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Biomedical subjects

Tuula Pirttilä

Publications and source records attributed to Tuula Pirttilä.

At least 19 recordsLinked to original sources
PubMed2006

CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.

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.

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PubMed2006

CSF Abeta42, Tau and phosphorylated Tau, APOE epsilon4 allele and MCI type in progressive MCI.

BACKGROUND: The patients with mild cognitive impairment (MCI) have an elevated risk for Alzheimer's disease (AD). Especially the amnestic MCI is seen as prodrome of AD. Apolipoprotein E (APOE) epsilon4 allele, abnormal CSF Abeta42, Tau and phosphorylated Tau (phospho-Tau) levels are associated with elevated risk for AD. METHODS: APOE genotyping was done by PCR based method and baseline CSF Abeta42, Tau and phospho-Tau were measured by ELISA from 60 controls and 79 MCI patients. RESULTS: Thirty-three MCI patients developed dementia during an average of 3.5 years follow-up. CSF Abeta42 was decreased and Tau and phospho-Tau were increased in the progressive MCI patients. The APOE epsilon4 allele was more frequent in the progressive MCI patients. The APOE epsilon4 allele showed a dose dependent association o the Abeta42 levels in the progressive MCI patients and to all of the markers in controls. CONCLUSIONS: Decreased CSF Abeta42 and elevated Tau or phospho-Tau together with APOE epsilon4 allele are highly predictive for the dementia in MCI patients with amnestic or executive symptoms.

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PubMed2006

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

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

Activities of Daily Living↗
PubMed2006

[Not Available].

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Journal Article↗
PubMed2005

Fine mapping of the multiple sclerosis susceptibility locus on 5p14-p12.

Linkage analyses have identified four major MS susceptibility loci in Finns. Here we have fine mapped the region on chromosome 5p in 28 Finnish MS families. Marker D5S416 provided the highest pairwise LOD score, and multipoint and haplotype analyses restrict the critical region to about 5.3 Mb on 5p15 between markers D5S1987 and D5S416. Ascertaining for HLA type and geographical origin indicated that families with and without the HLA DR15 risk haplotype, as well as families within and outside an internal high-risk region, contributed to the linkage to 5p, implying the general significance for this locus in Finnish MS families.

Chromosome Mapping↗
PubMed2005

Proteomic analysis of glial fibrillary acidic protein in Alzheimer's disease and aging brain.

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.

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PubMed2005

CSF Abeta42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment.

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.

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PubMed2005

Oxidative modification of proteins in the frontal cortex of Alzheimer's disease brain.

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.

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PubMed2005

Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia.

Intracytoplasmic aggregation of alpha-synuclein protein as Lewy bodies in the brainstem neurons is diagnostic for Parkinson's disease, whereas if this process also occurs in the cortical neurons, it is considered pathognomonic for dementia with Lewy bodies. However, the link between alpha-synuclein incorporation into inclusions, neuronal dysfunction, and clinical symptoms needs to be clarified. Another important issue of the pathogenetic puzzle is to understand where alpha-synuclein pathology begins and how it progresses in the brain. To study this, we collected all cases from autopsy material (N = 904) that had alpha-synuclein pathology in the dorsal motor nucleus of vagus, substantia nigra, and/or basal forebrain nuclei. In this way, our study has a unique design because the selection of material is entirely based on the presence of alpha-synuclein pathology regardless of clinical phenotype. Retrospective clinical assessment then showed that only 32 (30%) of 106 alpha-synuclein-positive cases were diagnosed with a neurodegenerative disorder. The distribution or load of alpha-synuclein pathology did not permit a dependable postmortem diagnosis of extrapyramidal symptoms or cognitive impairment. Some neurologically unimpaired cases had a reasonable burden of alpha-synuclein pathology in both brainstem and cortical areas, suggesting that alpha-synuclein-positive structures are not definite markers of neuronal dysfunction.

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PubMed2005

Widespread and abundant alpha-synuclein pathology in a neurologically unimpaired subject.

The intracytoplasmic aggregation of alpha-synuclein (alphaS) protein is a common denominator for a group of neurodegenerative disorders currently known as synucleinopathies. It is generally assumed that the incorporation of alphaS protein into compact inclusions compromises the function and viability of its host cell via mechanical disruption. Herein, we report a widespread and abundant alphaS pathology in an elderly subject, whose medical history gave no indication of any neurodegenerative disease. We compared neuronal and glial components in this neurologically unimpaired subject with a patient with a clinical syndrome of dementia with Lewy bodies (DLB) by using a range of antigenic determinants and an in situ end-labeling technique. We detected no differences in vascular pathologies, in gliosis, or in apoptosis that would have explained the incompatible clinical end-points. With respect to the Alzheimer's disease-related changes, the only differences noted were the beta-amyloid aggregates in the putamen found in the DLB patient alone. Our findings suggest that there must be some currently unidentified factors rather than alphaS-positive inclusions that are responsible for the neuronal dysfunction. The alphaS-positive inclusions may well represent detoxified reserves that cells can tolerate for years, and thus prevention of their development could actually accelerate the diseases process.

