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Hilkka S, Pirttilä T. · Kuopion yliopisto ja KYS: Neurologian Klinikka, Kuopio. · Duodecim. · Pubmed #15799249 No free full text.

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Pirttilä T, Wilcock G, Truyen L, Damaraju CV. · Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. · Eur J Neurol. · Pubmed #15525294 No free full text.

Abstract: In clinical trials, short-term galantamine treatment produces consistent positive effects on global ratings, cognitive tests, and assessments of activities of daily living and behavior in patients with mild-to-moderate Alzheimer's disease (AD), providing the rationale for longer-term, open-label treatment. In this continuation trial following enrollment in previous 12-month trials, patients received galantamine 24 mg/day for a total of 24 months (total exposure up to 36 months). Primary efficacy measures were the ADAS-cog/11 and DAD. Adverse events (AEs) were coded to WHO preferred terms, including AEs begun in previous trials. Initial improvement in cognitive function was followed by a gradual decline, as measured by increased ADAS-cog/11 scores. At 36 months, ADAS-cog/11 scores increased by a mean (SEM) of 12.4 (0.80) points (P < 0.001) versus a projected 22-point increase for untreated patients. Functional abilities, as measured by the DAD, had decreased significantly at each time point versus baseline (P < 0.001). The most common treatment-emergent AEs were agitation (16.1%), insomnia (12.4%), fall (11.2%), and urinary tract infection (10.2%). AEs were mainly mild to moderate, appropriate for an elderly population, with few judged treatment related. Galantamine 24 mg/day is safe and effective for long-term treatment of mild-to-moderate AD. Potential exists for prolonged benefit with galantamine therapy versus lack of treatment for the long-term.

Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K, Andreasen N, Hofmann-Kiefer K, DeBernardis J, Kerkman D, McCulloch C, Kohnken R, Padberg F, Pirttilä T, Schapiro MB, Rapoport SI, Möller HJ, Davies P, Hampel H. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center, Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany. · Arch Neurol. · Pubmed #12164722 links to  free full text

Abstract: BACKGROUND: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVES: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. DESIGN AND SETTING: Cross-sectional, multicenter, memory clinic-based studies. PARTICIPANTS: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls. MAIN OUTCOME MEASURES: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. RESULTS: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P =.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. CONCLUSION: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.

Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, Blennow K. · Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. · JAMA. · Pubmed #19622817 No free full text.

Abstract: CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

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.

Tukiainen T, Tynkkynen T, Mäkinen VP, Jylänki P, Kangas A, Hokkanen J, Vehtari A, Gröhn O, Hallikainen M, Soininen H, Kivipelto M, Groop PH, Kaski K, Laatikainen R, Soininen P, Pirttilä T, Ala-Korpela M. · Computational Medicine Research Group, Department of Biomedical Engineering and Computational Science, Helsinki University of Technology, P.O. Box 9203, FI-02015 HUT, Finland. · Biochem Biophys Res Commun. · Pubmed #18700135 No free full text.

Abstract: A three-molecular-window approach for (1)H NMR spectroscopy of serum is presented to obtain specific molecular data on lipoproteins, various low-molecular-weight metabolites, and individual lipid molecules together with their degree of (poly)(un)saturation. The multiple data were analysed with self-organising maps, illustrating the strength of the approach as a holistic metabonomics framework in solely data-driven metabolic phenotyping. We studied 180 serum samples of which 30% were related to mild cognitive impairment (MCI), a neuropsychological diagnosis with severely increased risk for Alzheimer's disease (AD). The results underline the association between MCI and the metabolic syndrome (MetS). Additionally, the low relativeamount of omega-3 fatty acids appears more indicative of MCI than low serum omega-3 or polyunsaturated fatty acid concentration as such. The analyses also feature the role of elevated glycoproteins in the risk for AD, supporting the view that coexistence of inflammation and the MetS forms a high risk condition for cognitive decline.

Leinonen V, Alafuzoff I, Aalto S, Suotunen T, Savolainen S, Någren K, Tapiola T, Pirttilä T, Rinne J, Jääskeläinen JE, Soininen H, Rinne JO. · Department of Neurosurgery, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland. · Arch Neurol. · Pubmed #18695050 No free full text.

