Regression-based cognitive change norms applied in biochemically defined predementia Alzheimer's disease.

OBJECTIVE: We aim to develop 2-year cognitive change norms for adults ages 41-84 for six cognitive tests, and to evaluate these norms in groups with AD biomarkers. BACKGROUND: Practice effects are common in repeated neuropsychological testing. Not accounting for practice effects may obscure cognitive decline in early Alzheimer's disease (AD). METHOD: We developed standardized regression-based change norms from normative samples consisting of healthy controls from the Dementia Disease Initiation study (n = 125), the Trønderbrain study (n = 57), and the Gothenburg mild cognitive impairment (MCI) study (n = 65). Norms were applied in a sample with cognitive symptoms (subjective cognitive decline or MCI) and AD cerebrospinal fluid (CSF) biomarkers (n = 246), classified according to the A/T/N system. RESULTS: The change norms adjusted for pertinent demographics and practice effects. The group with cognitive complaints displayed a trend toward cognitive decline compared to the normative group, with the A +T/N + subgroup showing the most marked decline. This was observed in tests of episodic memory and cognitive flexibility/divided attention. CONCLUSIONS: We present 2-year cognitive change norms for adults between 41 and 84 years, adjusted for practice and demographics. A web-based change norm calculator is provided. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer's disease: protocol for the ExPlas study.

INTRODUCTION: Given that exercise training reduces the risk of developing Alzheimer's disease (AD), induces changes in the blood composition and has widespread systemic benefits, it is reasonable to hypothesise that exercised plasma (ExPlas) may have rejuvenative properties. The main objective is to test safety and tolerability of transfusing ExPlas from young, healthy, fit adults to patients with mild cognitive impairment (MCI) or early AD. The study is a pilot for a future efficacy study. The key secondary objectives are examining the effect of plasma transfusions on cognitive function, fitness level, vascular risk profile, assessment of cerebral blood flow and hippocampal volume, quality of life, functional connectivity assessed by resting state functional MRI and biomarkers in blood and cerebrospinal fluid. METHODS AND ANALYSIS: ExPlas is a double-blinded, randomised controlled clinical single-centre trial. Patients up to 75 years of age with diagnosis early symptomatic phase AD will be recruited from two Norwegian hospitals. ExPlas is plasma drawn by plasmapheresis once a month for 4 months, from a total of 30 fit male donors (aged 18-40, BMI≤27 kg/m2 and maximal oxygen uptake>55 mL/kg/min). All units will be virus inactivated by the Intercept method in accordance with procedures at St. Olavs University Hospital. Comparison with isotonic saline allows differentiation from a non-blood product. The main study consists of 6 rounds of examinations in addition to 12 plasma transfusions divided over three 4-week periods during study year-1. It is also planned to conduct follow-up examinations 2 and 5 years after baseline ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants and participation is voluntary. All participants have a next of kin who will follow them throughout the study to represent the patient's interest. The study is approved by the Regional Committee for Medical and Health Research Ethics (REK 2018/702) and the Norwegian Medicines Agency (EudraCT No. 2018-000148-24). The study will be published in an open access journal and results will be presented at numerous national and international meetings as well as on social media platforms. TRIAL REGISTRATION NUMBER: EudraCT No. 2018-000148-24. CLINICALTRIALS: gov, NCT05068830.

Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden.

Importance: Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. Objectives: To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden. Design, Setting, and Participants: This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-ß 42 (Aß42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. Main Outcomes and Measures: Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. Results: A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; ß = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; ß = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aß42 burden (ß = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: ß = -0.884; 95% CI, 0.223 to -0.395; P < .001; CSF phosphorylated tau levels: ß = -0.672; 95% CI, -1.022 to -0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). Conclusions and Relevance: The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.

Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE ε4-carriers is well-established, the protein levels have received limited attention. METHODS: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 39), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 30), patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and α-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6. RESULTS: Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE Îµ2/ε3 versus APOE Îµ4/ε4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-ß (Aß42) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF Aß42, lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF α-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed. CONCLUSIONS: Our results demonstrate important associations between low plasma apoE levels, Aß pathology, and progression from aMCI to a clinical ADD diagnosis.

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.

Can exercise training teach us how to treat Alzheimer's disease?

Alzheimer's disease (AD) is the most common cause of dementia and there is currently no cure. Novel approaches to treat AD and curb the rapidly increasing worldwide prevalence and costs of dementia are needed. Physical inactivity is a significant modifiable risk factor for AD, estimated to contribute to 12.7% of AD cases worldwide. Exercise interventions in humans and animals have shown beneficial effects of exercise on brain plasticity and cognitive functions. In animal studies, exercise also improved AD pathology. The mechanisms underlying these effects of exercise seem to be associated mainly with exercise performance or cardiorespiratory fitness. In addition, exercise-induced molecules of peripheral origin seem to play an important role. Since exercise affects the whole body, there likely is no single therapeutic target that could mimic all the benefits of exercise. However, systemic strategies may be a viable means to convey broad therapeutic effects in AD patients. Here, we review the potential of physical activity and exercise training in AD prevention and treatment, shining light on recently discovered underlying mechanisms and concluding with a view on future development of exercise-free treatment strategies for AD.

