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Background Diagnosing frontotemporal dementia may be challenging. New methods for analysis of regional brain atrophy patterns on magnetic resonance imaging (MRI) could add to the diagnostic assessment. Therefore, we aimed to develop automated imaging biomarkers for differentiating frontotemporal dementia subtypes from other diagnostic groups, and from one another. Methods In this retrospective multicenter cohort study, we included 1213 patients (age 67 ± 9, 48% females) from two memory clinic cohorts: 116 frontotemporal dementia, 341 Alzheimer's disease, 66 Dementia with Lewy bodies, 40 vascular dementia, 104 other dementias, 229 mild cognitive impairment, and 317 subjective cognitive decline. Three MRI atrophy biomarkers were derived from the normalized volumes of automatically segmented cortical regions: 1) the anterior vs. posterior index, 2) the asymmetry index, and 3) the temporal pole left index. We used the following performance metrics: area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. To account for the low prevalence of frontotemporal dementia we pursued a high specificity of 95%. Cross-validation was used in assessing the performance. The generalizability was assessed in an independent cohort (n = 200). Results The anterior vs. posterior index performed with an AUC of 83% for differentiation of frontotemporal dementia from all other diagnostic groups (Sensitivity = 59%, Specificity = 95%, positive likelihood ratio = 11.8, negative likelihood ratio = 0.4). The asymmetry index showed highest performance for separation of primary progressive aphasia and behavioral variant frontotemporal dementia (AUC = 85%, Sensitivity = 79%, Specificity = 92%, positive likelihood ratio = 9.9, negative likelihood ratio = 0.2), whereas the temporal pole left index was specific for detection of semantic variant primary progressive aphasia (AUC = 85%, Sensitivity = 82%, Specificity = 80%, positive likelihood ratio = 4.1, negative likelihood ratio = 0.2). The validation cohort provided corresponding results for the anterior vs. posterior index and temporal pole left index. Conclusion This study presents three quantitative MRI biomarkers, which could provide additional information to the diagnostic assessment and assist clinicians in diagnosing frontotemporal dementia., Highlights • Quantitative MRI biomarkers (API, ASI, and TPL) for detection of FTD and its subtypes. • API differentiated FTD from other diagnostic groups with AUC of 83%. • ASI and TPL showed highest performance for PPA subtypes. • A subcortical bvFTD subtype resembling AD atrophy pattern seems undetectable for MRI.

Background The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a multicenter randomized controlled trial that reported beneficial effects on cognition for a 2-year multimodal intervention (diet, exercise, cognitive training, vascular risk monitoring) versus control (general health advice). This study reports exploratory analyses of brain MRI measures. Methods FINGER targeted 1260 older individuals from the general Finnish population. Participants were 60–77 years old, at increased risk for dementia but without dementia/substantial cognitive impairment. Brain MRI scans were available for 132 participants (68 intervention, 64 control) at baseline and 112 participants (59 intervention, 53 control) at 2 years. MRI measures included regional brain volumes, cortical thickness, and white matter lesion (WML) volume. Cognition was assessed at baseline and 1- and 2-year visits using a comprehensive neuropsychological test battery. We investigated the (1) differences between the intervention and control groups in change in MRI outcomes (FreeSurfer 5.3) and (2) post hoc sub-group analyses of intervention effects on cognition in participants with more versus less pronounced structural brain changes at baseline (mixed-effects regression models, Stata 12). Results No significant differences between the intervention and control groups were found on the changes in MRI measures. Beneficial intervention effects on processing speed were more pronounced in individuals with higher baseline cortical thickness in Alzheimer’s disease signature areas (composite measure of entorhinal, inferior and middle temporal, and fusiform regions). The randomization group × time × cortical thickness interaction coefficient was 0.198 (p = 0.021). A similar trend was observed for higher hippocampal volume (group × time × hippocampus volume interaction coefficient 0.1149, p = 0.085). Conclusions The FINGER MRI exploratory sub-study did not show significant differences between the intervention and control groups on changes in regional brain volumes, regional cortical thicknesses, or WML volume after 2 years in at-risk elderly without substantial impairment. The cognitive benefits on processing speed of the FINGER intervention may be more pronounced in individuals with fewer structural brain changes on MRI at baseline. This suggests that preventive strategies may be more effective if started early, before the occurrence of more pronounced structural brain changes. Trial registration ClinicalTrials.gov, NCT01041989. Registered January 5, 2010.

