Cohort profile: the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) - a national research and quality registry with a biomaterial collection.

PURPOSE: The Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) was established to harmonise and improve the quality of diagnostic practice across clinics assessing persons with cognitive symptoms in Norwegian specialist healthcare units and to establish a large research cohort with extensive clinical data. PARTICIPANTS: The registry recruits patients who are referred for assessment of cognitive symptoms and suspected dementia at outpatient clinics in Norwegian specialist healthcare units. In total, 18 120 patients have been included in NorCog during the period of 2009-2021. The average age at inclusion was 73.7 years. About half of the patients (46%) were diagnosed with dementia at the baseline assessment, 35% with mild cognitive impairment and 13% with no or subjective cognitive impairment; 7% received other specified diagnoses such as mood disorders. FINDINGS TO DATE: All patients have a detailed baseline characterisation involving lifestyle and demographic variables; activities of daily living; caregiver situation; medical history; medication; psychiatric, physical and neurological examinations; neurocognitive testing; blood laboratory work-up; and structural or functional brain imaging. Diagnoses are set according to standardised diagnostic criteria. The research biobank stores DNA and blood samples from 4000 patients as well as cerebrospinal fluid from 800 patients. Data from NorCog have been used in a wide range of research projects evaluating and validating dementia-related assessment tools, and identifying patient characteristics, symptoms, functioning and needs, as well as caregiver burden and requirement of available resources. FUTURE PLANS: The finish date of NorCog was originally in 2029. In 2021, the registry's legal basis was reformalised and NorCog got approval to collect and keep data for as long as is necessary to achieve the purpose of the registry. In 2022, the registry underwent major changes. Paper-based data collection was replaced with digital registration, and the number of variables collected was reduced. Future plans involve expanding the registry to include patients from primary care centres.

Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations.

BACKGROUND: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer's disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. OBJECTIVE: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. METHODS: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). RESULTS: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. CONCLUSION: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

Working Memory Training in Amnestic and Non-amnestic Patients With Mild Cognitive Impairment: Preliminary Findings From Genotype Variants on Training Effects.

Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations in APOE-epsilon (APOE-ε) and LMX1A genotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped for APOE-ε and LMX1A completed 4 weeks/20-25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups (p < 0.0001), but at 16 weeks the effects only remained in the naMCI group. Better performance was found after training for the naMCI patients with LMX1A-AA genotype and for the APOE-ε4 carriers. Only the naMCI-APOE-ε4 group showed improved Executive Function at 16 weeks. WMT improved working memory and some non-trained cognitive functions in individuals with MCI. The naMCI group had greater training gain than aMCI group, especially in those with LMX1A-AA genotype and among APOE-ε4-carriers. Further research with larger sample sizes for the subgroups and longer follow-up evaluations is warranted.

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.

Behavioural disturbances in patients with frontotemporal lobe degeneration focusing on caregiver burden at home and in nursing homes.

AIM AND OBJECTIVE: To explore the challenges faced by family caregivers of people with frontotemporal dementia and other forms of dementia affecting the frontal and temporal lobes causing behavioural disturbances through a qualitative approach with in-depth interviews. BACKGROUND: Studies of different forms of dementia involving degeneration of the frontal and temporal lobes have mainly focused on the neurophysiology and physiology of the disease and on caregivers' health. Few studies have described the challenges and burdens connected with everyday life and in relation to suitable nursing home placement that are faced by family caregivers. METHOD AND DESIGN: This study used a descriptive and explorative design. Eleven semi-structured interviews with family caregivers of patients from special units in four nursing homes were conducted in 2014. Data were analysed based on Kvale and Brinkmann's three contexts of interpretation: self-understanding, common sense and theoretical understanding. Checklist for qualitative studies: Standards for Reporting Qualitative Research (SRQR) http://www.equator-network.org/reporting-guidelines/srqr/ RESULTS: Two central themes were derived from the data: changes in behaviour and personality were perceived as incomprehensible, frightening and increasingly difficult to manage. Family caregivers experienced challenges in finding suitable care facilities when they were not able to continue providing home care. Due to behavioural disturbances and lack of relevant competencies among health personnel, family members were often moved between nursing homes. CONCLUSION: Pronounced personality and behavioural disturbances such as tactlessness and aggression in a family member with dementia are experienced by caregivers as stressful and burdensome and may lead to feelings of shame and guilt. A lack of suitable care facilities adds to the stress and difficulties of the families and entails an additional and unresolved burden. RELEVANCE TO CLINICAL PRACTICE: The study reveals a need for more knowledge among those organising health services as well as healthcare professional dealing with this patient category to ease the burden on next of kin.

