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This article presents an overview of imaging agents for PET that have been applied for research and diagnostic purposes in patients affected by dementia. Classified by the target which the agents visualize, seven groups of tracers can be distinguished, namely radiopharmaceuticals for: (1) Misfolded proteins (ß-amyloid, tau, α-synuclein), (2) Neuroinflammation (overexpression of translocator protein), (3) Elements of the cholinergic system, (4) Elements of monoamine neurotransmitter systems, (5) Synaptic density, (6) Cerebral energy metabolism (glucose transport/ hexokinase), and (7) Various other proteins. This last category contains proteins involved in mechanisms underlying neuroinflammation or cognitive impairment, which may also be potential therapeutic targets. Many receptors belong to this category: AMPA, cannabinoid, colony stimulating factor 1, metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), opioid (kappa, mu), purinergic (P2X7, P2Y12), sigma-1, sigma-2, receptor for advanced glycation endproducts, and triggering receptor expressed on myeloid cells-1, besides several enzymes: cyclooxygenase-1 and 2 (COX-1, COX-2), phosphodiesterase-5 and 10 (PDE5, PDE10), and tropomyosin receptor kinase. Significant advances in neuroimaging have been made in the last 15 years. The use of 2-[ 18 F]-fluoro-2-deoxy-D-glucose (FDG) for quantification of regional cerebral glucose metabolism is well-established. Three tracers for ß-amyloid plaques have been approved by the Food and Drug Administration and European Medicines Agency. Several tracers for tau neurofibrillary tangles are already applied in clinical research. Since many novel agents are in the preclinical or experimental stage of development, further advances in nuclear medicine imaging can be expected in the near future. PET studies with established tracers and tracers for novel targets may result in early diagnosis and better classification of neurodegenerative disorders and in accurate monitoring of therapy trials which involve these targets. PET data have prognostic value and may be used to assess the response of the human brain to interventions, or to select the appropriate treatment strategy for an individual patient., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Descendants of patients with dementia have a higher risk to develop dementia. This study aims to investigate the uptake and effectiveness of an online tailor-made lifestyle programme for dementia risk reduction (DRR) among middle-aged descendants of people with recently diagnosed late-onset dementia., Methods and Analysis: Demin is a cluster randomised controlled trial, aiming to include 21 memory clinics of which 13 will be randomly allocated to the passive (poster and flyer in a waiting room) and 8 to the active recruitment strategy (additional personal invitation by members of the team of the memory clinic). We aim to recruit 378 participants (40-60 years) with a parent who is recently diagnosed with Alzheimer's disease or vascular dementia at one of the participating memory clinics. All participants receive a dementia risk assessment (online questionnaire, physical examination and blood sample) and subsequently an online tailor-made lifestyle advice regarding protective (Mediterranean diet, low/moderate alcohol consumption and high cognitive activity) and risk factors (physical inactivity, smoking, loneliness, cardiovascular diseases (CVD), hypertension, high cholesterol, diabetes, obesity, renal dysfunction and depression) for dementia. The primary outcome is the difference in uptake between the two recruitment strategies. Secondary outcomes are change(s) in (1) the Lifestyle for Brain Health score, (2) individual health behaviours, (3) health beliefs and attitudes towards DRR and (4) compliance to the tailor-made lifestyle advice. Outcomes will be measured at 3, 6, 9 and 12 months after baseline. The effectiveness of this online tailor-made lifestyle programme will be evaluated by comparing Demin participants to a matched control group (lifelines cohort)., Ethics and Dissemination: This study has been approved by the Dutch Ministry of Health, Welfare and Sport according to the Population Screening Act. All participants have to give online informed consent using SMS-tan (transaction authentication number delivered via text message). Findings will be disseminated through peer-reviewed journals and (inter)national conferences., Trial Registration Number: NTR7434., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Aim: Coronary artery disease (CAD) and cognitive impairment are common in the elderly, with evidence for shared risk factors and pathophysiological processes. The coronary artery calcium (CAC) score is a marker of subclinical CAD, which may allow early detection of individuals prone to cognitive decline. Prior studies on associations of CAC and clinical CAD with cognitive impairment had discrepant results. This systematic review aims to evaluate the association of (sub)clinical CAD with cognitive function, cognitive decline, and diagnosis of mild cognitive impairment (MCI) or dementia., Methods: A systematic search was conducted in MEDLINE, Embase, and Web of Science until February 2019, supplemented with citations tracking. Two reviewers independently screened studies and extracted information including odds ratios (ORs) and hazard ratios (HRs)., Results: Forty-six studies, 10 on CAC and 36 on clinical CAD, comprising 1,248,908 participants were included in the systematic review. Studies about associations of (sub)clinical CAD with cognitive function and cognitive decline had heterogeneous methodology and inconsistent findings. Two population-based studies investigated the association between CAC and risk of dementia over 6-12.2 years using different CAC scoring methods. Both found a tendency toward higher risk of dementia as CAC severity increased. Meta-analysis in 15 studies (663,250 individuals) showed an association between CAD and MCI/dementia (pooled OR 1.32, 95%CI 1.17-1.48) with substantial heterogeneity (I 2 =87.0%, p＜0.001). Pooled HR of CAD for incident MCI/dementia over 3.2-25.5 years in six longitudinal studies (70,060 individuals) was 1.51 (95%CI 1.24-1.85), with low heterogeneity (I 2 =14.1%, p=0.32). Sensitivity analysis did not detect any study that was of particular influence on the pooled OR or HR., Conclusions: Limited evidence suggests the CAC score is associated with risk of dementia. In clinical CAD, risk of MCI and dementia is increased by 50%, as supported by stronger evidence.