Abstract: OBJECTIVE: To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens. DESIGN: Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens. SETTING: Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus. INTERVENTIONS: [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests. MAIN OUTCOME MEASURES: Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET. RESULTS: In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits. CONCLUSIONS: Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.

Korolainen MA, Pirttilä T. · Department of Neurology, Clinical Research Centre/Mediteknia, University of Kuopio and Kuopio University Hospital, Finland. · Acta Neurol Scand. · Pubmed #18547271 No free full text.

Abstract: OBJECTIVES: Many studies have shown differences in carbonylation and nitration of individual proteins in brain and body fluids of Alzheimer's disease (AD) patients. Therefore, we wanted to examine whether total levels of these oxidative stress markers of proteins were altered in AD. PATIENTS AND METHODS: Total levels of carbonyls and nitrotyrosine in cerebrospinal fluid, serum and plasma were measured in 22 AD patients and 18 age-matched controls using commercially available enzyme immunoassay kits. RESULTS: Protein carbonylation in cerebrospinal fluid did not differ between AD patients and controls but was decreased in APOE epsilon4 carriers as compared with non-carriers. Serum but not plasma levels of carbonyls tended to be decreased in AD patients as compared with aged controls. Nitrotyrosine concentrations did not differ between the groups. Surrogate cerebrospinal fluid markers for AD, beta-amyloid (1-42) and tau, correlated with blood carbonyl and nitrotyrosine levels. CONCLUSIONS: According to these preliminary data, changes in oxidative metabolism related to the pathogenesis of AD cannot be detected as increased cerebrospinal fluid, serum or plasma protein carbonylation or nitration.

Herukka SK, Pennanen C, Soininen H, Pirttilä T. · Department of Neurology, University of Kuopio, Kuopio, Finland. · J Alzheimers Dis. · Pubmed #18525127 No free full text.

Abstract: Cerebrospinal fluid (CSF) biomarkers and medial temporal lobe (MTL) atrophy predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). We investigated the association between the CSF biomarkers and MTL atrophy and the ability of these measures to predict AD in MCI patients in the same study population. The study included 21 MCI patients of whom eight progressed to AD during the study. CSF biomarkers were measured by using ELISA method and volumes of MTL structures were assessed by magnetic resonance imaging (MRI). Abeta42 levels were lower and tau and phospho-tau levels were higher in progressive subjects. The progressive subjects had lower volumes in all MRI measures. Tau and phospho-tau correlated inversely with hippocampal volumes and left entorhinal cortex volume in the whole study group. In the stable group, tau correlated with hippocampal volumes. Phospho-tau [corrected] had a negative correlation whereas Abeta42 [corrected] exhibited a positive correlation with left hippocampal volume in the progressive group. These results indicate that both measures may reflect the ongoing neurodegenerative process in the progressive MCI patients. However, the order of the changes in the CSF biomarkers and MTL atrophy remain unclear due to a small number of studied subjects and study design.

Lane R, Feldman HH, Meyer J, He Y, Ferris SH, Nordberg A, Darreh-Shori T, Soininen H, Pirttilä T, Farlow MR, Sfikas N, Ballard C, Greig NH. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936-1080, USA. · Pharmacogenet Genomics. · Pubmed #18334913 No free full text.

Abstract: OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.

Ojala J, Alafuzoff I, Herukka SK, van Groen T, Tanila H, Pirttilä T. · Department of Neuroscience and Neurology, University of Kuopio, Canthia, P.O. Box 1627, FIN-70211 Kuopio, Finland. · Neurobiol Aging. · Pubmed #17658666 No free full text.

Abstract: The inflammatory cytokines can initiate nerve cell degeneration and enhance the plaque production typically found in Alzheimer's disease (AD). Interleukin-18 (IL-18) is an inflammatory cytokine, which can induce the expression of interferon-gamma. This interleukin shares similarities with the IL-1 family of proteins. Like IL-1 beta, IL-18 is cleaved by caspase-1 (ICE) to an active secreted form. We examined the expressions of IL-18, -1 beta and ICE in different brain regions from AD patients that were categorized with respect to the Braak stage, and age-matched with non-demented controls. The levels of total-RNA and protein of IL-18 and ICE were increased, especially in the frontal lobe of AD patients and this change was not modified by ApoE genotype. Immunohistochemistry of AD brain samples detected IL-18 in microglia, astrocytes, and surprisingly in neurons, and it is also co-localized not only with amyloid-beta plaques but also with tau. In CSF, elevated IL-18 level was detected only in men and it also correlated with CSF tau in MCI. IL-18 may thus be a potential biomarker for men. Plasma levels of IL-18 showed no correlation with the disease. In conclusion, amyloid-beta may induce the synthesis of IL-18, and IL-18 kinases involved in tau phosphorylation as a part of the amyloid-associated inflammatory reaction.

Lämsä R, Helisalmi S, Hiltunen M, Herukka SK, Tapiola T, Pirttilä T, Vepsäläinen S, Soininen H. · Unit of Neurology, Clinical Department, Brain Research Unit, Clinical Research Center, Mediteknia, University of Kuopio, 70211 Kuopio, Finland. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17510943 No free full text.

Abstract: DHCR24 gene in chromosome 1 encodes seladin 1, a cholesterol synthesizing enzyme. Seladin 1 protects neurons from Abeta(42) mediated toxicity and participates in regulation of Abeta(42) formation by organizing the placement of APP cleaving beta-secretase in cholesterol-rich detergent-resistant membrane domains (DRMs). In Alzheimer's disease (AD) the level of seladin 1 in affected neurons is reduced, DRMs are disorganized and Abeta(42) formation is increased. To examine genetic association of the DHCR24 with AD, we genotyped four single nucleotide polymorphism (SNP) sites (rs638944, rs600491, rs718265, and rs7374) in 414 Finnish AD cases and 459 controls and calculated the allelic and genotypic distribution of both cases and controls. The single locus association analysis indicated that men carrying the T allele of rs600491 had an increased risk of AD (OR 1.7 95% CI 1.2-2.4; P = 0.004, Bonferroni corrected P = 0.048 with 12 tests). We estimated haplotypes of SNPs rs638944 and rs600491 between cases and controls and found overall distribution of haplotypes highly significant (P < 0.001). There was a common protective haplotype TC with frequency of 0.22 in cases and 0.30 in controls (P < 0.001) and a risk haplotype GC with frequency of 0.10 in cases and 0.05 in controls (P < 0.001). We also measured CSF Abeta(42), tau and phosphorylated tau (ptau) levels in a subgroup of AD cases (n = 44) and controls (n = 10) and found that AD cases that carry rs718265 GG had lower levels of Abeta(42) than other genotype carriers. Our findings indicate that DHCR24 gene may be associated with AD risk.

Rastas S, Verkkoniemi A, Polvikoski T, Juva K, Niinistö L, Mattila K, Länsimies E, Pirttilä T, Sulkava R. · Department of Neurology, University of Kuopio, Kuopio, Finland. · Stroke. · Pubmed #17395865 links to  free full text

Abstract: 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.

Korolainen MA, Nyman TA, Nyyssönen P, Hartikainen ES, Pirttilä T. · Department of Neurology, University of Kuopio and Kuopio University Hospital, Kuopio, Finland. · Clin Chem. · Pubmed #17289803 links to  free full text

Abstract: BACKGROUND: Carbonylation is an irreversible oxidative modification of proteins that has been linked to various conditions of oxidative stress, aging, physiological disorders, and disease. Increased oxidative stress is thus also considered to play a role in the pathogenesis of age-related neurodegenerative disorders such as Alzheimer disease (AD). In addition, it has recently become evident that the response mechanisms to increased oxidative stress may depend on sex. Several oxidized carbonylated proteins have been identified in plasma and brain of AD patients by use of 2-dimensional oxyblotting. METHODS: In this pilot study, we estimated the concentrations and carbonylation of the most abundant cerebrospinal fluid proteins in aging women and men, both AD patients suffering from mild dementia and individuals exhibiting no cognitive decline. Oxidized carbonylated proteins were analyzed with 2-dimensional multiplexed oxyblotting, mass spectrometry, and database searches. RESULTS: Signals for beta-trace, lambda chain, and transthyretins were decreased in probable AD patients compared with controls. The only identified protein exhibiting an increased degree of carbonylation in AD patients was lambda chain. The concentrations of proteins did not generally differ between men and women; however, vitamin D-binding protein, apolipoprotein A-I, and alpha-1-antitrypsin exhibited higher extents of carbonylation in men. CONCLUSIONS: None of the brain-specific proteins exhibited carbonylation changes in probable AD patients compared with age-matched neurological controls showing no cognitive decline. The carbonylation status of proteins differed between women and men. Two-dimensional multiplexed oxyblotting is applicable to study both the concentrations and carbonylation of cerebrospinal fluid proteins.

