Cognition, gender, and functional abilities in Alzheimer's disease: how are they related?

BACKGROUND: Few studies have investigated in detail which factors influence activities of daily (ADL) in Alzheimer's disease (AD). OBJECTIVE: To assess the influence of cognitive, gender, and other factors on ADL in patients with mild to moderate AD. METHODS: This study is part of the Prospective Registry on Dementia in Austria (PRODEM) project, a multicenter dementia research project. A cohort of 221 AD patients (130 females; means: age 76 years, disease duration 34.4 months, MMSE 22.3) was included in a cross-sectional analysis. Everyday abilities were assessed with the Disability Assessment for Dementia scale, and cognitive functions with the CERAD plus neuropsychological test battery. Two models of multiple linear regressions were performed to find factors predicting functional decline, one entering demographical and disease related factors, and a joint model combining demographical and disease variables with neuropsychological scores. RESULTS: Non-cognitive factors explained 18%, whereas the adding of neuropsychological variables explained 39% of variance. Poor figural and verbal memory, constructional abilities, old age, longer disease duration, depression, and male gender were independent risk factors for reduced ADL. Instrumental and basic ADL were predicted by similar factors, except gender (predicting only instrumental ADL) and phonological fluency (predictor of basic ADL). CONCLUSION: In addition to demographical factors, disease duration, and depression, neuropsychological variables are valuable predictors of the functional status in AD in an early disease stage.

Driving cessation and dementia: results of the prospective registry on dementia in Austria (PRODEM).

OBJECTIVE: To assess the influence of cognitive, functional and behavioral factors, co-morbidities as well as caregiver characteristics on driving cessation in dementia patients. METHODS: The study cohort consists of those 240 dementia cases of the ongoing prospective registry on dementia in Austria (PRODEM) who were former or current car-drivers (mean age 74.2 (±8.8) years, 39.6% females, 80.8% Alzheimer's disease). Reasons for driving cessation were assessed with the patients' caregivers. Standardized questionnaires were used to evaluate patient- and caregiver characteristics. Cognitive functioning was determined by Mini-Mental State Examination (MMSE), the CERAD neuropsychological test battery and Clinical Dementia Rating (CDR), activities of daily living (ADL) by the Disability Assessment for Dementia, behavior by the Neuropsychiatric Inventory (NPI) and caregiver burden by the Zarit burden scale. RESULTS: Among subjects who had ceased driving, 136 (93.8%) did so because of "Unacceptable risk" according to caregiver's judgment. Car accidents and revocation of the driving license were responsible in 8 (5.5%) and 1(0.7%) participant, respectively. Female gender (OR 5.057; 95%CI 1.803-14.180; p = 0.002), constructional abilities (OR 0.611; 95%CI 0.445-0.839; p = 0.002) and impairment in Activities of Daily Living (OR 0.941; 95%CI 0.911-0.973; p<0.001) were the only significant and independent associates of driving cessation. In multivariate analysis none of the currently proposed screening tools for assessment of fitness to drive in elderly subjects including the MMSE and CDR were significantly associated with driving cessation. CONCLUSION: The risk-estimate of caregivers, but not car accidents or revocation of the driving license determines if dementia patients cease driving. Female gender and increasing impairment in constructional abilities and ADL raise the probability for driving cessation. If any of these factors also relates to undesired traffic situations needs to be determined before recommendations for their inclusion into practice parameters for the assessment of driving abilities in the elderly can be derived from our data.

Four-repeat tauopathy clinically presenting as posterior cortical atrophy: atypical corticobasal degeneration?

A man aged 55 with negative family history presented with progressive decline in spatial orientation and visual functions for 2 years. He showed impaired optic fixation, optic ataxia, agraphia, acalculia, ideomotor apraxia, disturbed right-left differentiation but preserved color matching, memory and motor perception, gradually progressing to dementia, without extrapyramidal signs. Brain MRI and PET showed severe bilateral atrophy and hypometabolism in parieto-occipital areas with sparing of visual perception area and frontal lobes. Treatment with cholinesterase inhibitors had no effect. Death occurred 6½ years after onset of symptoms from bronchopneumonia. Clinical diagnosis was posterior cortical atrophy (Benson's syndrome). Autopsy showed severe bilateral parietal cortical atrophy, less severe in other brain regions without subcortical lesions. Histology revealed severe diffuse tauopathy with neuronal loss, neurofibrillary tangles, neuropil threads, and tau deposits in astroglia and oligodendroglia in parietal, temporal, occipital cortex, less in frontal cortex and hippocampus, putamen, claustrum, thalamus and subthalamus. Severely involved white matter showed many tau-positive threads, comma-like inclusions in oligodendroglia (coiled bodies) and in astroglia. Mild neuronal loss in substantia nigra was associated with massive tau pathology, also involving several brainstem nuclei, cerebellum being preserved. There were neither astrocytic plaques nor any amyloid pathology. Neuronal and glial inclusions were generally 4R-tau-positive and 3R-tau-negative. No TDP-43 and α-synuclein inclusions were detected. Spinal cord was not available. No mutations were found in the MAPT gene. This is the first published case with the fully developed clinical and neuroimaging picture of posterior cortical atrophy, morphologically presenting as a distinct phenotype of 4R-tauopathy that closely resembles (atypical) CBD.

