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PURPOSE: The reports regarding the status of the immune system in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have been inconclusive. We approached this question by comparing a strictly defined group of CFS/ME outpatients to healthy control individuals, and thereafter studied cytokines in subgroups with various psychiatric symptoms. MATERIALS AND METHODS: Twenty patients diagnosed with CFS/ME according to the Fukuda criteria and 20 age- and sex-matched healthy controls were enrolled in the study. Plasma was analysed by ELISA for levels of the cytokines TNF-α, IL-4, IL-6 and IL-10. Participants also answered questionnaires regarding health in general, and psychiatric symptoms in detail. RESULTS: Increased plasma levels of TNF-α in CFS/ME patients almost reached significance compared to healthy controls (p = .056). When studying the CFS/ME and control groups separately, there was a significant correlation between TNF-α and The Hospital Anxiety and Depression Scale (HADS) depressive symptoms in controls only, not in the CFS/ME group. A correlation between IL-10 and psychoticism was found in both groups, whereas the correlation for somatisation was seen only in the CFS/ME group. When looking at the total population, there was a significant correlation between TNF-α and both the HADS depressive symptoms and the SCL-90-R cluster somatisation. Also, there was a significant association between IL-10 and the SCL-90-R cluster somatisation when analyzing the cohort (patients and controls together). CONCLUSIONS: These findings indicate that immune activity in CFS/ME patients deviates from that of healthy controls, which implies potential pathogenic mechanisms and possible therapeutic approaches to CFS/ME. More comprehensive studies should be carried out on defined CFS/ME subgroups.
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Ansiedad/complicaciones , Citocinas/sangre , Depresión/complicaciones , Síndrome de Fatiga Crónica/sangre , Síndrome de Fatiga Crónica/complicaciones , Adulto , Ansiedad/sangre , Ansiedad/psicología , Estudios de Cohortes , Depresión/sangre , Depresión/psicología , Síndrome de Fatiga Crónica/psicología , Femenino , Humanos , Masculino , Salud Mental , Escalas de Valoración Psiquiátrica , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. METHODS AND RESULTS: Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. CONCLUSIONS: We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.
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Enfermedad de Alzheimer/genética , Proteína C-Reactiva/metabolismo , Dislipidemias/genética , Estudio de Asociación del Genoma Completo , Inflamación/genética , Lípidos/sangre , Herencia Multifactorial/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Biomarcadores/metabolismo , Encéfalo/metabolismo , Proteína C-Reactiva/genética , Dislipidemias/complicaciones , Femenino , Humanos , Inflamación/complicaciones , Lípidos/genética , Masculino , Enzima Bifuncional Peroxisomal/genética , Enzima Bifuncional Peroxisomal/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Sulfotransferasas/genética , Sulfotransferasas/metabolismoRESUMEN
BACKGROUND: α-Synuclein has been proposed as a potential biomarker for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). However, results from α-synuclein measurements in cerebrospinal fluid (CSF) have been inconclusive, and to our knowledge, longitudinal studies of changes prior to the AD diagnosis have not been investigated. METHODS: Levels of α-synuclein at baseline and after one and two years were measured in CSF, by enzyme-linked immunosorbent assay. Twenty-six patients with early AD (AD-AD), 48 patients with aMCI, subdivided as 23 that developed AD during follow-up (MCI-AD), and 25 that did not (MCI-MCI), and 25 healthy control individuals, were included. One-way ANOVA was applied to compare mean α-synuclein baseline values between all four study groups, and a linear mixed model was used to compare mean change over time between the three patient groups. Linear associations between α-synuclein and amyloid-ß 1-42 (Aß42), amyloid-ß 1-40 (Aß40), total tau and phosphorylated tau were also examined. RESULTS: A large variation in individual α-synuclein CSF levels was observed, particularly in the MCI-AD group. No significant differences were found in mean α-synuclein levels between all the study groups at baseline. When using a linear mixed model, no significant differences were found at follow-up for estimated mean changes between the patient groups. MCI-AD patients with short duration of symptoms prior to inclusion in the study (≤2 years) had considerably higher mean CSF α-synuclein levels compared to patients with a longer symptom duration (802.2 vs. 442.8 pg/mL, p = 0.01). No such difference was seen in the MCI-MCI or AD-AD groups. Significant linear associations (p < 0.0005) between α-synuclein and Aß40, total tau and phosphorylated tau were found. CONCLUSION: The observed difference in mean CSF α-synuclein level according to duration of symptoms in the MCI-AD group, may be an indication of changes related to disease progression. However, the lack of significant differences between groups, as well as the large individual variation in CSF levels of α-synuclein in the present study, suggest that α-synuclein is not a useful biomarker for AD.
