Sodium signal intensity of CSF using 1H-guided 23Na-MRI as a potential noninvasive biomarker in Alzheimer's disease.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is characterized by cognitive decline and mnestic deficits. The pathophysiology of AD is not fully understood, which renders the development of accurate tools for early diagnosis and effective therapies exceedingly difficult. In this study, we investigated the use of 23Na-MRI to measure the relative sodium signal intensities (rSSIs) in CSF in patients with AD and healthy controls. METHODS: We prospectively recruited 11 patients with biomarker-diagnosed early-stage AD, as well as 12 cognitively healthy age-matched controls. All participants underwent 23Na-MRI to measure rSSI. Statistical analyses were performed to compare CSF sodium signal intensities between groups and to evaluate the specificity and sensitivity of the rSSI in the diagnosis of AD. RESULTS: RSSIs in CSF were significantly higher in AD patients (mean = 68.6% ± 7.7%) compared to healthy controls (mean = 56.9% ± 5.5%) (p < .001). There was also a significant negative correlation between rSSI in CSF and hippocampus and amygdala volumes (r = -.54 and -.49, p < .05) as well as a positive correlation with total CSF volumes (r = .81, p < .05). Receiver operating characteristic analysis showed high diagnostic accuracy for rSSI in discriminating between AD patients and healthy controls (area under the curve = .94). CONCLUSION: Our study provides evidence that rSSI in CSF is increased in AD patients in comparison to healthy controls. rSSI may serve as a potential marker for early detection and monitoring of disease progression. Larger, longitudinal studies are needed to confirm our findings and to investigate the association between rSSI in CSF and the severity of cognitive impairment.

Reduced tactile sensitivity is associated with mild cognitive impairment.

BACKGROUND: Sensory impairment has been related to age-associated cognitive decline. While these associations were investigated primarily in the auditory and visual domain, other senses such as touch have rarely been studied. Thus, it remains open whether these results are specific for particular sensory domains, or rather point to a fundamental role of sensory deficits in cognitive decline. METHODS: Data from 31 participants with mild cognitive impairment (MCI), 46 participants with frailty, and 23 non-clinical control participants (NCCs) were included. We assessed sensory function using visual acuity and contrast sensitivity, hearing threshold, and mechanical detection threshold. Cognitive function in participants with MCI was assessed using associative memory performance. Group differences on sensory thresholds were tested using analyses of covariance with age, sex, and years of education as covariates. Associations between measures within participants with MCI were evaluated using Spearman correlations. FINDINGS: We found a significant difference in mechanical detection threshold between the groups (p < 0.001, η2 = 0.18). Participants with MCI showed significantly reduced tactile sensitivity compared to participants with frailty and NCCs. In participants with MCI, lower associative memory performance was significantly related to reduced tactile sensitivity (rs = 0.39, p = 0.031) and auditory acuity (rs = 0.41, p = 0.022). INTERPRETATION: Our results indicate that reduced tactile sensitivity is related to cognitive decline. Prospective studies should investigate the age-related alterations of multimodal sensory processes and their contribution to dementia-related processes. FUNDING: Deutsche Forschungsgemeinschaft (FL 156/41-1) and a grant of the Hector-Stiftung II, Weinheim, Germany.

Augmented reality versus standard tests to assess cognition and function in early Alzheimer's disease.

Augmented reality (AR) apps, in which the virtual and real world are combined, can recreate instrumental activities of daily living (IADL) and are therefore promising to measure cognition needed for IADL in early Alzheimer's disease (AD) both in the clinic and in the home settings. The primary aim of this study was to distinguish and classify healthy controls (HC) from participants with AD pathology in an early AD stage using an AR app. The secondary aims were to test the association of the app with clinical cognitive and functional tests and investigate the feasibility of at-home testing using AR. We furthermore investigated the test-retest reliability and potential learning effects of the task. The digital score from the AR app could significantly distinguish HC from preclinical AD (preAD) and prodromal AD (proAD), and preAD from proAD, both with in-clinic and at-home tests. For the classification of the proAD group, the digital score (AUCclinic_visit = 0.84 [0.75-0.93], AUCat_home = 0.77 [0.61-0.93]) was as good as the cognitive score (AUC = 0.85 [0.78-0.93]), while for classifying the preAD group, the digital score (AUCclinic_visit = 0.66 [0.53-0.78], AUCat_home = 0.76 [0.61-0.91]) was superior to the cognitive score (AUC = 0.55 [0.42-0.68]). In-clinic and at-home tests moderately correlated (rho = 0.57, p < 0.001). The digital score was associated with the clinical cognitive score (rho = 0.56, p < 0.001). No learning effects were found. Here we report the AR app distinguishes HC from otherwise healthy Aß-positive individuals, both in the outpatient setting and at home, which is currently not possible with standard cognitive tests.

Effects of an app-based sensorimotor training in promoting neuroplasticity and neuropsychological functioning in frailty: A randomized controlled trial.

BACKGROUND: Loss of sensorimotor stimulation and maladaptive plastic changes of the brain may play a major role in problematic aging phenomena such as frailty. However, it is not clear if interventions specifically targeting neuroplasticity can reverse or slow the development of frailty. OBJECTIVES: We compared the effect of a tablet-based neuroplasticity-oriented sensorimotor training (experimental group, EG) and a tablet-based relaxation training (control group, CG) on frailty and sensorimotor brain function. METHODS: Interventions consisted of daily 30 min sessions distributed over 90 days. Assessments took place at baseline, after 60 days, and after 90 days. A total of N = 48 frail older adults (EG: n = 24; CG: n = 24) were assigned to the two groups and reassessed after 60 days. Primary outcomes included frailty phenotype (FP) and frailty index (FI). Sensorimotor brain activity was evaluated using functional magnetic resonance imaging and single-pulse transcranial magnetic stimulation. RESULTS: After 60 days of training, both groups showed a reduction in the number of FP criteria (p < 0.001) with a trend towards a significant time-by-group interaction (p = 0.058) indicating a stronger reduction of frailty in the EG (p < 0.001) compared to the CG (p = 0.039). In addition, pain was significantly reduced in the EG but not the CG. No significant effects were found for measures of brain function. DISCUSSION: We provided initial evidence that a neuroplasticity-oriented sensorimotor training could be beneficial in counteracting frailty as well as chronic pain. Further studies are needed to determine the potentially underlying neuroplastic mechanisms and the influence of plasticity-related biomarkers as well as their clinical significance. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 (registered 11 September 2018).

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aß42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Apathy in patients with Alzheimer's disease is a cost-driving factor.

BACKGROUND: Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers. METHODS: Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utilization in Dementia (RUD) instrument assessed costs over a 1-month period prior to baseline. Cost predictors were determined via a least absolute shrinkage and selection operator (LASSO). RESULTS: On average, total monthly costs were €3070, of which €2711 accounted for caregivers' and €359 for patients' costs. An increase of one point in the Apathy Evaluation Scale resulted in a 4.1% increase in total costs. DISCUSSION: Apathy is a significant cost driving factor for total costs in mild to moderate DAT. Effective treatment of apathy might be associated with reduced overall costs in DAT.

Sensory and motor correlates of frailty: dissociation between frailty phenotype and frailty index.

BACKGROUND: Frailty has been associated with a decline in sensory and motor function. However, given that different frailty measures were shown to overlap but also differ in their diagnostic properties, sensory and motor correlates of frailty might be different depending on the operationalization of frailty. Our objective was to identify sensory and motor determinants of frailty and compare the results between frailty phenotype (FP) and frailty index (FI). METHODS: Data from 44 pre-frail and frail subjects aged 65 and above were used. Frailty was measured using the FP and the FI. Sensory function in the visual, auditory, and tactile domain was assessed using visual acuity, absolute hearing threshold and mechanical detection threshold. Upper extremity motor performance was evaluated by the Purdue Pegboard Test and the Short Physical Performance Battery was used to assess lower extremity motor function. Multiple logistic regression models were employed to determine associations of sensory and motor function with frailty vs. pre-frailty for both frailty measures. RESULTS: The frailty measures were moderately correlated (0.497, p ≤ 0.01) and had a Kappa agreement of 0.467 (p = 0.002). Using the FP, frailty was significantly associated with reduced upper extremity motor function only (OR = 0.50, 95% CI 0.29-0.87, p = 0.014). Frailty as assessed by the FI was significantly related to higher hearing thresholds (OR = 1.21, 95% CI 1.02-1.43, p = 0.027) and reduced lower extremity performance (OR = 0.32, 95% CI 0.13-0.77, p = 0.012). CONCLUSION: Frailty is related to reduced performance in measures of sensory and motor function. However, traditional measures of frailty might be differentially sensitive to capture sensory and motor decline, possibly contributing to the much-observed discordance between the diagnostic instruments. This should be taken into account by researchers and clinicians when planning and evaluating therapeutic interventions for frailty. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 . Registered 11 September 2018 - Retrospectively registered.

[The Cost of Early Diagnosis of Cognitive Decline in German Memory Clinics]. / Kosten der Diagnostik kognitiver Störungen in deutschen Gedächtnisambulanzen.

Dementias are expensive diseases: the net annual cost in European healthcare is about € 28.000 per case with a strong stage dependency, of which medical care accounts for about 19%. Diagnostic costs, on the other hand, account for only a small proportion of the total costs. With changes in the guidelines, biomarker tests are becoming increasingly important. At present, the concrete economic impact of biomarker-based diagnosis is largely unknown. To determine the actual costs of diagnostic procedures based on guidelines, we conducted a survey among the members of the German Memory Clinic Network (DNG). From 15 expert centres, the staff engagement time for all procedures was collected. Based on the individual engagement times of the different professions, the total of personnel costs for diagnostics was calculated using current gross personnel costs. The total sum of diagnostic costs (personnel plus procedures) was calculated for three different scenarios e. g. € 633,97 for diagnostics without biomarkers, € 1.214,90 for diagnostics with CSF biomarkers and € 4.740,58 € for diagnostics with FDG- plus Amyloid-PET. In addition, the actual diagnostic costs of the current practice in expert memory clinics were estimated, taking into account personnel costs, costs for the different procedures and the frequency of their use across all patients. This results in total average costs of € 1.394,43 per case as the mean across all centres (personnel costs € 351,72, costs for diagnostic procedures € 1.042,71). The results show that state-of-the-art diagnosis of dementia and pre-dementia states, such as mild cognitive impairment (MCI) requires financial resources, which are currently not fully reimbursed in Germany. The need for a biomarker-based etiological diagnosis of dementia and pre-dementia states will increase, due to availability of disease-modifying treatments. Therefore, the current gap of reimbursement must be filled by new models of compensation.

Don't forget about tau: the effects of ApoE4 genotype on Alzheimer's disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment-data from the Dementia Competence Network.

ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aß) and tau pathology, with the strongest evidence for effects on Aß, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aß42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aß42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aß42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aß 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aß42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-ß burden and tau aggregation at specific time points in AD pathogenesis.

[Disease-modifying treatment approaches for Alzheimer's disease]. / Krankheitsmodifizierende Therapieansätze bei Alzheimer-Krankheit.

Alzheimer's disease is one the major common diseases but so far only with symptomatic treatment options. New insights define the disease as a slowly progressive continuum with very long preclinical and early symptomatic phases. Innovative molecular treatment strategies are based on an improved understanding of the molecular neurobiology of the disease, opening up a variety of therapeutic targets. For the first time, an anti-amyloid antibody has been approved in the USA in 2021 as a disease-modifying treatment for Alzheimer's disease, representing a first highly controversial step towards a molecular, cause-oriented treatment. This review presents the most advanced molecular treatment strategies and discusses the implications of the approved antibody treatment for the clinical practice. The special features of this long-term treatment with i.v. infusions in a particularly vulnerable population and a special side effect profile will impose significant challenges for implementation in the practice and will require a high degree of cooperation within the healthcare system. The future of Alzheimer's treatment with a multimodal therapeutic approach with different classes of drugs will probably reinforce these trends.

Promoting neuroplasticity and neuropsychological functioning in frailty through an app-based sensorimotor training: study protocol for a randomized trial.

BACKGROUND: Frailty is characterized by an age-related decline in multiple physiological systems, leading to a high vulnerability to stressors, adverse health outcomes, and low quality of life. Neuroscientific models of pathological aging emphasize the loss of sensorimotor stimulation and reduced neuromodulatory capacities as core processes in age-related cognitive and bodily decline, which may be associated with maladaptive plastic changes in the brain. We plan to increase sensorimotor stimulation in frail persons through a newly developed app-based training program and link the training trials to biological and psychological correlates of age-associated vulnerability and health indices. METHODS: We will conduct a randomized trial, applying an app-based sensorimotor home training (N = 30) in people suffering from frailty. An app-based relaxation training will serve as an active control condition (N = 30). Both interventions will last for 90 days each. The sensorimotor training includes unimodal and multimodal sensory discrimination tasks in the visual, auditory, and tactile domain, as well as sensorimotor precision tasks. The tasks will be implemented using an adaptive training algorithm and enriched with motivational components embedded in a virtual training environment. We expect a pre-post reduction of frailty status and associated functional decline related to refinement of representational maps within the sensorimotor system and improved sensorimotor function such as extremity function. Secondary analyses will study the influence of BDNF genotype as moderating variable. Additional outcomes will include measures of perceptual and cognitive functioning, quality of life as well as BDNF serum levels. Measurements will take place before training (baseline), after 60 days (assessment 1), and at the end of the training after 90 days (assessment 2). DISCUSSION: In our randomized trial, we aim to characterize a multidimensional concept of frailty and to target maladaptive behaviors and neuroplasticity using an app-based sensorimotor training. This type of intervention might provide further knowledge and new possibilities for preventing decline and preserving function in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 . Registered 11 September 2018 - Retrospectively registered. Protocol version: Version 4 revised (issue date: 19 May 2021).

Rapid Support for Older Adults during the Initial Stages of the COVID-19 Pandemic: Results from a Geriatric Psychiatry Helpline.

BACKGROUND: The COVID-19 pandemic and governmental lockdown measures disproportionally impact older adults. This study presents the results from a psychiatric helpline for older adults in Mannheim, Germany, during the lockdown, set up to provide information and psychosocial support. We aim to elucidate the needs of older adults, their reported changes, and the psychological impact during the initial stages of the health crisis. METHODS: A total of 55 older adults called the psychiatric helpline between April and June 2020. Information on demographics, medical and psychiatric history. as well as changes in daily life due to the pandemic was collected anonymously. Mental health status was assessed using the 7-Item Hamilton Depression Rating Scale (HAMD-7) and the Hamilton Anxiety Rating Scale (HAM-A). RESULTS: Most callers were women, older adults (M = 74.69 years), single, and retired. In total, 69% of callers reported new or an increase in psychiatric symptoms, with anxiety and depressive symptoms being the most common ones. Age was significantly negatively correlated to higher levels of anxiety and depression symptoms. Individuals with a previous diagnosis of a psychiatric disease reported significantly higher levels of depressive and anxiety symptoms than those without a diagnosis. CONCLUSION: In older adults, the perceived psychological impact of the COVID-19 crisis appears to ameliorate with age. Individuals with a history of psychiatric disease are most vulnerable to negative mental health outcomes. Rapid response in the form of a geriatric helpline is a useful initiative to support the psychosocial needs of older adults during a health crisis.

Crossed Cerebellar Diaschisis in Alzheimer's Disease Detected by Arterial Spin-labelling Perfusion MRI.

BACKGROUND: Crossed cerebellar diaschisis (CCD) is a phenomenon with depressed metabolism and hypoperfusion in the cerebellum. Using arterial spin-labelling perfusion weighted magnetic resonance imaging (ASL PWI), we investigated the frequency of CCD in patients with Alzheimer's disease (AD) and differences between patients with and without CCD. PATIENTS AND METHODS: In patients with AD who underwent a standardized magnetic resonance imaging including ASL PWI cerebral blood flow was evaluated in the cerebellum, and brain segmentation/volumetry was performed using mdbrain (mediaire GmbH, Berlin, Germany) and FSL FIRST (Functional Magnetic Resonance Imaging of the Brain Software Library). RESULTS: In total, 65 patients were included, and 22 (33.8%) patients were assessed as being CCD-positive. Patients with CCD had a significantly smaller whole brain volume (862.8±49.9 vs. 893.7±62.7 ml, p=0.049) as well as white matter volume (352.9±28.0 vs. 374.3±30.7, p=0.008) in comparison to patients without CCD. CONCLUSION: It was possible to detect CCD by ASL PWI in approximately one-third of patients with AD and was associated with smaller whole brain and white matter volume.

Evaluation of Sodium (23Na) MR-imaging as a Biomarker and Predictor for Neurodegenerative Changes in Patients With Alzheimer's Disease.

BACKGROUND/AIM: Sodium (23Na) MR imaging is a noninvasive MRI technique that has been shown to be sensitive to visualize biochemical information about tissue viability, their cell integrity, and cell function in various studies. The aim of this study was to evaluate differences in regional brain 23Na signal intensity between Alzheimer's disease (AD) and healthy controls to preliminarily evaluate the capability of 23Na imaging as a biomarker for AD. PATIENTS AND METHODS: A total of 14 patients diagnosed with AD were included: 12 in the state of dementia and 2 with mild cognitive impairment (MCI), and 12 healthy controls (HC); they were all scanned on a 3T clinical scanner with a double tuned 1H/23Na birdcage head coil. After normalizing the signal intensity with that of the vitreous humor, relative tissue sodium concentration (rTSC) was measured after automated segmentation in the hippocampus, amygdala, basal ganglia, white matter (WM) and grey matter (GM) in both cerebral hemispheres. RESULTS: Patients with AD showed a significant increase in rTSC in comparison to healthy controls in the following brain regions: WM 13.6%; p=0.007, hippocampus 12.9%; p=0.003, amygdala 18.9%; p=0.0007. CONCLUSION: 23Na-MRI has the potential to be developed as a useful biomarker for the diagnosis of AD.

Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer's disease.

OBJECTIVE: Synaptic loss plays a major role in Alzheimer's disease (AD). However so far no neurochemical marker for synaptic loss has been introduced into clinical routine. By mass spectrometry beta-synuclein was established as a candidate marker. We now aimed to set up a novel ELISA for beta-synuclein for evaluation of its potential as a diagnostic and predictive marker for AD. METHODS: We analysed in total 393 patients from four specialised centres. The diagnostic groups comprised: AD (n=151), behavioural variant frontotemporal dementia (bvFTD, n=18), Parkinson syndrome (n=46), Creutzfeldt-Jakob disease (CJD, n=23), amyotrophic lateral sclerosis (ALS, n=29), disease control (n=66) and 60 non-neurodegenerative control patients. Results were compared with core AD biomarkers (total tau, phospho-tau and amyloid-ß peptide 1-42). Additionally, coexistence of beta-synuclein with vesicular glutamate transporter 1 (VGLUT1) was determined and beta-synuclein levels were quantified in brain homogenates. RESULTS: Beta-synuclein levels quantified with the newly established ELISA correlated strongly with antibody-free quantitative mass spectrometry data (r=0.92 (95% CI: 0.89 to 0.94), p<0.0001). Cerebrospinal fluid (CSF) beta-synuclein levels were increased in AD-mild cognitive impairment (p<0.0001), AD dementia (p<0.0001) and CJD (p<0.0001), but not in bvFTD, Parkinson syndrome or ALS. Furthermore, beta-synuclein was localised in VGLUT1-positive glutamatergic synapses, and its expression was significantly reduced in brain tissue from patients with AD (p<0.01). CONCLUSION: We successfully established a sensitive and robust ELISA for the measurement of brain-enriched beta-synuclein, which we could show is localised in glutamatergic synapses. We confirmed previous, mass spectrometry-based observations of increased beta-synuclein levels in CSF of patients with AD and CJD supporting its potential use as a marker of synaptic degeneration.

[Memory clinics in Germany-structural requirements and areas of responsibility]. / Gedächtnisambulanzen in Deutschland ­ strukturell-organisatorische Voraussetzungen und Aufgabenfelder.

BACKGROUND: Memory clinics (MC) are institutions specialized in the (differential) diagnostics, treatment, education, management and counseling of diseases related to dementia and their risk stages. In Germany, they have a variety of different organizational forms. Due to the growing diagnostic options in neurodegenerative diseases, the increasing demand for early detection and prediction as well as foreseeable new diagnostic procedures and disease-modifying treatment, it is important to standardize the structural prerequisites and areas of responsibility of MC. OBJECTIVE: The article proposes structural and organizational requirements and procedures and a harmonized mode of operation for MC in Germany. METHOD: Expert consensus of psychiatrists, neurologists and geriatricians from academic and nonacademic institutions. RESULTS: The MC should provide the specialist standards of psychiatry and/or neurology. They need to implement the recommendations of the national guidelines on dementia (S3LL) with respect to the (differential) diagnostics and treatment of dementia. With respect to the early detection and prediction of neurodegenerative disorders, they extend beyond the current German guideline standards. In MC, mild cognitive impairment (MCI) is understood as an at-risk or prodromal stage of diseases related to dementia and biomarkers are consistently applied for etiological (early and differential) diagnostics. There is a requirement for close interaction with specialized diagnostic disciplines. Furthermore, MC should also offer comprehensive advice on social and legal issues and provide caregiver support. They should integrate current knowledge from research into care and serve as regional expert centers. CONCLUSION: The MC should implement evidence-based standards in diagnostics and treatment and introduce innovations in the care of patients with cognitive disorders and at-risk and prodromal stages. Their role in the German healthcare system must be strengthened. Sufficient and sustained funding needs to be established, since current reimbursement does not cover costs.

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.

Association of lysophosphatidic acids with cerebrospinal fluid biomarkers and progression to Alzheimer's disease.

BACKGROUND: Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer's disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD. METHODS: The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts. We profiled LPA-derived metabolites using liquid chromatography-mass spectrometry. We evaluated the association of LPAs with CSF biomarkers of AD, Aß-42, p-tau, and total tau levels overall and stratified by APOE genotype and with MCI to AD progression. RESULTS: Five LPAs (C16:0, C16:1, C22:4, C22:6, and isomer-LPA C22:5) showed significant positive association with CSF biomarkers of AD, Aß-42, p-tau, and total tau, while LPA C14:0 and C20:1 associated only with Aß-42 and alkyl-LPA C18:1, and LPA C20:1 associated with tau pathology biomarkers. Association of cyclic-LPA C16:0 and two LPAs (C20:4, C22:4) with Aß-42 levels was found only in APOE ε4 carriers. Furthermore, LPA C16:0 and C16:1 also showed association with MCI to AD dementia progression, but results did not replicate in an independent cohort. CONCLUSIONS: Our findings provide evidence that LPAs may contribute to early AD pathogenesis. Future studies are needed to determine whether LPAs play a role in upstream of AD pathology or are downstream markers of neurodegeneration.