Managing depressive symptoms in people with mild cognitive impairment and mild dementia with a multicomponent psychotherapy intervention: a randomized controlled trial.

OBJECTIVE: To evaluate the feasibility and effectiveness of the CORDIAL program, a psychosocial intervention consisting of cognitive behavioral therapy (CBT), cognitive rehabilitation, and reminiscence to manage depressive symptoms for people with mild cognitive impairment (MCI) or dementia. DESIGN: We conducted a randomized controlled trial, based on a two-group (intervention and control), pre-/post-intervention design. SETTING: Participants were recruited from five different old age psychiatry and memory clinics at outpatients' hospitals. PARTICIPANTS: Hundred and ninety-eight people with MCI or early-stage dementia were included. INTERVENTION: The intervention group (n = 100) received 11 individual weekly sessions of the CORDIAL program. This intervention includes elements from CBT, cognitive rehabilitation, and reminiscence therapy. The control group (n = 98) received treatment-as-usual. MEASUREMENTS: We assessed Montgomery-Åsberg Depression Rating Scale (MADRS) (main outcome), Neuropsychiatric Inventory Questionnaire, and Quality of Life in Alzheimer's disease (secondary outcomes) over the course of 4 months and at a 10-month follow-up visit. RESULTS: A linear mixed model demonstrated that the depressive symptoms assessed by MADRS were significantly more reduced in the intervention groups as compared to the control group (p < 0.001). The effect persisted for 6 months after the intervention. No significant differences between groups were found in neuropsychiatric symptoms or quality of life. CONCLUSION: Our multicomponent intervention, which comprised 11 individual sessions of CBT, cognitive rehabilitation, and reminiscence therapy, reduced depressive symptoms in people with MCI and dementia.

Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effect of Self-Efficacy on Quality of Life in People With Mild Cognitive Impairment and Mild Dementia: The Mediating Roles of Depression and Anxiety.

OBJECTIVES: To examine the mediating effects of depression and anxiety in the relationship between self-efficacy and quality of life among people with mild cognitive impairment (MCI) or mild dementia. METHOD: A total of 196 patients diagnosed with MCI or dementia due to Alzheimer disease completed structured measures of self-efficacy, quality of life, and depressive and anxiety symptoms. We examined direct and mediated effects by fitting structural equation models to data. RESULTS: Our analyses supported that the effects of self-efficacy on quality of life may be partially mediated by depression and anxiety. Both anxiety and depression had significant mediating effects, with depression showing a stronger effect. CONCLUSION: These results suggest that increased self-efficacy may have a positive effect on quality of life in people with MCI or dementia-partly by reducing depression and anxiety. These findings may have important practical implications for tailoring therapeutic interventions.

Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10-8). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10-6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

Corrigendum: Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients With Mild Cognitive Impairment.

[This corrects the article DOI: 10.3389/fnagi.2018.00384.].

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients With Mild Cognitive Impairment.

In this cross-sectional study, we sought to describe cognitive and neuroimaging profiles of Memory clinic patients with Mild Cognitive Impairment (MCI). 51 MCI patients and 51 controls, matched on age, sex, and socio-economic status (SES), were assessed with an extensive neuropsychological test battery that included a measure of intelligence (General Ability Index, "GAI," from WAIS-IV), and structural magnetic resonance imaging (MRI). MCI subtypes were determined after inclusion, and z-scores normalized to our control group were generated for each cognitive domain in each MCI participant. MR-images were scored by visual rating scales. MCI patients performed significantly worse than controls on 23 of 31 cognitive measures (Bonferroni corrected p = 0.001), and on 8 of 31 measures after covarying for intelligence (GAI). Compared to nonamnestic MCI patients, amnestic MCI patients had lower test results in 13 of 31 measures, and 5 of 31 measures after co-varying for GAI. Compared to controls, the MCI patients had greater atrophy on Schelten's Medial temporal lobe atrophy score (MTA), especially in those with amnestic MCI. The only structure-function correlation that remained significant after correction for multiple comparisons was the MTA-long delay recall domain. Intelligence operationalized as GAI appears to be an important moderator of the neuropsychological outcomes. Atrophy of the medial temporal lobe, based on MTA scores, may be a sensitive biomarker for the functional episodic memory deficits associated with MCI.

Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci.

A large fraction of genetic risk factors for Alzheimer's Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer's Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10-6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.

Expression of nucleotide excision repair in Alzheimer's disease is higher in brain tissue than in blood.

Age-related changes are increased in patients with Alzheimer's disease (AD), including oxidative stress and DNA damage. We propose that genotoxic stress and DNA repair responses influence neurodegeneration in the pathogenesis of AD. Here, we focus on nucleotide excision repair (NER). Real-time qPCR and mass spectrometry were employed to determine the expression levels of selected NER components. The mRNA levels of the genes encoding the NER proteins RAD23B, RPA1, ERCC1, PCNA and LIG3 as well as the NER-interacting base excision repair protein MPG in blood and brain tissue from four brain regions in patients with AD or mild cognitive impairment and healthy controls (HC), were assessed. NER mRNA levels were significantly higher in brain tissue than in blood. Further, LIG3 mRNA levels in the frontal cortex was higher in AD versus HC, while mRNA levels of MPG and LIG3 in entorhinal cortex and RPA1 in the cerebellum were lower in AD versus HC. In blood, RPA1 and ERCC1 mRNA levels were lower in AD patients than in HC. Alterations in gene expression of NER components between brain regions were associated with AD, connecting DNA repair to AD pathogenesis and suggesting a distinct role for NER in the brain.

Association of Butyrylcholinesterase-K Allele and Apolipoprotein E ɛ4 Allele with Cognitive Decline in Dementia with Lewy Bodies and Alzheimer's Disease.

BACKGROUND: A common polymorphism of the butyrylcholinesterase gene, the K-variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias. OBJECTIVE: To determine the association of BCHE-K and APOEɛ4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients. METHODS: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TrønderBrain, were genotyped for BCHE-K and APOEɛ4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years. RESULTS: BCHE-K frequency was lower in DLB (33.9% ; p <  0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p = 0.11). More rapid cognitive decline was associated with the APOEɛ4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE-K carriers in the presence of the APOEɛ4 allele than in the absence of these polymorphisms. CONCLUSION: BCHE-K is associated with a reduced risk for AD and DLB whereas APOEɛ4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOEɛ4 and BCHE-K alleles require prospective confirmation in well-controlled trials.

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10(-15)).

A one-year randomized controlled psychosocial intervention study among family carers of dementia patients--effects on patients and carers.

OBJECTIVE: To test the effect of a short-term psychosocial intervention programme for family carers of patients with dementia and identify characteristics of carers and patients that responded positively. METHODS: The study was a multi-centre randomized controlled trial. Carers of 180 patients suffering from dementia recruited at 7 memory clinics at geriatric or psychiatric departments participated in the study. Carers of the intervention group were educated about dementia and in 6 group meetings taught how to use structured problem-solving. The control group received treatment as usual. The effect on patients was measured with the Neuropsychiatric Inventory and on carers with the Relatives' Stress Scale (RSS). RESULTS: The intention-to-treat efficacy analysis included 171 carer/patient dyads. The intervention did not have any effect on the primary outcome variables. The burden measured by the RSS increased in both groups; however, more carers of the control group converted from a low-burden group to a medium- or high-burden group after 4.5 months. In a subgroup analysis we found a statistically significant difference in the Neuropsychiatric Inventory score in favour of the intervention group among female patients. CONCLUSION: The predominately negative result of this study emphasizes the need of individually tailored interventions for carers and the use of narrow inclusion criteria when performing group-based interventions, such as the extent of burden as well as gender and kinship.