Background: Despite decades of research on the optimization of the diagnosis of Alzheimer's disease (AD), its biomarker-based diagnosis is being hampered by the lack of comparability of raw biomarker data. In order to overcome this limitation, the Erlangen Score (ES), among other approaches, was set up as a diagnostic-relevant interpretation algorithm., Objective: To validate the ES algorithm in a cohort of neuropathologically confirmed cases with AD (n = 106) and non-AD dementia (n = 57)., Methods: Cerebrospinal fluid (CSF) biomarker concentrations of Aβ1-42, T-tau, and P-tau181 were measured with commercially available single analyte ELISA kits. Based on these biomarkers, ES was calculated as previously reported., Results: This algorithm proved to categorize AD in different degrees of likelihood, ranging from neurochemically "normal", "improbably having AD", "possibly having AD", to "probably having AD", with a diagnostic accuracy of 74% using the neuropathology as a reference., Conclusion: The ability of the ES to overcome the high variability of raw CSF biomarker data may provide a useful diagnostic tool for comparing neurochemical diagnoses between different labs or methods used.

Background: Palliative care and Advance Care Planning (ACP) are increasingly recommended for an optimal management of late-stage dementia. In Belgium, euthanasia has been decriminalized in 2002 for patients who are "mentally competent" (interpreted as non-demented). It has been suggested that advance directives for euthanasia (ADE) should be made possible for dementia patients., Objective: This study presents the results of an internet survey among Belgian dementia specialists., Methods: In 2013, the Belgian Dementia Council (BeDeCo) organized a debate on end of life decisions in dementia. Participants were medical doctors who are specialists in the dementia field. After the debate, an anonymous internet survey was organized. The participation rate was 55%. The sample was representative of the BeDeCo members., Results: The results showed consensus in favor of palliative care and ACP, although ACP is not systematically addressed in practice. Few patients with dementia have requested euthanasia, but for those who did the participants had agreed to implement it for some patients. A majority of participants (94%) believe that most patients and their families are poorly informed about euthanasia. Although most participants (77%) said they approved the Law on euthanasia, 65% said they were against an extension of the Law to allow ADE for dementia., Conclusion: Palliative care and ACP are clearly accepted by professionals, although a gap between recommendation and practice remain. Euthanasia is a much more debated issue, even if a majority of professionals are, in principle, in favor of the current Law and seem to disapprove with a Law change allowing ADE for dementia. A better education for both health professionals and the lay public will be a key element in the future.

Background: Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt., Objective: Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis., Methods: Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42, T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses., Results: Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively., Conclusion: AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses.

Background: The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ 1-42 , t-tau, and p-tau 181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-tau rel ), may improve differential dementia diagnosis. The goal of this study is to investigate if p-tau rel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis., Methods: The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ 1-42 , t-tau, p-tau 181 , and p-tau rel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests., Results: The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-tau rel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-tau rel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-tau rel when differentiating between AD or non-AD dementias and controls., Conclusions: The addition of p-tau rel to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.

Background: Depressive symptoms are common in amnestic mild cognitive impairment (aMCI). The association between depressive symptoms and conversion to dementia is not yet clear. This longitudinal study was conducted to ascertain whether depressive symptoms in aMCI patients are predictive of conversion to dementia., Methods: 35 aMCI patients participated in this study. All participants underwent cognitive testing and were administered the geriatric depression scale (GDS) to determine the presence of depressive symptoms. A score equaling or higher than 11 on the GDS was taken as the cut-off point for presence of significant depressive symptoms. Conversion to dementia was assessed at follow-up visits after 1.5, 4, and 10 years., Results: 31.4% of the patients reported depressive symptoms at baseline. None of the cognitive measures revealed a significant difference at baseline between patients with and without depressive symptoms. After 1.5, 4, and 10 years respectively 6, 14, and 23 patients had converted to dementia. Although the GDS scores at baseline did not predict conversion to dementia, the cognitive measures and more specifically a verbal cued recall task (the memory impairment scale-plus) was a good predictor for conversion., Conclusions: Based on this dataset, the presence of depressive symptoms in aMCI patients is not predictive of conversion to dementia.

A new study describes a biomarker profile based on cerebrospinal fluid (CSF) tau and amyloid-β₁₋₄₂ in a uniquely large population with a variety of dementia diagnoses. This study confirms the differential diagnostic value of CSF biomarkers and further highlights the important neuropathological overlap between dementia aetiologies.