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.

The effect of psychosocial support on caregivers' perceived criticism and emotional over-involvement of persons with dementia: an assessor-blinded randomized controlled trial.

BACKGROUND: Many relatives of close family members suffering from dementia have taken on the caregiver role. While intervention studies have revealed promising results on caregiver burden, distress, and depression, there is a lack of knowledge about how caregivers' perceived relationship with their ill family member influences the burden of care. This study examined whether a psychosocial intervention influenced this perceived relationship from the caregivers' perspective. We also explored whether the caregivers' perception of the care receiver's attitude and behavior changed over time, and whether caregiver stress and mood differed following the intervention. METHODS: The participating caregivers and care receivers were randomly assigned to a psychosocial intervention comprising education about dementia, counselling and group sessions, or to treatment as usual. The study investigated caregivers' experience of expressed emotion using the Felt Expressed Emotion Rating Scale (FEERS), a self-report questionnaire that captures caregivers' perception of criticism (CC) and emotional over-involvement (EOI) exhibited by the family members with dementia. RESULTS: A total of 208 dyads were enrolled in the study. There were no significant differences between the intervention and control groups in the studied variables. Caregivers' perception of CC and EOI was low but fluctuated somewhat, whereas their mood and stress level were stable during the follow-up period. CONCLUSIONS: According to the FEERS, the intervention did not influence caregivers' perception of CC and EOI, and there was no difference between the intervention and control groups regarding caregivers' perceived relationship. Despite the increased symptoms of dementia, caregivers' level of distress and mood remained stable, and they seemed to maintain a positive perception of the quality of their relationship with the care receiver. TRIAL REGISTRATION: Clinical.Trials.gov Sept. 2009, NCT01287767.

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.

Adaptive Computerized Working Memory Training in Patients With Mild Cognitive Impairment. A Randomized Double-Blind Active Controlled Trial.

OBJECTIVE: We investigated if a 5-week computerized adaptive working memory training program (Cogmed®) of 20 to 25 sessions would be effective in improving the working memory capacity and other neuropsychological functions compared to a non-adaptive working memory training program (active-controlled) in adult patients with mild cognitive impairment (MCI). METHODS: This randomized double-blinded active control trial included 68 individuals aged 43 to 88 years, 45 men and 23 women, who were diagnosed with MCI at four Memory clinics. The study sample was randomized by block randomization to either adaptive or non-adaptive computerized working memory training. All participants completed the training, and were assessed with a comprehensive neuropsychological test battery before the intervention, and at 1 and 4 months after training. RESULTS: Compared to the non-adaptive training group, the adaptive training group did not show significantly greater improvement on the main outcome of working memory performance at 1 and 4 months after training. CONCLUSION: No difference were found between the two types of training on the primary outcome of working memory, or on secondary outcomes of cognitive function domains, in this sample of MCI patients. Hence, the hypothesis that the adaptive training program would lead to greater improvements compared to the non-adaptive training program was not supported. Within group analyses was not performed due to the stringent RCT design.

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.].

Music Therapy and Physical Activity to Ease Anxiety, Restlessness, Irritability, and Aggression in Individuals With Dementia With Signs of Frontotemporal Lobe Degeneration.

The purpose of the current study was to evaluate whether a combined intervention of physical activity and music therapy could reduce anxiety, restlessness, irritability, and aggression among individuals with severe dementia. An exploratory design was used to evaluate a combined intervention of physical activity, music therapy, and daily walking. Interventions were systematically implemented for 8 weeks. Target groups were individuals with dementia with frontal lobe symptoms in institutional care. Primary outcome measure was the Brøset Violence Checklist (BVC). Four men and two women (mean age = 84.3 years) and their primary caretakers (n = 6) participated. The most prominent symptoms among participants at baseline were confusion, irritability, and verbal threats. The individual BVC total scores indicated significant improvements (p = 0.03). Implementation of individualized music therapy combined with increased physical activity for 8 weeks was a feasible intervention that reduced anxiety, restlessness, irritability, and aggression in the current study. [Journal of Psychosocial Nursing and Mental Health Services, 57(5), 29-37.].

