What Matters to Patients with Alzheimer's Disease and Their Care Partners? Implications for Understanding the Value of Future Interventions.

Alzheimer's Disease (AD) is the most common cause of dementia. Recent thinking portrays AD as a continuum consisting of three stages: an asymptomatic preclinical period, a mild cognitive impairment phase, and dementia, which can be further classified as mild, moderate or severe. While many studies explore the cognitive and functional aspects of AD, fully understanding AD pathophysiology, as well as the potential value of pharmacological and psycho-social interventions, requires a deeper understanding of patient and care partner priorities, particularly in the early stages where such interventions may have the greatest impact in slowing or delaying progression. Available studies highlight a diverse range of patient and care partner priorities, including impacts on their emotions, moods, and social lives. These priorities have not been systematically incorporated in the clinical and value assessments of potential interventions. We propose approaches to better understand the humanistic impact of AD including conducting additional research into the impacts of interventions from the point of view of patients and care partners, expanding notions of 'value' and improving health system capacity for diagnosis.

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.

Targeting Lifestyle Behavior to Improve Brain Health: User-Experiences of an Online Program for Individuals with Subjective Cognitive Decline.

BACKGROUND: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users . OBJECTIVES: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health. DESIGN: 30-day user test; multi-method. SETTING: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne). PARTICIPANTS: Individuals with SCD (N=137, 65±9y, 57% female). MEASUREMENTS: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews. RESULTS: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs' usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health. CONCLUSIONS: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

Health Literacy in Individuals at Risk for Alzheimer's Dementia: A Systematic Review.

BACKGROUND: Health literacy (HL) refers to the capacity to access, understand, appraise and apply information for decision-making and acting in health-related matters. In the field of Alzheimer's disease (AD), expanding technologies of early disease detection, disease course prediction and eventually personalized prevention confront individuals at-risk with increasingly complex information, which demand substantial HL skills. Here we report current findings of HL research in at-risk groups. METHODS: Search strings, referring to HL, AD, amyloid and risk, were developed. A systematic review was conducted in PUBMED, Cochrane Library, PsycINFO, and Web of Science to summarize the state of evidence on HL in at-risk individuals for Alzheimer's dementia. Eligible articles needed to employ a validated tool for HL, mention the concept or one dimension (access, understand, appraise and apply information for decision-making and acting). RESULTS: 26 quantitative and 9 qualitative studies addressing at least one dimension of HL were included. Overall, there is evidence for a wish to gain knowledge about the own brain status and risk of dementia. Psychological distress may occur and the subjective benefit-risk estimation may be modified after risk disclosure. Effects on lifestyle and planning may occur. Overall understanding and appraisal of information related to AD risk seem variable with several impacting factors. In mild cognitive impairment (MCI) basic HL skill seem to be affected by cognitive dysfunction. CONCLUSIONS: Systematic assessment of HL in at-risk population for AD is sparse. Findings indicate the paramount importance of adequate communication with persons at risk, being sensitive to individual needs and preferences. Substantial research needs were identified.

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.

[The importance of molecular imaging (PET) in the diagnostics of dementia]. / Bedeutung molekularer Bildgebung (PET) in der Diagnostik von Demenzerkrankungen.

Due to the expanding older population and increasing prevalence of dementia and currently lacking curative therapy but potentially conceivable availability of molecular-specific treatment to delay the progression of cognitive decline, the early diagnosis of cognitive deficits and their etiological differential diagnosis becomes increasingly more important. The advances in nuclear medicine diagnostics in the field of neurodegenerative diseases within the last few years have been substantial. In this article the relevance of these technologies in the diagnostic process of dementia is described.

[Advance directive of probands in pharmaceutical research : A medical ethics discussion]. / Probandenverfügung in der Arzneimittelforschung : Eine medizinethische Diskussion.

In the fourth Act on the amendment of pharmaceutical legal and other regulations in November 2016, the legislature has designated the proband advance directive based on the instrument of patient advance directive to enable group beneficial research with persons not capable of giving consent. This article describes the existing conditional need for group beneficial research and presents the problem of the decisive instrument for advance directives at the center of the considerations. The features of the proband advance directive concluded by the legislature stand in opposition to a successful implementation, particularly due to the necessary concrete clarification content far in advance for informed research participants. This article describes solution possiblities, which refer to the realization of the instrument of a proxy research authorization as well as the consideration of an advance research planning based on the advance care planning.

Does Visual Impairment Affect Social Ties in Late Life? Findings of a Multicenter Prospective Cohort Study in Germany.

