Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer's disease.

PURPOSE: To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. METHODS: Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer's disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. RESULTS: In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The 'alcoholic beverages' PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. CONCLUSION: In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.

Characterization of Cerebellar Atrophy and Resting State Functional Connectivity Patterns in Sporadic Adult-Onset Ataxia of Unknown Etiology (SAOA).

Sporadic adult-onset ataxia of unknown etiology (SAOA) is a non-genetic neurodegenerative disorder of the cerebellum of unknown cause which manifests with progressive ataxia without severe autonomic failure. Although SAOA is associated with cerebellar degeneration, little is known about the specific cerebellar atrophy pattern in SAOA. Thirty-seven SAOA patients and 49 healthy controls (HCs) were included at two centers. We investigated the structural and functional characteristics of SAOA brains using voxel-based morphometry (VBM) and resting-state functional imaging (rs-fMRI). In order to examine the functional consequence of structural cerebellar alterations, the amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and then assessed their relation with disease severity, disease duration, and age of onset within these regions. Group differences were investigated using two-sample t tests, controlling for age, gender, site, and the total intracranial volume. The VBM analysis revealed a significant, mostly bilateral reduction of local gray matter (GM) volume in lobules I-V, V, VI, IX, X, and vermis VIII a/b in SAOA patients, compared with HCs. The GM volume loss in these regions was significantly associated with disease severity, disease duration, and age of onset. The disease-related atrophy regions did not show any functional alternations compared with HCs but were functionally characterized by high ALFF and poor DC compared with intact cerebellar regions. Our data revealed volume reduction in SAOA in cerebellar regions that are known to be involved in motor and somatosensory processing, corresponding with the clinical phenotype of SAOA. Our data suggest that the atrophy occurs in those cerebellar regions which are characterized by high ALFF and poor DC. Further studies have to show if these findings are specific for SAOA, and if they can be used to predict disease progression.

Interaction effects of subjective memory impairment and ApoE4 genotype on episodic memory and hippocampal volume.

BACKGROUND: The apolipoprotein E4 allele (ApoE4) is an established genetic risk factor for Alzheimer's disease (AD). However, its effects on cognitive performance and brain structure in healthy individuals are complex. We investigated the effect of ApoE4 on cognitive performance and medial temporal lobe volumetric measures in cognitively unimpaired young elderly with and without subjective memory impairment (SMI), which is an at-risk condition for dementia.MethodAltogether, 40 individuals with SMI and 62 without were tested on episodic memory and on tasks of speed and executive function. All participants were ApoE genotyped. 21 subjects with SMI and 47 without received additional structural magnetic resonance imaging. Volumetric measures of the hippocampus, the entorhinal cortex and the amygdala were obtained manually. RESULTS: In the SMI group, ApoE4 carriers performed worse on the episodic memory (p=0.049) and showed smaller left hippocampal volumes (p=0.030). In the individuals without SMI, the ApoE4 carriers performed better on episodic memory (p=0.018) and had larger right hippocampal volumes (p=0.039). The interaction of group (SMI/no SMI) and ApoE genotype was significant for episodic memory (p=0.005) and right and left hippocampal volumes (p=0.042; p=0.035). There were no within-group differences or interaction effects on speed and executive function composite measures or other volumetric measures. CONCLUSIONS: The negative effect of ApoE4 on episodic memory and hippocampal volume in SMI supports SMI as a prodromal condition of AD. The positive effects of ApoE4 in subjects without SMI adds to a number of reports on positive ApoE4 effects in young and very old individuals.

[The German Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD): more than Parkinson]. / Die "German study on the epidemiology of Parkinson's disease with dementia" (GEPAD): mehr als nur Parkinson.

UNLABELLED: It is unknown, how frequently Parkinson's disease (PD) is complicated by dementia, depression and other neuropsychiatric conditions. An epidemiologic characterisation of the situation in specialised neurologic settings is lacking. The Geman Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD) isa national representative epidemiological study of n=1449 PD patients in n=315 office-based neurological settings, designed to estimate the prevalence of dementia, depression and other neuropsychiatric conditions in patients with PD of all stages by using standardized clinical assessments. RESULTS: 28.6% met DSM-IV criteria for dementia. 33.6% met criteria for depression and 61% additionally had other clinically significant psychopathological syndromes. Only 29.4% had no neuropsychiatric conditions. GEPAD reveals for the first time comprehensively that the neuropsychiatric burden of PD patients in all stages and even early stages is considerable, posing challenging questions for research and clinical management.

[Therapy of psychological and behavioral symptoms in dementia]. / Therapie von psychischen und Verhaltenssymptomen bei Demenz.

