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Objective We aimed to investigate factors associated with self- and carer-rated quality of life (QoL) and caregiver burden related to very mild to severe clinical Alzheimer disease (AD). Methods One hundred patient-carer dyads were recruited, and assessments of relevant outcomes were performed, including sociodemographic characteristics, QoL, activities of daily living (ADL), cognitive performance, behavioural and psychological symptoms of dementia (BPSD), caregiver burden, and health resource utilisation. Results There was a strong correlation between carer- and self-rated QoL, with patients consistently rating their QoL higher than caregivers. Duration of illness did not affect the QoL ratings. There was an inverse association between both self- and carer-rated QoL with age, age at symptom onset, impairment of ADL, time spent on assisting the patient, and depression. Both self- and carer-rated QoL ratings were higher if the caregiver was a spouse vs a child. Carer-rated QoL was inversely associated with severity of dementia, BPSD, caregiver burden, and requirement to supervise the patient. The variables age at symptom onset, ADL, and living together with the primary caregiver explained 34.50% of the variance in self-rated QoL, whereas age at symptom onset, ADL, and BPSD explained 48.20% of the variance in carer-rated QoL. For caregiver burden, 26% of the variance was explained by the variables ADL, living together with the primary caregiver, and agitation. Conclusion Our study highlights the need for a stronger focus on QoL in clinical AD research by providing further pieces of evidence on the key determinants, including the important aspect of caregiver burden.

New diagnostic criteria for Alzheimer's disease (AD) treat different biomarkers of neuronal injury as equivalent. Here, we quantified the degree of agreement between hippocampal volume on structural magnetic resonance imaging, regional glucose metabolism on positron emission tomography, and levels of phosphorylated tau in cerebrospinal fluid (CSF) in 585 subjects from all phases of the AD Neuroimaging Initiative. The overall chance-corrected agreement was poor (Cohen κ, 0.24–0.34), in accord with a high rate of conflicting findings (26%–41%). Neither diagnosis nor APOE e4 status significantly influenced the distribution of agreement between the biomarkers. The degree of agreement tended to be higher in individuals with abnormal versus normal CSF β-amyloid (Aβ 1-42 ) levels. Prospective diagnostic criteria for AD should address the relative importance of markers of neuronal injury and elaborate a way of dealing with conflicting biomarker findings.

© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.

Background β-Site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid β production, which is a pathological hallmark of Alzheimer's disease (AD). Methods The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects. Results In the AD group, positive correlations between BACE1 activity and soluble APP β, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected. BACE1 activity was not associated with amyloid β 1–42 or soluble APP α concentrations in the AD group, and no associations between BACE1 activity and any of the protein concentrations were found in the control group. Conclusion Our results confirm the relevance of BACE1 and sortilin-related receptor with A-type repeats within the amyloid cascade and also provide a further piece of evidence for the link between amyloid and tau pathology in AD.

Background According to a widely accepted hypothesis, the amyloid precursor protein (APP) is processed by two competing pathways: the amyloidogenic β-secretase–mediated pathway or the nonamyloidogenic α-secretase–mediated pathway. APP is cleaved preferentially through the nonamyloidogenic pathway in normal brain, whereas the balance shifts to the amyloidogenic pathway in Alzheimer's disease (AD). The levels of the α-secretase–cleaved soluble APP (sAPPα) and β-secretase–cleaved soluble APP (sAPPβ) in cerebrospinal fluid (CSF) are likely to reflect these competing mechanisms. Methods We investigated the levels and the relationship between sAPPα and sAPPβ in the CSF of 64 patients with mild AD, 76 patients with mild cognitive impairment, and 12 cognitively healthy control subjects, as well as the effect of apolipoprotein E genotype and sex on soluble APP levels. Results There was a significant positive correlation between sAPPα and sAPPβ levels in all three groups. sAPPα and sAPPβ concentrations were higher in patients with mild cognitive impairment compared with patients with AD. In the AD group, females exhibited higher sAPPα and sAPPβ levels than males. No influence of the apolipoprotein E genotype on soluble APP concentrations was detected. Discussion The positive correlation between sAPPα and sAPPβ challenges the hypothesis that AD is caused by an imbalance of the α- and β-secretase APP proteolysis through competing mechanisms. Moreover, the differences in CSF levels of sAPPα and sAPPβ between male and female patients with AD may reflect a "sexual dimorphism" in the activity of the two APP processing pathways in AD.

Purpose: To investigate age-related regional perfusion changes focused on the medial temporal lobes and related parietal areas using a pulsed arterial spin labeling technique. Materials and Methods: Resting cerebral blood flow (CBF) maps were obtained from 44 healthy volunteers (18 male, 26 female; age range, 19 to 79 years) using a pulsed arterial spin labeling (PASL) MRI technique at 3 Tesla focused on the parietal and temporal lobes. Repeated measurements were performed in 20 subjects to assure the reliability and reproducibility of the applied PASL technique. Results: Focal age-related CBF decreases were detected in the parietal cortex, cuneus and caudate, whereas increases were seen in the lateral and medial temporal lobe such as hippocampus, the calcarine gyrus and the thalamus. Moreover, repeated measurements demonstrated a high reliability and reproducibility of the applied PASL technique. Conclusion: Data provide evidence for regionally dissociated patterns of perfusion increases and decreases during ageing in the temporal and parietal lobes. J. Magn. Reson. Imaging 2011;. © 2011 Wiley Periodicals, Inc.

classify patients with only one biomarker value beyond the cut-off. Alternative classification strategies must be developed. The aim of the current study was to apply a classification and decision tree model for better classification of AD patients from controls with subjective memory complaints (SMC).Methods:We included patients from the memory clinic based Amsterdam Dementia Cohort with defined diagnosis of AD (n1⁄4631), and SMC (n1⁄4251). Classification and regression treefit using R package ’tree’ was applied for optimal discrimination of AD vs SMC, including the variables amyloid beta 1-42 (abeta) total tau (tTau), ptau181, age and ApoE status. Sensitivity and specificity of these models were compared to single and combination cut offs of an independent cohort consisting of 432 AD patients and 287 controls. Results: The optimal decision treemodel for discrimination ofADpatient fromSMC included as first node Abeta(1-42) with 669.5 pg/mL as cut-point. The second and third nodes included tTau >322.5 pg/mL or Abeta(1-42) 322.5 pg/mL classifying 555 as AD including 26 SMC/ 529 AD; 3) Abeta (1-42) levels< 487 pg/mL classifying 64 as AD including 13 SMC/51 AD. Sensitivity of the training set was 88% at a specificity of 84%which is comparablewith the sensitivity and specificity of the independent test set 89% and 83% respectively. Conclusions: Classification and regression tree fit is a powerful tool to identify specific AD subgroups with unique biomarker characteristics. Depending on Abeta level patients (also SMC) can be classified as AD in several ways, either with normal CSF tTau or even with relatively high CSF abeta(1-42) level. The unique phenotypes enable application of personalized treatment of patients.