OBJECTIVE: To investigate how visual impairment affects social ties in late life longitudinally. DESIGN: Population-based prospective cohort study. SETTING: Individuals in old age were recruited via general practitioners' offices (at six study centers) in Germany. They were interviewed every 18 months. PARTICIPANTS: Individuals aged 75 years and above at baseline. Follow-up wave 2 (36 months after baseline, n=2,443) and wave 4 (72 months after baseline, n=1,618) were used for the analyses presented here. MEASUREMENTS: Social ties were assessed using the 14-item form of the questionnaire for social support (F-SozU K-14). Visual impairment was self-rated on a three level Likert scale (no impairment, mild visual impairment, or severe/profound visual impairment). RESULTS: Adjusting for sociodemographic factors, hearing impairment and comorbidity, fixed effects regressions revealed that the onset of mild visual impairment decreased the social support score, in particular the emotional support score. Additionally, the onset of mild hearing impairment decreased the social support score in men. Moreover, increasing age decreased the social support score in the total sample and in both sexes. Loss of spouse and increasing comorbidity did not affect the social support score. CONCLUSION: Our results highlight the importance of visual impairment for social ties in late life. Consequently, appropriate strategies in order to delay visual impairment might help to maintain social ties in old age.

Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

[Guideline-adherent inpatient psychiatric psychotherapeutic treatment of behavioral and psychological symptoms of dementia : Normative definition of personnel requirements]. / Leitliniengerechte stationäre psychiatrisch-psychotherapeutische Behandlung psychischer und Verhaltenssymptome bei Demenz : Normative Personalbedarfsermittlung.

BACKGROUND: Dementia is of increasing medical and societal relevance. Hospitalization of dementia patients is mostly due to behavioral and psychological symptoms of dementia (BPSD). There is a need for sufficient qualified personnel in hospitals in order to be able to effectively treat these symptoms. OBJECTIVES: This study aims at identifying the personnel requirements for guideline-conform, evidence-based inpatient treatment concepts for patients with BPSD and to compare these with the resources defined by the German psychiatric personnel regulations (Psych-PV). Furthermore, it was the aim to identify how often patients with dementia received non-pharmacological therapy during inpatient treatment. METHODS: Based on the current scientific evidence for treatment of BPSD, a schedule for a multimodal non-pharmacological treatment was defined and based on this the corresponding personnel requirements were calculated. Using the treatment indicators in psychiatry and psychosomatics (VIPP) database as a reference, it was calculated on what proportion of treatment days patients were classified into G1 according to the German Psych-PV and at least once received more than two treatment units per week. RESULTS: For the implementation of a guideline-oriented and evidence-based treatment plan, a higher need for personnel resources than that provided by the Psych-PV was detected in all areas. Currently patients with dementia who received at least more than two treatment units per week during inpatient hospitalization, were classified into G1 according to German Psych-PV on 17.9 % of treatment days. CONCLUSION: Despite evidence for the efficacy of non-pharmacological treatment measures on BPSD, these forms of treatment cannot be sufficiently provided under the current conditions. The realization of a new quality controlled therapeutic concept is necessary to enable optimized treatment of patients with BPSD.

Predictors of Frailty in Old Age - Results of a Longitudinal Study.

OBJECTIVES: To investigate time-dependent predictors of frailty in old age longitudinally. DESIGN: Population-based prospective cohort study. SETTING: Elderly individuals were recruited via GP offices at six study centers in Germany. The course of frailty was observed over 1.5 years (follow up wave 4 and follow up wave 5). PARTICIPANTS: 1,602 individuals aged 80 years and older (mean age 85.4 years SD 3.2, with mean CSHA CFS 3.5 SD 1.6) at follow up wave 4. MEASUREMENTS: Frailty was assessed by using the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA CFS), ranging from 1 (very fit) to 7 (severely frail). RESULTS: Fixed effects regressions revealed that frailty increased significantly with increasing age (ß=.2) as well as the occurrence of depression (ß=.5) and dementia (ß=.8) in the total sample. Changes in marital status and comorbidity did not affect frailty. While the effects of depression and dementia were significant in women, these effects did not achieve statistical significance in men. CONCLUSION: Our findings highlight the role of aging as well as the occurrence of dementia and depression for frailty. Specifically, in order to delay frailty in old age, developing interventional strategies to prevent depression might be a fruitful approach.

[Clinical Phenomenology of Autoimmune Encephalitis]. / Klinische Phänomenologie der Autoimmunenzephalitiden.

