Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort.

OBJECTIVE: Increased serum homocysteine and low folate levels are associated with a higher rate of conversion to dementia. This study examined the influence of vitamin B12/folic acid intake on the conversion from mild cognitive impairment (MCI) to dementia. PARTICIPANTS: A community dwelling cohort of older adults (N=81) from the Vienna Transdanube aging study with MCI. DESIGN: Prospective study with a retrospective evaluation of vitamin intake. MEASUREMENTS: Laboratory measurements, brain magnetic resonance imaging, and cognitive functioning were assessed at baseline and at five-year follow-up. RESULTS: The self-reported combined use of folic acid and vitamin B12 for more than one year was associated with a lower conversion rate to dementia. Serum levels of homocysteine and vitamin B12 as measured at baseline or at five years were not associated with conversion. Higher folate levels at baseline in females predicted a lower conversion rate to dementia. The assessment of brain morphological parameters by magnetic resonance imaging revealed higher serum folate at baseline, predicting lower medial temporal lobe atrophy and higher levels of homocysteine at baseline, predicting moderate/severe global brain atrophy at five years. Users of vitamin B12 or folate, independent of time and pattern of use, had lower grades of periventricular hyperintensities and lower grades of deep white matter lesions as compared to non-users. CONCLUSIONS: These results from a middle European study support observations on the protective ability of folate in MCI patients with respect to conversion to dementia; they also point to a participation of homocysteine metabolism on processes associated with brain atrophy.

The validity of amnestic MCI and non-amnestic MCI at age 75 in the prediction of Alzheimer's dementia and vascular dementia.

BACKGROUND: Clinical subtypes of mild cognitive impairment (MCI) were assigned as potential prodromes to various types of dementia. Amnestic MCI (aMCI) is said to have a high likelihood of progressing to Alzheimer's dementia (AD) and non-amnestic MCI (naMCI) subtypes are assumed to have a higher likelihood of progressing to non-AD dementia. The aim of this study was to investigate the prognostic accuracy of aMCI and naMCI for the development of AD, vascular dementia (VaD), and mixed dementia. METHODS: In this longitudinal study, 487 subjects without dementia (cognitively healthy: n = 387; MCI cases: n = 115) aged 75 years at baseline, who participated in a population-based cohort study (Vienna Transdanube Aging study), were available for analysis. The observation period was 90 months. The diagnoses of the clinical MCI subtypes were made according to common criteria. The outcome (AD, VaD, mixed dementia) was described for both MCI subtypes. Diagnostic values of aMCI and naMCI according to incident AD, VaD, and mixed dementia were determined. RESULTS: AD was the most common type of dementia following both MCI subtypes. Participants with aMCI were more likely to progress to AD than participants with naMCI. The proportion of incident VaD and mixed dementia did not differ concerning the MCI subtypes. The positive predictive value for both MCI subtypes was low (range: 1%-46%), whereas the negative predictive value was high (range: 86%-99%). CONCLUSIONS: The increased risk of clinical MCI subtypes for a particular type of dementia could only be confirmed for aMCI and incident AD.

The role of memory-related gene polymorphisms, KIBRA and CLSTN2, on replicate memory assessment in the elderly.

The role of the CLSTN2 (rs6439886) and KIBRA (rs17070145) SNPs in cognitive impairment was analysed in a 75-76 years old group. Various memory assessment tests were carried out on individuals at baseline and during follow-up investigations, and biallelic genotyping was performed. No influence of the allele status of either SNPs was observed on any memory test. No increased risk of any type of late development, and cognitive impairment was associated with rs6439886 or rs17070145.

Risk factors for cerebrovascular and cardiovascular diseases beyond age 75 years.

Globally, cardiovascular diseases (CVDs) are the number one cause of all mortalities. Of these deaths, 7.6 million are due to heart attacks, and 5.7 millions are due to stroke. The Vienna Transdanube Aging Study (VITA), a population-based cohort study, enabled us to evaluate associations between the known major risk factors for cerebrovascular and CVDs and their appearance beyond age 75 years. Using a single birth cohort, age was excluded as confounding factor. In the baseline investigations in the Danube Hospital, 606 individuals took part and were examined completely at baseline. After 60 months, 508 patients were re-examined. Each participant underwent an indepth investigation with the duration of 7 h, including neuropsychological testing, as well as analyses of biochemical, clinical chemical and genetic parameters, and magnetic resonance imaging (MRI) of the brain. In the present study, only a history of cerebral and cardiovascular events at the baseline or smoking was associated significantly with the appearance of CVDs. In a multiple model both risk factors-history of cerebral and cardiovascular events at the baseline (p = 0.0003, OR 2.36, 95% CI 1.49-3.76) and smoking (p = 0.0005, OR 1.57, 95% CI 1.22-2.03)-remained significant. However, the predictive value of this assessment model was low. The rescaled r² of the model was 0.088. A significant correlation was found only between exposure to cigarette smoke or a history of previous CVDs, such as stroke or myocardial infarction. Smoking or earlier CVDs greatly increase the risk for further cerebral and cardiovascular events in persons after 75 years.

