Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer's disease but not Lewy body dementias.

BACKGROUND: Chronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer's disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: Post-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed. RESULTS: We found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.

A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of ß-amyloid-(Aß)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aß deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical ß and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aß-preventing (Aß1-19) and Aß-degradation products (Aß1-20 and Aß1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

Diagnostic and treatment delay among new pulmonary tuberculosis patients in Southern India: A cross-sectional study.

Background: Delay in diagnosis and treatment enhances tuberculosis (TB) transmission and mortality. Understanding causes for delay can help in TB elimination by 2025, the stated goal of India. Objectives: Estimate diagnostic and treatment delay in Ernakulam district of Kerala, identify associated factors, and determine health-seeking behavior and knowledge regarding TB among new pulmonary TB patients. Materials and Methods: Community-based cross-sectional study among the new pulmonary TB patients registered under Revised National TB Control Program. Patients interviewed in-person and data collected using pretested semi-structured questionnaire. Descriptive statistics expressed as frequency, percent, interquartile range, median, and mean. The Chi-square test was used to assess statistical significance (P < 0.05) of association. Backward conditional method logistic regression done using variables with P < 0.2 in univariate analysis and adjusting for possible confounders. Results: Two hundred and twenty-nine patients interviewed and the median patient, health-care system, and treatment delay were 25 days, 22 days, and 1 day, respectively. While the patient delay (>30 days) and treatment delay (>2 days) were seen in 47.6% and 41% of patients, respectively, health-care system delay was seen in 79.9% of the patients. Choosing pharmacy for initial treatment (adjusted odds ratio [aOR] = 5.217), unskilled occupation (aOR = 3.717), female gender (aOR = 3.467), previously not heard about TB (aOR = 3.410), and lower education level (aOR = 2.774) were the independent predictors of the patient delay. Visiting two or more doctors (aOR = 5.855) and initially visiting a doctor of undergraduate qualification (aOR = 3.650) were the independent predictors of health-care system delay. The diagnosis in private sector (aOR = 8.989), not being admitted (aOR = 3.441), and age above 60 years (aOR = 0.394) was the independent predictors of treatment delay. Conclusion: Initial treatment from pharmacy, consulting multiple physicians, and diagnosis by private sector cause significant delay in diagnosis and treatment of pulmonary TB.

Prevalence and severity of coronal and radicular caries among patients with type 2 diabetes mellitus: A cross sectional study.

Background: Studies among type 2 diabetes mellitus patients have reported total caries experience; however the severity and clinical consequences of untreated dental caries are often ignored. Methods: For this study, 150 well (I) and poorly controlled (II) diabetic participants were recruited. The spectrum of caries was evaluated using DMFT (Decayed, Missing and Filled Tooth) index, Dental Caries Severity Classification Scale, PUFA (Pulpal involvement, Ulceration, Fistula and Abscess) index, RCI (Root Caries Index) and the severity of radicular caries by Root Surface Caries Severity Index. Results: The prevalence of coronal and root caries was 90.7% and 23.3%, respectively. There was significant difference among caries experiences for D, M and DMFT. In group II, severity of coronal caries and mean rank of P, F, A and PUFA scores were higher, so were prevalence of root caries and severity of RD2, RD3 and RD4. HbA1c level had positive correlation with DMFT and PUFA scores (r = 0.458 and 0.522), so was the duration of diabetes with coronal caries, DMFT, PUFA score, root caries and RCI score (r = 0.235, 0.320, 0.273, 0.308 and 0.323). Conclusion: This is probably the first study to examine the severity of coronal caries, prevalence of untreated dental caries and severity of radicular caries in diabetic patients. Uncontrolled diabetes causes substantial increase in prevalence and severity of coronal and radicular caries.

Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex.

