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1.
Acta Neuropathol ; 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31414210

RESUMO

Extracellular deposition of amyloid ß-protein (Aß) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical and clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between Aß and τ pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice overexpressing human APP with the Swedish mutation (670/671 KM → NL) (APP23), human wild-type APP (APP51/16), or a proenkephalin signal peptide linked to human Aß42 (APP48) with τ-transgenic mice overexpressing human mutant 4-repeat τ-protein with the P301S mutation (TAU58). In 6-month-old APP23xTAU58 and APP51/16xTAU58 mice, soluble Aß was associated with the aggravation of p-τ pathology propagation into the CA1/subiculum region, whereas 6-month-old TAU58 and APP48xTAU58 mice neither exhibited significant amounts of p-τ pathology in the CA1/subiculum region nor displayed significant levels of soluble Aß in the forebrain. In APP23xTAU58 and APP51/16xTAU58 mice showing an acceleration of p-τ propagation, Aß and p-τ were co-immunoprecipitated with cellular prion protein (PrPC). A similar interaction between PrPC, p-τ and Aß was observed in human AD brains. This association was particularly noticed in 60% of the symptomatic AD cases in our sample, suggesting that PrPC may play a role in the progression of AD pathology. An in vitro pull-down assay confirmed that PrPC is capable of interacting with Aß and p-τ. Using a proximity ligation assay, we could demonstrate proximity (less than ~ 30-40 nm distance) between PrPC and Aß and between PrPC and p-τ in APP23xTAU58 mouse brain as well as in human AD brain. Proximity between PrPC and p-τ was also seen in APP51/16xTAU58, APP48xTAU58, and TAU58 mice. Based on these findings, it is tempting to speculate that PrPC is a critical player in the interplay between Aß and p-τ propagation at least in a large group of AD cases. Preexisting p-τ pathology interacting with PrPC, thereby, appears to be a prerequisite for Aß to function as a p-τ pathology accelerator via PrPC.

2.
JAMA Psychiatry ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31339527

RESUMO

Importance: Impairment of methylation status (ie, methionine to homocysteine ratio) may be a modifiable risk factor for structural brain changes and incident dementia. Objective: To investigate the association of serum markers of methylation status and sulfur amino acids with risk of incident dementia, Alzheimer disease (AD), and the rate of total brain tissue volume loss during 6 years. Design, Setting, and Participants: This population-based longitudinal study was performed from March 21, 2001, to October 10, 2010, in a sample of 2570 individuals aged 60 to 102 years from the Swedish Study on Aging and Care in Kungsholmen who were dementia free at baseline and underwent comprehensive examinations and structural brain magnetic resonance imaging (MRI) on 2 to 3 occasions during 6 years. Data analysis was performed from March 1, 2018, to October 1, 2018. Main Outcomes and Measures: Incident dementia, AD, and the rate of total brain volume loss. Results: This study included 2570 individuals (mean [SD] age, 73.1 [10.4] years; 1331 [56.5%] female). The methionine to homocysteine ratio was higher in individuals who consumed vitamin supplements (median, 1.9; interquartile range [IQR], 1.5-2.6) compared with those who did not (median, 1.8; IQR, 1.3-2.3; P < .001) and increased per each quartile increase of vitamin B12 or folate. In the multiadjusted model, an elevated baseline serum total homocysteine level was associated with an increased risk of dementia and AD during 6 years: for the highest homocysteine quartile compared with the lowest, the hazard ratios (HRs) were 1.60 (95% CI, 1.01-2.55) for dementia and 2.33 (95% CI, 1.26-4.30) for AD. In contrast, elevated concentrations of methionine were associated with a decreased risk of dementia (HR, 0.54; 95% CI, 0.36-0.81) for the highest quartile compared with the lowest. Higher values of the methionine to homocysteine ratio were significantly associated with lower risk of dementia and AD: for the fourth methionine-homocysteine quartile compared with the first quartile, the HR was 0.44 (95% CI, 0.27-0.71) for incident dementia and 0.43 (95% CI, 0.23-0.80) for AD. In the multiadjusted linear mixed models, a higher methionine to homocysteine ratio was associated with a decreased rate of total brain tissue volume loss during the study period (ß [SE] per 1-SD increase, 0.038 [0.014]; P = .007). Conclusions and Relevance: The methionine to homocysteine status was associated with dementia development and structural brain changes during the 6-year study period, suggesting that a higher methionine to homocysteine ratio may be important in reducing the rate of brain atrophy and decreasing the risk of dementia in older adults.