Objective: Iodine-123 metaiodobenzylguanidine (MIBG) cardiac scintigraphy has shown the potential to discriminate dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, these studies did not reflect clinical practice, as patients with ischemic heart disease, heart failure, diabetes mellitus, arterial hypertension, and hyperlipidemia and patients treated with antidepressants like trazodone were excluded., Methods: This study aimed to evaluate the use of MIBG cardiac scintigraphy to diagnose DLB in clinical practice. Moreover, the potential diagnostic value of MIBG cardiac scintigraphy in patients with clinically ambiguous dementia diagnosis (DLB versus AD) was tested. Eighty-five patients with a possible clinical diagnosis of DLB entered the study. MIBG uptake was determined by calculating the heart-to-mediastinum-uptake ratio (H/M)., Results: The average H/M ratio was 1.42 ± 0.35. The number of core features for DLB and the H/M ratio were negatively correlated (p = 0.001; r = -0.360). With an H/M ratio cutoff of 1.68 in 20 patients with clinically ambiguous dementia diagnoses (DLB versus AD) at the moment of MIBG cardiac scintigraphy, 95% (19/20) of the patients were correctly classified as compared with clinical or definite diagnosis at follow-up, with sensitivity and specificity values for diagnosing DLB of 100% (16/16) and 75% (3/4), respectively. The H/M ratio was influenced only by age (p = 0.046; r = -0.217) and gender (p = 0.024) and not by any other variable studied., Conclusions: The MIBG cardiac scintigraphy H/M ratio is a possible diagnostic biomarker for DLB in routine clinical practice and might have an added diagnostic value in case of doubt between DLB and AD., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objective: This study investigated the long-term safety of rivastigmine (12 mg/d capsules, 9.5 mg/24 h patch) and effects on motor symptoms in patients with mild-to-moderately severe Parkinson disease dementia., Methods: This was a 76-week, prospective, open-label, randomized study in patients aged 50 to 85 years. Primary outcomes included incidence of, and discontinuation due to, predefined adverse events (AEs) potentially arising from worsening of Parkinson disease motor symptoms with capsules. Secondary outcomes included frequency of AEs/serious AEs. Efficacy outcomes included Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI-10), and Mattis Dementia Rating Scale (MDRS)., Results: Five hundred eighty-three patients were randomized to rivastigmine capsules (n = 295) or patch (n = 288). Incidence of predefined AEs was 36.1% for capsules, 31.9% for patch; discontinuation due to worsening of motor symptoms was 4.4% and 2.4%, respectively. Most common AEs were nausea (capsules, 40.5%; patch, 8.3%), tremor (24.5%; 9.7%), fall (17.0%; 20.1%), vomiting (15.3%; 2.8%), and application site erythema (0%; 13.9%). Significant efficacy in favor of capsules was observed at weeks 24 to 76 on MDRS; 24 and 76 on NPI-10; weeks 52 and 76 on ADCS-ADL. In patients with Mini-Mental State Examination (MMSE) greater than 21, no differences in efficacy on MDRS and ADCS-ADL were observed at any time point; significant differences in favor of capsules were maintained in patients with MMSE less than or equal to 21., Conclusions: This study supports the long-term safety of rivastigmine in Parkinson disease dementia. The rate of worsening of motor symptoms was in the range expected due to the natural progression of Parkinson disease, no new or unexpected safety issues emerged in the long-term.

Aims: Cognitive impairment and dementia are common features of Parkinson's disease (PD). Patients with Parkinson's disease dementia (PDD) often have significant cholinergic defects, which may be treated with cholinesterase inhibitors (ChEIs). The objective of this review was to consider available efficacy, tolerability, and safety data from studies of ChEIs in PDD., Discussions: A literature search resulted in the identification of 20 relevant publications. Of these, the treatment of PD patients with rivastigmine, donepezil, or galantamine was the focus of six, eleven, and two studies respectively, while one study reported use of both tacrine and donepezil. The majority of studies were small (<40 patients), with the exception of two large randomized controlled trials (RCTs) that are the main focus of this review. In the smaller studies, treatment benefits were reported on a range of outcome measures, though results were extremely variable. While the full results of a large RCT of donepezil in patients with PDD are not yet available, significant treatment differences were reported on the CIBIC-plus at the highest treatment dose. A trend toward improvement was also observed in treated patients on the ADAS-cog. The second large RCT found significant improvements in rivastigmine-treated patients compared with placebo on both the ADAS-cog (P < 0.001) and the ADCS-CGIC (P < 0.007), as well as on all secondary efficacy outcomes. Consequently, rivastigmine is now widely approved for the symptomatic treatment of mild to moderate PDD., Conclusions: Taken together, these studies suggest that ChEIs are efficacious in the treatment of PDD., (© 2010 Blackwell Publishing Ltd.)