Background We developed multifactorial models for predicting incident dementia and brain pathology in the oldest old using the Vantaa 85+ cohort. Methods We included participants without dementia at baseline and at least 2 years of follow-up (N = 245) for dementia prediction or with autopsy data (N = 163) for pathology. A supervised machine learning method was used for model development, considering sociodemographic, cognitive, clinical, vascular, and lifestyle factors, as well as APOE genotype. Neuropathological assessments included β-amyloid, neurofibrillary tangles and neuritic plaques, cerebral amyloid angiopathy (CAA), macro- and microscopic infarcts, α-synuclein pathology, hippocampal sclerosis, and TDP-43. Results Prediction model performance was evaluated using AUC for 10 × 10-fold cross-validation. Overall AUCs were 0.73 for dementia, 0.64–0.68 for Alzheimer’s disease (AD)- or amyloid-related pathologies, 0.72 for macroinfarcts, and 0.61 for microinfarcts. Predictors for dementia were different from those in previous reports of younger populations; for example, age, sex, and vascular and lifestyle factors were not predictive. Predictors for dementia versus pathology were also different, because cognition and education predicted dementia but not AD- or amyloid-related pathologies. APOE genotype was most consistently present across all models. APOE alleles had a different impact: ε4 did not predict dementia, but it did predict all AD- or amyloid-related pathologies; ε2 predicted dementia, but it was protective against amyloid and neuropathological AD; and ε3ε3 was protective against dementia, neurofibrillary tangles, and CAA. Very few other factors were predictive of pathology. Conclusions Differences between predictors for dementia in younger old versus oldest old populations, as well as for dementia versus pathology, should be considered more carefully in future studies. Electronic supplementary material The online version of this article (10.1186/s13195-018-0450-3) contains supplementary material, which is available to authorized users.

Background/Aims: A bi-directional communication between the immune system and the central nervous system has been recently suggested. Among many cytokines, the role of IL-4 - with anti-inflammatory properties- in counteracting age-related inflammatory changes in the brain is strongly supported among studies. With this study, we aimed at investigating the association between volumetric measures of hippocampal subregions -in healthy older controls (HC), subjects affected by mild cognitive impairment (MCI) and Alzheimer’s Disease (AD)- with circulating levels of IL-4. Methods: From AddNeuroMed Project 113 HC, 101 stable MCI (sMCI), 22 converter MCI (cMCI) and 119 AD were included. Hippocampal subfield volumes were analyzed using Freesurfer 6.0.0 on high-resolution sagittal 3D-T1W MP-RAGE acquisitions. Plasmatic IL-4 was measured using ELISA assay. Results: IL-4 was found to be a) positively associate with left subiculum volume (β=0.226, p=0.037) in sMCI and b) negatively associate with left subiculum volume (β=-0.253, p=0.011) and left presubiculum volume (β=-0.257, p=0.011) in AD. Conclusion: Our results indicate a potential neuroprotective effect of IL-4 on the areas of the hippocampus more vulnerable to aging and neurodegeneration.

ObjectivesGlobal ageing is linked to an increased burden of cardiovascular disease and dementia, which calls for better prevention strategies. Self-management and eHealth applications are regarded as promising strategies to support prevention. The aim of this study was to explore nurses’ best practices concerning behaviour change guidance for cardiovascular (CV) prevention in order to learn how to optimally integrate them into a coach-supported internet platform for CV self-management.DesignQualitative focus group study in Finland and the Netherlands. Discussions were audiotaped and transcribed. Data were thematically analysed following principles of grounded theory.SettingDutch and Finnish primary care settings.ParticipantsSix Finnish and seven Dutch primary care nurses with experience in CV prevention.ResultsSimilar best practices were found in both countries and comprised of (1) establishing a relationship of trust, (2) managing awareness and expectations and (3) appropriate timing and monitoring of the process of behaviour change. However, the Finnish and Dutch nurses used different approaches for accomplishment of these practices, which was reflected in their recommendations for online support. Both groups emphasised that online support should be combined with human support and integrated into regular care. Finnish nurses had more confidence in patient self-management and remote communication than Dutch nurses, who emphasised the importance of face-to-face contact and preferred to keep control of medical aspects of prevention.ConclusionsDifferences in Dutch and Finnish’s nurses’ practices for supporting CV prevention appear to reflect their local healthcare practices, which should be taken into account when designing internet platforms for health self-management. Including cognitive health as a goal of CV prevention might stimulate motivation for health behaviour change.Trial registration numberISRCTN48151589; Pre-results.