CSF neurofilament light may predict progression from amnestic mild cognitive impairment to Alzheimer's disease dementia.

Neurofilament light (NfL) is a promising biomarker of neurodegeneration in Alzheimer's disease (AD). In this study, cerebrospinal fluid (CSF) NfL was measured in a 24-month longitudinal cohort consisting of control (n = 52), amnestic mild cognitive impairment (aMCI) (n = 55), and probable AD dementia (n = 28) individuals. The cohort was reevaluated after 6-10 years. Baseline CSF NfL was significantly elevated in aMCI and probable AD dementia groups compared to controls (p < 0.0001). CSF NfL was significantly lower in stable aMCI patients compared to aMCI patients who converted to probable AD dementia within the 24-month period (p = 0.004). Substituting T-tau for NfL in the core AD biomarkers model (Aß42/P-tau/T-tau) did not improve ability to separate control and AD, or stable and converter aMCI patients. Our results support that elevated CSF NfL could predict progression in aMCI patients, but its utility cannot improve the core AD biomarkers.

Time to Diagnosis in Young Onset Alzheimer's Disease: A Population-Based Study from Central Norway.

BACKGROUND: Young onset dementia is associated with a longer time to diagnosis compared to late onset dementia. Earlier publications have indicated that atypical presentation is a key contributing factor to the diagnostic delay. Our hypothesis was that even the most common presentation of Alzheimer's disease is associated with a substantial diagnostic delay in patients < 65 years. OBJECTIVE: To determine the time to diagnosis, and time lags in the diagnostic pathway in typical young onset Alzheimer's disease in central Norway. METHODS: The main sources of patients were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav's Hospital), and Department of Psychiatry, Levanger Hospital. Other sources included key persons in the communities, collaborating hospital departments examining patients with suspected cognitive impairment, and review of hospital records of all three hospitals in the area. Information on the time lags, and the clinical assessment, including the use of biomarkers, was collected from hospital notes. Caregivers were interviewed by telephone. RESULTS: Time from first symptom to diagnosis in typical young onset Alzheimer's disease was 5.5 years (n = 223, SD 2.8). Time from onset to contact with healthcare services (usually a general practitioner) was 3.4 years (SD 2.3). Time from contact with healthcare services to the first visit at a hospital was 10.3 months (SD 15.5). Time from first visit at a hospital to diagnosis was 14.8 months (SD 22.6). The analysis of cerebrospinal fluid core biomarkers was performed after 8.3 months (SD 20.9). CONCLUSION: Typical Alzheimer's disease is associated with a substantial diagnostic delay in younger patients. Raising public awareness, and education of healthcare professionals on the aspects of young onset Alzheimer's disease is warranted. CSF core biomarkers should be performed earlier in the hospital evaluation process.

Demographically adjusted trail making test norms in a Scandinavian sample from 41 to 84 years.

OBJECTIVE: The trail making test (TMT) is one of the most widely used neuropsychological tests. TMT-A provides measures of visual scanning/visuomotor speed and TMT-B involves additional demands on executive functions. Derived scores TMT B-A and TMT B/A enhance measures of executive functioning. However, simple B-A subtraction may lead to false estimates of executive dysfunction in clinical samples. Norms for TMT have been published in several countries but are currently lacking for Scandinavia. METHODS: A total of 292 healthy controls between age 41 and 84 years were included from the Norwegian "Dementia Disease Initiation" (DDI) study (n = 170) and the Gothenburg Mild Cognitive Impairment (MCI) study (n = 122). We used a regression-based procedure to develop demographically adjusted norms for basic (TMT-A and TMT-B) and derived measures (TMT B-A and B/A). We also propose a regression-based alternative to the TMT B-A measure named "TMT-ß". The proposed norms were compared to norms from Heaton et al. and Tombaugh. RESULTS: Due to differences in the estimated normative effects of demographics on performance, the proposed norms for TMT were better suited in the Scandinavian sample compared with published non-Scandinavian norms. The proposed TMT-ß measure was highly correlated to TMT B-A (r = 0.969, p < 0.001). CONCLUSION: We here propose demographically adjusted norms for the TMT for ages 41 through 84 years based on a Scandinavian sample. We also present the regression-based derived measure TMT-ß which may resolve issues with the conventional TMT B-A measure.

Factors influencing employment after minor stroke and NSTEMI.