With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes - which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Background: To study frontal lobe symptoms in relation to dementia severity within and across diagnostic dementia categories, a cross-sectional analysis of behavioural data was performed., Methods: Patients with probable Alzheimer's disease (AD) (n = 456), frontotemporal dementia (FTD) (n = 55) and dementia with Lewy bodies (DLB) (n = 48) were included. Dementia severity and frontal lobe symptoms were assessed by means of the global deterioration scale and the Middelheim frontality score (MFS)., Results: In FTD, no difference in MFS total scores between patients belonging to the mild and severe dementia stages was found (p = 0.828). In AD and DLB groups, significantly higher MFS total scores were found in severe dementia stages compared to mild dementia stages (p < 0.001). Comparing MFS total scores between FTD and AD patients, significantly higher scores were achieved in FTD patients, irrespective of dementia severity (p < 0.001)., Conclusions: In FTD patients, frontal lobe symptoms were severe in the mild, moderate and severe dementia stages although the nature of frontal lobe symptoms depended on disease severity. AD and DLB patients displayed more frontal lobe symptoms in the advanced disease stages as compared to disease onset, suggesting gradual frontal lobe involvement as the disease progresses. The nature of frontal lobe symptoms related to dementia severity differed between AD, DLB and FTD patients, suggesting different patterns of frontal lobe involvement. Last but not the least, these data point to the potential diagnostic value of behavioural observation of frontal lobe symptoms for (differential) dementia diagnosis, especially at the earliest disease stages. These findings await confirmation through a prospective, longitudinal study., (Copyright © 2010 John Wiley & Sons, Ltd.)

This study aimed to investigate whether cerebrospinal fluid (CSF) biomarkers could have helped the clinician in differential dementia diagnosis in case of clinically ambiguous diagnoses, as compared to autopsy-confirmed dementia diagnosis as gold standard. Twenty-two patients of our autopsy-confirmed dementia population totalling 157 patients had an ambiguous clinical diagnosis at CSF sampling and were included in statistical analysis. CSF levels of β-amyloid peptide (Aβ(1-42)), total tau protein (T-tau) and tau phosphorylated at threonine 181 (P-tau(181P)) were determined. A biomarker-based model was applied to discriminate between AD and NON-AD dementias. AD and NON-AD patients showed no significant differences in Aβ(1-42) and T-tau concentrations, whereas P-tau(181P) concentrations were significantly higher in AD compared to NON-AD patients. The biomarker-based diagnostic model correctly classified 18 of 22 (82%) patients with clinically ambiguous diagnoses. Using a biomarker-based model in patients with clinically ambiguous diagnoses, a correct diagnosis would have been established in the majority of autopsy-confirmed AD and NON-AD cases, indicating that biomarkers have an added diagnostic value in cases with ambiguous clinical diagnoses., (Copyright © 2008 Elsevier Inc. All rights reserved.)

Biomarkers indicating biological age are of significant interest for prevention, diagnosis and monitoring (and the treatment) of age-related diseases. We previously reported an alteration of serum N-glycan profile in old humans using "DNA Sequencer Adapted-Fluorophore Assisted Carbohydrate Electrophoresis" (DSA-FACE). To validate the shift in serum N-glycan profile during ageing, we studied serum N-glycan profiles in different age groups of healthy volunteers, patients with dementia, and patients with Cockayne syndrome, a genetic DNA repair disorder involving neurodegeneration and premature ageing. We found that the log of the ratio of two glycans (NGA2F and NA2F), named GlycoAgeTest, remained steady up to the age of 40years and thereafter gradually increased to reach its highest level in nonagenarians. Patients with dementia or Cockayne syndrome had a higher GlycoAgeTest level than age-matched healthy individuals. We thus demonstrate that the value of GlycoAgeTest is better than chronological age for estimating the physiological age of a human individual, and that it could be used as an ageing biomarker for healthy humans. Our data indicate that the GlycoAgeTest could be used as a non-invasive surrogate marker for general health, for forecasting disease progression during ageing, and for monitoring the efficacy of anti-ageing food compounds., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To determine the reliability of the 30-item Geriatric Depression Scale (GDS-30) for the screening of depressive symptoms in dementia and mild cognitive impairment (MCI) using the Cornell Scale for Depression in Dementia (CSDD) as the 'gold standard'., Methods: Diagnosed according to strictly applied clinical diagnostic criteria, patients with MCI (n = 156) and probable Alzheimer's disease (AD) (n = 247) were included. GDS-30, CSDD, Mini Mental State Examination (MMSE) and Global Deterioration Scale were assessed in all patients at inclusion. The AD group was divided in three subgroups: mild AD (MMSE>or=18) (n = 117), moderate AD (MMSE< 18 and >or=10) (n = 89) and severe AD (MMSE<10) (n = 38)., Results: In MCI patients, moderate but highly significant correlations were found between GDS-30 and CSDD scores (Pearson: r = 0.565; p < 0.001). In mildly (r = 0.294; p = 0.001), moderately (r = 0.273; p = 0.010) and severely (r = 0.348; p = 0.032) affected AD patients, only weak correlations between GDS-30 and CSDD scores were calculated. ROC curve analysis showed that sensitivity and specificity values of respectively 95% and 67% were achieved when a GDS-30 cut-off score of 8 was applied in MCI patients. In AD patients, too low sensitivity and specificity values did not allow selecting an optimal cut-off score by means of ROC curve analysis., Conclusion: Using the CSDD as 'gold standard', we demonstrated that the GDS-30 is a reliable screening tool for depressive symptoms in MCI but not in AD patients., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