3.
Biochem J ; 476(14): 2093-2109, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31300465

RESUMO

One hallmark of Alzheimer's disease (AD) is the presence of amyloid plaques, which mainly consist of the amyloid precursor protein (APP) cleavage product amyloid ß (Aß). For cleavage to occur, the APP must be endocytosed from the cell surface. The phosphatidylinositol binding clathrin assembly protein (PICALM) is involved in clathrin-mediated endocytosis and polymorphisms in and near the gene locus were identified as genetic risk factors for AD. PICALM overexpression enhances APP internalization and Aß production. Furthermore, PICALM shuttles into the nucleus, but its function within the nucleus is still unknown. Using co-immunoprecipitation, we demonstrated an interaction between PICALM and APP, which is abrogated by mutation of the APP NPXY-motif. Since the NPXY-motif is an internalization signal that binds to phosphotryrosine-binding domain-containing adaptor proteins (PTB-APs), we hypothesized that PTB-APs can modulate the APP-PICALM interaction. We found that interaction between PICALM and the PTB-APs (Numb, JIP1b and GULP1) enhances the APP-PICALM interaction. Fluorescence activated cell sorting analysis and internalization assays revealed differentially altered APP cell surface levels and endocytosis rates that depended upon the presence of PICALM and co-expression of distinct PTB-APs. Additionally, we were able to show an impact of PICALM nuclear shuttling upon co-expression of PTB-APs and PICALM, with the magnitude of the effect depending on which PTB-AP was co-expressed. Taken together, our results indicate a modulating effect of PTB-APs on PICALM-mediated APP endocytosis and localization.

4.
Z Gerontol Geriatr ; 52(4): 309-315, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161337

RESUMO

As a result of the aging population dementia is a growing challenge, especially in healthcare. Nevertheless, cognitive disorders are often not systematically evaluated, especially during hospital stays for other reasons; however, cognitive impairment is associated with a number of geriatric syndromes, including falls, delirium, dysphagia and lack of adherence to treatment plans. This article considers the current state of diagnosis and treatment of dementia. Non-pharmacological therapeutic approaches as well as current and future pharmacological treatment options are discussed. The drugs of choice for the symptomatic treatment of cognitive deficits in Alzheimer's disease and Parkinson-associated dementia are cholinesterase inhibitors and memantine; there is no specific pharmacological treatment for other types of dementia. Prevention and treatment of cardiovascular risk factors can potentially retard the progression of possibly all forms of dementia.

5.
Clin Biochem ; 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31129184

RESUMO

BACKGROUND: Total tau (tTau) and phosphorylated 181P tau (pTau) are supportive diagnostic cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease. Manual CSF tau assays are limited by lot-to-lot and between-laboratory variability and long incubation/turnaround times. Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF immunoassays were developed for fully automated cobas e analyzers, allowing broader access in clinical practice and trials. METHODS: Analytical performance, reproducibility, method comparisons with commercially available assays, and lot-to-lot and platform comparability (cobas e 601/411) of the Elecsys® CSF assays were assessed. Tau distributions and concentration ranges were evaluated in CSF samples from two clinical cohorts. RESULTS: Both assays showed high sensitivity (limit of quantitation [LoQ]: 63 pg/mL [tTau]; 4 pg/mL [pTau]) and linearity over the measuring range (80-1300 pg/mL; 8-120 pg/mL), which covered the entire concentration range measured in clinical samples. Lot-to-lot and platform comparability demonstrated good consistency (Pearson's r: 0.998; 1.000). Multicenter evaluation coefficients of variation (CVs): repeatability, < 1.8%; intermediate precision, < 2.8%; between-laboratory variability, < 2.7% (both assays); and total reproducibility, < 6.7% (tTau) and < 4.7% (pTau). Elecsys® CSF assays demonstrated good correlation with commercially available tau assays. CONCLUSIONS: Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF assays demonstrate good analytical performance with clinically relevant measuring ranges; data support their use in clinical trials and practice.