[Memantine for treatment of behavioural disturbances and psychotic symptoms in moderate to moderately severe Alzheimer dementia: a naturalistic study in outpatient services in Austria]. / Memantin in der Behandlung von Verhaltensauffälligkeiten und psychotischen Symptomen bei moderater bis mittelschwerer Alzheimer-Demenz: Eine naturalistische Studie im ambulanten Bereich in Osterreich.

We conducted an open, 16-week study on the efficacy of memantine on behavioral disturbances and psychotic symptoms in moderate to moderately severe Alzheimer s disease in daily routine. Fifty-three patients of 20 outpatient centers in Austria were recruited. The Neuropsychiatric Inventory (NPI) was defined as main outcome measure. After 16 weeks the total NPI score improved by 4,6 points (p<0.01). The caregiver distress score was also significantly reduced. The most pronounced improvements were seen in the NPI components depression (-24,6%), aberrant motor behavior (-16,9%), agitation/agression, fear, apathy, disinhibition and disturbances in appetite and eating behavior (-11,3%, each). Our naturalistic study is in line with the results of controlled trials in moderate and severe Alzheimer dementia stages. Controlled clinical trials which have behavioral disturbances and psychotic symptoms as primary endpoint are needed to define the true potential of memantine in mild dementia stages.

[Therapy of Alzheimer's disease: current status and future development]. / Therapie der Alzheimer Demenz: derzeitiger Stand und zukünftige Entwicklung.

Cholinesterase inhibitors and memantine can slow the course of Alzheimer's disease. In Austria the frequency of treatment is in the upper third among countries of the EU. Yet, the majority of Alzheimer patients does not receive adequate medication. Compliance to treatment is low. Studies on cholinesterase inhibitors show that only one third and one fifth of patients adhere to medication after 3 months and 12 months, respectively. Causes for low compliance are only partly patient-related, many factors are system-inherent. Knowledge of these factors is a pre-requisite for the treating physician to improve current unfavourable situation. Present treatment strategies are symptomatic, causal disease-modifying therapies are urgently needed. Research activity in the field is high and dominated by the amyloid hypothesis. We here review the basis and recent studies on secretase-inhibitors, immunization, aggregation of Abeta, statins and PPARgamma-agonists. Research towards strategies against tau-pathology is less dominant and focuses on inhibition of kinases and increase of activity of phosphatases. Causal therapies would have great effects on a population basis even if efficacy is only moderate. A disease-modifying therapy which delays the onset of Alzheimer disease by 5 years, will probably reduce the number of patients by nearly 50% during the next 50 years.

Transient global amnesia: diffusion-weighted imaging lesions and cerebrovascular disease.