We wanted to investigate whether the difference between actual and premorbid intelligence can be useful to make an early differentiation between Alzheimer's disease (AD) and depression among elderly. A Dutch version of the National Adult Reading Test (NLV), a measure of premorbid IQ and the Raven Coloured Progressive Matrices (RCPM), a measure of actual intelligence were administered to patients with mild (34) and moderate (27) AD, depressed elderly (36) and healthy control subjects (51). Logistic regression analyses revealed that intellectual decline (i.e. subtracting NLV percentile score from RCPM percentile score) was only able to predict group membership when moderate AD patients were compared to depressed and healthy individuals. Our results indicate that intellectual decline may not be a concomitant of elderly depression. However, the differentiation between mild AD and elderly depression can not be made by means of the difference between premorbid (NLV) and actual (RCPM) intelligence scores.

To establish diagnostic performance of the cerebrospinal fluid (CSF) biomarkers beta-amyloid peptide (Abeta(1-42)), total tau-protein (T-tau) and tau phosphorylated at threonine 181 (P-tau(181P)) compared to clinical diagnosis, biomarker levels were determined in CSF samples from 100 autopsy-confirmed dementia and 100 control subjects. As the control and dementia groups were not age-matched and given the significant associations of biomarker concentrations with age in controls, age-corrected biomarker concentrations were calculated. New models were constructed by means of logistic regression. Using all biomarkers, dementia could be discriminated from controls (sensitivity (S)=86%, specificity (Sp)=89%). T-tau and Abeta(1-42) optimally discriminated Alzheimer's disease (AD) from other dementias (NONAD) and controls (S=90%, Sp=89%). AD was optimally discriminated from NONAD using P-tau(181P) and Abeta(1-42) (S=80%, Sp=93%). Diagnostic accuracy of the latter model (82.7%) was comparable to clinical diagnostic accuracy (81.6%) that was based on a whole clinical work-up (including imaging). Using this model, in cases with clinically doubtful diagnoses, a correct diagnosis would have been established in 4/6 autopsy-confirmed AD and 3/3 autopsy-confirmed NONAD cases. The value of biomarkers in differential dementia diagnosis was shown, using pathological diagnosis as a reference. New models have been developed, achieving sensitivity, specificity and diagnostic accuracy levels, consistently exceeding 80%.

Background/aims: The aim of this study was to determine the consistency of neuropsychiatric subsyndromes of the Neuropsychiatric Inventory across several clinical and demographic subgroups (e.g. dementia subtypes, dementia severity, medication use, age and gender) in a large sample of outpatients with dementia., Methods: Cross-sectional data of 2,808 patients with dementia from 12 centres from the European Alzheimer's Disease Consortium were collected. Principal component analysis was used for factor analysis. Subanalyses were performed for dementia subtypes, dementia severity, medication use, age and gender., Results: The results showed the relatively consistent presence of the 4 neuropsychiatric subsyndromes 'hyperactivity', 'psychosis', 'affective symptoms' and 'apathy' across the subanalyses. The factor structure was not dependent on dementia subtypes, age and gender but was dependent on dementia severity and cholinesterase use. The factors hyperactivity and affective symptoms were present in all subanalyses, but the presence of the factors apathy and psychosis was dependent on use of cholinesterase inhibitors and dementia severity, respectively., Conclusion: The present study provided evidence of the relative consistency of neuropsychiatric subsyndromes across dementia subtypes, age and gender, thereby stressing the importance of thinking about neuropsychiatric subsyndromes instead of separate symptoms. However, the subsyndromes apathy and psychosis were dependent on use of cholinesterase inhibitors and dementia severity., ((c) 2007 S. Karger AG, Basel.)

Background and Aim: Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson's disease (PDD). However, since anticholinergic drugs have a role in the management of tremor in patients with Parkinson's disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD., Methods: The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine., Results: During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson's Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worsening parkinsonism, bradykinesia and rigidity were all <5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Post-hoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study., Conclusion: Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.