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BACKGROUND: Results conflict concerning the relevance of APOE alleles on the development of dementia with Lewy bodies (DLB), though they are well established in connection with Alzheimer's disease (AD). The role of APOE alleles in a Norwegian cohort of patients with DLB was therefore examined compared with patients with AD and healthy control individuals. METHODS: The study included 156 patients with DLB diagnosed according to the consensus criteria guidelines, 519 patients diagnosed with AD according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ARDRA) criteria and 643 healthy elderly volunteers. Patients were recruited through hospitals, outpatient clinics, nursing homes or from local care authorities in central and south-western parts of Norway. Healthy individuals were recruited from caregivers and societies for retired people. RESULTS: Subjects carrying an APOE ε2 allele had a reduced risk for developing DLB (OR 0.4, CI 0.3 to 0.8, p=0.004), and the onset of disease was delayed by 4 years (p=0.01, Mann-Whitney U test). Conversely, the APOE ε4 allele increased the risk for development of DLB (OR 5.9, CI 2.7 to 13.0, p<0.0005 for homozygotes). Similar results were found for patients with AD regarding the effect of APOE ε2, though the protective effect appeared to be slightly less pronounced than in DLB. This study is one of the largest regarding DLB and APOE to date. CONCLUSION: The results indicate that APOE ε2, a protective factor in AD, has a clear beneficial effect on the development of DLB also.
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Apolipoproteína E2/genética , Enfermedad por Cuerpos de Lewy/genética , Edad de Inicio , Anciano , Alelos , Enfermedad de Alzheimer/genética , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Noruega/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: The objectives of this study were to explore the relationship between olfactory impairment, cognitive measures, and brain structure volumes in healthy elderly individuals, compared to patients with amnestic mild cognitive impairment (aMCI) or early Alzheimer's disease (AD). The primary aim was to elucidate possible differences in cognitive scores and brain structure volumes between aMCI/AD patients with relatively intact odor identification (OI) ability and those with reduced ability. METHODS: Twelve patients with aMCI, six with early AD, and 30 control subjects were included. OI abilities were assessed with the Brief Smell Identification Test (B-SIT) and Sniffin Sticks Identification Test (SSIT). Neuropsychological tests of executive functions and memory were performed. Brain structural volumes were obtained from T1 weighted 3D MRI at 3 Tesla. Statistical comparisons between the patients with aMCI and AD indicated no significant differences in performance on most tests. Since the groups were small and AD patients were in an early phase of disease, all patients were subsequently considered together as a single group for studying OI. Patients were subdivided into relatively intact (scores >50%) and reduced OI (≤ 50% score) on the olfactory tests. RESULTS: The aMCI/AD group with reduced OI ability, as measured by both B-SIT and SSIT, had significantly smaller hippocampal volume as compared to the patient group with OI scores > 50%. There was a significant association between OI scores and hippocampal volume in the patient (not the control) group. Similar changes with tests of executive function and memory were not found. Low OI scores on B-SIT were associated with conversion from aMCI to AD in patients. The reduced OI patient group was significantly faster on Rey complex figure copying than the fairly intact OI group. CONCLUSION: The results from this pilot study suggest that the reduction in the size of hippocampus in connection with early AD is associated more with loss of OI ability rather than loss of memory, thus demonstrating that impaired OI is an early marker of medial temporal lobe degeneration.
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Enfermedad de Alzheimer/complicaciones , Disfunción Cognitiva/complicaciones , Hipocampo/patología , Trastornos del Olfato/patología , Anciano , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos del Olfato/etiología , Proyectos PilotoRESUMEN
BACKGROUND: Multiple sclerosis (MS) is the most common demyelinating disease and characterized by immunological changes. Oligoclonal bands of IgG in CSF not seen in corresponding serum have been used for many years as part of the diagnostic criteria. However, considerably less is known about the role of IgM, despite several studies showing marked changes to IgM metabolism in MS. Bands of oligoclonal IgM (o-IgM) are more difficult to determine than oligoclonal IgG, thus limiting their study, and there is no agreement as to whether o-IgM in CSF should be part of the clinical work-up of MS. Nevertheless, there is a possibility that such bands might provide a prognostic marker if a cut-off could be established. MATERIALS AND METHODS: In this pilot study, paired samples of CSF and serum from 37 patients with relapsing-remitting MS (RRMS) and 57 controls with no subsequent signs of neurological disease were analysed for total IgM, and bands of o-IgM were visualised by isoelectric focusing and western blot. Patient records were used to compare mean changes in Expanded Disability Status Scale (EDSS) over a maximum of 17 years. RESULTS: None of the controls displayed extra o-IgM in CSF compared to corresponding serum, whereas additional o-IgM band(s) were seen in CSF in most patient samples (70%). After five years of disease, there was a significant difference in the EDSS between patients with no extra o-IgM compared to patients with at least one extra o-IgM band. This difference increased over time. If a cut-off of two or more extra bands of o-IgM in CSF was applied, this difference was not found. CONCLUSION: These exploratory data suggest that o-IgM support the prognostic potential for RRMS, and though tentative, the occurrence of any bands of o-IgM restricted to CSF seems to result in poorer prognosis. Despite the small size of the groups, the data infer that the absence of CSF-restricted o-IgM is good news for the patient. The results need to be reproduced in a more comprehensive study.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Bandas Oligoclonales , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Estudios Retrospectivos , Esclerosis Múltiple/diagnóstico , Proyectos PilotoRESUMEN
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.