6.
J Am Med Dir Assoc ; 20(2): 138-146, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638832

RESUMO

When treating older adults, a main factor to consider is physical frailty. Because specific assessments in clinical trials are frequently lacking, critical appraisal of treatment evidence with respect to functional status is challenging. Our aim was to identify and categorize assessments for functional status given in clinical trials in older adults to allow for a retrospective characterization and indirect comparison of treatment evidence from these cohorts. We conducted 4 separate systematic reviews of randomized and nonrandomized controlled clinical trials in older people with hypertension, diabetes, depression, and dementia. All assessments identified that reflected functional status were analyzed. Assessments were categorized across 4 different functional status levels. These levels span from functionally not impaired, slightly impaired, significantly impaired, to severely impaired/disabled. If available from the literature, cut-offs for these 4 functioning levels were extracted. If not, or if the existing cut-offs did not match the predefined functional levels, cut-off points were defined by an expert group composed of geriatricians, pharmacists, pharmacologists, neurologists, psychiatrists, and epidemiologists using a patient-centered approach. We identified 51 instruments that included measures of functional status. Although some of the assessments had clearly defined cut-offs across our predefined categories, many others did not. In most cases, no cut-offs existed for slightly impaired or severely impaired older adults. Missing cut-offs or values to adjust were determined by the expert group and are presented as described. The functional status assessments that were identified and operationalized across 4 functional levels could now be used for a retrospective characterization of functional status in randomized controlled trials and observational studies. Allocated categories only serve as approximations and should be validated head-to-head in future studies. Moreover, as general standard, upcoming studies involving older adults should include and explicitly report functional impairment as a baseline characteristic of all participants enrolled.

7.
Trials ; 20(1): 71, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30665435

RESUMO

BACKGROUND: Postoperative delirium is a common disorder in older adults that is associated with higher morbidity and mortality, prolonged cognitive impairment, development of dementia, higher institutionalization rates, and rising healthcare costs. The probability of delirium after surgery increases with patients' age, with pre-existing cognitive impairment, and with comorbidities, and its diagnosis and treatment is dependent on the knowledge of diagnostic criteria, risk factors, and treatment options of the medical staff. In this study, we will investigate whether a cross-sectoral and multimodal intervention for preventing delirium can reduce the prevalence of delirium and postoperative cognitive decline (POCD) in patients older than 70 years undergoing elective surgery. Additionally, we will analyze whether the intervention is cost-effective. METHODS: The study will be conducted at five medical centers (with two or three surgical departments each) in the southwest of Germany. The study employs a stepped-wedge design with cluster randomization of the medical centers. Measurements are performed at six consecutive points: preadmission, preoperative, and postoperative with daily delirium screening up to day 7 and POCD evaluations at 2, 6, and 12 months after surgery. Recruitment goals are to enroll 1500 patients older than 70 years undergoing elective operative procedures (cardiac, thoracic, vascular, proximal big joints and spine, genitourinary, gastrointestinal, and general elective surgery procedures). DISCUSSION: Results of the trial should form the basis of future standards for preventing delirium and POCD in surgical wards. Key aims are the improvement of patient safety and quality of life, as well as the reduction of the long-term risk of conversion to dementia. Furthermore, from an economic perspective, we expect benefits and decreased costs for hospitals, patients, and healthcare insurances. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00013311 . Registered on 10 November 2017.


Assuntos
Disfunção Cognitiva/prevenção & controle , Delírio/prevenção & controle , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Segurança do Paciente , Complicações Pós-Operatórias/prevenção & controle , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Análise Custo-Benefício , Estudos Transversais , Interpretação Estatística de Dados , Humanos , Avaliação de Resultados (Cuidados de Saúde) , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamanho da Amostra
8.
J Alzheimers Dis ; 67(2): 481-488, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30594925

RESUMO

Reliable blood biomarkers for Alzheimer's disease (AD) are missing. We measured astroglial GFAP in patients with AD (n = 28), frontotemporal dementia (bvFTD, n = 35), Parkinson's disease (n = 11), Lewy body dementias (n = 19), and controls (n = 34). Serum GFAP was increased in AD (p < 0.001) and DLB/PDD (p < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r= -0.42, p < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be the first blood biomarker in the differential diagnosis of AD and bvFTD.

