Slowly progressive frontotemporal lobar degeneration caused by the C9ORF72 repeat expansion: a 20-year follow-up study.

A hexanucleotide expansion in chromosome 9 open-reading frame 72 (C9ORF72) has been found to be a major cause of frontotemporal lobar degeneration (FTLD). We describe a 20-year follow-up of a unique case with very slowly progressive FTLD caused by the C9ORF72 repeat expansion. In serial neuropsychological examinations, the patient's cognitive decline was exceptionally slow and after 20 years the patient still was mainly independent in activities of daily living. Our case indicates that there is great individual variation in the progression and duration of C9ORF72-associated FTLD, and also language variants or mixed phenotypes may be present.

CERAD Neuropsychological Total Scores Reflect Cortical Thinning in Prodromal Alzheimer's Disease.

BACKGROUND: Sensitive cognitive global scores are beneficial in screening and monitoring for prodromal Alzheimer's disease (AD). Early cortical changes provide a novel opportunity for validating established cognitive total scores against the biological disease markers. METHODS: We examined how two different total scores of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery and the Mini-Mental State Examination (MMSE) are associated with cortical thickness (CTH) in mild cognitive impairment (MCI) and prodromal AD. Cognitive and magnetic resonance imaging (MRI) data of 22 progressive MCI, 78 stable MCI, and 98 control subjects, and MRI data of 103 AD patients of the prospective multicenter study were analyzed. RESULTS: CERAD total scores correlated with mean CTH more strongly (r = 0.34-0.38, p < 0.001) than did MMSE (r = 0.19, p = 0.01). Of those vertex clusters that showed thinning in progressive MCI, 60-75% related to the CERAD total scores and 3% to the MMSE. CONCLUSION: CERAD total scores are sensitive to the CTH signature of prodromal AD, which supports their biological validity in detecting early disease-related cognitive changes.

CERAD-neuropsychological battery in screening mild Alzheimer's disease.

OBJECTIVES: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery (nb) is used as an evaluation tool for dementia. In Finland, CERAD-nb was introduced in 1999 and has been proposed to be used in primary health care. However, some of its parts need reassessment and focusing. The goal of this study was to examine the sensitivity and specificity of the subtests and their cut-off points most appropriate for identifying mild Alzheimer's disease (AD). MATERIALS AND METHODS: The study population consisted of 171 patients with mild AD and 315 cognitively normal elderly. Both groups underwent CERAD-nb investigation as a part of a wider examination procedure. RESULTS: The most efficient subtests to discriminate patients with mild AD from the normal elderly were Wordlist delayed recall and savings, Wordlist learning and Wordlist recognition and a new variable of Total recall. Optimal cut-off points for each subtest are suggested. The sensitivities of the verbal memory subtests varied between 0.75 and 0.94, the specificities between 0.80 and 0.93 and the areas under the receiver operating characteristics curve between 0.89 and 0.96. CONCLUSIONS: The CERAD-nb is capable of differentiating cases with mild AD from normal elderly individuals particularly with its verbal memory subtests. New cut-off scores for CERAD's subtests validated in the study further enhance the differentiating power, and with these clarifications, CERAD-nb is considered appropriate to be used as a screening tool for AD even in primary health care.

Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study.

OBJECTIVES: To examine the associations between serum homocysteine (tHcy), holotranscobalamin (holoTC, the biologically active fraction of vitamin B12) and folate and cognitive functioning in a longitudinal population-based study of Finnish elderly subjects. SUBJECTS AND DESIGN: tHcy, holoTC and folate were measured at baseline in 274 dementia-free subjects aged 65-79years from the Cardiovascular Risk Factors, Aging and Dementia study. Subjects were re-examined 7years later, and global cognition, episodic memory, executive functioning, verbal expression and psychomotor speed were assessed. RESULTS: Higher baseline tHcy levels were associated with poorer performance in global cognition, relative difference: 0.90 [95% confidence interval (CI) 0.81-0.99]; episodic memory: 0.87 (95% CI 0.77-0.99); executive functions: 0.86 (95% CI 0.75-0.98); and verbal expression: 0.89 (95% CI 0.81-0.97) at follow-up. Increased holoTC levels were related to better performance on global cognition: 1.09 (95% CI 1.00-1.19); executive functions: 1.11 (95% CI 1.01-1.21); and psychomotor speed: 1.13 (95% CI 1.01-1.26). After excluding 20 cases of incident dementia, increased tHcy remained associated with poorer performance in episodic memory, execution functions and verbal expression. Higher holoTC levels tended to be related to better performance in executive functions and psychomotor speed, while elevated serum folate concentrations were significantly related to higher scores in global cognition and verbal expression tests. CONCLUSIONS: tHcy, holoTC and folate levels are related to cognitive performance 7years later even in nondemented elderly subjects. Randomized trials are needed to determine the impact of vitamin B12 and folate supplementation on preventing cognitive decline in the elderly.