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.

Experience of companionship among family caregivers of persons with dementia: A qualitative study.

We examined how caregivers experienced the influence of dementia on their relationships with afflicted family members. Family caregivers (n = 15; 11 women and four men; age 39-92 years) of people with dementia participated in semi-structured interviews. The data were analyzed according to Kvale and Brinkman. The analysis identified one overarching theme, experiences of companionship, and four subthemes, namely experiences of loss and loneliness; role change; communication alteration; and caring considerations and coping resources. The caregivers described their companionship with the family member, including warm feelings of reciprocity, as well as contradictory feelings, such as feelings of being burdened. They expressed a desire to continue caring for their relative and emphasized the positive aspects of their relationship. Knowledge about dementia, together with a good relationship with their ill family member, facilitated the caring role. These results highlight the importance of receiving information about dementia-related challenges and the implications of being a caregiver.

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.

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.

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.

The coping experiences of spouses of persons with dementia.

AIMS AND OBJECTIVES: To explore how spouses who are caregivers to persons with dementia experience everyday life 6-12 months after participation in the intervention condition in the Norwegian Cognitive Behavioural Therapy for Early Dementia (N-CORDIAL) study. BACKGROUND: There is no current medical curative treatment for cognitive impairment and dementia-associated conditions. These conditions will lead to an increased need for daily assistance and care, as well as greater stress for caregivers. The Norwegian CORDIAL Study is a manual-based randomised controlled trial based on the German CORDIAL study (cognitive rehabilitation and cognitive behavioural treatment for early dementia in Alzheimer's disease), consisting of cognitive rehabilitation, cognitive behavioural therapy and life review methods. DESIGN AND METHODS: A descriptive exploratory study with qualitative semi-structured in-depth interviews with six spouses of persons with dementia who had participated in the Norwegian CORDIAL study. The transcribed text was analysed by systematic text condensation. RESULT: The main theme identified, "An everyday search for meaning," referred to the stress experienced by the caregivers and their coping strategies in everyday life. CONCLUSION: The caregivers had gained increased awareness of coping strategies in everyday life 6-12 months after the intervention. Caregivers who experienced fewer neuropsychiatric symptoms in their spouses with dementia benefitted most from the intervention. RELEVANCE TO CLINICAL PRACTICE: The study is relevant to clinical practice as interventions focusing on how to improve coping strategies may reduce caregiver stress and contribute to postponement of nursing home placement.

Dignity in people with frontotemporal dementia and similar disorders - a qualitative study of the perspective of family caregivers.

BACKGROUND: Frontotemporal dementia (FTD) constitutes on average 10-15% of dementia in younger persons (≤65 years old), but can also affect older people. These patients demonstrate a decline in social conduct, and/or language aphasias, apathy, and loss of insight that is gradual and progressive. Preservation of dignity seems to be highly relevant both before and after admission to different types of institutionalized care, but the research is scant. From the perspective of close relatives, this study aims to develop knowledge related to dignified or undignified care of patients with FTD and similar conditions. METHODS: A qualitative, descriptive, and explorative design were employed to address the aims of this study. We interviewed nine relatives of people with FTD and similar conditions living in nursing homes, and two relatives of people living at home but attending day center 5 days a week. RESULTS: Relatives described the transition from being a close relative to someone who had little influence or knowledge of what constituted the care and the daily life of their loved ones. According to relatives' descriptions, patients are deprived of dignity in various ways: through limited interaction with peers and close relatives, limited confirmation of identity through staff who know them well, lack of possibilities for making autonomous decisions or entertaining meaningful roles or activities. Examples provided from the day care centres show how dignity is maintained through identity-strengthening activities conducted in different places, under various kinds of supervision and care, and together with people representing different roles and functions. CONCLUSIONS: Maintaining a link with the world outside the institution, through closer cooperation between the institution and family members, and/or by the use of day care centres, seems to facilitate prevention of many of the factors that may threaten dignified care.