Reading a word activates morphologically related words in the mental lexicon. People with Alzheimer's disease (AD) or Mild Cognitive Impairment (MCI) often have difficulty retrieving words, though the source of this problem is not well understood. To better understand the word recognition process in aging and in neurodegenerative disorders such as MCI and AD, we investigated the nature of the activation of morphologically related family members in 22 Finnish speakers with AD, 24 with MCI, and 17 cognitively healthy elderly. We presented Finnish monomorphemic (base form) nouns in a single-word lexical decision experiment to measure the speed of word recognition and its relation to morphological and lexical variables. Morphological variables included morphological family size (separate for compounds and derived words) and pseudo-morphological family size (including the set of words that have a partially overlapping form but that do not share an actual morpheme, e.g., pet and carpet, or corn and corner). Pseudo-morphological family size was included to examine the influence of words with orthographic (or phonological) overlap that are not semantically related to the target words. Our analyses revealed that younger and elderly controls and individuals with MCI or AD were influenced by true morphological overlap (overlapping forms that also share meaning), as well as by the word's pseudo morphological family. However, elderly controls and individuals with MCI or AD seemed to rely more on form overlap than young adults. This demonstrates that an increased reliance on form-based aspects of language processing in Alzheimer's disease is not necessarily due to a partial loss of access to semantics, but might be explained in part by a common age-related change of processes in written word recognition. (C) 2018 The Author(s). Published by Elsevier Ltd.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-β (Aβ) pathology. Objective: To compare the [ 11 C]PIB PET uptake in the patients with suspected iNPH to Aβ and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aβ, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD). Methods: Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aβ and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [ 11 C]PIB PET. Aβ, total tau, and Pτ 181 were measured by ELISA from the ventricular (n = 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1). Results: [ 11 C]PIB uptake in the right frontal cortex (ρ= 0.60, p < 0.01) and the combined neocortical [ 11 C]PIB uptake score (ρ= 0.61, p < 0.01) were associated with a higher Aβ load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [ 11 C]PIB uptake was also associated with the ventricular CSF Aβ (ρ= -0.58, p = 0.03). Conclusions: The findings show that [ 11 C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aβ pathology in the patients with iNPH might also warrant treatment with current AD drugs.

The possibilities of computer-based cognitive training (CCT) in postponing the onset of dementia are currently unclear, but promising. Our aim is to investigate older adults ' adherence to a long-term CCT program, and which participant characteristics are associated with adherence to the CCT. This study was part of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Participants were 60-77-year-old individuals with increased dementia risk, recruited from previous population-based studies. The participants included in this study (n = 631) had been randomized to receive a multi-domain lifestyle intervention, including CCT. The measure of adherence was the number of completed CCT sessions (max = 144) as continuous measure. Due to a substantial proportion of participants with 0 sessions, the zero inflated negative binomial regression analyses were used to enable assessment of both predictors of starting the training and predictors of completing a higher number of training sessions. Several cognitive, demographic, lifestyle, and health-related variables were examined as potential predictors of adherence to CCT. Altogether, 63% of the participants participated in the CCT at least once, 20% completed at least half of the training, and 12% completed all sessions. Previous experience with computers, being married or cohabiting, better memory performance, and positive expectations toward the study predicted greater odds for starting CCT. Previous computer use was the only factor associated with a greater number of training sessions completed. Our study shows that there is a large variation in adherence to a long-lasting CCT among older adults with an increased risk of dementia. The results indicate that encouraging computer use, and taking into account the level of cognitive functioning, may help boost adherence to CCT.

Background: Determining the underlying etiology of dementia can be challenging. Computer- based Clinical Decision Support Systems (CDSS) have the potential to provide an objective comparison of data and assist clinicians. Objectives: To assess the diagnostic impact of a CDSS, the PredictND tool, for differential diagnosis of dementia in memory clinics. Methods: In this prospective multicenter study, we recruited 779 patients with either subjective cognitive decline (n=252), mild cognitive impairment (n=219) or any type of dementia (n=274) and followed them for minimum 12 months. Based on all available patient baseline data (demographics, neuropsychological tests, cerebrospinal fluid biomarkers, and MRI visual and computed ratings), the PredictND tool provides a comprehensive overview and analysis of the data with a likelihood index for five diagnostic groups; Alzheimer´s disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and subjective cognitive decline. At baseline, a clinician defined an etiological diagnosis and confidence in the diagnosis, first without and subsequently with the PredictND tool. The follow-up diagnosis was used as the reference diagnosis. Results: In total, 747 patients completed the follow-up visits (53% female, 69±10 years). The etiological diagnosis changed in 13% of all cases when using the PredictND tool, but the diagnostic accuracy did not change significantly. Confidence in the diagnosis, measured by a visual analogue scale (VAS, 0-100%) increased (ΔVAS=3.0%, p Conclusion: Adding the PredictND tool to the diagnostic evaluation affected the diagnosis and increased clinicians’ confidence in the diagnosis indicating that CDSSs could aid clinicians in the differential diagnosis of dementia.

Objectives: To define CSF β-amyloid 1–42 (Aβ42) cutpoints to detect cortical amyloid deposition as assessed by 11C-Pittsburgh compound B ([11C]PiB)-PET and to compare these calculated cutpoints with cutpoints currently used in clinical practice.Methods: We included 433 participants (57 controls, 99 with mild cognitive impairment, 195 with Alzheimer disease [AD] dementia, and 82 with non-AD dementia) from 5 European centers. We calculated for each center and for the pooled cohort CSF Aβ42 and Aβ42/tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [11C]PiB-PET images.Results: Amyloid-PET–based calculated CSF Aβ42 cutpoints ranged from 521 to 616 pg/mL, whereas existing clinical-based cutpoints ranged from 400 to 550 pg/mL. Using the calculated cutpoint from the pooled sample (557 pg/mL), concordance between CSF Aβ42 and amyloid-PET was 84%. Similar concordance was found when using a dichotomized Aβ42/tau ratio. Exploratory analysis showed that participants with a positive amyloid-PET and normal CSF Aβ42 levels had higher CSF tau and phosphorylated tau levels and more often had mild cognitive impairment or AD dementia compared with participants who had negative amyloid-PET and abnormal CSF Aβ42 levels.Conclusions: Amyloid-PET–based CSF Aβ42 cutpoints were higher and tended to reduce intercenter variability compared with clinical-based cutpoints. Discordant participants with normal CSF Aβ42 and a positive amyloid-PET may be more likely to have AD-related amyloid pathology than participants with abnormal CSF Aβ42 and a negative amyloid-PET.Classification of evidence: This study provides Class II evidence that an amyloid-PET–based CSF Aβ42 cutpoint identifies individuals with amyloid deposition with a sensitivity of 87% and specificity of 80%.

Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimer's disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation. Here, we have investigated ubiquilin-1 expression in human brain in relation to AD-related neurofibrillary pathology and the effects of ubiquilin-1 overexpression on BACE1, tau, neuroinflammation, and neuronal viability in vitro in co-cultures of mouse embryonic primary cortical neurons and microglial cells under acute neuroinflammation as well as neuronal cell lines, and in vivo in the brain of APdE9 transgenic mice at the early phase of the development of Aβ pathology. Ubiquilin-1 expression was decreased in human temporal cortex in relation to the early stages of AD-related neurofibrillary pathology (Braak stages 0-II vs. III-IV). There was a trend towards a positive correlation between ubiquilin-1 and BACE1 protein levels. Consistent with this, ubiquilin-1 overexpression in the neuron-microglia co-cultures with or without the induction of neuroinflammation resulted in a significant increase in endogenously expressed BACE1 levels. Sustained ubiquilin-1 overexpression in the brain of APdE9 mice resulted in a moderate, but insignificant increase in endogenous BACE1 levels and activity, coinciding with increased levels of soluble Aβ40 and Aβ42. BACE1 levels were also significantly increased in neuronal cells co-overexpressing ubiquilin-1 and BACE1. Ubiquilin-1 overexpression led to the stabilization of BACE1 protein levels, potentially through a mechanism involving decreased degradation in the lysosomal compartment. Ubiquilin-1 overexpression did not significantly affect the neuroinflammation response, but decreased neuronal viability in the neuron-microglia co-cultures under neuroinflammation. Taken together, these results suggest that ubiquilin-1 may mechanistically participate in AD molecular pathogenesis by affecting BACE1 and thereby APP processing and Aβ accumulation.

Idiopathic normal pressure hydrocephalus (iNPH) is a late-onset surgically alleviated, progressive disease. We characterize a potential familial subgroup of iNPH in a nation-wide Finnish cohort of 375 shunt-operated iNPH-patients. The patients were questionnaired and phone-interviewed, whether they have relatives with either diagnosed iNPH or disease-related symptomatology. Then pedigrees of all families with more than one iNPH-case were drawn. Eighteen patients (4.8%) from 12 separate pedigrees had at least one shunt-operated relative whereas 42 patients (11%) had relatives with two or more triad symptoms. According to multivariate logistic regression analysis, familial iNPH-patients had up to 3-fold risk of clinical dementia compared to sporadic iNPH patients. This risk was independent from diagnosed Alzheimer's disease and APOE epsilon 4 genotype. This study describes a familial entity of iNPH offering a novel approach to discover the potential genetic characteristics of iNPH. Discovered pedigrees offer an intriguing opportunity to conduct longitudinal studies targeting potential preclinical signs of iNPH. (C) 2016 Elsevier B.V. All rights reserved.

Background: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer's disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust.Objectives: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts. Methods: Our study used Illumina HumanHT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE 4 status were used as covariates for all analysis. Results: Gene and pathway level models performed similarly to each other and to a model based on demographic information only. Conclusions: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach.

The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH).We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age65 years).While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52-67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers.This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.

Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P

Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer’s disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer’s disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer’s disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer’s disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer’s disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer’s disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism.

Background Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia. Methods We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1–42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (−) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics. Results MTA and t-tau were elevated in the Aβ − WMH+, Aβ + WMH−, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline. Conclusions In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up. Electronic supplementary material The online version of this article (doi:10.1186/s13195-017-0328-9) contains supplementary material, which is available to authorized users.