9.
Am J Med ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30502316

RESUMO

OBJECTIVE: To examine the association of serum glucose, insulin, and insulin resistance with cognitive functioning seven years later in a longitudinal population-based study of Finnish older adults. METHODS: Serum glucose and insulin were measured at baseline in 269 dementia-free individuals aged 65-79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. Insulin resistance was estimated with the homeostasis model assessment (HOMA). Participants were re-examined seven years later, and global cognition, episodic memory, executive functioning, verbal expression, and psychomotor speed were assessed both at baseline and at follow-up. Multiple linear regression was used to investigate the associations with cognitive performance at follow-up, after adjusting for several potential confounders, including common vascular risk factors. RESULTS: In the multivariable-adjusted linear regression models, no associations of insulin resistance with cognitive functioning were observed. After excluding 19 incident dementia cases, higher baseline HOMA values were related to worse performance in global cognition (ß (standard error (SE)): -0.050 (0.02); P = 0.043) and psychomotor speed (ß (SE): -0.064 (0.03); P = 0.043) seven years later. Raised serum insulin levels were associated with lower scores on global cognition (ß (SE): -0.054 (0.03); P = 0.045) and tended to relate to poorer performance in psychomotor speed (ß (SE): -0.061 (0.03); P = 0.070). CONCLUSIONS: Serum insulin and insulin resistance may be independent predictors of cognitive performance seven years later in elderly individuals without dementia. Randomized controlled trials are needed to determine this issue.

10.
Front Aging Neurosci ; 10: 299, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30327598

RESUMO

Prevention of neurocognitive disorders is currently one of the greatest unmet medical challenges. The cognitive effects of solving jigsaw puzzles (JPs) have not been studied so far, despite its frequent use as a leisure activity in all age cohorts worldwide. This study aimed at closing this gap between a lack of science and a frequent real-world use by investigating the cognitive abilities recruited by JP as well as the cognitive benefits of lifetime and 30-day JP experience. A total of 100 cognitively healthy adults (≥50 years of age) were randomized to either a 30-day home-based JP intervention (≥1 h/day) plus four sessions of cognitive health counseling (JP group) or four sessions of cognitive health counseling only (counseling group). We measured global visuospatial cognition by averaging the scores of eight z-standardized visuospatial cognitive abilities (perception, constructional praxis, mental rotation, speed, flexibility, working memory, reasoning, and episodic memory). JP skill was assessed with an untrained 40 piece JP and lifetime JP experience with retrospective self-report. JP skill was associated with all assessed cognitive abilities (rs ≥ 0.45, ps < 0.001), and global visuospatial cognition (r = 0.80 [95% CI: 0.72-0.86], p < 0.001). Lifetime JP experience was associated with global visuospatial cognition, even after accounting for other risk and protective factors (ß = 0.34 [95% CI: 0.18-0.50], p < 0.001). The JP group connected on average 3589 pieces in 49 h. Compared to the counseling group, they improved in JP skill (Cohen's d = 0.38 [95% CI: 0.21-0.54], p < 0.001), but not in global visuospatial cognition (Cohen's d = -0.08, [CI: -0.27 to 0.10], p = 0.39). The amount of jigsaw puzzling was related to changes in global visuospatial cognition within the JP group, only after accounting for baseline performance (ß = 0.33 [95% CI: 0.02-0.63], p = 0.03). In sum, our results indicate that jigsaw puzzling strongly engages multiple cognitive abilities and long-term, but not short-term JP experiences could relevantly benefit cognition. Trial Registration: ClinicalTrials.gov Identifier: NCT02667314.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30309882

RESUMO

OBJECTIVE: To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS). METHODS: This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology. RESULTS: Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time. CONCLUSIONS: Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.

12.
Neurology ; 91(15): e1390-e1401, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30209235

RESUMO

OBJECTIVE: To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). METHODS: Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. RESULTS: At baseline, serum NfL level correlated with CSF NfL (bvFTD r = 0.706, p < 0.0001; AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD (p <0 0.0001 vs Con and MCI, p = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006; [follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 0.0001; 95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] r = 0.6624, p < 0.0001; [follow-up] r = 0.5659, p = 0.0003) but not with regional brain volumes. CONCLUSIONS: As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.