Plasma Abeta42 and Abeta40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study.

BACKGROUND: Single measurements of plasma Aß are not useful in the diagnostics of Alzheimer's disease (AD). However, changes in plasma Aß levels during repeated testing may be helpful in the prediction and evaluation of progression of the incipient AD or mild cognitive impairment. OBJECTIVE: To examine the relation of baseline and serial plasma Aß levels to cognitive change in follow-up. METHODS: 269 subjects (52 cognitively impaired and 217 controls) from a population-based cohort were clinically followed up from 3 to 6 years. Serial plasma samples were available from 70 subjects who were followed up for 3 years and 43 subjects followed for 6 years. The plasma Aß levels were measured using ELISA. RESULTS: Subjects who declined cognitively during the follow-up had lower levels of plasma Aß42 at the baseline. Plasma Aß42 and the Aß42/Aß40 ratio decreased (-2.4 pg/ml for Aß42 in 6 years) in those who declined in follow-up, whereas Aß42 and the Aß42/Aß40 ratio increased in the subjects who remained cognitively stable or improved in follow-up. Subjects using acetylsalicylic acid, dipyridamole, antidiabetic or anticoagulant drugs as well as subjects with coronary heart disease had higher levels of Aß40. CONCLUSIONS: Low or decreasing plasma Aß42 during the follow-up is associated with cognitive decline. Serial measurement of plasma Aß42 may be useful in the detection of the subjects who are at risk for cognitive decline.

Atrophic enlargement of CSF volume after subarachnoid hemorrhage: correlation with neuropsychological outcome.

BACKGROUND AND PURPOSE: Ventricular dilation and sulcal enlargement are common sequelae after aSAH. Our aim was to quantify the late ventricular dilation and volumes of the CSF spaces after aSAH and to determine if they correlate with neurologic and cognitive impairments frequently detected in these patients. MATERIALS AND METHODS: 3D T1-weighted images needed for volumetry were available in 76 patients 1 year after aSAH, along with 75 neuropsychological assessments. Volumes of CSF segments and ICV were quantified by SPM in 76 patients and 30 control subjects to determine CSF/ICV ratios. The mCMI was calculated to roughly evaluate the ventricular dilation. The contributing factors for enlarged ventricles and CSF volumes were reviewed from radiologic, clinical, and neuropsychological perspectives. RESULTS: The mCMI was higher in patients with aSAH (0.23 +/- 0.06) compared with control subjects (0.20 +/- 0.04; P = .020). In line with these planimetric measurements, the SPM-based CSF/ICV ratios were higher in patients with aSAH (35.58 +/- 7.0) than in control subjects (30.36 +/- 6.25; P = .001). Preoperative hydrocephalus, higher HH and Fisher grades, and focal parenchymal lesions on brain MR imaging, but not the treatment technique, were associated with ventricular enlargement. The clinical outcome and presence of neuropsychological deficits correlated significantly with CSF enlargement. CONCLUSIONS: Ventricular and sulcal enlargement, together with reduced GM volumes, after aSAH may indicate general atrophy rather than hydrocephalus. Enlarged CSF spaces correlate with cognitive deficits after aSAH. A simple measure, mCMI proved to be a feasible tool to assess the diffuse atrophic brain damage after aSAH.

PET amyloid ligand [11C]PIB uptake and cerebrospinal fluid beta-amyloid in mild cognitive impairment.

BACKGROUND: In mild cognitive impairment (MCI), Alzheimer's disease (AD)-type cerebrospinal fluid (CSF) biomarker profiles predict rapid progression and conversion to AD. An increased brain amyloid burden in AD and MCI has been demonstrated with PET using [(11)C]PIB (Pittsburgh compound B). Little is known about the relationship between these biomarkers in MCI. METHODS: We studied 15 patients with amnestic MCI and 22 controls with PET using [(11)C]PIB. In MCI patients, CSF levels of Abeta42, pTAU, totalTAU and the Abeta42/pTAU ratio were measured. RESULTS: In MCI patients, CSF Abeta42 was abnormal in 53% of patients, totalTAU in 67%, pTAU in 64% and the Abeta42/pTAU ratio in 64%. A composite neocortical [(11)C]PIB uptake score was increased in 87% of the MCI patients. Only 54% of [(11)C]PIB-positive subjects showed AD-type Abeta42 values. During a 2-year follow-up, 6 MCI patients converted to AD, all of them had increased neocortical PIB scores at the MCI stage. Abnormal CSF Abeta42 was found in 3 patients, pTAU in 3 patients and Abeta42/pTAU ratio in 4 patients. CONCLUSION: Follow-up studies are needed to confirm whether [(11)C]PIB uptake might be more sensitive than CSF Abeta42 concentration in detecting increased amyloid burden in MCI, as suggested by the results of this study.

Heterogeneity of cerebral perfusion 1 week after haemorrhage is an independent predictor of clinical outcome in patients with aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid haemorrhage (aSAH) can be associated with acute global and regional decrease in cerebral perfusion. Furthermore, cerebral vasospasm may lead to development of delayed ischaemic deficits. The aim of the study was to find out whether cerebral perfusion heterogeneity, an indicator of cerebral microvascular function and autoregulation, measured by single-photon emission tomography (SPET), is able to predict the long-term clinical outcome of aSAH. METHODS: The perfusion SPET data of 55 patients with aSAH were analysed by dividing the brain into 384 regions of interest. Spatial perfusion heterogeneity was assessed by calculating the relative dispersions (RD, coefficient of variation) from the SPETs performed before treatment (RD1) and 1 week after early surgical or endovascular treatment of the ruptured aneurysm (RD2). Both RDs were compared to the clinical outcome (Glasgow Outcome Scale, GOS), neuropsychological test scores and late ischaemic findings in MRI 1 year after SAH. RESULTS: High RD2 (OR 1.96; 95% CI 1.18-3.26; p = 0.009) and poor clinical condition (Hunt and Hess grade) on admission (OR 6.60; 95% CI 1.78-24.52; p = 0.005) proved to be independent predictors of poor or moderate clinical outcome (GOS 1-4). RD2 was higher in patients with ischaemic findings in 12-month MRI than in those without ischaemic findings (p = 0.008). RD2 also correlated with neuropsychological outcome 1 year after aSAH. CONCLUSIONS: Perfusion heterogeneity is an independent predictor of the clinical outcome of aSAH and may thus be a valuable measure in the assessment of the disease.

Apolipoprotein E epsilon 4 allele is associated with increased atrophy in progressive mild cognitive impairment: a voxel-based morphometric study.

BACKGROUND: The apolipoprotein E (APOE) epsilon4 allele is a risk factor for Alzheimer's disease. Earlier studies have shown differences in brain structure according to the APOE epsilon4 status. OBJECTIVE: To assess possible differences in brain structure according to the APOE epsilon4 status in mild cognitive impairment (MCI) subjects in relation to conversion to dementia. METHODS: In a follow-up study of 56 MCI subjects, 13 MCI subjects progressed to dementia (PMCI) during a mean follow-up time of 31 months. Brain structure differences in both stable MCI (SMCI) and PMCI epsilon4 carriers and noncarriers in the baseline MRI scan were assessed with voxel-based morphometry. RESULTS: The SMCI epsilon4 carriers had atrophy in the amygdala and hippocampus compared to the SMCI noncarriers. The PMCI epsilon4 carriers revealed atrophy of the left inferior frontal gyrus and parietal cortex compared to the PMCI noncarriers. CONCLUSION: The rate of brain atrophy in certain brain areas may be increased in epsilon4-positive MCI subjects progressing to dementia.

Association of metabolic syndrome with Alzheimer disease: a population-based study.

OBJECTIVE: To assess the association of metabolic syndrome (MetS) with Alzheimer disease (AD). METHODS: The authors derived subjects from a population-based study of 980 randomly selected elderly subjects. After exclusion of all non-Alzheimer dementia cases, the final study population included 959 subjects (337 men and 622 women) aged 69 to 78 years. The presence of MetS was defined according to the National Cholesterol Education Program (Adult Treatment Panel III) criteria, and the diagnosis of AD was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association. RESULTS: Of the study subjects, 418 (43.6%) had MetS. Probable or possible AD was diagnosed in 45 subjects (4.7%). AD was more frequently detected in subjects with MetS than in subjects without MetS (7.2 vs 2.8%; p < 0.001). The prevalence of AD was higher in women with MetS vs women without the syndrome (8.3 vs 1.9%; p < 0.001), but in men with MetS, the prevalence of AD was not increased (3.8 vs 3.9%; p = 0.994). In univariate logistic regression analysis, MetS was significantly associated with AD (odds ratio [OR] 2.71; 95% CI 1.44 to 5.10). In multivariate logistic regression analysis including also apolipoprotein E4 phenotype, education, age, and total cholesterol, MetS was significantly associated with AD (OR 2.46; 95% CI 1.27 to 4.78). If only nondiabetic subjects were included in the multivariate analysis, MetS was still significantly associated with AD (OR 3.26; 95% CI 1.45 to 7.27). CONCLUSION: Metabolic syndrome is associated with Alzheimer disease in elderly subjects.

Subarachnoid hemorrhage is followed by temporomesial volume loss: MRI volumetric study.

OBJECTIVE: To assess whether subarachnoid hemorrhage (SAH) and its treatment is followed by volume loss in temporomesial structures. METHODS: One hundred fifty-five consecutive patients with aneurysmal SAH were randomly assigned to surgical or endovascular treatment. Volumetric MRI was performed in 77 SAH patients with good or moderate clinical outcome 1 year after hemorrhage. A comprehensive neuropsychological test battery was used to evaluate the cognitive performance of the subjects. Thirty healthy individuals were imaged as MRI controls. RESULTS: The normalized hippocampal (HC) volumes were 24.7/23.7 (right/left), and the amygdaloid (AM) volumes were 21.0/20.5 in the matched control population. In SAH patients, the corresponding volumes were smaller, HC 23.2/21.3 (p = 0.072/0.002) and AM 18.4/18.7 (p = 0.012/0.045). In addition, the AM ipsilateral to the ruptured aneurysm was smaller in patients who had undergone surgical treatment (15.7) vs endovascular treatment (20.3; p < 0.001). Treatment modality did not significantly affect the measured HC volumes. The hippocampal but not amygdaloid volumes correlated with the scores of several neuropsychological tests. CONCLUSION: Subarachnoid hemorrhage and its treatment may be followed by atrophy in temporomesial structures. A clear correlation was demonstrated between neuropsychological performance and reduced temporomesial volumes.

A voxel based morphometry study on mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to confer an increased risk of progressing to dementia and most often Alzheimer's disease (AD). Various approaches such as imaging of the brain have been applied to predict the conversion of MCI to dementia. A number of volumetric magnetic resonance imaging (MRI) studies have detected atrophy of the medial temporal lobe in subjects with MCI, but for the other cerebral regions the results have been inconsistent. OBJECTIVE: To study the pattern of brain atrophy in MCI. METHODS: Thirty two controls and 51 individuals with MCI deriving from population based cohorts were studied by MRI using voxel based morphometry. The threshold of t maps was set at p < 0.001. RESULTS: Individuals with MCI had significant unilateral atrophy in the medial temporal lobe on the right side. Less extensive atrophy was found elsewhere-for example, in the temporal lobe, left superior parietal lobule, left anterior cingulate gyrus, and bilaterally in the thalami. CONCLUSIONS: The MRI findings in MCI resemble those seen in early AD.

Polymorphisms in the CYP19 gene confer increased risk for Alzheimer disease.

BACKGROUND: Brain aromatase may be neuroprotective by increasing the local estrogen levels in injured neurons. Aromatase is encoded by the CYP19 gene located at 15q21.1, a chromosomal region in linkage disequilibrium (LD) with Alzheimer disease (AD) in this sample. OBJECTIVE: To investigate whether nine single-nucleotide polymorphisms (SNP) spanning the CYP19 gene were associated with AD. METHODS: Three hundred ninety-four patients were compared with 469 nondemented control subjects using single-locus and haplotype approaches. Haplotypes were identified using the expectation/maximization algorithm and latent class analysis, which included additional information on age, sex, and APOE polymorphism. RESULTS: Allelic and genotypic frequencies for three adjacent SNP differed between AD and control groups. Both haplotype approaches identified an approximately 60% increase (p = 0.02) in the risk of AD for one haplotype and similar levels of excess risk irrespective of APOE polymorphism and gender. CONCLUSION: Genetic variation in the brain aromatase gene may modify the risk for AD.