Human DNA methylation data have been used to develop biomarkers of ageing, referred to as 'epigenetic clocks', which have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks have been shown to be highly accurate in blood but are less precise when used in older samples or in tissue types not included in training the model, including brain. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life course (n = 1397, ages = 1 to 108 years). This dataset was split into 'training' and 'testing' samples (training: n = 1047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel independent human cortex dataset (n = 1221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination, optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically outperformed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.

Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia.

INTRODUCTION: The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition. METHODS: Data came from 670 cases from the Brains for Dementia research program. Cases were categorized into PurP, mixed SevP, or a main disease with additional LowP; 508 cases had a clinical dementia rating. RESULTS: 69.9% of cases had LowP, 22.7% had PurP, and 7.5% had mixed SevP. Additional LowP increased the likelihood of having mild dementia versus mild cognitive impairment (MCI) by almost 20-fold (odds ratio = 19.5). DISCUSSION: Most aged individuals have multiple brain pathologies. The presence of one additional LowP can significantly worsen cognitive decline, increasing the risk of transitioning from MCI to dementia 20-fold. Multimorbidity should be considered in dementia research and clinical studies.

Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach.

See Attems and Jellinger (doi:10.1093/brain/awx360) for a scientific commentary on this article.Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.

Factors affecting withdrawal and donation attrition in the brains for dementia research cohort.

OBJECTIVES: To measure two forms of attrition in a cohort of volunteer brain donors: Withdrawal during life and non-donation at death. To test whether cognitive impairment independently predicts attrition. METHOD: Attrition rates were calculated for all registered participants and for all brain donors who had completed a baseline and follow-up assessment of cognition, health, and lifestyle. Attrition reasons were described, and attrition rates were compared by gender, age group, and cognitive status. Multivariate logistic regression was used to identify the factors which independently predicted during life and at death. RESULTS: A total of 3276 brain donors registered and 2307 (70.4%) remained in the cohort. Attrition rate overall was 5.9% for withdrawal and 13.8% for donation. Family disagreement and the brain bank not being informed of participant death were the most common reasons for withdrawal and donation attrition. Withdrawal was associated with having cognitive impairment (OR 2.0 95% CI 1.1-3.5), increased age (OR 3.1 95% CI 1.4-6.9), and lower education (OR 1.8 95% CI 1.2-2.8). Participants exhibiting cognitive decline between assessments were more likely to withdraw (OR 4.9 95% CI 1.7-13.6). Participants living alone were almost twice as likely to die without donating (OR 1.9 95% CI 1.1-3.3). CONCLUSIONS: Attrition rates were relatively low, and consistent with other studies cognitive impairment, increased age, and less education predicted study withdrawal. Deaths of participants living alone were less likely to result in donation. Tailored, regular retention practices aimed at resolving family disagreement regarding donation decisions are required.

Associations between ZnT3, tau pathology, agitation, and delusions in dementia.

OBJECTIVE: Neuropsychiatric symptoms such as agitation and delusions occur frequently in Lewy body dementia and Alzheimer's disease and represent significant burden and unmet treatment need. The underlying aetiology remains poorly understood. METHODS: We used a multidimensional linear model to look for associations between measurements of agitation, delusions, amyloid, tau and α-synuclein pathology, and synaptic proteins (ZnT3, PSD95, synaptophysin, and ß-III-tubulin) across multiple brain regions in post-mortem tissue from a cohort of 130 Lewy body dementia and Alzheimer's disease patients and non-demented controls. RESULTS: We found both agitations and delusions to be significantly associated with increased tau pathology and decreased levels of ZnT3. ZnT3 packages Zn2+ into synaptic vesicles to be released as a long-term modulator of synaptic activity. CONCLUSIONS: Our finding adds to the evidence that zinc modulating compounds are of interest for treatment or symptomatic relief in these dementias.

A pilot study of potential brain donor satisfaction and attitudes towards telephone assessment.