13.
Cytometry A ; 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30211978

RESUMO

More than 60 years ago, the idea was introduced that NADH autofluorescence could be used as a marker of cellular redox state and indirectly also of cellular energy metabolism. Fluorescence lifetime imaging microscopy of NADH autofluorescence offers a marker-free readout of the mitochondrial function of cells in their natural microenvironment and allows different pools of NADH to be distinguished within a cell. Despite its many advantages in terms of spatial resolution and in vivo applicability, this technique still requires improvement in order to be fully useful in bioenergetics research. In the present review, we give a summary of technical and biological challenges that have so far limited the spread of this powerful technology. To help overcome these challenges, we provide a comprehensible overview of biological applications of NADH imaging, along with a detailed summary of valid imaging approaches that may be used to tackle many biological questions. This review is meant to provide all scientists interested in bioenergetics with support on how to embed successfully NADH imaging in their research.

14.
Ann Clin Transl Neurol ; 5(7): 815-831, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30009199

RESUMO

Objective: Amyloid ß (Aß) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post-translationally modified Aß in plaques characterizes distinct biochemical stages of Aß maturation. However, the molecular composition of vascular Aß deposits in CAA and its relation to plaques remain enigmatic. Methods: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Aß in the medial temporal and occipital lobe of 24 controls, 27 pathologically-defined preclinical AD, and 20 symptomatic AD cases. Results: Sequential deposition of Aß in CAA resembled Aß maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of Aß in the absence of pyroglutaminated AßN3pE and phosphorylated AßpS8. B-CAA stage 2 showed additional AßN3pE and B-CAA stage 3 additional AßpS8. Based on the Aß maturation staging in CAA and plaques, three case groups for Aß pathology could be distinguished: group 1 with advanced Aß maturation in CAA; group 2 with equal Aß maturation in CAA and plaques; group 3 with advanced Aß maturation in plaques. All symptomatic AD cases presented with end-stage plaque maturation, whereas CAA could exhibit immature Aß deposits. Notably, Aß pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia. Interpretation: Balance of Aß maturation in CAA and plaques defines distinct pathological subgroups of ß-amyloidosis. The association of CAA-related Aß maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Aß pathology subgroups, and the subgroup-related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.

15.
Sci Rep ; 8(1): 9419, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925891

RESUMO

Major Depressive Disorder (MDD) has been associated with telomere dysfunction and alterations in mitochondrial activity, which seem to be co-regulated in human cells. To investigate this co-regulation in MDD, we assessed telomere length (TL) in peripheral blood mononuclear cells (PBMC) and selected immune cell subsets by quantitative fluorescence in situ hybridization and mitochondrial respiratory activity in PBMC by high-resolution respirometry in a study cohort of 18 MDD patients and 21 non-depressed controls. We provide initial evidence for a differential vulnerability to telomere attrition in selected adaptive immune cell populations. Here we found the highest difference in TL between depressed and control subjects for memory cytotoxic T cells. Depression was associated with reduced mitochondrial activity (mitochondrial bioenergetics), but increased mitochondrial density (mitochondrial biogenesis) in PBMC. Exploratory post-hoc analyses indicated that the changes in TL and immune cell bioenergetics were most pronounced in MDD patients who reported experiences of childhood sexual abuse. Among MDD patients, PBMC TL was as a trend positively associated with mitochondrial density and negatively associated with mitochondrial leak respiration, but not with mitochondrial activity related to biological energy production. These initial findings support the hypothesis of a co-regulation between telomeres and mitochondrial biogenesis but not mitochondrial bioenergetics among MDD patients.

17.
Acta Neuropathol ; 135(5): 681-694, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29574591

RESUMO

Cerebral amyloid angiopathy (CAA) is caused by the deposition of the amyloid ß-protein (Aß) in the wall of cerebral and leptomeningeal blood vessels and is related to Alzheimer's disease (AD). Capillary Aß deposition is observed in a subset of CAA cases and represents a distinct type of CAA named capillary CAA or CAA type 1. This type of CAA is strongly associated with the presence of the apolipoprotein E ε4 allele. CAA type 1-associated AD cases often exhibit a more severe Aß plaque pathology but less widespread neurofibrillary tangle (NFT) pathology. The objective of this study was to analyze whether capillary CAA and its effects on cerebral blood flow have an impact on dementia. To address this objective, we performed neuropathological evaluation of 284 autopsy cases of demented and non-demented individuals. We assessed the presence of CAA and its subtypes as well as for that of hemorrhages and infarcts. Capillary CAA and CAA severity were associated with allocortical microinfarcts, comprising the CA1 region of the hippocampus. Allocortical microinfarcts, capillary CAA and CAA severity were, thereby, associated with cognitive decline. In conclusion, allocortical microinfarcts, CAA severity, and the capillary type of CAA were associated with one another and with the development of cognitive decline. Thus, AD cases with CAA type 1 (capillary CAA) appear to develop dementia symptoms not only due to AD-related Aß plaque and NFT pathology but also due to hippocampal microinfarcts that are associated with CAA type 1 and CAA severity, and that damage a brain region important for memory function.