Prevalence of mild cognitive impairment: a population-based study in elderly subjects.

OBJECTIVES: Mild cognitive impairment (MCI) has been suggested as a term for a boundary area between normal aging and dementia, especially Alzheimer's disease (AD). In follow-up studies, more than 50% of MCI subjects have been converted to dementia in 3-4 years. However, the epidemiology of MCI is not well known. This study was designed to determine the prevalence of MCI in an elderly population. METHODS: A total of 806 subjects (60-76 years of age) from a population-based random sample of 1150 subjects living in the city of Kuopio in eastern Finland were evaluated. Neuropsychological tests and a structured interview including the modified Clinical Dementia Rating (CDR) were used to apply the diagnostic criteria of MCI as proposed by Mayo Clinic Alzheimer's Disease Research Centre. Thus, subjects having a test score more than 1.5 SDs below the age appropriate mean in memory tests and a CDR score of 0.5 but no dementia, were diagnosed as having MCI. RESULTS: A total of 43 subjects, 5.3%, met the MCI criteria. MCI was more prevalent in older and less-educated subjects, but no difference was found between men and women. The CDR appeared to be the most important part of the criteria. The memory tests had less impact on prevalence variables. CONCLUSIONS: The low prevalence of MCI indicate that in a population-based study design its criteria may identify a more homogeneous group of subjects at the lower end of the cognitive continuum as contrasted with various other criteria of cognitive impairment in the elderly population. This is compatible with follow-up studies showing a high probability of dementia in the MCI group. Thus, probable candidates for trials of preventive intervention for dementia can be screened from the elderly population using these diagnostic criteria.

Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study.

OBJECTIVE: To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life. DESIGN: Prospective, population based study. SETTING: Populations of Kuopio and Joensuu, eastern Finland. PARTICIPANTS: Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65-79 took part in the re-examination in 1998. MAIN OUTCOME MEASURES: Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life. RESULTS: People with raised systolic blood pressure (>/=160 mm Hg) or high serum cholesterol concentration (>/=6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease. CONCLUSION: Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.

Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study.

OBJECTIVE: To evaluate the impact of midlife elevated serum cholesterol levels and blood pressure on the subsequent development of mild cognitive impairment (MCI) and to investigate the prevalence of MCI in elderly Finnish population, applying the MCI criteria devised by the Mayo Clinic Alzheimer's Disease Research Center. BACKGROUND: MCI has been considered as a predictor of AD. Vascular risk factors may be important in the development of cognitive impairment and AD. However, the role of vascular risk factors in MCI and the prevalence of MCI still remain virtually unknown. METHODS: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1,449 subjects aged 65 to 79 years were reexamined in 1998. RESULTS: Eighty-two subjects, 6.1% of the population (average age, 72 years) met the criteria for MCI. Midlife elevated serum cholesterol level (> or =6.5 mmol/L) was a significant risk factor for MCI (OR, 1.9; 95% CI, 1.2 to 3.0, adjusted for age and body mass index); the effect of systolic blood pressure approached significance. CONCLUSION: Data point to a role for midlife vascular risk factors in the development of MCI in late life.

Mood improvement reduces memory complaints in depressed patients.

BACKGROUND: The aim was to examine associations between memory complaints, cognitive performance and mood in 174 adult, clinically depressed, neurologically healthy patients at baseline and during six months of follow-up. METHODS: Subjective memory disturbance was assessed using the Memory Complaint Questionnaire (MCQ). Levels of cognitive function, including memory, were assessed using a battery of neuropsychological tests. Mood and personality traits were assessed using rating scales, including the Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS) and the 90-item Symptom Check List (SCL-90). RESULTS: At baseline, patients complaining of memory disturbances had higher BDI and HDRS scores than patients not complaining of memory problems. They also did less well in objective memory performances but not in other cognitive functions. Complaints of memory problems decreased during the follow-up. This change was associated with mood improvement and with reductions in other mental symptoms but not with changes in cognitive performance. In logistic regression analysis factors independently associated with MCQ change were age (OR 0.96) and BDI change (OR 1.06). CONCLUSIONS: Subjective memory problems usually decline if depression is alleviated.