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PubMed2004

Both N-methyl-D-aspartate (NMDA) and non-NMDA receptors mediate glutamate-induced cleavage of the cyclin-dependent kinase 5 (cdk5) activator p35 in cultured rat hippocampal neurons.

Cyclin-dependent kinase 5 (cdk5) regulates crucial neurobiological events, and deregulation of cdk5 has been implicated in several neurodegenerative disorders. The deregulation is suggested to occur due to cleavage of the cdk5 activator protein p35 to a smaller p25 fragment by the calcium-activated protease calpain. Here we have elucidated the role of different calcium-permeable ionotropic glutamate receptors in the induction of p35 cleavage in cultured rat hippocampal neurons. The glutamate receptor agonists glutamic acid, N-methyl-D-aspartate (NMDA), kainic acid, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) were all able to induce p35 cleavage, in a manner depending on extracellular calcium. The effect of glutamate was mediated by NMDA receptors, as it was prevented by the NMDA antagonist MK-801. Cyclothiazide (CTZ), an inhibitor of AMPA receptor desensitization, enhanced glutamate-induced p35 cleavage. In immature 6-day-old cultures the non-NMDA agonist kainic acid provoked p35 cleavage, whereas glutamate and NMDA were ineffective. The data suggest that both NMDA and non-NMDA receptors are able to induce p35 cleavage. Different factors, such as maturation state of neurons or desensitization properties of non-NMDA receptors, may determine which receptor predominantly mediates the effect of glutamate on p35 cleavage.

Animals↗
PubMed2004

Potential cost-effectiveness of a family-based program in mild Alzheimer's disease patients.

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.

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PubMed2004

[Pain and cognition].

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Adaptation, Psychological↗
PubMed2003

Differentiation of geriatric major depression from Alzheimer's disease with CSF tau protein phosphorylated at threonine 231.

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.

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PubMed2002

Cleavage of the cyclin-dependent kinase 5 activator p35 to p25 does not induce tau hyperphosphorylation.

Hyperphosphorylated tau protein is the primary component of neurofibrillary tangles observed in several neurodegenerative disorders. It has been hypothesized that in certain pathological conditions, the calcium activated protease, calpain, would cleave the cyclin-dependent kinase 5 (cdk5) activator p35 to a p25 fragment, which would lead to augmented cdk5 activity, and cdk5-mediated tau hyperphosphorylation. To test this hypothesis, we induced calpain-mediated p35 cleavage in rat hippocampal neuronal cultures and studied the relationship between p25 production, cdk5 activity, and tau phosphorylation. In glutamate-treated cells p35 was cleaved to p25 and this was associated with elevated cdk5 activity. However, tau phosphorylation was concomitantly decreased at multiple sites. The calpain inhibitor MDL28170 prevented the cleavage of p35 but had no effect on tau phosphorylation, suggesting that calpain-mediated processes, i.e., the cleavage of p35 to p25 and cdk5 activation, do not contribute to tau phosphorylation in these conditions. Treatment of the neuronal cultures with N-methyl-D-aspartic acid or with calcium ionophores resulted in an outcome highly similar to that of glutamate. We conclude that, in neuronal cells, the cleavage of p35 to p25 is associated with increased activity of cdk5 but not with tau hyperphosphorylation.

Animals↗
PubMed2002

Influence of phosphorylation of p35, an activator of cyclin-dependent kinase 5 (cdk5), on the proteolysis of p35.

Cyclin-dependent kinase 5 (cdk5) is involved in the development of the nervous system and neuronal process outgrowth, and it regulates several intracellular processes including cytoskeletal dynamics. Dysregulation of cdk5 has been implicated in many disorders of the nervous system. The activity of the kinase is regulated by binding of cdk5 activators (p35, p39, p67). We examined the phosphorylation of p35, and the role of phosphorylation in regulating the proteolysis of the p35 protein. By detecting changes in electrophoretic mobility, we observed that a significant proportion of p35 is phosphorylated in rat brain tissue. In cultured neurons, the phosphorylation was prevented by roscovitine, an inhibitor of cdk5 and some other cdks. The phosphatase inhibitor okadaic acid induced p35 degradation in neuronal cultures which was sensitive to the proteasome inhibitor lactacystin. These latter results agree with some previous studies showing that phosphorylation regulates proteasomal degradation of p35. Treatment of brain homogenate with okadaic acid in the presence of ATP led to accumulation of p35 phosphorylated also by a kinase that was not inhibited by roscovitine. This implies that the effect of okadaic acid on p35 degradation could also be contributed by a non-cdk kinase. The calpain protease has been shown to cleave p35. Our results suggest that this process may also be modulated by p35 phosphorylation under some conditions. We conclude that p35 phosphorylation influences the proteasome-mediated degradation of p35 and calpain-mediated cleavage of p35 to p25.

Acetylcysteine↗