18.
Exp Neurol ; 304: 1-13, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29466703

RESUMO

One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid ß (Aß). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aß production and soluble APPß (sAPPß) levels. Aß is known to impair synaptic function; however, much less is known about the physiological functions of sAPPß. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPß exist. The intracellular pathways of sAPPß are largely unknown. Since sAPPß is generated alongside Aß by ß-secretase (BACE1) cleavage, we tested the hypothesis that sAPPß effects differ from sAPPα effects as a neurotrophic factor. We therefore performed a head-to-head comparison of both mammalian recombinant peptides in developing primary hippocampal neurons (PHN). We found that sAPPα significantly increases axon length (p = 0.0002) and that both sAPPα and sAPPß increase neurite number (p < 0.0001) of PHN at 7 days in culture (DIV7) but not at DIV4. Moreover, both sAPPα- and sAPPß-treated neurons showed a higher neuritic complexity in Sholl analysis. The number of glutamatergic synapses (p < 0.0001), as well as layer thickness of postsynaptic densities (PSDs), were significantly increased, and GABAergic synapses decreased upon sAPP overexpression in PHN. Furthermore, we showed that sAPPα enhances ERK and CREB1 phosphorylation upon glutamate stimulation at DIV7, but not DIV4 or DIV14. These neurotrophic effects are further associated with increased glutamate sensitivity and CREB1-signaling. Finally, we found that sAPPα levels are significantly reduced in brain homogenates of AD patients compared to control subjects. Taken together, our data indicate critical stage-dependent roles of sAPPs in the developing glutamatergic system in vitro, which might help to understand deleterious consequences of altered APP shedding in AD patients, beyond Aß pathophysiology.

19.
Front Aging Neurosci ; 10: 5, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29456500

RESUMO

The auditory mismatch negativity (MMN) is an event-related potential (ERP) peaking about 100-250 ms after the onset of a deviant tone in a sequence of identical (standard) tones. Depending on the interstimulus interval (ISI) between standard and deviant tones, the MMN is suitable to investigate the pre-attentive auditory discrimination ability (short ISIs, ≤ 2 s) as well as the pre-attentive auditory memory trace (long ISIs, >2 s). However, current results regarding the MMN as an index for mild cognitive impairment (MCI) and dementia are mixed, especially after short ISIs: while the majority of studies report positive associations between the MMN and cognition, others fail to find such relationships. To elucidate these so far inconsistent results, we investigated the validity of the MMN as an index for cognitive impairment exploring the associations between different MMN indices and cognitive performance, more specifically with episodic memory performance which is among the most affected cognitive domains in the course of Alzheimer's dementia (AD), at baseline and at a 5-year-follow-up. We assessed the amplitude of the MMN for short ISI (stimulus onset asynchrony, SOA = 0.05 s) and for long ISI (3 s) in a neuropsychologically well-characterized cohort of older adults at risk of dementia (subjective memory impairment, amnestic and non-amnestic MCI; n = 57). Furthermore, we created a novel difference score (ΔMMN), defined as the difference between MMNs to short and to long ISI, as a measure to assess the decay of the auditory memory trace, higher values indicating less decay. ΔMMN and MMN amplitude after long ISI, but not the MMN amplitude after short ISI, was associated with episodic memory at baseline (ß = 0.38, p = 0.003; ß = -0.27, p = 0.047, respectively). ΔMMN, but not the MMN for long ISIs, was positively associated with episodic memory performance at the 5-year-follow-up (ß = 0.57, p = 0.013). The results suggest that the MMN after long ISI might be suitable as an indicator for the decline in episodic memory and indicate ΔMMN as a potential biomarker for memory impairment in older adults at risk of dementia.

20.
J Neurol Neurosurg Psychiatry ; 89(3): 239-247, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29142138

RESUMO

OBJECTIVES: Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1). METHODS: Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression. RESULTS: In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68). CONCLUSIONS: CHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.

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