Serum androgen levels and their association to depression and Alzheimer dementia in a cohort of 75-year-old men over 5 years: results of the VITA study.

The role of androgens on cognitive function and mood is not well documented yet. We therefore evaluated all male participants (n=247, mean age 75.7 years) of a population-based study regarding testosterone, dehydroepiandrosterone sulfate (DHEAS), depression and Alzheimer Dementia (AD) for 5 years using the DSM-IV and NINCDS-ADRDA criteria. At study entry, low serum testosterone levels (<350 ng per 100 ml) were present in 45 (30.8%), low DHEAS (<50 microg per 100 ml) in 44 (30.1%), depression in 11 (7.5%) and AD in 7 (4.7%) men. After 5 years, the number of men with low testosterone levels increased to 52 (+15.5%), for low DHEAS to 57 (+29.5%) for depression to 34 (+219%) and for AD to 43 (+515%). Testosterone levels were not associated to prevalence or incidence of depression or dementia. Mean testosterone was 398.1 ng per 100 ml in depressive men and 431.7 ng per 100 ml in those without depression (P=0.57) and 406.3 ng per 100 ml in those with AD versus 429.5 ng per 100 ml without AD (P=0.66).

Screening for Alzheimer's dementia at age 78 with short psychometric instruments.

BACKGROUND: To date, no single instrument has proved to be adequate for screening for Alzheimer's dementia (AD). The aim of this study was to identify a combination of instruments which were highly sensitive for screening late onset AD. METHODS: Subjects were drawn from the Vienna TransDanube Aging (VITA) study. This is an interdisciplinary, longitudinal community-based cohort study of the 21st and 22nd district of Vienna (Austria). Data refer to the cohort of 478 individuals at age 78 who took part in the first follow-up investigation of the VITA study. The psychometric instruments which were investigated were: the Ten-Point Clock Test, the Human-Figure Drawing Test, a Delayed Selective Reminding Test, Naming, the Trail Making Test-B, and Verbal Fluency. Further instruments were the Pocket Smell Test, and Subjective Memory Complaints. Data were analyzed using logistic regression analyses and cross validation. RESULTS: A combination of the Delayed Selective Reminding Test and Verbal Fluency was best for screening AD (R2 = 0.38, main model). An area under the ROC curve of 0.829 was reached. This model discriminated between subjects with incident AD and subjects who did not have incident AD with a sensitivity of 91% and a specificity of 56%. CONCLUSION: The combination of an episodic memory test and a test of verbal fluency was an effective way of screening for AD.

Tumor growth of suspected meningiomas in clinically healthy 80-year-olds: a follow up five years later.

BACKGROUND: The incidence of clinically silent meningiomas in 75-year-old individuals was determined five years ago in the Vienna Transdanube Ageing Study (VITA). At the time a watch-and-wait approach was recommended in cases of incidentally discovered meningiomas. METHODS: 420 out of the initial cohort of 532 test persons underwent control investigations after 2.5 and 5 years. Six of the nine known tumors were measured again and the patients underwent clinical, neurological and psychological tests. Changes in tumor size were determined and all new tumors seen on MRI investigation were carefully reviewed. RESULTS: Tumor growth was minimal in all six cases that were followed over the entire period. Two of the original meningioma patients had died and one patient had undergone tumor resection. CONCLUSIONS: The watch-and-wait approach recommended after the VITA study was confirmed by the present investigation. Tumor growth was slow in all cases; no clinical symptoms have been registered thus far. The intervals between control investigations may even be prolonged depending on the location of the tumor. In this age group the operation appears to pose a greater risk than the presence of an asymptomatic tumor.

VITA study: white matter hyperintensities of vascular and degenerative origin in the elderly.