Background: About 40% of the patients with Parkinson's disease (PD) have depressive symptoms, either major depression (MD) or subthreshold depression. Depression was found to be associated with age and age at onset of PD, female gender, more severe parkinsonism, in particular with left-sided and akinetic-rigid symptoms, more functional impairment and cognitive impairment.However, the findings are inconsistent and partly contradictory and most of the studies focused on major depression in PD without dementia. The aim of this study was to examine the relationship between subthreshold depression and other clinical features in 538 PD patients with dementia but without MD drawn from a randomized, placebo-controlled multicentre trial of rivastigmine in PD., Results: One hundred and sixteen patients (21%) had subthreshold depression. Depression was associated with a younger age and age at onset and female gender, but not with severity of parkinsonism, cognition or activities of daily living or laterality of motor symptoms. However, in male patients, an association between depression and left-sided parkinsonism was found., Conclusion: In contrast to previous findings in PD patients with major depression but without dementia, we found no relationship between subthreshold depression and other clinical symptoms in patients with PDD., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Background: Dementia typically includes behavioral and psychological symptoms of dementia (BPSD) as well as cognitive decline. Psychosis of Alzheimer's disease (AD) is a specific component of AD, characterized by delusions, misidentifications, and hallucinations., Methods: This study is a meta-analysis of patients with psychosis of AD from four large placebo-controlled clinical trials of risperidone in dementia. Three trials included patients diagnosed with heterogeneous symptoms of BPSD (those with psychosis of AD were included in this analysis), while one trial included only those diagnosed with psychosis of AD. Efficacy was measured using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) Psychosis subscale and Clinical Global Impression (CGI)., Results: Primary analyses in the psychosis of AD population demonstrated that risperidone significantly improved scores on the BEHAVE-AD Psychosis subscale and CGI scale compared with placebo. Secondary analyses demonstrated that patients with more severe symptoms showed a more pronounced response to treatment with risperidone compared with placebo than those patients with less severe symptoms. Extrapyramidal symptoms and somnolence were more frequent with risperidone than placebo (p=0.04). Cerebrovascular adverse events and all-cause mortality were observed more frequently, although not statistically significantly, with risperidone versus placebo., Conclusions: This meta-analysis of psychosis of AD showed improvement in psychotic symptoms and general clinical improvement in patients with psychosis of AD treated with risperidone compared with placebo. The benefits of treatment were most significant in patients with severe symptoms. The safety profile of risperidone in this psychosis of AD population was similar to the more general BPSD population., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Background/aims: The aim of this study was to identify neuropsychiatric subsyndromes of the Neuropsychiatric Inventory in a large sample of outpatients with Alzheimer's disease (AD)., Methods: Cross-sectional data of 2,354 patients with AD from 12 centres from the European Alzheimer's Disease Consortium were collected. Principal component analysis was used for factor analysis., Results: The results showed the presence of 4 neuropsychiatric subsyndromes: hyperactivity, psychosis, affective symptoms and apathy. The subsyndrome apathy was the most common, occurring in almost 65% of the patients., Conclusion: This large study has provided additional robust evidence for the existence of neuropsychiatric subsyndromes in AD., ((c) 2007 S. Karger AG, Basel.)

In addition to cognitive deterioration, Alzheimer's disease patients exhibit behavioral and psychological signs and symptoms of dementia. Behavioral alterations are a major source of caregiver stress and an important contributor in the decision to institutionalize patients. The amyloid precursor protein (APP) 23 transgenic mouse model develops amyloid plaques from the age of 6 months onward and exhibits tau pathology, which is absent in most other amyloid-based models. Besides mimicking the demented patients' memory deficits, these transgenic mice present with various behavioral disturbances, thereby approximating the clinical situation remarkably well. Using an isolation-induced/resident-intruder paradigm of aggression, the authors revealed increased aggressiveness in male APP23 mice at the ages of 6 and 12 months. The presence of aggressive disturbances in this valuable mouse model opens perspectives to evaluate aggression-modulating therapies., (2006 APA, all rights reserved)

We aimed to determine prospectively whether rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, provided benefits in patients with and without visual hallucinations in a population with dementia associated with Parkinson's disease (PDD). This was a 24-week double-blind placebo-controlled study. Primary efficacy measures were the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary efficacy measures included activities of daily living, behavioral symptoms, and executive and attentional functions. Patients were stratified according to the presence of visual hallucinations at baseline. The study included 188 visual hallucinators (118 on rivastigmine, 70 on placebo) and 348 nonvisual hallucinators (239 on rivastigmine, 109 on placebo). Rivastigmine provided benefits in both visual hallucinators and nonvisual hallucinators. Absolute responses to rivastigmine on the ADAS-cog were comparable over 6 months, although rivastigmine-placebo differences tended to be larger in visual hallucinators (4.27; P = 0.002) than in nonhallucinators (2.09; P = 0.015). On the ADCS-CGIC, differences between rivastigmine and placebo were 0.5 in visual hallucinators (P = 0.030) and 0.3 in nonhallucinators (P = 0.111). Rivastigmine provided benefits on all secondary efficacy measures, and placebo declines and treatment differences were more marked in visual hallucinators. Adverse events were reported more frequently by rivastigmine-treated patients, although this difference was less marked in visual hallucinators. Visual hallucinations appear to predict more rapid decline and possibly greater therapeutic benefit from rivastigmine treatment in PDD.

Recent advances in the understanding of the pathophysiological mechanisms underlying Alzheimer's disease have pointed to novel strategies for drug development. Animal models have contributed considerably to these advances, and will have a key role in the evaluation of therapeutics that could have the potential not just to alleviate the dementia associated with Alzheimer's disease, but to modify the disease process. Here, we summarize and critically evaluate current rodent models of dementia, and discuss their role in drug discovery and development.