Antibody-associated disorders of the central nervous system constitute a heterogeneous group of disorders that can be roughly divided into two categories: Classic paraneoplastic syndromes associated with so-called well-characterized antibodies (paraneoplastic neurological disorders, PND) and autoimmune disorders with antibodies to membrane-bound or synaptic antigens (autoimmune encephalitis, AE). The discovery of autoimmune encephalitis has led to a paradigm shift in diagnosis and therapy as well as a reclassification of some neuropsychiatric syndromes that were previously classified as idiopathic or simply covered with descriptive terms.In this review article, especially clinical aspects of autoimmune encephalitis will be discussed, as there has been a rapid increase in knowledge in this regard within the past decade; increasingly overlap syndromes and associations with other disease entities have been detected. In addition to general aspects, characteristics of anti-NMDAR-, anti-LGI1-, anti-GABAA and GABABR, anti-AMPAR-, anti-CASPR2-, anti-mGluR, anti-GlycinR-, anti-GAD, anti- DPPX- and anti-D2 R encephalitis and the anti-IgLON5 encephalopathy will be presented.

[Cognitive Behavioral Therapy and Assertive Community Treatment Reduces Days in Hospital and Delays Hospital Admission in Severe Psychotic Disorders]. / Kognitive Verhaltenstherapie und Assertive Community Treatment reduzieren die Anzahl stationärer Tage und verlängern die Zeit bis zu einer stationären Aufnahme bei schweren psychotischen Störungen.

The primary aim of this study was to assess the effectiveness of integrated home treatment (IV, i. e. intensive cognitive behavioral therapy and pharmacotherapy provided within a framework of assertive community treatment) in individuals with severe mental disorders (n = 13) within the German healthcare system. A treatment-as-usual group (TAU, n = 13) was identified by propensity score matching. Symptoms (CGI), functioning (GAF) and service engagement (SES) were assessed. Quality of life (MSLQ-R) was rated by the IV patients. A reduction of days spent in hospital [IV: 2.3 (6.1); TAU: 33.6 (53.6); Z = 45; p = 0.044], time to admission (IV: 384 days 95% CI 309 - 459.1; TAU: 234.9 days 95% CI 127.2 - 342.5; log rank: Chi-square = 4.31, p < 0.05), severity of the illness (p < 0.01), positive symptoms (p < 0.001), and cognitive symptoms (p < 0.05), as well as functioning (p < 0.05) and service engagement (p < 0.05) was observed in IV patients. Despite differences on a descriptive level, differences in total admissions (IV: 15.3%; TAU: 53.8%; odds ratio = 0.155, 95% CI 0.0243 - 1.00) were not significant. A methodological limitation is that symptom ratings were not performed by independent and blinded raters.

Effects of deep brain stimulation on prepulse inhibition in obsessive-compulsive disorder.

Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation.

[Treating Late Life Depression with Antidepressants--A Summary of Recommendations in International Guidelines]. / Medikamentöse Behandlung der Depression im Alter--Empfehlungen aus Internationalen Leitlinien und aktueller Literatur.

Late life depression is associated with severe health consequences, e.g. elevated risk of medical comorbidity and decreased quality of life. This paper summarizes the recommendations of the international guidelines on evidence-based pharmacological treatment of depression in late life in a systematic review. Pharmacological treatments for depression recommended by most of the guidelines, however, hardly address the issue of the possible side effects of antidepressants and other factors of multi-medication on the elderly. Different guidelines pay different degrees of attention to the specific group of geriatric patients. There is a lack of evidence-based treatment recommendation that takes into consideration the specific age-related issues of sensitivity to adverse effects or pharmacokinetic interaction. Further research is required to provide a database for more refined recommendations in guidelines.

Mortality in incident dementia - results from the German Study on Aging, Cognition, and Dementia in Primary Care Patients.

OBJECTIVE: Dementia is known to increase mortality, but the relative loss of life years and contributing factors are not well established. Thus, we aimed to investigate mortality in incident dementia from disease onset. METHOD: Data were derived from the prospective longitudinal German AgeCoDe study. We used proportional hazards models to assess the impact of sociodemographic and health characteristics on mortality after dementia onset, Kaplan-Meier method for median survival times. RESULTS: Of 3214 subjects at risk, 523 (16.3%) developed incident dementia during a 9-year follow-up period. Median survival time after onset was 3.2 years (95% CI = 2.8-3.7) at a mean age of 85.0 (SD = 4.0) years (≥2.6 life years lost compared with the general German population). Survival was shorter in older age, males other dementias than Alzheimer's, and in the absence of subjective memory complaints (SMC). CONCLUSION: Our findings emphasize that dementia substantially shortens life expectancy. Future studies should further investigate the potential impact of SMC on mortality in dementia.