BACKGROUND AND PURPOSE: A hypoxic-ischemic origin of transient global amnesia (TGA) has been suggested on the basis of the observation of infarctlike diffusion-weighted imaging (DWI) abnormalities in some affected individuals. We tested this hypothesis by comparing vascular risk factors, magnetic resonance imaging (MRI) markers of cerebral small-vessel disease, and other evidence of a cerebrovascular disorder between TGA patients with (DWI+) and without (DWI-) DWI lesions and normal community-based controls. METHODS: We retrospectively identified 86 patients hospitalized for TGA (mean+/-SD age, 65.9+/-10.9 years; 62% female). Brain MRI at 1.5 T was assessed for DWI lesions exhibiting restricted diffusion (ie, DWI+), white-matter hyperintensities, lacunes, and chronic infarcts (median time lag to clinical onset, 66.6+/-54.6 hours). Vascular risk factors and findings from duplex sonography, ECG, and echocardiography were recorded. A 1:2 age- and sex-matched sample of 172 elderly subjects (mean+/-SD age, 65.6+/-9.3 years; 62% female) free of neuropsychiatric disease served for comparison. RESULTS: DWI lesions were observed in 10 patients with TGA (11.5%; mean+/-SD age, 68.3+/-5.4 years; 8 women). They were all small and located in the mesiotemporal region (9 left hemisphere, 5 right hemisphere). The vascular risk profile of TGA patients and concomitant changes on brain MRI were comparable with those of healthy controls and did not show significant differences between DWI+ and DWI- subjects. A comprehensive diagnostic workup also provided no evidence for a higher rate of cerebrovascular disorder-related abnormalities in either the total group of TGA patients or TGA DWI+ patients. CONCLUSIONS: These findings do not support a cerebrovascular etiology of TGA, even in those individuals showing acute DWI lesions. Other pathophysiologic mechanisms need to be explored.

Depressive symptoms following herpes simplex encephalitis--an underestimated phenomenon?

OBJECTIVE: In view of the herpes simplex virus' neurotropism for the limbic system and the temporal lobe, little is known about potential negative effects of this necrotizing encephalitis on affective functioning and health-related quality of life (HRQoL) after recovery. We therefore set out to explore an association between herpes simplex virus encephalitis (HSE) and both depressive symptoms and HRQoL. METHODS: A structured telephone interview was conducted in 26 subjects (F/M=10/16; age at follow-up, 49.3+/-15.0 years; range, 29-80) at a mean time interval of 5.2+/-3.1 years (range, 1-11) after their initial diagnosis of HSE. WHO-5 Well-Being Index (WHO-5) was used as screening instrument for depression, and Short Form-12 was used as HRQoL instrument. We also determined the spatial extent of morphologic abnormalities on magnetic resonance imaging (MRI). RESULTS: Ten of the interviewees (38.5%) had a WHO-5 score below 13, which is considered indicative of a depressive disorder. Accordingly, concerning their HRQoL, patients felt more impaired by affective than by physical symptoms. MRI ratings and WHO-5 score were not correlated. CONCLUSIONS: While this pilot study does not allow to establish a causal relationship with focal brain damage, findings suggest both a high frequency of depressive symptoms and a low quality of life with respect to mental health following HSE. These results should be confirmed by a prospective trial.

Magnetic resonance spectroscopy of memory and frontal brain region in early multiple sclerosis.

In vivo proton magnetic resonance spectroscopy (1H-MRS) has been used to assess biochemical changes that occur in demyelinating lesions and in normal appearing white matter (NAWM) in multiple sclerosis (MS) patients. N-acetylaspartate (NAA) levels in MS patients may indicate neural viability. In early stages of MS, patients may suffer from slight cognitive impairment. The objective of this study was to investigate memory function in relation to biochemical properties of frontal brain areas of MS patients. Twenty-one patients with relapsing-remitting MS and 21 healthy comparison subjects were examined psychometrically using the Wechsler Memory Scale (WMS) and the Multiple Sclerosis Functional Composite (MSFC) scale, and (1H-MRS) was used to examine frontal deep white matter (left hemisphere) and the frontal cingulate gyrus (Brodmann areas 24/32, bihemispheric). A significant reduction of the NAA/Creatine (Cr) ratio in the frontal cingulate gyrus among the MS patient group was detected when compared to healthy subjects. A significant decrease in the NAA/Cr ratio was also found in volumes of cerebral deep white matter, including plaques, in the MS patients. No NAA/Cr ratio changes were found in NAWM. Differences in MSFC results did not reach statistical significance, but the WMS general memory score showed a significant statistical difference between the patient group and healthy subjects. Regression analysis showed the gray matter NAA/Cr ratio of the frontal cingulate gyrus to be significantly related to distinct memory functions. The authors conclude that (1H-MRS) of gray matter in early stages of MS may be pertinent in the detections of early metabolic disturbances, particularly in subjects with or without minor neurological impairment. Findings suggest a general relationship between the metabolic status of the frontal cortices and memory function.

Tumefactive demyelinating lesions: conventional and advanced magnetic resonance imaging.