Objectives: This study examines the correlation between actigraphic measures and a validated assessment scale of agitated behaviour in dementia, the Cohen-Mansfield Agitation Inventory (CMAI)., Methods: A total of 110 patients were included. Patients either suffered from Alzheimer dementia (AD), mixed dementia (MXD), frontotemporal dementia (FTD) or diffuse Lewy body disease (DLB). All patients underwent actigraphic recordings for 48 h. CMAI was scored by professional caretakers, who were responsible for the patient during his or her actigraphic recording., Results: Patients with high total CMAI scores (>or= 50) clearly had higher levels of activity during the day as measured by means of actigraphy than patients with low total CMAI scores (ANOVA, F=126.75, p<0.0001). Patients with low MMSE scores (<20) also had higher activity levels during the day than patients with higher MMSE scores (ANOVA, F= 85.74, p<0.0001). Correlations between ctigraphic data and CMAI total scores were moderate but highly significant., Conclusion: We conclude that actigraphy is a useful tool to examine agitated behaviour in dementia., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Behavioral and psychological symptoms of dementia (BPSD), constitute a major clinical component of Alzheimer's disease (AD). There is a growing interest in BPSD as they are responsible for a large share of the suffering of patients and caregivers, and they strongly determine the patient's lifestyle and management. Better detection and understanding of these symptoms is essential to provide appropriate management. This article is a consensus produced by the behavioral group of the European Alzheimer's Disease Consortium (EADC). The aim of this article is to present clinical description and biological correlates of the major behavioral and psychological symptomatology in AD. BPSD is not a unitary concept. Instead, it should be divided into several symptoms or more likely: groups of symptoms, each possibly reflecting a different prevalence, course over time, biological correlate and psychosocial determinants. There is some clinical evidence for clusters within groups of BPSD. Biological studies indicate that patients with AD and BPSD are associated with variations in the pathological features (atrophy, brain perfusion/metabolism, histopathology) when compared to people with AD without BPSD. An individually tailored approach taking all these aspects into account is warranted as it may offer more, and better, pharmacological and non-pharmacological treatment opportunities.

Objective: Limited work has addressed the construct validity of the Cohen-Mansfield Agitation Inventory (CMAI) in nursing home patients. The authors tested the CMAI factor structure by use of data from three samples of nursing home patients categorized a priori as having at least mild behavioral and psychological symptoms of dementia., Methods: CMAI data were from the baseline assessment of three randomized, placebo-controlled trials of risperidone for treating elderly nursing home patients. Exploratory factor analyses were conducted on two trials (N = 304; N = 344), and the results of these exploratory factor analyses were then tested with confirmatory factor analysis by use of data from a third trial (N = 617)., Results: Principal-components analysis suggested the presence of four factors: 1) Aggressive Behavior (hitting, kicking, scratching, biting, pushing, grabbing, throwing things, cursing or verbal aggression, spitting, tearing things/destroying property, hurting self or others, screaming); 2) Physically Non-Aggressive Behavior (pacing, trying to get to a different place, general restlessness, inappropriate dressing or disrobing, handling things inappropriately, performing repetitious mannerisms); 3) Verbally Agitated Behavior (complaining, constant requests for attention, repetitive questions, negativism); and 4) Hiding and Hoarding. Confirmatory factor analysis indicated that the four-factor solution was a reasonable fit to the data., Conclusion: Four factors emerged on the CMAI in nursing home patients with behavioral and psychological symptoms of dementia. The results obtained converge reasonably with previous publications concerning the factor structure of the CMAI, which, taken together, suggest a fairly robust factor structure for the instrument.

Background: Despite striking neuropsychological and behavioural differences between Alzheimer's disease (AD) and frontotemporal dementia (FTD), clinical diagnostic criteria failed to discriminate FTD from AD patients. We therefore developed the Middelheim Frontality Score (MFS), a disease-long clinical and behavioural assessment tool that measures frontal lobe features, and set up this prospective study in clinically diagnosed AD and FTD patients to assess discriminatory power and intra- and inter-rater variability., Methods: Patients with probable AD (n = 400) and FTD (n = 62) were included. The MFS was obtained by summating the scores obtained in a standardized fashion on ten items yielding a total maximal score of 10. Information was obtained through an interview of the patient and her/his caregiver, clinical files and behavioural observation., Results: Comparing mean total MFS scores, FTD patients (6.3 +/- 1.8) had significantly higher scores than AD patients (3.1 +/- 1.8) (p < 0.001). Distribution of scores on individual MFS items was significantly different between both disease groups (chi(2) = 76.2; p < 0.001). A moderately positive and highly significant correlation was shown between the total MFS score and diagnosis FTD (r = 0.478; p < 0.0001). Applying a total MFS score of 5 as discriminatory cut-off, a specificity of 89.0% and a sensitivity of 88.7% were achieved. Intra- and inter-rater variability was calculated in a different study population by means of retest correlation, revealing moderate to strong positive correlations of high statistical significance., Conclusions: The MFS is a clinical and behavioural assessment scale that measures frontal lobe features and that was shown to reliably discriminate FTD from AD patients.