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Enfermedad de Alzheimer , Anciano , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides , Apolipoproteína E4 , Estudios de Casos y Controles , Proteínas Klotho , Proteínas tau , Heterocigoto , Femenino , Adulto , Anciano de 80 o más AñosRESUMEN
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 ε2/ε3 versus APOE ε4/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.
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Enfermedad de Alzheimer , Apolipoproteínas E , Disfunción Cognitiva , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E3/líquido cefalorraquídeo , Apolipoproteína E3/genética , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteína E4/genética , Apolipoproteínas E/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Femenino , Humanos , Calicreínas , Fragmentos de Péptidos/líquido cefalorraquídeo , alfa-Sinucleína , Proteínas tau/líquido cefalorraquídeoRESUMEN
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.
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Enfermedad de Alzheimer , COVID-19 , Adulto , Humanos , Masculino , SARS-CoV-2 , Enfermedad de Alzheimer/terapia , Transfusión de Componentes Sanguíneos , Calidad de Vida , Plasma , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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 patientsâ<â65 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 (nâ=â223, 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.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Diagnóstico Tardío , Progresión de la Enfermedad , Pruebas de Estado Mental y Demencia , Vigilancia de la Población , Anciano , Enfermedad de Alzheimer/epidemiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Vigilancia de la Población/métodosRESUMEN
Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co-segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism.
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Asparagina/genética , Histidina/genética , Mutación/genética , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Anciano , Anciano de 80 o más Años , Línea Celular Transformada , Femenino , Pruebas Genéticas , Guanosina Trifosfato/metabolismo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Noruega , Enfermedad de Parkinson/diagnóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Escalas de Valoración Psiquiátrica , Tomografía Computarizada de Emisión de Fotón Único/métodos , Transfección/métodosRESUMEN
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.
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Demencia/epidemiología , Adulto , Edad de Inicio , Enfermedad de Alzheimer/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Noruega/epidemiologíaRESUMEN
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 (nâ=â102) 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: Aâ+âTâ+âN+ 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-Tâ+âN+), 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.
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Péptidos beta-Amiloides/clasificación , Enfermedades Neurodegenerativas/clasificación , Proteínas tau/clasificación , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/clasificación , Amnesia/líquido cefalorraquídeo , Amnesia/clasificación , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/clasificación , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Pronóstico , Proteínas tau/líquido cefalorraquídeoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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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 (nâ=â390). 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.
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Demencia/diagnóstico , Demencia/epidemiología , Pruebas de Estado Mental y Demencia , Vigilancia de la Población , Adulto , Edad de Inicio , Bases de Datos Factuales/tendencias , Demencia/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Vigilancia de la Población/métodos , PrevalenciaRESUMEN
The APOEÉ4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOEÉ3 conventionally is considered as 'risk neutral' although APOEÉ3-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 APOEÉ3 (nâ=â31 control subjects, and nâ=â14 MCI versus nâ=â5 AD patients) or APOEÉ4 genotype (nâ=â1 control subject, nâ=â21 MCI and nâ=â7 AD patients). Total plasma apoE levels were lower in APOEÉ4-carriers and overall correlated significantly to CSF Aß42, p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOEÉ3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOEÉ3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, pâ=â0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, pâ=â0.008). 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 APOEÉ3 subjects.