Behavioral and psychological symptoms of dementia (BPSD) represent a severe burden for patients and caregivers. The causes are disease-related neurobiological changes which increase the vulnerability to respond to external triggers with BPSD. Consequently, external factors (e.g. communication, milieu) are the primary target for treatment and also prevention of BPSD. Psychosocial interventions with the focus on the patient or on the caregivers are the core elements of BPSD therapy. If psychosocial interventions are not efficacious or only insufficiently applicable, pharmacological treatment may need to be initiated. Pharmacological treatment of BPSD has been less intensely investigated as treatment of cognition and function in dementia. However, recommendations can be given. This review follows the S3 guidelines on dementia published by the German Societies for Psychiatry and Psychotherapy (DGPPN) and Neurology (DGN) which address BPSD extensively.

Longitudinal study of the socioeconomic burden of Parkinson's disease in Germany.

OBJECTIVE: To determine the health economic burden on patients with Parkinson's disease (PD) in Germany over a 12-month observation period and provide a comprehensive analysis of cost-driving factors. METHODS AND PATIENTS: Patients with PD (n = 145) were recruited from two clinical departments, two office-based neurologists and 12 GPs. Clinical evaluations were performed at baseline, 3, 6 and 12 months. Disease severity was measured using the Unified Parkinson's Disease Rating Scale (UPDRS). Cost data were assessed based on a patient diary and via personal structured interviews at the respective time-points. Costs were calculated from the societal perspective (2009 euro). Cost-driving factors were identified by multivariate regression analysis. RESULTS: Mean annual costs totalled euro20 095 per patient. Amongst direct costs, the highest expenditures (euro13 158) were for drugs (euro3526) and inpatient care including nursing homes (euro3789). Indirect costs accounted for 34.5% (euro6937) of total costs. Costs of home care provided by family accounted for 20% of direct costs. Cost-driving factors were identified for total costs (UPDRS, fluctuations, dyskinesia and younger age), direct costs (UPDRS, fluctuations), patient expenditures (UPDRS, depression) and drug costs (younger age). CONCLUSION: Parkinson's disease has a chronic course with growing disability and considerable socioeconomic burden. Disease progression leads to an increasing number of patients who require costly institutionalized care. Home care is a major factor influencing patients' families. Healthcare programmes aimed at reducing the burden of PD on society and individuals should consider cost-driving factors of PD.

Autonomic dysfunction in 3414 Parkinson's disease patients enrolled in the German Network on Parkinson's disease (KNP e.V.): the effect of ageing.

We analysed non-motor symptoms (NMS) related to autonomic dysfunction in 3414 patients with Parkinson's disease (PD) enrolled in the multicentre registry of the German Competence Network on PD. Orthostatic hypotension (> 20 mmHg systolic or > 10 mmHg diastolic) was reported for 10% of women and 11% of men, urinary incontinence for 22% of women and 21% of men, sexual dysfunction for 8% of women and 30% of men (50% of whom reported erectile dysfunction) and sleep disturbances for 43% of women and 35% of men. Autonomic symptoms occurred in a frequency similar to severe disabling dyskinesia which was reported for 16% of women and 11% of men. A logistic regression analyses with age, sex and disease duration as covariates revealed a significant correlation of orthostatic hypotension and urinary incontinence with age and disease duration whilst sexual dysfunction was related to age only. These observations suggests that the effects of the PD process and ageing contribute to non-levodopa responsive NMS. Sleep disturbances were more common in women and a correlation was found with disease duration only supporting the notion that sleep is specifically affected in PD.

Pharmacotherapy of Parkinson's disease in Germany.

Treatment standards or guidelines have been developed for most features of Parkinson's disease (PD). However, data on the actual treatment that is put into practice are scarce. In 2000, a nationwide survey on the topic of sudden onset of sleep (SOS) in PD was initiated among the members of the German patient support group (deutsche Parkinson-Vereinigung, dPV). A part of this mailed questionnaire survey covering the antiparkinsonian and concomitant medication of the participants is presented here. This study analyses data sets from more than 6,500 PD patients. The mean dopaminergic dose was equivalent to 599 +/- 387 mg levodopa/die. The most frequently administered drugs were levodopa (94.2 %), dopamine agonists (DA) (71.7 %), amantadine (40.1 %), selegiline (27.6 %), entacapone (20.4 %), budipine (12.3 %), and anticholinergics (11.8 %). Costs of pharmacotherapy were estimated to be approximately 399 million/year in Germany. PD drug therapy in general strongly depended on age, disease duration, and the level of care. The treatment guidelines were apparently not consistently followed underlining the need for their continuous propagation throughout the medical community. In addition our data suggest that non-motor symptoms in PD are not adequately treated and that concomitant sedative medication contributes to the occurrence of SOS.

Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease.

OBJECTIVE: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer's disease (AD). Recently, it has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Abeta. This study reports the results from a pilot study using IVIgG in patients with AD. METHODS: Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Abeta/Abeta(1-42) measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG. RESULTS: Following IVIgG, total Abeta levels in the CSF decreased by 30.1% (17.3-43.5%) compared to baseline (p<0.05). Total Abeta increased in the serum by 233% (p<0.05). No significant change was found in Abeta(1-42) levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7+/-2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline. CONCLUSION: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.