iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain samples.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95 % of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.

Semi-quantification and grading of amyloid PET: A project of the European Alzheimer's Disease Consortium (EADC).

BACKGROUND: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. METHODS: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to 18F-florbetaben (53 subjects), 18F-flutemetamol (62 subjects), 18F-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. CONCLUSION: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale.

[Detection and prevention in later life: risk profiles for physical, psychological, social and environmental frailty.] / Detectie en preventie van kwetsbaarheid: Op zoek naar risicoprofielen voor fysieke, psychische, sociale en omgevingskwetsbaarheid.

In order to provide proactive care and support for older people attention is needed for the prevention of frailty among older adults. Subsequently, accurate case finding of those who are more at risk of becoming frail is crucial to undertake specific preventive actions. This study investigates frailty and risk profiles of frailty among older people in order to support proactive detection. Hereby, frailty is conceived not only as a physical problem, but also refers to emotional, social, and environmental hazards. Using data generated from the Belgian Ageing Studies (N = 21,664 home-dwelling older people), a multinomial logistic regression model was tested which included socio-demographic and socio-economic indicators as well as the four dimensions of frailty (physical, social, psychological and environmental). Findings indicate that for both men and women having moved in the previous 10 years and having a lower household income are risk factors of becoming multidimensional frail. However, studying the different frailty domains, several risk profiles arise (e. g. marital status is important for psychological frailty), and gender-specific risk groups are detected (e. g. non-married men). This paper elaborates on practical implications and formulates a number of future research recommendations to tackle frailty in an ageing society.

Procarboxypeptidase U (proCPU, TAFI, proCPB2) in cerebrospinal fluid during ischemic stroke is associated with stroke progression, outcome and blood-brain barrier dysfunction.

Essentials Little is known of procarboxypeptidase U (proCPU) in cerebrospinal fluid (CSF) of stroke patients. ProCPU levels were studied in CSF of controls and non-thrombolyzed acute ischemic stroke patients. ProCPU is elevated in CSF of stroke patients compared with controls. ProCPU in CSF correlates with stroke progression, outcome, and blood-brain barrier dysfunction. SUMMARY: Background Procarboxypeptidase U (proCPU, TAFI, proCPB2), the zymogen of CPU, which is a potent antifibrinolytic enzyme and a modulator of inflammation, has previously been investigated in plasma of stroke patients, but so far, no information on the proCPU levels in cerebrospinal fluid (CSF) during acute ischemic stroke (AIS) is available. Objectives This case-control observational study investigates proCPU in CSF of AIS patients compared with controls with an intact blood-brain barrier (BBB) and evaluates the relationship of CSF/plasma proCPU ratios with stroke parameters. Methods A sensitive HPLC-based enzymatic assay was used to determine proCPU levels in CSF of non-thrombolyzed patients in the hyperacute phase (< 24 h after onset) of AIS (n = 72). Individuals (n = 32) without stroke, an intact BBB and no apparent abnormalities in biochemical and microbiological tests, served as controls. Relations between the CSF/plasma proCPU ratio and (i) stroke severity, (ii) stroke progression/recurrence, (iii) stroke outcome and (iv) BBB dysfunction (CSF/serum albumin ratio) were assessed. Results Mean (SEM) proCPU levels were elevated in the CSF of stroke patients compared with controls (4.36 (0.23) U L-1 vs. 3.50 (0.23) U L-1 ). Higher median [IQR] CSF/plasma proCPU ratios were found in patients with stroke progression ((6.0 [4.2-6.9]) × 10-3 ) and poor outcome ((6.4 [3.9-7.0]) × 10-3 ) after 3 months (modified Rankin Scale; mRS > 3) compared with patients without progression ((3.9 [2.7-5.4]) × 10-3 ) or better outcome ((4.0 [2.8-5.0]) × 10-3 ). In stroke patients with a disrupted BBB, proCPU ratios were higher compared with stroke patients with an intact BBB ((6.4 [5.8-9.0]) × 10-3 vs. (3.7 [2.8-5.0]) × 10-3 ). Conclusions ProCPU is increased in CSF during hyperacute ischemic stroke and is associated with stroke progression and outcome after 3 months, most likely due to BBB dysfunction in the hyperacute phase of ischemic stroke.

Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

SolCos model-based individual reminiscence for older adults with mild to moderate dementia in nursing homes: a randomized controlled intervention study.

WHAT IS KNOWN ON THE SUBJECT?: To stimulate reminiscence of older adults with dementia performed individually or through group sessions is a well-known practice in nursing homes resulting in effects on behaviour and well-being as an alternative for medication. Robust scientific proof of the effectiveness of individual reminiscence therapy performed in nursing homes is sparse. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: We have provided individual standardized reminiscence therapy to residents with dementia. The therapy was developed and tested in a previous study and performed in this study by trained nursing home volunteers. In comparison with a control group who received usual care, residents who received the reminiscence therapy showed significant less depressive symptoms. Moreover, residents were, in general, attentive, open and collaborative during the sessions and volunteers experienced the sessions as useful and pleasant. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Individual reminiscence therapy can be learned and used by nursing home volunteers to improve care in nursing homes. ABSTRACT: Aim To investigate the effect of a standardized individualized intervention based on the SolCos transformational reminiscence model on depressive symptoms (primary outcome), cognition and behaviour (secondary outcomes) for older people with mild to moderate dementia, performed by trained nursing home volunteers as facilitators. Background Because of limited pharmacological treatment options for older adults with dementia relevant physical, sensory, psychological or social interventions offer alternative opportunities. Method Randomized controlled trial (ISRCTN74355073) was set up in two nursing homes with 29 and 31 residents in the intervention and the control groups respectively. Eighteen nursing home volunteers were trained to perform the reminiscence therapy. Various assessment scales were measured pre- and post-sessions. Results Linear regression analysis showed an impact on depressive symptoms. However, no impact was identified on cognition and behaviour. Facilitators experienced the sessions as useful and pleasant, and study participants were, in general, attentive, open and collaborative. Discussion Study results showed that organizing standardized individual reminiscence therapy with nursing home volunteers was feasible and study participants' attention and participation were overall good. Further study initiatives to explore the potential of individual reminiscence therapy within a person-centred framework are recommended in order to improve care in nursing homes.

The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter.

Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.

Poststroke depression and its multifactorial nature: results from a prospective longitudinal study.

OBJECTIVE: Poststroke depression (PSD) is commonly observed in stroke patients and has a negative impact on functional outcome and quality of life. Therefore, a prospective, longitudinal epidemiological study was conducted aiming to determine prevalence and risk factors for PSD at 1, 3, 6, 12 and 18 months poststroke. METHODS: A total of 222 patients were included in the study and 201 patients entered data analysis. Demographic data, vascular risk factors, stroke characteristics, functional and neurocognitive outcome measures and psychosocial factors were considered as potential risk factors for PSD. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and Åsberg Depression Rating Scale (MADRS). RESULTS: PSD was present at 1, 3, 6, 12 and 18 months poststroke in 24.5%, 27.1%, 28.3%, 19.8% and 26.3% of the patients respectively. Univariate regression analyses revealed that PSD was significantly associated with stroke severity, physical disability, cognitive impairment and stroke outcome during the 18 months time frame of the study. Reduced social activities and the presence of apraxia were consistently associated with PSD whereas aphasia was only significantly associated in the first 6 months after stroke. Patients with relational problems had a 3 times greater risk of becoming depressed at 18 months poststroke than patients without relational problems (OR=3.09; 95% CI=1.31-7.26). CONCLUSIONS: Risk factors for PSD seem variable indicating the need for clinicians to consider the dynamic and multifactorial nature of PSD emphasizing the importance of a rigorous and long-term monitoring and support of stroke patients and their caregivers.

Rationale and clinical data supporting nutritional intervention in Alzheimer's disease.

Adequate nutrition plays an important role in the maintenance of cognitive function, particularly during aging. Malnutrition is amongst the risk factors for developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Epidemiological studies have associated deficiencies in some nutrients with a higher risk of cognitive dysfunction and/or AD. Cognitive decline in AD is correlated with synaptic loss and many of the components required to maintain optimal synaptic function are derived from dietary sources. As synapses are part of the neuronal membrane and are continuously being remodelled, the availability of sufficient levels of nutritional precursors (mainly uridine monophosphate, choline and omega-3 fatty acids) to make the phospholipids required to build neuronal membranes may have beneficial effects on synaptic degeneration in AD. In addition, B-vitamins, phospholipids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses. Despite this, no randomized controlled trial has hitherto provided evidence that any single nutrient has a beneficial effect on cognition or lowers the risk for AD. However, a multi-target approach using combinations of (micro)nutrients might have beneficial effects on cognitive function in neurodegenerative brain disorders like AD leading to synaptic degeneration. Here we review the clinical evidence for supplementation, based on a multi-target approach with a focus on key nutrients with a proposed role in synaptic dysfunction. Based on preclinical evidence, a nutrient mixture, Souvenaid(®) (Nutricia N.V., Zoetermeer, The Netherlands) was developed. Clinical trials with Souvenaid(®) have shown improved memory performance in patients with mild AD. Further clinical trials to evaluate the effects of nutritional intervention in MCI and early dementia due to AD are on-going.

Psychosocial problems associated with depression at 18 months poststroke.

OBJECTIVE: With a prevalence that varies between 20% and 65%, poststroke depression (PSD) is a frequent sequel of stroke. The aim of this study was to determine incidence and risk factors for PSD 18 months after stroke. METHODS: As part of the Middelheim Interdisciplinary Stroke Study, patients were followed up for 18 months in this prospective and longitudinal epidemiological study. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and Åsberg Depression Rating Scale. Activities, including social activities, were measured with the Stroke Impact Scale (SIS). Relational problems since stroke onset were defined by a questionnaire. RESULTS: Data analysis was performed on 125 patients who completed follow-up assessments. Depression (CSD score ≥8) was diagnosed in 28% of the patients. Patients with PSD were more dependent for activities of daily living and displayed more physical and cognitive impairment than patients without PSD. The risk to become depressed decreased with 5% when the patient's activities increased with one unit on the SIS (odds ratio (OR) = 0.95; 95% confidence interval (CI) = 0.93-0.97). Patients with persistent relational problems since stroke onset had approximately four and a half times greater risk of becoming depressed than patients without (OR = 4.48; 95%CI = 1.17-16.87). CONCLUSIONS: Multiple regression models indicated that the most determining features for developing PSD at 18 months poststroke include reduced activity and relationship problems due to stroke. Further studies on risk factors for PSD are essential, including psychosocial aspects, given its negative impact on rehabilitation and quality of life.

Clinical indications for analysis of Alzheimer's disease CSF biomarkers.

The cerebrospinal fluid (CSF) biomarkers ß-amyloid1-42 (Aß1-42), total tau protein (T-tau) and hyperphosphorylated tau (P-tau181P) are well-validated and are increasingly used in clinical practice as an affirmative diagnostic tool for Alzheimer's disease (AD). These biomarkers have also been implemented in the revised diagnostic criteria of AD. The combination of the CSF biomarkers Aß1-42, T-tau and P-tau181P results in high levels of sensitivity, specificity and diagnostic accuracy for discriminating AD from controls (including psychiatric disorders like depression). These biomarkers can be applied for diagnosing AD in the prodromal phase of the disease (mild cognitive impairment). In case of doubt between vascular dementia (VaD) or mixed AD-VaD pathology in dementia patients, the determination of CSF Aß1-42, T-tau and P-tau181P levels is of help to confirm or exclude the AD component in the pathophysiology of the dementia syndrome. However, their discriminatory power for the differential diagnosis of dementia is suboptimal. Other CSF biomarkers like Aß1-40, and those that are reflective of the pathology of non-AD dementias, could improve the accuracy of differential dementia diagnosis. The added differential diagnostic value of the CSF biomarkers Aß1-42, T-tau and P-tau181P could lie within those cases in which the routine clinical diagnostic work-up is not able to discriminate between AD or non-AD dementias. In summary, the CSF biomarkers Aß1-42, T-tau and P-tau181P can be used in clinical practice to discriminate AD from healthy aging (including psychiatric disorders like depression), to diagnose AD in its prodromal phase or in atypical forms with prominent non-memory impairment, to identify AD in patients with mixed pathologies and in case of an ambiguous (AD versus non-AD) dementia diagnosis.

A prospective study on the prevalence and risk factors of poststroke depression.

BACKGROUND AND PURPOSE: Poststroke depression (PSD) is common. Early detection of depressive symptoms and identification of patients at risk for PSD are important as PSD negatively affects stroke outcome and costs of medical care. Therefore, the aim of this study was to determine incidence and risk factors for PSD at 3 months after stroke. METHODS: We conducted a prospective, longitudinal epidemiological study aiming to determine incidence and risk factors for PSD at 1, 3, 6, 12 and 18 months poststroke. The present data analysis covers the convalescent phase of 3 months poststroke. Participants in this study were inpatients, admitted to a stroke unit with first or recurrent stroke. Demographic data and vascular risk factors were collected and patients were evaluated at baseline and 3 months poststroke for functional and cognitive deficits, stroke characteristics, stroke severity and stroke outcome. Signs and symptoms of depression were quantified by means of the Cornell Scale for Depression (CSD) and Montgomery and Åsberg Depression Rating Scale (MADRS). Significantly associated variables from univariate analysis were analyzed by using multiple linear and logistic regression methods. RESULTS: Data analysis was performed in 135 patients who completed follow-up assessments at 3 months poststroke. Depression (CSD score ≥8) was diagnosed in 28.1% of the patients. Patients with PSD were significantly more dependent with regard to activities of daily living (ADL) and displayed more severe physical and cognitive impairment than patients without PSD. A higher prevalence of speech and language dysfunction and apraxia were observed in patients with PSD (36.8 and 34.3%, respectively) compared to non-depressed stroke patients (19.6 and 12.4%; p = 0.036 and p = 0.004, respectively). Applying multiple linear regressions, cognitive impairment and reduced mobility as part of the Stroke Impact Scale were independently associated with PSD, as scored using CSD and MADRS (r(2) = 0.269 and r(2) = 0.474, respectively). CONCLUSIONS: The risk of developing PSD is increased in patients with more functional and cognitive impairment, greater dependency with regard to ADL functions and with occurrence of speech and language dysfunctions and apraxia. Multiple regression models indicated that the most determining features for depression risk in the convalescent phase after stroke include reduced mobility and cognitive impairment. Further studies on risk factors for PSD are essential, given its negative impact on rehabilitation and quality of life. Identification of risk factors for PSD may allow more efficacious preventive measures and early implementation of adequate antidepressive treatment.

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: a pilot study.

BACKGROUND: Antipsychotic use for behavioural and psychological symptoms of dementia (BPSD) is controversial. Guidelines advise to reduce antipsychotics given the adverse effects and limited efficacy, to limit dose and treatment duration as well as to undertake discontinuation. METHODS: A pilot study with 40 hospitalised geriatric cognitively impaired patients, in which the effects of abrupt antipsychotic discontinuation were investigated, using neuropsychiatric inventory (NPI) scores before and one month after discontinuation. Withdrawal symptoms were monitored thrice a day with a checklist during five consecutive days. RESULTS: Participants (n = 40) had a mean age of 84 years (range 67-95) and 53% were male. The total mean baseline NPI score was 21 (SD 12) with predominantly behavioural rather than psychological disturbances. After abrupt discontinuation, mild withdrawal symptoms were observed in 72% of the patients, with frequencies of symptoms peaking on day 2 (53%) and day 3 (48%). After one month, 31 patients (85%) were still off antipsychotics and improved on the majority of NPI domains, with a total mean NPI score decreasing from 18 (SD 13) to 12 (SD 8, p = 0.003). In the relapse group, there was no deterioration associated with the abrupt discontinuation and subsequent resumption of therapy with a total mean NPI score decreasing from 31 (SD 12) at baseline to 27 (SD 8) at one-month follow-up (p = 0.345). CONCLUSION: Abrupt antipsychotic discontinuation appears to be feasible in older individuals with BPSD. Systematically performed discontinuation efforts in clinical practice are needed to differentiate between patients where antipsychotics have no added value and patients where the benefits outweigh the risks.

Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.

Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ɛ4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1₋42 levels, suggesting a role for the CR1 protein in Aß metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Genetic contribution of FUS to frontotemporal lobar degeneration.

BACKGROUND: Recently, the FUS gene was identified as a new causal gene for amyotrophic lateral sclerosis (ALS) in approximately 4% of patients with familial ALS. Since ALS and frontotemporal lobar degeneration (FTLD) are part of a clinical, pathologic, and genetic disease spectrum, we investigated a potential role of FUS in FTLD. METHODS: We performed mutational analysis of FUS in 122 patients with FTLD and 15 patients with FTLD-ALS, as well as in 47 patients with ALS. Mutation screening was performed by sequencing of PCR amplicons of the 15 FUS exons. RESULTS: We identified 1 patient with FTLD with a novel missense mutation, M254V, that was absent in 638 control individuals. In silico analysis predicted this amino acid substitution to be pathogenic. The patient did not have a proven family history of neurodegenerative brain disease. Further, we observed the known R521H mutation in 1 patient with ALS. No FUS mutations were detected in the patients with FTLD-ALS. While insertions/deletions of 2 glycines (G) were suggested to be pathogenic in the initial FUS reports, we observed an identical GG-deletion in 2 healthy individuals and similar G-insertions/deletions in 4 other control individuals, suggesting that G-insertions/deletions within this G-rich region may be tolerated. CONCLUSIONS: In a first analysis of FUS in patients with frontotemporal lobar degeneration (FTLD), we identified a novel FUS missense mutation, M254V, in 1 patient with pure FTLD. At this point, the biologic relevance of this mutation remains elusive. Screening of additional FTLD patient cohorts will be needed to further elucidate the contribution of FUS mutations to FTLD pathogenesis.

Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.

BACKGROUND: Families associated with missense mutations in the valosin-containing protein (VCP) present with a rare autosomal dominant multisystem disorder of frontotemporal lobar degeneration (FTLD), inclusion body myopathy (IBM), and Paget disease of bone (PDB), referred to as IBMPFD. METHODS: We used exon-based genomic DNA sequencing to test for VCP mutations in 123 unrelated Belgian patients with FTLD and their relatives, and the absence of such mutations in 157 control individuals. We analyzed haplotype sharing among mutation carriers by genotyping 8 microsatellite markers in the VCP locus. We obtained family history and clinical and pathologic data using established diagnostic instruments. RESULTS: Mutation analysis of VCP identified 2 Belgian patients with FTLD carrying the p.Arg159His mutation, which segregated in their families. In one family, patients presented with FTLD only, whereas in the other family, patients developed FTLD, PDB, or both without signs of IBM for any of the mutation carriers. We had previously identified p.Arg159His in an Austrian family with patients exhibiting both IBM and PDB. Haplotype sharing analysis indicated that the 3 p.Arg159His families are unrelated. Clinical follow-up of the Austrian family identified dementia symptoms in 1 patient. Autopsy data of 3 patients of the 2 Belgian families revealed FTLD pathology with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP-43 protein. CONCLUSIONS: In 3 unrelated families with IBMPFD segregating VCP p.Arg159His, we observed a high degree of clinical heterogeneity and variable penetrance of the 3 cardinal clinical phenotypes: inclusion body myopathy, Paget disease of bone, and frontotemporal lobar degeneration. In contrast, the neuropathologic phenotype was consistent with FTLD-TDP type 4.

Verbal cued recall as a predictor of conversion to Alzheimer's disease in Mild Cognitive Impairment.

OBJECTIVE: This study was set up to investigate whether neuropsychological tests are able to predict conversion to AD among Mild Cognitive Impairment (MCI) patients. METHODS: At baseline the cognitive part of the Cambridge Examination for Mental Disorders of the Elderly (CAMCOG), the Mini Mental Status Examination (MMSE), the Geriatric Depression Scale (GDS), a Dutch variation of Rey's Auditory Verbal Learning Test, the Memory Impairment Screen plus (MISplus) and the Visual Association Test (VAT) were administered to 40 patients diagnosed with MCI. After 18 months, MCI-patients were reassessed and a follow-up diagnosis was established. Of those who were seen for follow-up (n = 31), seven fulfilled (NINCDS-ADRDA) criteria of probable AD, while 24 did not convert. RESULTS: A binary logistic regression analysis showed that the MISplus contributed most to the prediction of conversion (OR = 0.28, 95% CI 0.099-0.790). With a cut-off of 2 out of 6, a positive predictive value of 71.5%, a negative predictive value of 91.5% and an overall diagnostic accuracy of 87.0% were achieved. CONCLUSIONS: This prospective, longitudinal study shows that a score of 0 or 1 out of 6 on the MISplus may be a good indicator of future (within 18 months) progression to AD among MCI-patients.