AIM: To study the effect of cognitive function, fatigue and emotional symptoms on employment after a minor ischemic stroke compared to non-ST-elevation myocardial infarction (NSTEMI). MATERIAL AND METHODS: We included 217 patients with minor ischemic stroke and 133 NSTEMI patients employed at baseline aged 18-70 years. Minor stroke was defined as modified Rankin scale (mRS) 0-2 at day seven or at discharge if before. Included NSTEMI patients had the same functional mRS. We applied a selection of cognitive tests and the patients completed questionnaires measuring symptoms of anxiety, depression and fatigue at follow up. Stroke patients were tested at three and 12 months and NSTEMI at 12 months. RESULTS: The patients still employed at 12 monthswere significantly younger than the unemployed patients and the NSTEMI patients employed were significantly older than the stroke patients (59 vs 55 years, p < .001). In total, 82 % of stroke patients and 90 % of the NSTEMI patients employed at baseline were still employed at 12 months (p = 06). Stroke patients at work after 12 months had higher education than unemployed patients. There were no difference between employed and unemployed patients in risk factors or location of cerebral ischemic lesions. Cognitive function did not change significantly in the stroke patients from three to 12 months. For stroke patients, we found a significant association between HADS-depression and unemployment at 12 months (p = 04), although this association was not present at three months. Lower age and higher educational level were associated with employment at 12 months for all patients. DISCUSSION AND CONCLUSION: Age and education are the main factors influencing the ability to stay in work after a minor stroke. Employed stroke patients were younger than the NSTEMI patients, but there was no difference in the frequencies in remaining employed. The employment rate at 12 months was high despite the relatively high prevalence of cognitive impairment in both groups.

Cerebrospinal fluid neuronal pentraxin receptor as a biomarker of long-term progression of Alzheimer's disease: a 24-month follow-up study.

Lower cerebrospinal fluid (CSF) levels of neuronal pentraxin receptor (NPTXR) are associated with Alzheimer's disease (AD), but few studies show longitudinal changes in CSF NPTXR. In the present study, CSF NPTXR was measured at 0, 12, and 24 months using an enzyme-linked immunosorbent assay. The study groups included 28 patients with mild cognitive impairment (MCI) (MCI-MCI), 27 MCI patients who progressed to AD (MCI-AD) during the study, and 28 AD patients (AD-AD). Baseline levels were assessed for 46 control individuals. AD patients had lower baseline CSF NPTXR than controls (p = 0.023). Linear mixed models estimated a 6.7% annualized decrease in CSF NPTXR in the AD-AD group, significantly different from MCI-MCI (p = 0.03) and MCI-AD groups (p = 0.048). CSF NPTXR did not correlate with CSF Aß42 and weakly correlated with CSF Aß40, T-tau, P-tau (all R2 < 0.22, p < 0.06). These trends suggest CSF NPTXR may be a candidate biomarker of AD progression but not sufficiently sensitive to resolve when patients convert from MCI to dementia.

Incidence of Young Onset Dementia in Central Norway: A Population-Based Study.

BACKGROUND: The epidemiology of young onset dementia is little researched compared to late onset dementia. Information on incidence rates is vital for medical professionals, and for government planning purposes. OBJECTIVE: To determine the incidence of young onset dementia in a defined catchment area of central Norway. METHODS: The target area was Trøndelag county in central Norway with a total population of 449,796 inhabitants per January 1, 2016. We applied multiple case ascertainment strategies with sources from both primary and secondary healthcare facilities. Included patients received a diagnosis of dementia according to DSM-IV in the ages 30 to 64 years during the years 2015-2017. Subtypes of dementia were diagnosed according to standardized criteria. Incidence rates for dementia and Alzheimer's disease with dementia were calculated according to age and sex. RESULTS: A total of 89 incident cases were included. Incidence rates for dementia were 14.8 and 25.0 per 100,000 person-years for the age range 30-64 and 45-64, respectively. Corresponding incidence rates for Alzheimer's disease were 6.7 and 11.8. Alzheimer's disease represented half of all dementias. A majority of patients above the age of 50 had neurodegenerative disease, whereas non-degenerative disorders were more prevalent in younger patients. CONCLUSION: Young onset dementia is a significant contributor to the overall occurrence of dementia in central Norway, and Alzheimer's disease is by far the most common diagnosis.

The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up.

BACKGROUND: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts. OBJECTIVE: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion. METHODS: Patients (n = 102) clinically diagnosed as Alzheimer's disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (Aß42, phosphorylated tau, and total tau) were applied to the A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard. RESULTS: A + T + N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T + N+), and those with triple negative status. A-T-N- individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery. CONCLUSION: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status.

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.

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.

Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer's Disease.

The APOEɛ4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOEɛ3 conventionally is considered as 'risk neutral' although APOEɛ3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOEɛ3 (n = 31 control subjects, and n = 14 MCI versus n = 5 AD patients) or APOEɛ4 genotype (n = 1 control subject, n = 21 MCI and n = 7 AD patients). Total plasma apoE levels were lower in APOEɛ4-carriers and overall correlated significantly to CSF Aß42, p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOEɛ3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOEɛ3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOEɛ3 subjects.

The development of cognitive and emotional impairment after a minor stroke: A longitudinal study.

OBJECTIVES: To study the development of cognitive and emotional symptoms between 3 and 12 months after a minor stroke. MATERIAL AND METHODS: We included patients from stroke units at hospitals in the Central Norway Health Authority and from Haukeland University Hospital. We administered a selection of cognitive tests, and the patients completed a questionnaire 3 and 12 months post-stroke. Cognitive impairment was defined as impairment of ≥2 cognitive tests. RESULTS: A total of 324 patients completed the 3-month testing, whereas 37 patients were lost to follow-up at 12 months. The results showed significant improvement of cognitive function defined as impairment of ≥2 cognitive tests (P = .03) from months 3 to 12. However, most patients still showed cognitive impairment at 12 months with a prevalence of 35.4%. There is significant association between several of the cognitive tests and hypertension and smoking (P = .002 and .05). The prevalence of depression, but not anxiety, increased from 3 to 12 months (P = .04). The prevalence of fatigue did not change and was thus still high with 29.5% after 12 months. CONCLUSIONS: This study shows that an improvement of cognitive function still occurs between 3 and 12 months. Despite this, the prevalence of mostly minor cognitive impairment still remains high 12 months after the stroke. The increasing prevalence of depressive symptoms highlights the importance of being vigilant of depressive symptoms throughout the rehabilitation period. Furthermore, high prevalence of fatigue persisted.

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.

Cognitive and Emotional Impairment after Minor Stroke and Non-ST-Elevation Myocardial Infarction (NSTEMI): A Prevalence Study.

AIM: To study the prevalence of cognitive and emotional impairment following a minor ischemic stroke compared to an age-matched group with non-ST-elevation myocardial infarction (NSTEMI). METHODS: We included patients aged 18-70 years with a minor ischemic stroke defined as modified Rankin Scale (mRS) 0-2 at day 7 or at discharge if before and age-matched NSTEMI patients with the same functional mRS. We applied a selection of cognitive tests and the patients completed a questionnaire comprising of Hospital Anxiety and Depression scale (HADS) and Fatigue Severity Scale (FSS) at follow-up 12 months after the vascular event. Results of cognitive tests were also compared to normative data. RESULTS: 325 ischemic stroke and 144 NSTEMI patients were included. There was no significant difference in cognitive functioning between ischemic stroke and NSTEMI patients. Minor stroke patients and to a lesser extent NSTEMI patients scored worse on more complex cognitive functions including planning and implementation of activities compared to validated normative data. For the minor stroke patients the location of the ischemic lesion had no influence on the result. The prevalence of anxiety, depression, and fatigue was significantly higher in the stroke group compared to the NSTEMI group. Depression was independently associated with reduced cognitive function. DISCUSSION AND CONCLUSION: Minor ischemic stroke patients, and to lesser degree NSTEMI patients, had reduced cognitive function compared to normative data, especially executive functioning, on 12-month follow-up. The difference in cognitive function between stroke and NSTEMI patients was not significant. Depression was associated with low scores on cognitive tests highlighting the need to adequately address emotional sequelae when considering treatment options for cognitive disabilities.

The Prevalence and Subtypes of Young Onset Dementia in Central Norway: A Population-Based Study.

BACKGROUND: Young onset dementia poses several challenges for the individual, health care, and society that are not normally relevant for late onset dementia, but is little researched. OBJECTIVE: To determine the prevalence and subtypes of young onset dementia in a defined catchment area in central Norway. METHODS: The main sources of patient identification were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav's Hospital), and Department of Psychiatry, Levanger Hospital. Both departments are the main sites for referral of young onset dementia (onset before age 65 years) in the county, covering approximately 90% of the catchment area of the study. Other sources included key persons in the communities, collaborating hospital departments examining dementia, and review of hospital records of all three hospitals in the area. Included patients met the DSM-IV criteria for dementia. The prevalence of dementias was calculated by sex and age. RESULTS: All patients identified with dementia and onset before 65 years on census date were included in the study (n = 390). Patients younger than 65 on census date were included in the calculation of prevalence, giving a result of 76.3 per 100 000 persons at risk in the age category of 30-65 years, and 163.1 per 100,000 for the category 45-64 years. Etiology was heterogeneous, but the main subtype of dementia was Alzheimer's disease. CONCLUSIONS: Young onset dementia affects a significant number of people in central Norway. Prevalence figures are higher than previously reported from England and Japan, but are similar to a more recent study from Australia.