Asunto(s)
Apolipoproteína E3 , Homocisteína/sangre , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/sangre , Apolipoproteína A-II/metabolismo , Apolipoproteína E3/sangre , Apolipoproteína E3/genética , Apolipoproteína E4/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Femenino , Homocigoto , Humanos , Masculino , Estructura Cuaternaria de ProteínaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Sitios de Carácter Cuantitativo/genética , Adulto , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Riesgo , Adulto JovenRESUMEN
OBJECTIVE: Reduced habituation and increased intensity-dependence of cortical auditory-evoked potentials have been reported in migraine, but it is not known if brainstem mechanisms are chiefly or partly responsible for this hypersensitivity, if brainstem excitability or habituation changes across the migraine cycle, or how excitability relates to symptoms and serotonin metabolism. METHODS: Brainstem auditory-evoked potentials (BAEPs) to 40, 55, and 70dB binaural rarefaction clicks were recorded in four blocks of 750 stimuli in a blinded longitudinal study in 41 migraine patients. Serotonin was measured in a blood sample from the cubital vein. The test day was classified as baseline, attack, pre-attack or post-attack. RESULTS: Pre-attack BAEP changes were not found. Wave I, V and interpeak III-V latency increased after the attack. III-V latency correlated with headache history duration and usual headache attack duration. Habituation in wave IV-V dispersion to 40dB was found in controls but not in migraine (p=0.04). Serotonin correlated with BAEP amplitude in controls. Low serotonin correlated with more autonomic symptoms. BAEP intensity-dependence was normal in migraine. CONCLUSIONS: BAEP latencies, but not amplitude, increase temporarily after a migraine attack. Abnormal habituation of brainstem wave IV-V dispersion in migraine may suggest increased excitation in colliculus inferior at low sound intensities, but no relation to the migraine cycle was found for wave IV-V amplitude, dispersion or habituation. The correlation between BAEP amplitude and serotonin was deranged in migraine patients, but reappeared temporarily within 72h after an attack. SIGNIFICANCE: No evidence for pre-attack brainstem auditory sensitization was found in migraine. Intensity-dependence of AEP in migraine is probably not a passive reflection of brainstem dysfunction. BAEP changes seem to reflect a slight impact of migraine on serotonergic brainstem pathways.
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Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Habituación Psicofisiológica/fisiología , Trastornos Migrañosos/sangre , Trastornos Migrañosos/fisiopatología , Serotonina/sangre , Adulto , Electroencefalografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Estudios Longitudinales , MasculinoRESUMEN
OBJECTIVE: It has not been previously studied with a paired longitudinal design if visual excitability changes occur in the preattack period across the migraine cycle, or how excitability and habituation relate to migraine-attack severity, clinical photophobia and serotonin metabolism. METHODS: Monocular 62' check reversals were applied in 33 adult migraine patients without aura (MwoA), 8 with aura (MA) and 31 controls. VEP was recorded in four blocks of 50 stimuli. P1 (P100) and N2 (N145) latency and N1P1 and P1N2 amplitude were measured. Serotonin was measured in plasma and platelets sampled before each session. Sessions were classified as preattack, attack, postattack or interictal. RESULTS: Migraine patients had significantly higher P1N2 amplitude before the attack compared to a paired interictal recording (n=13, p=0.03), but habituation difference was not found. MA patients had significantly higher P1N2 and N1P1 amplitude than controls and MwoA. P1 latency correlated positively with headache history duration. During attack, a positive correlation between P1N2 amplitude habituation and serotonin emerged in MA patients. CONCLUSIONS: Increased VEP P1N2 amplitude was observed within a few days before the attack. Visual cortex excitability seems to be generally increased in MA as compared to MwoA patients and controls. SIGNIFICANCE: Increased excitability of the visual cortex seems to be detectable in the preattack state, supporting the concept of a cyclic CNS dysfunction in migraine.
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Potenciales Evocados Visuales/fisiología , Habituación Psicofisiológica/fisiología , Trastornos Migrañosos/fisiopatología , Tiempo de Reacción/fisiología , Adulto , Plaquetas/química , Plaquetas/metabolismo , Electroencefalografía , Femenino , Humanos , Estudios Longitudinales , Masculino , Trastornos Migrañosos/metabolismo , Fotofobia/etiología , Serotonina/análisisRESUMEN
BACKGROUND: The main objective of this study was to investigate the angiotensin converting enzyme (ACE) genotype as a possible risk factor for migraine (both with and without aura) compared to controls. We also wanted to examine whether a clinical response to an ACE inhibitor, lisinopril, or an angiotensin II receptor blocker, candesartan, in migraine prophylaxis was related to ACE genotype. METHODS: 347 migraine patients aged 18-68 (155 migraine without aura (MoA), 187 migraine with aura (MwA) and 5 missing aura subgroup data) and 403 healthy non-migrainous controls > 40 years of age were included in the study. A polymerase chain reaction (PCR) was performed on the genomic DNA samples to obtain the ACE insertion (I)/deletion(D) polymorphisms. RESULTS: No significant differences between migraine patients and controls were found with regard to ACE genotype and allele distributions. Furthermore, there was no significant difference between the controls and the MwA or MoA subgroups. CONCLUSION: In our sample there is no association between ACE genotype or allele frequency and migraine. In addition, ACE genotype in our experience did not predict the clinical response to lisinopril or candesartan used as migraine prophylactics.