Predictors of Nursing Home Placement in a Cohort of European People with Alzheimer's Disease and Other Dementia Cases Enrolled in SCU-B or Non SCU-B Centers: The RECage Study.

Background: Nursing home placement (NHP) can be the final step of patients with Alzheimer's disease. Objective: We aimed to identify NHP predictors among 508 people with dementia with a 3-year follow-up. Methods: We analyzed data from the international observational RECage study, involving 508 people with especially Alzheimer's disease and comparing a cohort enrolled by five centers with a Special Care Unit for BPSD (behavioral and psychological symptoms of dementia) and another one enrolled by six centers lacking this facility. The tertiary objective of the study was to assess the possible role of the SCU-B in delaying NHP. We assessed the relationship of the baseline characteristics with NHP by means of univariate analysis followed by Cox's multivariate model. Results: Patients' mean age was 78.1 years, 54.9% were women. Diagnosis mean age was 75.4 (±8.32) years; the main diagnosis was Alzheimer's disease (296; 58.4%). During follow-up, 96 (18.9%) patients died and 153 (30.1%) were institutionalized without a statistically significant difference between the two cohorts (p = 0.9626). The mean NHP time was 902 (95% CI: 870-934). The multivariable analysis without death as a competing risk retained four independent predictors of NHP: age increase (hazard ratio (HR) = 1.023, 95% CI: 1.000-1.046), patient education level increase (HR = 1.062, 95% CI: 1.024-1.101), Neuropsychiatric Inventory total increase (HR = 1.018; 95% CI: 1.011-1.026), and total Mini-Mental State Examination as a favorable factor (HR = 0.948, 95% CI: 0.925-0.971). Gender (females versus males: HR = 1.265, 95% CI: 0.899-1.781) was included in the final Cox's model for adjusting the estimates for. Conclusions: Our data partially agree with the predictors of NHP in literature including the effect of high education level. No caregivers' factors were statistically significant. Clinical trial registration: NCT03507504.

European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders.

The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.

Respectful Caring for the Agitated Elderly (ReCAGE): A Multicentre, Prospective, Observational Study to Evaluate the Effectiveness of Special Care Units for People with Dementia.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) bring complexity in the clinical management of people with dementia; therefore, it is important to evaluate different models of care, such as Special Care Units (SCU-B).∥Objective:To evaluate the SCU-B effectiveness toward alleviating BPSD and improving the quality of life (QoL) of patients and their caregivers.∥Methods:ReCAGE was a multicenter, controlled, longitudinal study where 508 patients with BPSD were enrolled in two cohorts: 262 patients from centers endowed with a SCU-B, and 246 from centers without SCU-B. Statistical analyses included factorial ANCOVA for comparison among centers. The primary endpoint was effectiveness of the SCU-B, measured through the Neuropsychiatric Inventory (NPI) changes. Secondary endpoints were change in QoL of patients and caregivers, and the tertiary endpoint was time to nursing home admission.∥Results:The NPI scores decreased in both arms, with a statistically significant difference from baseline to 36 months (p < 0.0001) in both cohorts. Over time, NPI decreased more steeply during the first year in the SCU-B arm, but in the following two years the slope was clearly in favor of the control arm. This different pattern of the two cohorts reached statistical significance at the interaction "cohort by time" (p < 0.0001). Conflicting results were found regarding the outcomes of quality of life, while there were no differences in time to institutionalization in both cohorts.∥Conclusion:The RECage study did not confirm the long-term superiority of the pathway comprising a SCU-B. A post-hoc analysis revealed data supporting their acute effectiveness during behavioral crises.

Correction: Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study.

[This corrects the article DOI: 10.1371/journal.pone.0285807.].

Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study.

INTRODUCTION: Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer's disease, and what gaps remain. METHODS: Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach. RESULTS: Four main themes emerged after analysis: data management, participant's wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites. DISCUSSION: The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study.

Anti-amyloid antibody therapies in Alzheimer's disease.

After years of failed attempts to develop a disease-modifying therapy for Alzheimer's disease, consistent evidence in support of clinical efficacy was finally presented for a monoclonal antibody targeting the amyloid-ß protofibrils. In addition to meeting the primary outcome of slowing clinical disease progression over 18 months, secondary clinical outcomes and amyloid-ß lowering on PET also underpin the positive results of the trial. In this opinion piece, we highlight the key characteristics of the previous unsuccessful trials and analyse the potential reasons why those attempts to develop a treatment for early Alzheimer's disease failed. We compare the safety profiles of the different antibodies and highlight cautionary measures for their routine clinical use. Last, we discuss the role of blood-based biomarkers in transforming the clinical care pathway to facilitate the uptake of antibody treatments, proposing an integrated case-finding and treatment model crossing the different healthcare sectors. Taken together, a real breakthrough may have been achieved by proving that amyloid-ß reduction results in clinical benefits, rather than just biomarker changes. At the same time, routine use of the new generation of drugs will show if statistical efficacy translates into clinically meaningful change. This may just be the beginning of a new era of Alzheimer's disease drug development.

Lecanemab in Early Alzheimer's Disease.

BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

European consensus for the diagnosis of MCI and mild dementia: Preparatory phase.

INTRODUCTION: Etiological diagnosis of neurocognitive disorders of middle-old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results. METHODS: Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions. RESULTS: We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI-mild dementia), and detailed pre-assessment screening (clinical-neuropsychological evaluations, brain imaging, and blood tests). DISCUSSION: The Delphi consensus on these assumptions set the stage for the development of the first pan-European workflow for biomarkers' use in the etiological diagnosis of middle-old age neurocognitive disorders at MCI-mild dementia stages. HIGHLIGHTS: Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe. A consensus of experts will define a workflow for the rational use of biomarkers. The diagnostic workflow will be patient-centered and based on clinical presentation. The workflow will be updated as new evidence accrues.

Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease.

BACKGROUND: Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. METHODS: We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. RESULTS: We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. CONCLUSIONS: CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

Quality of Life and Caregiver Burden of Alzheimer's Disease Among Community Dwelling Patients in Europe: Variation by Disease Severity and Progression.

BACKGROUND: Alzheimer's disease (AD) is a significant burden on patients and caregivers. How this burden increases as disease progresses has not been well researched. OBJECTIVE: To assess the association of caregiver burden and quality of life with Alzheimer's disease severity and disease progression in community-dwelling patients in Germany, Spain, and the UK. METHODS: This was a prospective observational longitudinal study of mild-to-moderate AD patients (assessed by Mini-Mental State Examination, MMSE), and their caregivers. The humanistic burden was assessed using these instruments: [Rapid Assessment of Physical Activity (RAPA), EuroQoL-5-Dimension Level (EQ-5D-5L)] and caregiver-reported [Dependence Scale (DS), EQ-5D-5L, Zarit Burden Interview (ZBI)]. Caregiver-reported healthcare resource use was assessed using the Resource Use in Dementia (RUD) and ad-hoc questions. RESULTS: Of 616 patients recruited, 338 and 99 were followed-up at 12 and 18 months, respectively. The caregiver-reported EQ-5D-5L scores of patients' health-related quality of life (HRQoL) showed a negative trend over time (baseline: 0.76; 18 months: 0.67) while patient-reported HRQoL remained at 0.85. DS scores tended to worsen. Disease progression was an independent predictor of HRQoL and increased dependence.Mean ZBI score increased over time reflecting an increase in caregiver burden; MMSE being an independent predictor for caregiver burden. Patient resource utilization and caregiver time for caregiving tended to increase over time. CONCLUSION: We found significant association between disease progression and caregiver and patient burden. Independently, both disease-specific outcomes and disease burden measures increased over time, but as disease progresses, we also found incremental burden associated with it.

CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals.

We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p181-tau and amyloid ß 1-42 (Aß42) CSF analysis showed that in the hyperplasticity subtype p181-tau increased (ß = 2.6 pg/mL per year, p = 0.01) and Aß42 decreased over time (ß = -4.4 pg/mL per year, p = 0.03), in the innate immune activation subtype p181-tau increased (ß = 3.1 pg/mL per year, p = 0.01) while in the blood-brain barrier dysfunction subtype Aß42 decreased (ß = -3.7 pg/mL per year, p = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.

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.

Assessing the Progression of Alzheimer's Disease in Real-World Settings in Three European Countries.

BACKGROUND: There exists considerable variation in disease progression rates among patients with Alzheimer's disease (AD). OBJECTIVE: The primary objective of this observational study is to assess the progression of AD by characterizing cognitive, functional, and behavioral changes during the follow-up period between 6 and 24 months. METHODS: A longitudinal prospective study with community-dwelling patients with an established clinical diagnosis of AD of mild to moderate severity was conducted in Germany, Spain and the UK. A sample of 616 patients from 69 sites was included. RESULTS: Patients had a mean of 1.9 years (SD = 1.9) since AD diagnosis at study inclusion. Cognitive symptoms were reported to have first occurred a mean of 1.1 years (SD = 1.7) prior to AD diagnosis and 1.4 (SD = 1.8) years prior to AD treatment. Patients initially diagnosed with mild and moderate AD spent a median (95%CI) of 3.7 (2.8; 4.4) and 11.1 (6.1, 'not reached') years until progression to moderate and severe AD, respectively, according to the Mini-Mental State Examination (MMSE) scores. A mixed model developed for cognitive, functional, and neuropsychiatric scores, obtained from study patients at baseline and during follow-up period, showed progressive deterioration of AD patients over time. CONCLUSION: The study showed a deterioration of cognitive, functional, and neuropsychiatric functions during the follow-up period. Cognitive deterioration was slightly faster in patients with moderate AD compared to mild AD. The duration of moderate AD can be overestimated due to the use of retrospective data, lack of availability of MMSE scores in clinical charts and exclusion of patients at time of institutionalization.

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.

ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer's disease.

Alzheimer's disease (AD) pathology is partly characterized by accumulation of aberrant forms of tau protein. Here we report the results of ADAMANT, a 24-month double-blinded, parallel-arm, randomized phase 2 multicenter placebo-controlled trial of AADvac1, an active peptide vaccine designed to target pathological tau in AD (EudraCT 2015-000630-30). Eleven doses of AADvac1 were administered to patients with mild AD dementia at 40 µg per dose over the course of the trial. The primary objective was to evaluate the safety and tolerability of long-term AADvac1 treatment. The secondary objectives were to evaluate immunogenicity and efficacy of AADvac1 treatment in slowing cognitive and functional decline. A total of 196 patients were randomized 3:2 between AADvac1 and placebo. AADvac1 was safe and well tolerated (AADvac1 n = 117, placebo n = 79; serious adverse events observed in 17.1% of AADvac1-treated individuals and 24.1% of placebo-treated individuals; adverse events observed in 84.6% of AADvac1-treated individuals and 81.0% of placebo-treated individuals). The vaccine induced high levels of IgG antibodies. No significant effects were found in cognitive and functional tests on the whole study sample (Clinical Dementia Rating-Sum of the Boxes scale adjusted mean point difference -0.360 (95% CI -1.306, 0.589)), custom cognitive battery adjusted mean z-score difference of 0.0008 (95% CI -0.169, 0.172). We also present results from exploratory and post hoc analyses looking at relevant biomarkers and clinical outcomes in specific subgroups. Our results show that AADvac1 is safe and immunogenic, but larger stratified studies are needed to better evaluate its potential clinical efficacy and impact on disease biomarkers.

Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.

Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.

Targeted Mass Spectrometry Suggests Beta-Synuclein as Synaptic Blood Marker in Alzheimer's Disease.

Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read-out for patient diagnosis and possible follow-up in clinical trials. Several synaptic markers for AD are described in cerebrospinal fluid (CSF), but studies in blood have failed so far. Using quantitative mass spectrometry (IP-MS, MRM) we observed increased concentrations of the presynaptic protein beta-synuclein (ßSyn) in CSF and blood of AD patients (n = 64, p < 0.01) and confirmed this finding in two validation cohorts (AD: n = 40 and n = 49, controls: n = 44 and n = 25). ßSyn was already increased in patients with mild cognitive impairment (p < 0.01) and was also markedly increased in Creutzfeldt-Jakob disease (CJD; n = 25, p < 0.001) but not behavioral variant frontotemporal dementia (n = 16), dementia with Lewy bodies/Parkinson's disease dementia (n = 13), Parkinson's disease (n = 25), or amyotrophic lateral sclerosis (n = 30). The diagnostic sensitivity and specificity for CJD versus other neurodegenerative diseases was ≥96%. These findings suggest ßSyn as a candidate blood marker for synaptic degeneration that might be used in clinical AD trials and patient follow-up as part of the recently suggested ATN biomarker panel. It can also serve in the differential diagnosis of CJD.

Cognitive behavioural therapy for the treatment of late life depression: study protocol of a multicentre, randomized, observer-blinded, controlled trial (CBTlate).

BACKGROUND: Late-life depression (LLD) is one of the most prevalent mental disorders in old age. It is associated with various adverse outcomes and frequent use of health care services thereby remaining a serious public health concern. Compared with depression in early adulthood, most treatment options of LLD are less effective. Psychotherapy may be particularly beneficial for LLD due to specific psychological conditions in old age and a low risk of side effects. Although cognitive behavioural therapy (CBT) is highly established and effective in depression in young and mid-life there is only a limited number of small studies on CBT in LLD. An LLD-specific CBT has not yet been compared to an active, but unspecific supportive psychological intervention in a multicentre trial. METHODS: Here we present the design of the CBTlate trial, which is a multicentre, randomized, observer-blinded, active-controlled, parallel group trial. CBTlate aims at including 248 patients with LLD of both genders at 7 sites in Germany. The purpose of the study is to test the hypothesis that a 15-session individually-delivered CBT specific for LLD is of superior efficacy in reducing symptoms of depression in comparison with a supportive unspecific intervention (SUI) of the same quantity. The intervention includes 8 weeks of individual treatment sessions twice per week and a follow-up period of 6 months after randomization. The primary end point is the severity of depression at the end of treatment measured by the self-rated 30-item Geriatric Depression Scale (GDS). Secondary endpoints include depressive symptoms at week 5 and at follow-up (6 months after randomization). Additional secondary endpoints include the change of depressive symptoms assessed with a clinician-rating-scale and a patient reported outcome instrument for major depressive disorder, anxiety symptoms, sleep, cognition, quality of life, and overall health status from baseline to end-of treatment and to end of follow-up. Add-on protocols include MRI and the collection of blood samples. DISCUSSION: This study is the first multicentre trial of a specific CBT intervention for LLD compared to an unspecific supportive psychological intervention administered in a specialist setting. It has important implications for developing and implementing efficient psychotherapeutic strategies for LLD and may be a significant step to broaden treatment options for people suffering from LLD. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03735576, registered on 24 October 2018); DRKS (DRKS00013769, registered on 28 June 2018).

Association of Cerebral Amyloid-ß Aggregation With Cognitive Functioning in Persons Without Dementia.

Importance: Cerebral amyloid-ß aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-ß aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. Conclusions and Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.