In rare instances, demyelinating disorders present with radiological features that mimic a brain tumour. This often leads to biopsy, which--apart from carrying significant morbidity--frequently turns out as nondiagnostic or dispensable. We therefore set out to assess the contribution of repeated conventional magnetic resonance imaging (MRI), 1H-MR spectroscopy and magnetization transfer imaging in establishing a correct diagnosis of tumefactive demyelinating lesions (TDLs). We studied two females and one male, who presented with TDLs that led to brain biopsy in two cases, for up to three years. TDLs were characterized by the following features: (a) delayed or absent response to high-dose steroids together with progressive lesion growth over several weeks; (b) late or sparse enhancement, ill-defined borders, signal inhomogeneity and considerable concomitant oedema; and (c) normalization of initial increases in lipid and lactate peaks within three to four weeks, followed by persistent, marked reductions of the neuronal marker NAA and MTR values around or below 30%. These imaging characteristics reflected the histological correlate of marked demyelination in the absence of significant inflammation. MRI techniques thus appear to have the potential to establish a correct diagnosis of this subtype of TDLs. Awareness of these possibilities might obviate the need for biopsy at least in some cases in future.

Qualitative MRI: evidence of usual aging in the brain.

The understanding of aging in our society with steadily increasing life expectancy is an important challenge in medical science since socioeconomic pressure increases in parallel. Magnetic resonance imaging is a most useful tool to explore age related changes in the central nervous system especially in the brain. This article will focus on current knowledge and importance of such changes. Special attention will paid to white matter hyperintensities in terms of occurrence and progression and cerebral microbleeds in terms of their association to various diseases and their possible influence on thrombolytic therapy. Furthermore the meaning of darkening of the basal ganglia will be discussed and, in more general terms, the occurrence of virchow robin spaces and changes in cerebral metabolites assessable by proton magnetic resonance spectroscopy.

Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele.

BACKGROUND: In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging. OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4. DESIGN: A 2-year clinical and (1)H-MRS follow-up cohort study. SETTING: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. PATIENTS: We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months. MAIN OUTCOME MEASURE: Levels of N-acetylaspartate as measured by (1)H-MRS. RESULTS: Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19). CONCLUSIONS: The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.

Slow progression of white-matter changes.

A three-year follow-up of 273 participants (mean age 60 years) of the Austrian Stroke Prevention Study provides the first information on the rate, clinical predictors, and cognitive consequences of MRI white-matter lesions in elderly individuals without neuropsychiatric disease. Lesion progression was found in 17.9% of individuals over a time period of 3 years. Diastolic blood pressure and early confluent or confluent white-matter hyperintensities at baseline were the only significant predictors of white-matter hyperintensity progression. Lesion progression had no influence on the course of neuropsychologic test performance over the observational period, but the statistical power of this analysis was low.

The natural course of MRI white matter hyperintensities.

The rate and extent of progression of white matter hyperintensities (WMH) over time in elderly subjects is yet unclear. These abnormalities may represent an early form of subcortical vascular dementia. As to whether such changes could be used, as a surrogate marker for this subtype of vascular dementia remains to be determined. So far there exists only a very limited number of studies determining the rate, clinical predictors and cognitive consequences of WMH evolution. There is evidence that these changes do progress over time, however the results of the different studies cannot be compared due to methodological differences. The Austrian Stroke Prevention Study reported that 17.9% of normal individuals show progression over time. The only published quantitative data demonstrated an absolute increase of 1.1 cm(3) over an observational period of 4 years in healthy subjects. Diastolic blood pressure, early confluent or confluent WMH at baseline and genetic variants in the angiotensinogen gene are so far the only known predictors of WMH progression. The Austrian Stroke Prevention Study did not find an association between the evolution of WMH and cognitive functioning but the statistical power of this analysis was small and the relationship needs to be further explored.

Evolution of white matter lesions.

A 3-year follow-up of 273 participants (mean age 60 years) of the Austrian Stroke Prevention Study provides first information on the rate, clinical predictors and cognitive consequences of MRI white matter lesions (WML) in elderly individuals without neuropsychiatric disease. Lesion progression was found in 17.9% of individuals over a time period of 3 years. Diastolic blood pressure and early confluent or confluent white matter hyperintensities at baseline were the only significant predictors of white matter hyperintensity progression. Genetic association studies in the setting of the Austrian Stroke Prevention Study provide first evidence for genetic susceptibility factors for progression of WML. We observed associations with the paraoxonase Leu-->Met 54 polymorphism and with the M235T polymorphism of the angiotensinogen gene. Lesion progression had no influence on the course of neuropsychologic test performance over the observational period, but the statistical power of this analysis was low.