APOE-epsilon4 is associated with weight loss in women with AD: a population-based study.

OBJECTIVE: To investigate whether the APOE-epsilon4 allele is associated with weight loss in patients with AD or in nondemented elderly subjects. BACKGROUND: Weight loss has been considered a typical feature of AD. APOE-epsilon4 is a risk factor for AD and was recently proposed to be associated with weight loss in elderly women. It is not known whether APOE-epsilon4 is associated with weight loss in patients with AD or in the general population. METHODS: Weight and BMI measurements at an average interval of 3.5 years and APOE phenotype determination were performed in an elderly population (n = 980), including 46 patients with AD and 911 control subjects at the end of the follow-up. RESULTS: On average, patients with AD with the epsilon4 allele lost 1.9 +/- 4.0 kg (BMI 0.8 +/- 1.8 kg/m2) whereas epsilon4 noncarriers gained 1.2 +/- 3.8 kg (BMI 0.4 +/- 1.5 kg/m2) (both p < 0.05), after controlling for diabetes and exercise. However, when men and women were analyzed separately, weight loss was observed only in those women with AD with the epsilon4 allele. Clinically significant weight loss, defined as loss of > or = 5% of body weight, occurred more frequently in both patients with AD (30% versus 6%; p < 0.05) and control subjects (28% versus 18%; p < 0.001) carrying the epsilon4 allele. CONCLUSIONS: The APOE-epsilon4 allele may contribute to the unexplained weight loss in AD, especially in women.

Molecular evolution of puumala hantavirus in Fennoscandia: phylogenetic analysis of strains from two recolonization routes, Karelia and Denmark.

Like other members of the genus HANTAVIRUS: in the family BUNYAVIRIDAE:, Puumala virus (PUUV) is thought to be co-evolving with its natural host, the bank vole Clethrionomys glareolus. To gain insight into the evolutionary history of PUUV in northern Europe during the last post-glacial period, we have studied wild-type PUUV strains originating from areas along two postulated immigration routes of bank voles to Fennoscandia. Full-length sequences of the S RNA segment and partial sequences (nt 2168-2569) of the M segment were recovered by RT-PCR directly from bank vole tissues collected at three locations in Russian Karelia and one location in Denmark. Phylogenetic analysis showed that strains from Karelia and Finland belong to the same genetic lineage, supporting the hypothesis that PUUV spread to present Finland via a Karelian land-bridge. The Danish PUUV strains showed no particularly close relatedness to any of the known PUUV strains and formed a distinct phylogenetic lineage on trees calculated for both S and M segment sequences. Although no direct link between the Danish PUUV strains and those of the southern Scandinavian lineage was found, within the S segment of Danish PUUV strains, two regions with higher similarity to either northern Scandinavian or - to a less extent - southern Scandinavian genetic lineages were revealed, suggesting evolutionary connections of their precursors.

Verbal fluency activates the left medial temporal lobe: a functional magnetic resonance imaging study.

Verbal fluency tests (VFTs) are suggested to assess frontal lobe function. This view is supported by functional imaging studies that report left frontal activation during VFTs. VFTs require retrieval of semantically associated words from long-term memory storage. The neural networks that participate in this process, however, are largely unknown. These neural networks are of interest, given that patients with early Alzheimer's disease, typically without frontal pathology, are often impaired in VFTs. In the present study, functional magnetic resonance imaging was performed to determine brain activation areas during VFTs in young subjects. In the activation task, category fluency was contrasted with orderly listing of numbers. As judged from using this comparison, there was activation in the left medial temporal lobe, in the inferior frontal and retrosplenial cortices bilaterally, and in the left superior parietal lobule. Left medial temporal lobe activation was present in 13 of the 14 study subjects either in the hippocampal formation (11 of 14) or in the posterior parahippocampal gyrus (12 of 14). These results suggest that the medial temporal lobe is required for the process of retrieval by category. Functional magnetic resonance imaging combined with a category fluency task may provide a new method to study patients with early Alzheimer's disease.