Purpose The aim of this study was to examine the association of serum glucose, insulin, and insulin resistance with cognitive functioning 7 years later in a longitudinal population-based study of Finnish older adults. Methods Serum glucose and insulin were measured at baseline in 269 dementia-free individuals aged 65-79 years, from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). Participants were reexamined 7 years later, and global cognition, episodic memory, executive functioning, verbal expression, and psychomotor speed were assessed, both at baseline and at follow-up. Multiple linear regression was used to investigate the associations with cognitive performance at follow-up, after adjusting for several potential confounders, including common vascular risk factors. Results In the multivariable-adjusted linear regression models, no associations of insulin resistance with cognitive functioning were observed. After excluding 19 incident dementia cases, higher baseline HOMA-IR values were related to worse performance in global cognition (β [standard error (SE)] -.050 [0.02]; P = .043) and psychomotor speed (β [SE] -.064 [.03]; P = [.043]) 7 years later. Raised serum insulin levels were associated with lower scores on global cognition (β [SE] -.054 [.03]; P = .045) and tended to relate to poorer performance in psychomotor speed (β [SE] -.061 [.03]; P = .070). Conclusions Serum insulin and insulin resistance may be independent predictors of cognitive performance 7 years later in elderly individuals without dementia. Randomized controlled trials are needed to determine this issue.

To investigate the effect of a 2-year multidomain lifestyle intervention on daily functioning of older people.A 2-year randomized controlled trial (ClinicalTrials.gov, NCT01041989).Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability.A total of 1260 older adults, with a mean age of 69 years at the baseline, who were at risk of cognitive decline.A multidomain intervention, including simultaneous physical activity intervention, nutritional counseling, vascular risk monitoring and management, and cognitive training and social activity.The ability to perform daily activities (activities of daily living [ADLs] and instrumental ADLs) and physical performance (Short Physical Performance Battery).The mean baseline ADL score was 18.1 (SD = 2.6) points; the scale ranges from 17 (no difficulties) to 85 (total ADL dependence). During the 2-year intervention, the ADL disability score slightly increased in the control group, while in the intervention group, it remained relatively stable. Based on the latent growth curve model, the difference in the change between the intervention and control groups was -0.95 (95% confidence interval [CI] = -1.61 to -0.28) after 1 year and -1.20 (95% CI = -2.02 to -0.38) after 2 years. In terms of physical performance, the intervention group had a slightly higher probability of improvement (from score 3 to score 4; P = .041) and a lower probability of decline (from score 3 to scores 0-2; P = .043) for chair rise compared to the control group.A 2-year lifestyle intervention was able to maintain the daily functioning of the at-risk older population. The clinical significance of these results in this fairly well-functioning population remains uncertain, but the study results hold promise that healthy eating, exercise, and cognitive and social activity may have favorable effects on functional independence in older people.

Background The neuropathology of Alzheimer's disease (AD) has previously been shown to be rather common among the elderly. Objective The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEɛ4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. Methods This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEɛ4 status were analyzed. Results Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. Conclusion AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes.

Purpose Subjects with Alzheimer's disease (AD) have been shown to be at a higher risk for epilepsy. The vast majority of the previous studies have not included a full neuropathological examination. Methods The objective of this study was to assess the prevalence of epilepsy and clinicopathological characteristics in a well-defined study group of 64 subjects with AD. We evaluated the clinicopathological findings in 64 subjects (mean age at death 85 ± 8.6 years) from a longitudi-nal study cohort of patients with dementia. Results Eleven out of the 64 subjects (17%) had a history of epilepsy, which is comparable to previous studies. The subjects with AD and epilepsy were significantly younger at the time of AD diagnosis and at the time of hospitalisation. In addition, their duration of AD was longer. Concomitant neuropathology in addition to AD was common in both groups and the ApoE genotypes did not differ significantly between the groups. Conclusion The strength of this study is a thorough neuropathological examination of all study subjects. Our findings support the previous literature regarding the prevalence of epilepsy in subjects with AD. We have shown that the subjects with AD and epilepsy differ significantly from the subjects without epilepsy.

Aims: We assessed the value of automated MRI quantification methods in the differential diagnosis of behavioral-variant frontotemporal dementia (bvFTD) from Alzheimer disease (AD), Lewy body dementia (LBD), and subjective memory complaints (SMC). We also examined the role of the C9ORF72-related genetic status in the differentiation sensitivity. Methods: The MRI scans of 50 patients with bvFTD (17 C9ORF72 expansion carriers) were analyzed using 6 quantification methods as follows: voxel-based morphometry (VBM), tensor-based morphometry, volumetry (VOL), manifold learning, grading, and white-matter hyperintensities. Each patient was then individually compared to an independent reference group in order to attain diagnostic suggestions. Results: Only VBM and VOL showed utility in correctly identifying bvFTD from our set of data. The overall classification sensitivity of bvFTD with VOL + VBM achieved a total sensitivity of 60%. Using VOL + VBM, 32% were misclassified as having LBD. There was a trend of higher values for classification sensitivity of the C9ORF72 expansion carriers than noncarriers. Conclusion: VOL, VBM, and their combination are effective in differential diagnostics between bvFTD and AD or SMC. However, MRI atrophy profiles for bvFTD and LBD are too similar for a reliable differentiation with the quantification methods tested in this study.

Objective Apolipoprotein E (APOE) ε4 allele is a well‐established risk factor in Alzheimer's disease (AD). Here, we assessed the effects of APOE polymorphism on cardiovascular, metabolic, and inflammation‐related parameters in population‐based cohorts. Methods Association of cardiovascular, metabolic, and inflammation‐related parameters with the APOE polymorphism in a large Finnish Metabolic Syndrome in Men (METSIM) cohort and Finnish Geriatric Intervention study to prevent cognitive impairment and disability (FINGER) were investigated. Brain‐specific effects were addressed in postmortem brain samples. Results Individuals carrying the APOE ε4 allele displayed significantly elevated serum/plasma LDL cholesterol and apolipoprotein B levels. APOE ε3ε4 and ε4ε4 significantly associated with lower levels of plasma high‐sensitivity C‐reactive protein (hs‐CRP). Plasma amyloid‐β 42 (Aβ42) and reduced hs‐CRP levels showed an association independently of the APOE status. Interpretation These data suggest that the APOE ε4 allele associates with lower levels of hs‐CRP in individuals without dementia. Moreover, Aβ42 may encompass anti‐inflammatory effects reflected by reduced hs‐CRP levels.

There is increasing evidence showing that brain atrophy varies between patients with Alzheimer's disease (AD), suggesting that different anatomical patterns might exist within the same disorder. We investigated AD heterogeneity based on cortical and subcortical atrophy patterns in 299 AD subjects from 2 multicenter cohorts. Clusters of patients and important discriminative features were determined using random forest pairwise similarity, multidimensional scaling, and distance-based hierarchical clustering. We discovered 2 typical (72.2%) and 3 atypical (28.8%) subtypes with significantly different demographic, clinical, and cognitive characteristics, and different rates of cognitive decline. In contrast to previous studies, our unsupervised random forest approach based on cortical and subcortical volume measures and their linear and nonlinear interactions revealed more typical AD subtypes with important anatomically discriminative features, while the prevalence of atypical cases was lower. The hippocampal-sparing and typical AD subtypes exhibited worse clinical progression in visuospatial, memory, and executive cognitive functions. Our findings suggest there is substantial heterogeneity in AD that has an impact on how patients function and progress over time.

Contains fulltext : 190311.pdf (Publisher’s version ) (Closed access) Importance: Cerebral amyloid-beta aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-beta aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score

Objective Occasionally, a favorable clinical disease-specific outcome does not reflect into improved generic health-related quality of life (HRQoL) in patients with idiopathic normal-pressure hydrocephalus (iNPH) at 1 year after the installation of a cerebrospinal fluid shunt. Our aim was to identify factors causing this discrepancy. Methods The 1-year HRQoL outcomes of 141 patients with iNPH were evaluated with the generic 15D instrument, in which the minimum clinically important change/difference on the 0–1 scale has been estimated to be ±0.015. A 12-point iNPH grading scale (iNPHGS) was used as a clinical disease-specific outcome measure, in which a 1-point decrease is considered to be clinically important. We identified 29 (21%) patients with iNPH from our prospective study whose HRQoL deteriorated or remained the same despite of a favorable iNPHGS outcome. We analyzed this discrepancy using patients' clinical variables and characteristics. Results Multivariate binary logistic regression analysis indicated that a greater (worse) iNPHGS score at baseline (adjusted odds ratio [OR], 1.7; 95% confidence interval [CI] 1.3–2.3; P < 0.001), comorbid chronic pulmonary disease (40% vs. 20%; adjusted OR 17.8; 95% CI 3.6–89.9; P < 0.001), and any comorbid nonmetastatic tumor (62% vs. 17%; adjusted OR 11.5; 95% CI 1.5–85.3; P = 0.017) predicted discrepancy between iNPHGS and 15D outcomes. Conclusions Frail patients suffering from certain pre-existing comorbidities may not experience improvement in generic HRQoL despite of a favorable clinical disease-specific response. Acknowledging the comorbidity burden of the patient may help clinicians and the patients to understand the conflict between patient-reported and clinical outcomes., final draft, peerReviewed

To validate a visual rating scale of frontal atrophy with quantitative imaging and study its association with clinical status, APOE e4, CSF biomarkers, and cognition. The AddNeuroMed and ADNI cohorts were combined giving a total of 329 healthy controls, 421 mild cognitive impairment patients, and 286 Alzheimer’s disease (AD) patients. Thirty-four patients with frontotemporal dementia (FTD) were also included. Frontal atrophy was assessed with the frontal sub-scale of the global cortical atrophy scale (GCA-F) on T1-weighted images. Automated imaging markers of cortical volume, thickness, and surface area were evaluated. Manual tracing was also performed. The GCA-F scale reliably reflects frontal atrophy, with orbitofrontal, dorsolateral, and motor cortices being the regions contributing most to the GCA-F ratings. GCA-F primarily reflects reductions in cortical volume and thickness, although it was able to detect reductions in surface area too. The scale showed significant associations with clinical status and cognition. The GCA-F scale may have implications for clinical practice as supportive diagnostic tool for disorders demonstrating predominant frontal atrophy such as FTD and the executive presentation of AD. We believe that GCA-F is feasible for use in clinical routine for the radiological assessment of dementia and other disorders. • The GCA-F visual rating scale reliably reflects frontal brain atrophy. • Orbitofrontal, dorsolateral, and motor cortices are the most contributing regions. • GCA-F shows significant associations with clinical status and cognition. • GCA-F may be supportive diagnostic tool for disorders demonstrating predominant frontal atrophy. • GCA-F may be feasible for use in radiological routine.

Background The CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) Dementia Risk Score is a validated tool to predict late-life dementia risk (20 years later), based on midlife vascular risk factors. The goal was to render this prediction tool widely accessible. Methods The CAIDE Risk Score (mobile application) App was developed based on the CAIDE Dementia Risk Score, involving information on age, educational level, hypertension, hypercholesterolemia, obesity, and physical inactivity. Results The CAIDE Risk Score App is an evidence-based practical tool, which allows users to detect their individual risk, provides guidance for risk modification, and suggests consulting a health care practitioner if needed. Moreover, it allows practitioners to discuss preventive measures and monitor risk reduction. Conclusions The CAIDE Risk Score App is the first to predict the risk for dementia through an important evidence-based tool. The App can encourage users to actively decrease their modifiable risk factors and postpone cognitive impairment and dementia.

BACKGROUND: There is an urgent need to discover Alzheimer's disease (AD) biomarkers that are both easily measured and reliable. Research into blood-based biomarkers for AD using transcriptomics and proteomics has been an attractive and promising area of research. However, to date researchers have not looked into the possibility of AD medication being a confounding factor in these studies.OBJECTIVE: This study explored whether acetylcholinesterase inhibitors (AChEIs), the main class of AD medication, are a confounding factor in AD blood biomarker studies.METHODS: The most promising blood transcriptomic and proteomic biomarkers from two recent studies were analyzed to determine if they were differentially expressed between AD subjects on AChEIs and subjects that were not.RESULTS: None of the gene or protein biomarkers analyzed were found to be significantly altered between subjects in either group.CONCLUSION: This study found no evidence that AChEIs are a confounding factor in these published AD blood biomarker studies. Further work is needed to confirm that this is also the case for other proposed biomarkers.

The amyloid cascade hypothesis for the pathogenesis of Alzheimer's disease (AD) was proposed over twenty years ago. However, the mechanisms of neurodegeneration and synaptic loss have remained elusive delaying the effective drug discovery. Recent studies have revealed that amyloid-β peptides as well as phosphorylated and fragmented tau proteins accumulate within mitochondria. This process triggers mitochondrial fission (fragmentation) and disturbs Krebs cycle function e.g. by inhibiting the activity of 2-oxoglutarate dehydrogenase. Oxidative stress, hypoxia and calcium imbalance also disrupt the function of Krebs cycle in AD brains. Recent studies on epigenetic regulation have revealed that Krebs cycle intermediates control DNA and histone methylation as well as histone acetylation and thus they have fundamental roles in gene expression. DNA demethylases (TET1-3) and histone lysine demethylases (KDM2-7) are included in the family of 2-oxoglutarate-dependent oxygenases (2-OGDO). Interestingly, 2-oxoglutarate is the obligatory substrate of 2-OGDO enzymes, whereas succinate and fumarate are the inhibitors of these enzymes. Moreover, citrate can stimulate histone acetylation via acetyl-CoA production. Epigenetic studies have revealed that AD is associated with changes in DNA methylation and histone acetylation patterns. However, the epigenetic results of different studies are inconsistent but one possibility is that they represent both coordinated adaptive responses and uncontrolled stochastic changes, which provoke pathogenesis in affected neurons. Here, we will review the changes observed in mitochondrial dynamics and Krebs cycle function associated with AD, and then clarify the mechanisms through which mitochondrial metabolites can control the epigenetic landscape of chromatin and induce pathological changes in AD.

Various radiological markers have been proposed for diagnostics in idiopathic normal pressure hydrocephalus (iNPH). We examined the usefulness of radiological markers in the diagnostics and prediction of shunt response in iNPH. In this retrospective cohort study, we evaluated brain CT or MRI scans of 390 patients with suspected iNPH. Based on a 24-h intraventricular pressure monitoring session, patients were classified into a non-NPH (n = 161) or probable iNPH (n = 229) group. Volumes of cerebrospinal fluid compartments (lateral ventricles, sylvian and suprasylvian subarachnoid spaces and basal cisterns) were visually assessed. Disproportionally enlarged subarachnoid spaces, flow void, white matter changes, medial temporal lobe atrophy and focally dilated sulci were evaluated. Moreover, we measured quantitative markers: Evans’ index (EI), the modified cella media index, mean width of the temporal horns and callosal angle. iNPH was more likely in patients with severe volumetric disproportion between the suprasylvian and sylvian subarachnoid spaces than in those without disproportion (OR 7.5, CI 95 % 4.0–14.1, P

Summary Background Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies. In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a proof-of-concept randomised controlled trial, we aimed to assess a multidomain approach to prevent cognitive decline in at-risk elderly people from the general population. Methods In a double-blind randomised controlled trial we enrolled individuals aged 60–77 years recruited from previous national surveys. Inclusion criteria were CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score of at least 6 points and cognition at mean level or slightly lower than expected for age. We randomly assigned participants in a 1:1 ratio to a 2 year multidomain intervention (diet, exercise, cognitive training, vascular risk monitoring), or a control group (general health advice). Computer-generated allocation was done in blocks of four (two individuals randomly allocated to each group) at each site. Group allocation was not actively disclosed to participants and outcome assessors were masked to group allocation. The primary outcome was change in cognition as measured through comprehensive neuropsychological test battery (NTB) Z score. Analysis was by modified intention to treat (all participants with at least one post-baseline observation). This trial is registered at ClinicalTrials.gov, number NCT01041989. Findings Between Sept 7, 2009, and Nov 24, 2011, we screened 2654 individuals and randomly assigned 1260 to the intervention group (n=631) or control group (n=629). 591 (94%) participants in the intervention group and 599 (95%) in the control group had at least one post-baseline assessment and were included in the modified intention-to-treat analysis. Estimated mean change in NTB total Z score at 2 years was 0·20 (SE 0·02, SD 0·51) in the intervention group and 0·16 (0·01, 0·51) in the control group. Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002–0·042, p=0·030). 153 (12%) individuals dropped out overall. Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control). Interpretation Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population. Funding Academy of Finland, La Carita Foundation, Alzheimer Association, Alzheimer's Research and Prevention Foundation, Juho Vainio Foundation, Novo Nordisk Foundation, Finnish Social Insurance Institution, Ministry of Education and Culture, Salama bint Hamdan Al Nahyan Foundation, Axa Research Fund, EVO funding for University Hospitals of Kuopio, Oulu, and Turku and for Seinajoki Central Hospital and Oulu City Hospital, Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare, and af Jochnick Foundation.

Background: Alzheimer's disease (AD) is a highly heritable disease, but until recently few replicated genetic markers have been identified. Markers identified so far are likely to account for only a tiny fraction of the heritability of AD and many more genetic risk alleles are thought to be undiscovered. Objective: Identifying genetic markers for AD using combined analysis of genetics and brain imaging data. Methods: Imaging quantitative trait loci (iQTLs) has recently emerged as an interesting research area for linking genetics of brain changes to AD. We consider a genome-wide association scan of 109 brain-wide regional imaging phenotypes to identify genetic susceptibility loci for AD from a combined set of 1,045 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the AddNeuroMed studies. We use one-SNP-at-a-time as well as multi-SNP Hyperlasso based iQTL methods for the analysis. Results: We identified several novel markers associated with AD, namely HOMER2 (rs1256429; intronic, p = 8.7 × 10-10), EOMES (rs2724509; flanking), JAM2 (rs2829841; intronic), and WEE1 (rs10770042; coding). The SNP rs1256429 (HOMER2) was one of the top hits in Hyperlasso as well as in the single-SNP analysis showing an association with the volume of the right thalamus and AD, a brain region reported to be linked with AD in several studies. Conclusion: We believe that the markers identified in this study are novel additions to the existing list of genetic variants associated with AD which can be validated in future replicated studies.

We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.

Background CAIDE Dementia Risk Score is a validated tool for estimating 20-year dementia risk in the general population based on a midlife risk profile. Objective To investigate the associations between CAIDE score and dementia-related brain changes up to 30 years later on magnetic resonance imaging (MRI). Methods Participants in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples surveyed in 1972, 1977, 1982, or 1987. A first re-examination was conducted in 1998, and a second re-examination in 2005-2008 (total follow-up time up to 30 years). The MRI study population included 112 individuals with MRIs from the first re-examination, and a different group of 69 individuals with MRIs from the second re-examination. MRIs from 1998 were used to determine gray matter volume, and to visually rate white matter hyperintensities (WMH) of presumed vascular origin and medial temporal lobe atrophy (MTA). MRIs from 2005-2008 were used to assess cortical thickness, gray matter and WMH volume, and to visually rate MTA. CAIDE scores were calculated for participants in both re-examinations based on midlife sociodemographic and vascular factors and additionally apolipoprotein E status. Results Higher midlife CAIDE score was associated with more severe WMH 20 years later: RR (95% CI) was 1.69 (1.15-2.08); and with higher WMH volume (β 0.27, p = 0.036) and higher MTA score (RR 1.91, 95% CI 1.16-2.34) up to 30 years later. Conclusion CAIDE Dementia Risk Score in midlife was most consistently associated with WMH later in life. A relation with MTA was observed in individuals with longer follow-up time.

© 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).

We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DE-SCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out cross-validation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, they were 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression.

BACKGROUND Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH. OBJECTIVE We aim to evaluate the role of AD-related polymorphisms in iNPH. METHODS Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. RESULTS Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. CONCLUSIONS Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.