Lämsä R, Helisalmi S, Herukka SK, Tapiola T, Pirttilä T, Vepsäläinen S, Hiltunen M, Soininen H. · Clinical Department, Unit of Neurology, Brain Research Unit, Clinical Research Center, Mediteknia, University of Kuopio, Finland. · Neurobiol Aging. · Pubmed #17239995 No free full text.

Abstract: We genotyped SNPs rs11668477, rs12983082, rs11669576, rs2738444, rs5925 and rs1433099 in 405 Finnish AD cases and 463 controls and conducted a single allele and genotypic distribution comparison and estimated the haplotype frequencies between cases and controls and evaluated the level of biomarkers in haplotype carriers. We observed that T allele of rs2738444 was overrepresented in AD women with p=0.014 (Bonferroni corrected p=0.252). A specific haplotype block consisting of SNPs rs11669576, rs2738444 and rs5925 was identified and in women the haplotype GTT was overrepresented in AD cases when compared to controls with p=0.008. We measured CSF Abeta(42), tau and phosphorylated tau (ptau) levels in a subgroup of cases and controls and found that some genotypes were associated with increased levels of tau and ptau or a decreased Abeta(42) level in women. The specific risk haplotype GTT was associated with an increased level of tau and ptau in both men and women. Our findings suggest that LDLR gene may be associated with AD risk and its CSF biomarkers, especially in women.

Buerger K, Ewers M, Pirttilä T, Zinkowski R, Alafuzoff I, Teipel SJ, DeBernardis J, Kerkman D, McCulloch C, Soininen H, Hampel H. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center, Department of Psychiatry, Ludwig-Maximilian University Munich, Germany. · Brain. · Pubmed #17012293 links to  free full text

Abstract: Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.

Frey HJ, Mattila KM, Korolainen MA, Pirttilä T. · Brain Research Center, University of Tampere, Medical School, Building B, FIN-33014, Tampere, Finland. · Neurochem Res. · Pubmed #16362769 No free full text.

Abstract: The etiopathogenesis of Alzheimer's disease (AD) is still unclear, although clinical diagnostic criteria exist and the neuropathology of AD has been studied in great detail during the last 20 years. The present study addresses certain problems in the search for biological markers for the diagnosis, as well as in the follow-up of the course of AD and its differential diagnosis and reports some of our own observations in comparison with other studies. These include protein, genetic and neuroimaging markers. The definitions of biological markers and search strategies are also discussed.

Korolainen MA, Goldsteins G, Nyman TA, Alafuzoff I, Koistinaho J, Pirttilä T. · Department of Neuroscience and Neurology, University of Kuopio, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland. · Neurobiol Aging. · Pubmed #16298240 No free full text.

Abstract: There is a large body of evidence highlighting the importance of oxidative stress in the pathogenesis of Alzheimer's disease (AD). We have previously standardised a method that can be applied to study oxidative changes in individual brain proteins by using two-dimensional oxyblots (Korolainen MA, Goldsteins G, Alafuzoff I, Koistinaho J, Pirttilä T. Proteomic analysis of protein oxidation in Alzheimer's disease brain. Electrophoresis 2002;23(19):3428-33). Here we have identified proteins that exhibited oxidative changes in AD when compared to age-matched controls and these protein changes have been further examined in relation to the neuropathological data. Indeed, several Tris-HCl soluble proteins tended to be less oxidised in AD when compared to controls. Two enzymes, mitochondrial glutamate dehydrogenase and cytosolic malate dehydrogenase, were increased in amount but showed significantly decreased degree of oxidation in AD brains when compared to controls. Furthermore, some changes related to the amounts or oxidation statuses of proteins were associated with the duration of the clinical impairment and also with the neuropathology. These results do not contradict the hypothesis of increased oxidative stress in AD but may represent co-existing compensatory changes in response to oxidative stress.

Korolainen MA, Auriola S, Nyman TA, Alafuzoff I, Pirttilä T. · Department of Neuroscience and Neurology, University of Kuopio, Harjulantie 1D, P.O. Box 1627, FIN-70211 Kuopio, Finland. · Neurobiol Dis. · Pubmed #15979880 No free full text.

Abstract: Chronic inflammation is known to play an important role in the heterogeneous pathogenesis of Alzheimer's disease (AD). Activated astrocytes expressing glial fibrillary acidic protein (GFAP) are closely associated with AD pathology, such as tangles, neuritic plaques and amyloid depositions. Altogether, 46 soluble isoforms of GFAP were separated and most of them quantified by two-dimensional immunoblotting in frontal cortices of AD patients and age-matched controls. A 60% increase in the amount of more acidic isoforms of GFAP was observed in AD and these isoforms were both phosphorylated and N-glycosylated, while more basic isoforms were O-glycosylated and exhibited no quantitative differences between post-mortem AD and control brains. These data highlight the importance of exploring isoform-specific levels of proteins in pathophysiological conditions since modifications of proteins determine their activity state, localization, turnover and interaction with other molecules. Mechanisms, structures and functional consequences of modification of GFAP isoforms remain to be clarified.

Herukka SK, Hallikainen M, Soininen H, Pirttilä T. · Department of Neurology,University of Kuopio, Finland. . · Neurology. · Pubmed #15824371 No free full text.

Abstract: Baseline CSF amyloid beta-peptide-42 (Abeta42), tau, and phosphorylated tau (P-tau) levels from 46 control subjects and 78 patients with mild cognitive impairment (MCI) were measured. Twenty-three patients with MCI developed dementia during the study. Abnormal biomarkers were found early in the course of Alzheimer disease (AD). The most predictive assay for AD among the patients with MCI was the combination of Abeta42 and P-tau.

Martikainen J, Valtonen H, Pirttilä T. · Center for Pharmaceutical Policy and Economics, Department of Social Pharmacy, University of Kuopio, Finland. · Eur J Health Econ. · Pubmed #15452750 No free full text.

Abstract: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease characterized by a progressive deterioration in cognitive functions. AD will have a major impact on public health in the coming decades. The objective of this study was to evaluate the potential cost-effectiveness of a cognitive-behavioral family intervention (CBFI) program in patients with mild Alzheimer's disease in Finland. A second-order Monte Carlo technique was used to simulate the effectiveness of the intervention in AD patients and their informal caregivers over the course of 5 years. A Bayesian approach was applied to answer the question: how likely is it that the CBFI program is cost-effective? Based on existing information, the incremental net health benefit of the CBFI program is positive with over 0.9 probability, which indicates that the CBFI program has the highest probability of being optimal by providing greater net benefits than current practice. Furthermore, changes in the health-related quality of life of the caregivers were insensitive to AD patients' disease stage and settings of care. From the methodological point of view, the acceptability curve with a Bayesian approach provides a flexible way to characterize uncertainty surrounding cost-effectiveness parameters.

Buerger K, Zinkowski R, Teipel SJ, Arai H, DeBernardis J, Kerkman D, McCulloch C, Padberg F, Faltraco F, Goernitz A, Tapiola T, Rapoport SI, Pirttilä T, Möller HJ, Hampel H. · Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. · Am J Psychiatry. · Pubmed #12562590 links to  free full text

Abstract: OBJECTIVE: Differentiation of geriatric major depression from Alzheimer's disease is hampered by overlapping symptoms. Increased CSF concentrations of tau protein phosphorylated at threonine 231 (p-tau(231)) have been suggested as a biomarker for Alzheimer's disease. The authors asked whether p-tau(231) levels improve the differential diagnosis between geriatric major depression and Alzheimer's disease. METHOD: Included were 34 depression subjects, 64 with probable Alzheimer's disease, 17 with possible Alzheimer's disease, and 21 healthy comparison subjects. P-tau(231) concentrations were measured with an enzyme-linked immunosorbent assay. RESULTS: P-tau(231) levels were significantly higher in Alzheimer's disease than in geriatric major depression patients and healthy comparison subjects. For differentiation of probable Alzheimer's disease from major depression, p-tau(231) correctly allocated 87% of subjects. When possible mild Alzheimer's disease was compared to major depression, p-tau(231) correctly allocated 78% of subjects. CONCLUSIONS: CSF p-tau(231) should be evaluated as a potential biological marker for differentiation of geriatric depression from Alzheimer's disease.

Korolainen MA, Goldsteins G, Alafuzoff I, Koistinaho J, Pirttilä T. · Department of Neuroscience and Neurology, A.I Virtanen Institute for Molecular Sciences, University of Kuopio, Finland. · Electrophoresis. · Pubmed #12373773 No free full text.

Abstract: There is a growing body of evidence that oxidative stress plays a major role in Alzheimer's disease (AD) pathogenesis. Identification of oxidatively altered proteins in AD is important for understanding the relationship between protein oxidation, protein aggregation and neurodegeneration. In this communication, we report a method that can be applied to study oxidative changes of individual proteins in brain. In order to analyze protein oxidation by detection of protein-bound carbonyls, cytosolic protein extracts were derivatized with 2,4-dinitrophenylhydrazine (DNPH) and then separated by two-dimensional (2-D) gel electrophoresis. After electrotransfer to polyvinylidene difluoride (PVDF) membranes, proteins were first stained with Sypro Ruby protein stain, and then the oxidized proteins were detected with anti-dinitrophenyl (DNP) antibody. About 150 proteins and more than 100 oxidized proteins were detected and quantified in both AD and control cases by 2-D image analysis. The amount of protein-bound carbonyls was decreased for six and increased for one protein in AD. The amount of protein was increased for three proteins in AD. Furthermore, the degree of oxidation was calculated as the ratio of protein-bound carbonyls to the total amount of an individual protein. Two proteins showed a significant decrease in the degree of oxidation in AD. Our results suggest that the balance of protein oxidation and degradation is altered in AD.

Tapiola T, Pirttilä T, Mehta PD, Alafuzofff I, Lehtovirta M, Soininen H. · Department of Neuroscience and Neurology, University Hospital and University of Kuopio, Finland. · Neurobiol Aging. · Pubmed #11016543 No free full text.

Abstract: We investigated the usefulness of cerebrospinal fluid (CSF) beta-amyloid42 (Abeta42), beta-amyloid40 (Abeta40) and tau analyses in the diagnosis of Alzheimer's disease (AD). The study included 41 definite AD cases, 80 patients with probable AD. 27 with other dementias and 39 neurological controls. Abeta42, Abeta340 and tau protein concentrations in CSF were measured of using ELISA assays. Abeta42 levels were decreased and tau increased in AD. Combination of Abeta42 and tau resulted a sensitivity of 50.4% for AD and specificities of 94.8% for controls and 85.2% for other dementias. Ninety-one percent of the patients with Abeta42 below the cutoff value (340 pg/ml) and tau above the cutoff value (380 pg/ml) had AD. AD patients carrying apoE epsilon4 allele had lower Abeta42 (P < 0.005) and higher tau (P < 0.05) levels than those without an E4 allele, and 18 (81.8%) of the 22 AD patients who had normal Abeta42 and tau levels were apoE e4 allele non-carriers. Low Abeta42 and high tau concentration in CSF strongly support the diagnosis of AD. Measurement of Abeta42 may help the early diagnosis of cases at risk for AD such as apoE E4 allele carriers.

Tapiola T, Pirttilä T, Mikkonen M, Mehta PD, Alafuzoff I, Koivisto K, Soininen H. · Department of Neuroscience and Neurology, University Hospital and University of Kuopio, Kuopio, Finland. · Neurosci Lett. · Pubmed #10686392 No free full text.

Abstract: Earlier studies have shown elevated levels of tau protein and decreased levels of amyloid beta42 in cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD). We investigated the concentrations of Abeta42, Abeta40 and tau in CSF from AD patients on the baseline and after follow-up period of 3 years using ELISA assays. There was a significant decrease of Abeta42 (P<0.05) and Abeta40 (P<0.05) levels with time. AD patients with the duration of the disease 2 years or less at baseline had more pronounced decrease of Abeta42 concentrations compared to those with the duration of the disease more than 2 years at baseline (P<0.05). CSF tau protein concentrations increased in 9/17 but decreased in 8/17 patients. These results suggest that Abeta42 and Abeta40 may be useful in monitoring the long-term progression of AD particularly in the early stages of the disease.