracy has not been previously addressed. In this study we compared the diagnostic accuracy of these two methods in 57 patients with probable AD according to the NINCDS-ADRDA criteria, and 34 age- and gender-matched control subjects. The discriminatory power of the hippocampal volumes and delayed recall performance, Russel's Adaptation of the Visual Reproduction Test (VRT), were compared in discrimination function and receiver operator characteristic analyses. Right and left hippocampal volumes resulted in correct classification of 85.7-86.8% of the study subjects, respectively, while performance in the VRT resulted in correct classification of 93.4% of subjects. The area under curve value was 0.93 for the left hippocampus and 0.96 for the VRT. These data suggest that assessment of delayed recall with the VRT is of high diagnostic accuracy, and may surpass the diagnostic accuracy of hippocampal volumetry.

Helisalmi S, Hiltunen M, Valonen P, Mannermaa A, Koivisto AM, Lehtovirta M, Ryynänen M, Soininen H. · Department of Neurology, University Hospital and University of Kuopio, Puijonlaaksontie 2, FIN-70211 Kuopio, Finland. · J Neurol. · Pubmed #10525981 No free full text.

Abstract: Apolipoprotein E (APOE) epsilon4 allele is a major risk factor for the development of Alzheimer's disease (AD). It has been suggested that the quantitative expression of APOE alleles results from mutations in the promoter region of this gene. We studied the -491A/T promoter polymorphism and whether it is dependent on the APOE epsilon4 allele in clinic-based AD (n = 106) and community-based control (n = 123) samples. The -491A/T and APOE polymorphisms were analyzed using the polymerase chain reaction method and restriction fragment length polymorphism analysis. The APOE epsilon4 allele was strongly associated with AD when compared with controls, P < 0.001 (odds ratio 5.85, 95% CI 3.29- 10. 41). The genotype distribution of the -491A/T polymorphism did not significantly differ between the study groups (P = 0.063), and the -491A allele was not associated with any significant risk in the AD group when compared to controls (odds ratio 1.82, 95% CI 0.95-3.49). However, haplotype estimation analysis indicated linkage disequilibrium between APOE -491A/T polymorphism and the APOE epsilon4 allele. Our findings confirm APOE polymorphism still to be the most efficient predictor of risk in AD.

Håkansson K, Rovio S, Helkala EL, Vilska AR, Winblad B, Soininen H, Nissinen A, Mohammed AH, Kivipelto M. · School of Social Sciences, Department of Psychology, Växjö University, Sweden. · BMJ. · Pubmed #19574312 links to  free full text

Abstract: OBJECTIVES: To evaluate whether mid-life marital status is related to cognitive function in later life. DESIGN: Prospective population based study with an average follow-up of 21 years. SETTING: Kuopio and Joensuu regions in eastern Finland. PARTICIPANTS: Participants were derived from random, population based samples previously investigated in 1972, 1977, 1982, or 1987; 1449 individuals (73%), aged 65-79, underwent re-examination in 1998. MAIN OUTCOME MEASURES: Alzheimer's disease and mild cognitive impairment. RESULTS: People cohabiting with a partner in mid-life (mean age 50.4) were less likely than all other categories (single, separated, or widowed) to show cognitive impairment later in life at ages 65-79. Those widowed or divorced in mid-life and still so at follow-up had three times the risk compared with married or cohabiting people. Those widowed both at mid-life and later life had an odds ratio of 7.67 (1.6 to 40.0) for Alzheimer's disease compared with married or cohabiting people. The highest increased risk for Alzheimer's disease was in carriers of the apolipoprotein E e4 allele who lost their partner before mid-life and were still widowed or divorced at follow-up. The progressive entering of several adjustment variables from mid-life did not alter these associations. CONCLUSIONS: Living in a relationship with a partner might imply cognitive and social challenges that have a protective effect against cognitive impairment later in life, consistent with the brain reserve hypothesis. The specific increased risk for widowed and divorced people compared with single people indicates that other factors are needed to explain parts of the results. A sociogenetic disease model might explain the dramatic increase in risk of Alzheimer's disease for widowed apolipoprotein E e4 carriers.

Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y, Tsolaki M, Minthon L, Wallin AK, Hampel H, Bürger K, Pirttila T, Soininen H, Rikkert MO, Verbeek MM, Spiru L, Blennow K. · Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht, 6200 MD Maastricht, Netherlands. · Lancet Neurol. · Pubmed #19523877 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.

Helisalmi S, Väkevä A, Hiltunen M, Soininen H. · Institute of Clinical Medicine, Unit of Neurology and Brain Research Unit, Clinical Research Center, Mediteknia, Kuopio University, Kuopio, Finland. · Dement Geriatr Cogn Disord. · Pubmed #19293566 No free full text.

Abstract: BACKGROUND: In the present study we determined whether the cystatin c gene (CST3) is genetically associated with late-onset Alzheimer's disease (AD). METHODS: Two informative flanking single nucleotide polymorphisms (SNP), rs2424577 and rs3827143, of the CST3 gene and apolipoprotein E (APOE) gene were assessed in 568 Finnish AD patients and 688 cognitively healthy controls. Samples were genotyped with the TaqMan technique, and we conducted a single allele and genotypic distribution comparison as well as an estimation of haplotype frequencies between cases and controls. RESULTS: The APOE genotype distribution differed as expected between the AD cases and controls (p < 0.001). On the whole, any significant differences in AD risk were not found in single SNP and haplotype analyses for the CST3 gene between the whole study cohorts or in the stratified subgroups. Interestingly, AG-genotype carriers of rs3827143 showed a significant difference (p = 0.04) between cases and controls when compared to AA-genotype carriers, but this finding remained insignificant in the adjusted model. CONCLUSION: Although flanking SNP cover the whole gene transcript with strong linkage disequilibrium, our data show that the CST3 gene is not associated with AD risk in the Finnish population.

Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttilä T. · Department of Neuroscience and Neurology, Clinical Research Center/Mediteknia, Kuopio University Hospital, University of Kuopio, Finland. · Arch Neurol. · Pubmed #19273758 No free full text.

Abstract: BACKGROUND: There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and beta-amyloid 42 (Abeta42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. OBJECTIVE: To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. DESIGN: Cross-sectional study to correlate levels of CSF Abeta42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain. SETTING: Academic research. Patients The study included 123 patients (79 with clinically diagnosed AD, 29 with other dementia, and 15 with other neurologic disease). All underwent clinical evaluation and provided antemortem lumbar CSF samples, and neuropathologic data were collected from September 11, 1990, to March 13, 2003, in the Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. MAIN OUTCOME MEASURES: Levels of CSF Abeta42, total tau, and phosphorylated tau protein were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Abeta, hyperphosphorylated tau, and alpha-synuclein. RESULTS: Cerebrospinal fluid Abeta42 and tau protein levels were related to amyloid load and the presence of neurofibrillary pathologic abnormalities in the brain. Cerebrospinal fluid Abeta42 level correlated inversely with total Abeta load in the brain, and CSF tau level correlated with results of immunohistochemistry for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Abeta42 level and of increased CSF tau level. Based on the ratio of phosphorylated tau level to Abeta42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of pathologic neuritic plaque in the brain. CONCLUSIONS: Cerebrospinal fluid Abeta42 and tau proteins are biomarkers of AD-associated pathologic changes in the brain. The combination of abnormally low CSF Abeta42 level and abnormally high CSF tau level predicted the presence of AD pathologic features with high accuracy. This combination assay may be helpful in diagnosing the presence of AD pathologic changes in the brain.

Nordberg A, Darreh-Shori T, Peskind E, Soininen H, Mousavi M, Eagle G, Lane R. · Karolinska Institute, Division of Alzheimer Neurobiology, Karolinska University Hospital Huddinge, Stockholm, Sweden. · Curr Alzheimer Res. · Pubmed #19199870 No free full text.

Abstract: BACKGROUND: The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. METHODS AND FINDINGS: AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman's colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by 10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. CONCLUSION: The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation.

Jauhiainen AM, Kangasmaa T, Rusanen M, Niskanen E, Tervo S, Kivipelto M, Vanninen RL, Kuikka JT, Soininen H. · Unit of Neurology, Institute of Clinical Medicine, Mediteknia, Kuopio, Finland. · Dement Geriatr Cogn Disord. · Pubmed #18987469 No free full text.

Abstract: AIMS: The present study investigated cerebral glucose metabolism and structural atrophy in controls and subjects with mild cognitive impairment (MCI). METHODS: The study included 13 controls, 7 MCI subjects considered as prodromal Alzheimer's disease (MCI of the Alzheimer type, aMCI) and 7 MCI subjects having cognitive decline due to other causes, established by clinical evaluation (MCI of the non-Alzheimer type, naMCI). Glucose metabolism in the frontal, parietal and posterior cingulate cortices, the hippocampus and parahippocampal gyrus was evaluated using Statistical Parametric Mapping 2 (SPM2). Structural analysis of the whole-brain grey matter was performed with voxel-based morphometry in SPM2. RESULTS: Significant hypometabolism was found in the medial temporal lobe in aMCI subjects compared to the controls and naMCI subjects. In addition, both the aMCI and naMCI patients had hypometabolism of the posterior cingulum relative to controls. The naMCI subjects showed atrophy of frontal and occipital areas compared to controls and aMCI patients, whereas the aMCI subjects did not show atrophy compared to the other groups. CONCLUSION: aMCI subjects have reduced glucose uptake levels, particularly in areas susceptible to pathological changes in Alzheimer's disease, and the changes are more pronounced in aMCI than naMCI subjects. Our results also suggest that functional changes may be more prominent than structural changes in MCI.

Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Capellari S, Ferrer I, Gelpi E, Kövari V, Kretzschmar H, Nagy Z, Parchi P, Seilhean D, Soininen H, Troakes C, Budka H. · Institute of Neurology, Medical University of Vienna, Vienna, Austria. · Dement Geriatr Cogn Disord. · Pubmed #18849605 links to  free full text

Abstract: BACKGROUND: Dementia results from heterogeneous diseases of the brain. Mixed disease forms are increasingly recognized. METHODS: We performed a survey within brain banks of BrainNet Europe to estimate the proportion of mixed disease forms underlying dementia and age- and gender-specific influences. RESULTS: Data collected in 9 centres from 3,303 individuals were analysed. The proportion of patients with mixed diagnoses among all cases with Alzheimer disease (AD), vascular pathology (VP), argyrophilic grain dementia (AGD), and synucleinopathies, such as Lewy body dementia (LBD), Parkinson disease (PD) and synuclein pathology only in the amygdala, was 53.3%. Mixed pathology was more frequently reported with LBD, PD, AGD, and VP than with AD. The percentage of mixed diagnoses for AGD and VP significantly differed between centres. In patients younger than 75 years, synucleinopathies, and pure forms of AD, VP, and AGD were more frequent in men. Above 75 years of age, more women had pure AD and pure AGD. CONCLUSIONS: The most obvious neuropathological alteration should not terminate the diagnostic procedure since copathology is likely to be found. Neuropathological interpretation of AGD and VP has not been sufficiently established in a consensus. Pure forms of synucleinopathies are unlikely sole substrates for dementia.

Jauhiainen AM, Pihlajamäki M, Tervo S, Niskanen E, Tanila H, Hänninen T, Vanninen RL, Soininen H. · Institute of Clinical Medicine, Unit of Neurology, University of Kuopio, Kuopio, Finland. · Hippocampus. · Pubmed #18777563 No free full text.

Abstract: We investigated structural and functional changes in the medial temporal lobe (MTL) using magnetic resonance imaging (MRI) and compared the discriminative power of these measures with neuropsychological testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Functional MRI (fMRI) was performed in 21 elderly controls, 14 MCI subjects, and 15 mild AD patients during encoding and cued retrieval of word-picture pairs. A region-of-interest-based approach in SPM2 was used to extract the extent of hippocampal activation. The volumes of the hippocampus and entorhinal cortex (EC) were manually outlined from anatomical MR images. Discriminant analyses were conducted to assess the ability of hippocampal fMRI, MTL volumetry, and neuropsychological measures to classify subjects into clinical groups. Entorhinal but not hippocampal volumes differed significantly between the control and MCI subjects. Both entorhinal and hippocampal volumes differed between MCI and AD patients. There were no significant differences in the extent of hippocampal fMRI activation during encoding or retrieval between the groups. Entorhinal volume was the best discriminator with a discriminating accuracy of 85.7% between controls and MCI, 86.2% between MCI and AD, and 97.2% between controls and AD. Delayed recall of a wordlist classified the subjects, second best, with a discriminating accuracy of 81.8% between controls and MCI, 75% between MCI and AD and 93.5% between controls and AD. The accuracy of hippocampal volumetry ranged from 42.9 to 69.4%, and hippocampal fMRI activation during encoding and retrieval had a classification accuracy of only 41.4-57.7% between the groups. Our results suggest that evaluation of entorhinal atrophy, in addition to the prevailing diagnostic criteria, seems promising in the identification of prodromal AD. Future technical improvements may improve the utilization of hippocampal fMRI for early diagnostic purposes.