Over the past decade, clinical Alzheimer's disease research has been challenged with an increased interest in noncognitive symptomatology, commonly referred to as behavioural and psychological signs and symptoms of dementia (BPSD). In accordance, major attention is being paid to behavioural alterations in the phenotyping of transgenic mouse models. Besides an age-dependent decline of cognitive functions, the APP23 model was previously shown to exhibit cage activity disturbances, reminiscent of diurnal rhythm disturbances in Alzheimer patients. To further scrutinize these observations, circadian patterns of horizontal locomotor activity were assessed in 3-, 6- and 12-month-old APP23 mice and wild-type littermates in a test paradigm continuously recording cage activity over a period ranging from 1 to 3 days. At the age of 3 months, APP23 profiles resembled the wild-type pattern to a large extent, although minor differences were already noticeable. Six-month-old APP23 mice displayed an altered activity profile with a first indication of increased activity during the second half of the active phase, reminiscent of sundowning behaviour in Alzheimer patients. This bimodal overnight activity pattern became even more evident at the age of 12 months. The APP23 model was therefore shown to display an age-dependent development of cage activity disturbances and sundowning-like behaviour. A comparison is made with actigraphic recordings of human Alzheimer patients exhibiting sundowning behaviour. This first report of diurnal rhythm disturbances and sundowning-like phenomena in a transgenic mouse model greatly adds to the validity of the APP23 model.

Objective: To examine the effect of risperidone on specific behavioral and psychological symptoms of dementia (BPSD)., Method: We conducted a post hoc exploratory analysis of an integrated database from 3 randomized, controlled trials of risperidone versus placebo in treating 1150 nursing home residents with BPSD. Changes in scores were measured for items on the Cohen-Mansfield Agitation Inventory (CMAI) and Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD)., Results: On the CMAI, risperidone was significantly more effective in treating hitting (p = .000), hurt self or other (p = .005), cursing or verbal aggression (p = .000), repetitive sentences or questions (p = .001), scratching (p = .041), general restlessness (p = .001), grabbing onto people (p = .028), constant request for attention (p = .041), pacing and aimless wandering (p = .013), and performing repetitious mannerisms (p = .045). On the BEHAVE-AD, risperidone was significantly more effective in treating physical threats and/or violence (p = .000), verbal outbursts (p = .000), other anxieties (p = .01), agitation (p = .000), tearfulness (p = .03), and nonparanoid delusions (p = .02)., Conclusions: The items from the BEHAVE-AD and CMAI that were improved with risperidone included psychotic, agitated, and aggressive symptoms. These data suggest that risperidone is more effective than placebo in treating a variety of symptoms associated with dementia.

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Background: Dementia is a multifactorial disease, with Alzheimer's disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined. Objective: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia. Methods: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally. Results: Amyloid-β (Aβ)42 and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40. Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors. Conclusions: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy.Objective: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis.Methods: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG).Results: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95% . Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD.Conclusion: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools. [ABSTRACT FROM AUTHOR]

Background: Nocturnal cerebrospinal fluid (CSF) and blood melatonin levels are altered in Alzheimer's disease (AD). However, literature remains inconclusive on daytime blood melatonin levels. A positive correlation between melatonin levels and Mini-Mental State Examination (MMSE) scores in AD subjects has been evidenced following cross-sectional analyses. Whereas a correlation between serum and spinal CSF melatonin has been shown in healthy volunteers, an equal investigation in AD patients still has to be undertaken.Objective: 1) To evaluate whether serum melatonin levels correlate with spinal CSF melatonin levels in AD. 2) To compare daytime CSF and serum melatonin levels between patients with AD dementia, mild cognitive impairment due to AD, and healthy controls, and to evaluate whether melatonin can affect cognitive decline in AD.Methods: Subjects with AD and healthy controls included in two existing cohorts, of whom a CSF and serum sample was available at the neurobiobank and had at least 6 months of neuropsychological follow-up, were included in the present study. Melatonin concentrations were measured with liquid chromatography-mass spectrometry.Results: Daytime serum melatonin levels correlated with spinal CSF melatonin levels in AD (r = 0.751, p < 0.001). No significant differences regarding daytime melatonin levels were found between patients and controls. No correlations were observed between daytime melatonin levels and MMSE score changes.Conclusion: Daytime serum melatonin accurately reflects CSF melatonin levels in AD, raising the possibility to assess melatonin alterations by solely performing blood sampling if also confirmed for night-time values. However, daytime melatonin levels are not associated with changes of cognitive impairment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms. Society is desperately in need for interventions that alleviate the economic and social burden related to AD. Circadian dysrhythmia, one of these symptoms in particular, immensely decreases the self-care ability of AD patients and is one of the main reasons of caregiver exhaustion. Studies suggest that these circadian disturbances form the root of sleep-wake problems, diagnosed in more than half of AD patients. Sleep abnormalities have generally been considered merely a consequence of AD pathology. Recent evidence suggests that a bidirectional relationship exists between sleep and AD, and that poor sleep might negatively impact amyloid burden, as well as cognition. The suprachiasmatic nucleus (SCN), the main circadian pacemaker, is subjected to several alterations during the course of the disease. Its functional deterioration might fulfill a crucial role in the relation between AD pathophysiology and the development of sleep abnormalities. This review aims to give a concise overview of the anatomy and physiology of the SCN, address how AD pathology precisely impacts the SCN and to what degree these alterations can contribute to the progression of the disease. [ABSTRACT FROM AUTHOR]

Background: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).Objective: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.Methods: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.Results: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).Conclusion: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin. [ABSTRACT FROM AUTHOR]