OBJECTIVE: Test the feasibility of assessing cognition, psychiatric symptoms and daily living skills of potential brain donors by telephone and compare satisfaction and attitudes across telephone and face-to-face assessment. METHOD: Data were collected from 108 healthy participants from the Brains for Dementia Research cohort. Purposive sampling was used to assess feasibility and a randomised control trial design compared satisfaction and attitudes towards telephone and face-to-face assessment. Non-parametric tests were conducted to compare groups, and logistic regression was performed to assess the relationship between satisfaction and participant characteristics. RESULTS: Of the 80 participants offered telephone assessment, 67 (83.8%) agreed, 2 (2.5%) had a significant hearing impairment, 4 (5.0%) had potential memory problems and 7 (8.7%) declined. On average, telephone assessments lasted 38 min and duration was negatively associated with Telephone Interview of Cognitive Status-Modified scores (p = 0.001) and positively associated with age (p = 0.040), Neuropsychiatric Inventory scores (p = 0.019), Geriatric Depression Scale (p = 0.035) and Global Deterioration Scale (p = 0.022). Satisfaction was high in respect to organisational and personal aspects; ratings did not differ significantly across telephone and face-to-face assessment groups and were not related to socio-demographic characteristics. Participants undergoing telephone assessment were significantly more likely to hold positive attitudes towards this mode of assessment. CONCLUSIONS: Telephone assessment is feasible, time-efficient and acceptable to healthy, potential brain donors. When used with other assessment modes and within the context of established contact, telephone assessment offers greater flexibility to researchers and participants and represents an effective mechanism for overcoming the challenges of growing, ageing cohorts and uncertain resources. Copyright © 2016 John Wiley & Sons, Ltd.

Apathy associated with neurocognitive disorders: Recent progress and future directions.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCDs) such as Alzheimer's disease and mild cognitive impairment. Although the definition of apathy is inconsistent in the literature, apathy is primarily defined as a loss of motivation and decreased interest in daily activities. METHODS: The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Syndromes Professional Interest Area (NPS-PIA) Apathy workgroup reviewed the latest research regarding apathy in NCDs. RESULTS: Progress has recently been made in three areas relevant to apathy: (1) phenomenology, including the use of diagnostic criteria and novel instruments for measurement, (2) neurobiology, including neuroimaging, neuropathological and biomarker correlates, and (3) interventions, including pharmacologic, nonpharmacologic, and noninvasive neuromodulatory approaches. DISCUSSION: Recent progress confirms that apathy has a significant impact on those with major NCD and those with mild NCDs. As such, it is an important target for research and intervention.

An isoform-specific role of FynT tyrosine kinase in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in old age and is characterized by the accumulation of ß-amyloid plaques and neurofibrillary tangles (NFT). Recent studies suggest that Fyn tyrosine kinase forms part of a toxic triad with ß-amyloid and tau in the disease process. However, it is not known whether Fyn is associated with the pathological features of AD in an isoform-specific manner. In this study, we identified selective up-regulation of the alternative-spliced FynT isoform with no change in FynB in the AD neocortex. Furthermore, gene ontology term enrichment analyses and cell type-specific localization of FynT immunoreactivity suggest that FynT up-regulation was associated with neurofibrillary degeneration and reactive astrogliosis. Interestingly, significantly increased FynT in NFT-bearing neurons was concomitant to decreased FynB immunoreactivity, suggesting an involvement of alternative splicing in NFT formation. Furthermore, cultured cells of astrocytic origin have higher FynT to FynB ratio compared to those of neuronal origin. Lastly, primary rat mixed neuron-astrocyte cultures treated with Aß25-35 showed selective up-regulation of FynT expression in activated astrocytes. Our findings point to an isoform-specific role of FynT in modulating neurofibrillary degeneration and reactive astrogliosis in AD. Fyn kinase is known to interact with ß-amyloid and tau, and contributes to Alzheimer's disease pathogenesis. In this study, it is shown that the alternatively spliced FynT isoform is specifically up-regulated in the AD neocortex, with no change in FynB isoform. The increased FynT correlated with markers of neurofibrillary degeneration and reactive astrogliosis. In primary mixed cultures, treatment with amyloid peptides specifically up-regulated FynT in activated astrocytes. This study points to altered alternative splicing as a potential pathogenic mechanism in AD.