The etiology of white matter hyperintensities (WMH) seen on T2-weighted cranial magnetic resonance images is a matter of debate. We investigated deep and periventricular WMH in the brains of a community-based cohort of 532 subjects aged 75-76 years. The objective of this study was to determine whether WMH at age of 75 years were associated rather with vascular factors than with degenerative factors. Arterial hypertension treated with antihypertensive drugs favored WMH, and WMH were found more frequently in subjects with focal vascular lesions. Additionally, we found significant associations between both, deep white matter and periventricular hyperintensities, and focal atrophy of medial temporal lobe structures. The odds ratio for deep WMH in subjects with more severe medial temporal atrophy was 4.4 (95%-CI: 1.9-9.8) that for periventricular hyperintensities was 3.9 (95%-CI: 1.7-8.8). These findings might indicate that not only vascular factors alone but also degenerative factors favor the occurrence of WMH after the age of 75 years.

Conversion from subtypes of mild cognitive impairment to Alzheimer dementia.

OBJECTIVE: To compare the rates of conversion to Alzheimer dementia (AD) between subtypes of mild cognitive impairment (MCI) in a community-based birth cohort investigated at age 75 and followed up after 30 months. METHODS: The Vienna Trans-Danube Aging Study investigated every inhabitant of the area on the left shore of the river Danube who was born between May 1925 and June 1926. With use of the official voting registry, 1505 subjects were contacted and 697 participated. Data refer to the cohort of 581 nondemented individuals who completed extensive neuropsychological examination at baseline. Follow-up after 30 months was possible in 476 probands (35 deceased). RESULTS: The 141 patients with MCI at baseline were classified into two subtypes. At follow-up, 41 of these patients with MCI were diagnosed with AD. Conversion rates to AD were 48.7% (CI: 32.4 to 65.2) for amnestic MCI and 26.8% (CI: 17.6 to 37.8) for nonamnestic MCI. Another 49 AD cases originated from cognitive health at baseline (12.6%; CI: 9.4 to 16.3). CONCLUSIONS: Patients with mild cognitive impairment (MCI) showed a high probability to be diagnosed with Alzheimer dementia (AD) after 30 months. Subtypes of MCI were not useful in defining early stages of various types of dementia: Not only amnestic MCI but also nonamnestic MCI converted frequently to AD, and conversion to vascular dementia and dementia with Lewy bodies was not restricted to nonamnestic MCI.

Relation between vascular risk factors and cognition at age 75.

OBJECTIVE: Recent trends in dementia research emphasize that not only cerebrovascular events but also vascular risk factors induce, favour or cause cognitive impairment and Alzheimer's disease. MATERIAL AND METHODS: We evaluated vascular risk factors (blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, HbA1c, homocysteine, lipoprotein(a), fibrinogen, C-reactive protein and smoking habits) in a community-based cohort of 75-year-old individuals of two districts in Vienna (247 men, 359 women) and correlated these risk factors with overall cognition. RESULTS: Pathological vascular risk factors were found frequently in the age cohort. However, the expected associations between the Mini-Mental State Examination and any cardiovascular risk factors were missing. Only individuals with a positive history of smoking showed lower cognitive capacities. CONCLUSIONS: We assume that cognitive dysfunction in old age is connected to factors other than the known classical and novel risk factors for the development of cardiovascular disease.

Association study of BDNF and CNTF polymorphism to depression in non-demented subjects of the "VITA" study.

BACKGROUND: Neurotrophic factors are known to play an important role in the survival and differentiation of many types of neurons during development. Both brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) may act cooperatively in modulating the development and functioning of synapses. Both these neurotrophic factors were intensely investigated with regard to depression without conclusive results. METHODS: We have investigated the possible use of both CNTF null-mutation and BDNF polymorphism C270T as biomarkers for depression in the Vienna Transdanube Aging (VITA) study. The VITA is a prospective community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. RESULTS: We found no association between CNTF null-mutation and BDNF C270T polymorphism to any depressive symptoms after exclusion of demented subjects. CONCLUSION: These results call in question the hypothesis that either BDNF or CNTF can be used as molecular markers for depression or late onset depression in the elderly.

Data from the VITA Study do not support the concept of vascular depression.

OBJECTIVE: Cerebrovascular lesions that are apparent in magnetic resonance scans and regioselective atrophy of the brain have been proposed as a causative or exacerbating factor in depression with late-life onset. The objective of this study was to investigate whether deep white matter or periventricular hyperintensities, small ischemic lesions, and brain atrophy contribute to late-onset depression in the nondemented elderly. METHOD: Based on a group of 606 individuals of identical age (75.8 years, standard deviation: 0.45 years) residing in two districts of Vienna, the authors built a case-control cohort (ratio: 1:4) consisting of 51 individuals with late-onset major or minor depression matched with 204 subjects of identical gender and education status without depression, resulting in two groups that were homogenous with respect to age, place of residence, gender, and education. Scores for focal brain lesions, mediotemporal lobe atrophy, and ventricular enlargement as well as risk factors for vascular disease were compared with cognition and depression status. RESULTS: Depressed individuals had significantly lower scores than nondepressed subjects in all measures of cognitive and executive function. No significant relation was found between a diagnosis of depression and any type of discrete brain lesions, but measures of brain atrophy (Cella Media indices, mediotemporal atrophy) showed a clear statistical relation to depression. No relationship was found between depression and lipid parameters. CONCLUSION: The authors found no indication that white matter hyperintensities or minor ischemic lesions played a role in our depressed cohort, casting doubt on the vascular hypothesis of late-onset depression.

VITA: subtypes of mild cognitive impairment in a community-based cohort at the age of 75 years.

BACKGROUND: Mild cognitive impairment (MCI) is defined to diagnose prodromal dementia and prodromal Alzheimer dementia, in particular. OBJECTIVE: The main aim of this study is to identify subtypes of MCI in comparison to the frequency of Petersen's MCI-amnestic in an elderly age-cohort. PARTICIPANTS: The study is based on the cross sectional data from the Vienna-Transdanube-Aging (VITA) study. The data refer to the age cohort of 592 individuals at age 75 to 76 years who completed extensive neuropsychological examination. RESULTS: Dementia was present in 15 subjects (2.5%, CI: 1.4-4.1). 141 subjects (23.8%, CI: 20.4-27.5) of the entire age cohort 75 (n = 592) showed cognitive impairment without dementia concerning one or more cognitive functions (1.5 SD paradigm). These subjects were assigned to three subtypes of MCI: Selective Memory Impairment: n = 22 (3.7%, CI: 2.3-5.6), Memory Impairment+Non-Memory Impairment: n = 31 (5.2%, CI: 3.6-7.4) and Non-Memory Impairment: n = 88 (14.9%, CI: 12.1-18.0). CONCLUSIONS: The frequency of MCI-amnestic, the so-called prestage of AD according to Petersen, was very low (0.5%, CI: 0.1-1.5) compared to the estimated incidence rates of AD at this age. Established criteria of MCI could be modified in order to include a higher percentage of high-risk subjects for later developing Alzheimer dementia.

Oxidative stress related markers in the "VITA" and the centenarian projects.

Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.

Mitochondrial genotype and risk for Alzheimer's disease: cross-sectional data from the Vienna-Transdanube-Aging "VITA" study.

The Vienna Transdanube Aging (VITA) study searches for early markers of Alzheimer's disease (AD) by examining the mental status in a community-based cohort of 606, 75-years old volunteers that are then related to various clinical and genetic analyses. To determine whether mutations in mtDNA are involved in expression of AD, the mtDNA of 79 "control" participants is screened for alterations by sequencing of "hot-spot-regions". This study on mtDNA mutations has eliminated the influence of aging on the occurrence of mtDNA alterations by sequencing samples from persons at the age of exactly 75 years. Thus, our cohort reveals a snap-shot of mitochondrial sequences of elderly persons. So far, a high percentage (56%) of persons with known or unknown mutations in the fragments analyzed were found. These data will be compared in due time to a cohort of participants with proven late-onset AD.

Vienna Transdanube Aging "VITA": study design, recruitment strategies and level of participation.

The Vienna Transdanube Aging study "VITA" is a prospective, interdisciplinary cohort-study of all 75-years old inhabitants of the 21. and 22. district of Vienna (n = 1,745), which started in May 2000. The study design is described in this paper for the first time. The main scientific question of the study concerns the prediction of incident dementia in the elderly. The main statistical analysis will compare 8 predictors: episodic memory, verbal fluency, subjective memory complaints, depression, APOE-epsilon4, MAO-B activity in thrombocytes, MRT hippocampal atrophy, and MRT atrophy of the substantia innominata. The whole investigation comprises medical and psychosocial interviews, psychological tests, psychiatric and neurological scales, blood characteristic, genetic factors and cranial magnetic resonance imaging. Various variables will be compared with each other concerning sensitivity and specificity of prediction of cognitive decline. The dependent variable of the intended statistical analysis will be the individual's difference between Mini Mental State Examination scores at the two times of investigation. A high level of participation in geriatric epidemiological studies increases the general applicability of results but recruitment procedures must not ignore the individual's right to privacy and integrity. Using a liberal recruitment procedure as recommended by the local ethics commission the level of participation is between 36.7% and 44.3%.