Dementia in Parkinson's disease is associated with enhanced mitochondrial complex I deficiency.

BACKGROUND: Dementia is a common feature of Parkinson's disease (PD), but the neuropathological changes associated with the development of Parkinson's disease dementia (PDD) are only partially understood. Mitochondrial dysfunction is a hallmark of PD but has not been studied in PDD. METHODS: Molecular and biochemical approaches were used to study mitochondrial activity and quantity in postmortem prefrontal cortex tissue. Tissues from pathologically confirmed PD and PDD patients and from age-matched controls were used to analyze the activity of mitochondrial enzyme complex nicotinamide adenine dinucleotide:ubiquinone oxidoreductase, or complex I (the first enzyme in the mitochondrial respiratory chain), mitochondrial DNA levels, and the expression of mitochondrial proteins. RESULTS: Complex I activity was significantly decreased (27% reduction; analysis of variance with Tukey's post hoc test; P < 0.05) in PDD patients, and mitochondrial DNA levels were also significantly decreased (18% reduction; Kruskal-Wallis analysis of variance with Dunn's multiple comparison test; P < 0.05) in PDD patients compared with controls, but neither was significantly reduced in PD patients. Overall, mitochondrial biogenesis was unaffected in PD or PDD, because the expression of mitochondrial proteins in patients was similar to that in controls. CONCLUSIONS: Patients with PDD have a deficiency in mitochondrial complex I activity and reduced mitochondrial DNA levels in the prefrontal cortex without a change in mitochondrial protein quantity. Therefore, mitochondrial complex I deficiency and reduced mitochondrial DNA in the prefrontal cortex may be a hallmark of dementia in patients with PD.

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia.

INTRODUCTION: Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. METHODS: A total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. RESULTS: We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. DISCUSSION: Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases.

Depression and synaptic zinc regulation in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia.

OBJECTIVE: Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study. METHODS: We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression. RESULTS: Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (ß = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (ß = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (ß = -0.433, df = 37, t = -2.924, p = 0.006). CONCLUSION: Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target.

Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aß production.

Understanding the mechanisms that control processing of the amyloid precursor protein (APP) to produce amyloid-ß (Aß) peptide represents a key area of Alzheimer's disease research. Here, we show that siRNA-mediated loss of calsyntenin-1 in cultured neurons alters APP processing to increase production of Aß. We also show that calsyntenin-1 is reduced in Alzheimer's disease brains and that the extent of this reduction correlates with increased Aß levels. Calsyntenin-1 is a ligand for kinesin-1 light chains and APP is transported through axons on kinesin-1 molecular motors. Defects in axonal transport are an early pathological feature in Alzheimer's disease and defective APP transport is known to increase Aß production. We show that calsyntenin-1 and APP are co-transported through axons and that siRNA-induced loss of calsyntenin-1 markedly disrupts axonal transport of APP. Thus, perturbation to axonal transport of APP on calsyntenin-1 containing carriers induces alterations to APP processing that increase production of Aß. Together, our findings suggest that disruption of calsyntenin-1-associated axonal transport of APP is a pathogenic mechanism in Alzheimer's disease.

Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias.

Dementia with Lewy bodies and Parkinson's disease dementia are different clinical phenotypes of Lewy body dementias differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found losses of GluA2/3/4 immunoreactivities in Lewy body dementias which correlated with higher pre-death Hoehn and Yahr scores and with longer Parkinson's disease duration before dementia onset, but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias.

Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome. METHODS: In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. FINDINGS: We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). INTERPRETATION: There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients. FUNDING: Lundbeck.

Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future.

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis.