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1.
Alzheimers Res Ther ; 13(1): 38, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557920

RESUMO

BACKGROUND: Elevated cerebrospinal fluid (CSF) concentrations of total tau (T-tau) and phosphorylated tau at Thr181 (P-tau181) protein are typical of Alzheimer's disease (AD). However, the T-tau assay measures only the mid-region of the protein, while tau in CSF is instead composed of a series of fragments. One fragment species in particular, N-224, shows increased levels in AD compared to controls. In this multicentre study, we performed a clinical validation of the N-224 assay in cohorts including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, non-AD dementias and controls. METHODS: Cohorts consisted of 30 SCD and 30 probable AD from the Amsterdam Dementia Cohort (cohort 1) and 539 controls, 195 SCD, 232 MCI, 137 AD and 253 non-AD from the Swedish BioFINDER study (cohort 2). All samples had AD core biomarkers (Aß42, T-tau, P-tau181) measurements. N-224 was measured with an in-house ultrasensitive Simoa assay. RESULTS: N-224 levels were significantly higher in AD compared to SCD (cohort 1: p = 0.003) and in AD compared to all other diagnostic groups in cohort 2 (control, SCD, MCI and non-AD, p < 0.0001). Within the non-AD group, N-224 showed significantly lower concentrations compared to AD in Parkinson's disease (PD, p < 0.0001), Parkinson's disease dementia (PDD, p = 0.004), progressive supranuclear palsy (PSP, < 0.0001), multiple system atrophy (MSA, p = 0.002) and parkinsonisms not otherwise specified (NOS, p = 0.007). In cohort 1, higher concentrations of N-224 were associated to lower Mini-Mental State Examination (MMSE) scores (R2 = 0.318, ß = 0.564, p ≤ 0.0001) and could accurately identify a pathological (< 24) MMSE score (p < 0.0001, AUC = 0.824). CONCLUSIONS: N-224 tau can distinguish AD subjects from SCD and can discriminate subgroups of non-AD dementias from AD. Therefore, N-224 may be a useful addition to the tau biomarker toolbox for the study of tau species in CSF and for better understanding disease pathogenesis.

2.
Alzheimers Res Ther ; 13(1): 35, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546722

RESUMO

BACKGROUND: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease. METHODS: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. RESULTS: Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. CONCLUSIONS: These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

3.
Ann Neurol ; 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33583080

RESUMO

OBJECTIVE: To study the genetic contribution to the start of Alzheimer's disease with amyloid and tau biomarkers in cognitively intact older identical twins. METHODS: We studied in 96 monozygotic twin-pairs relationships between Aß aggregation as measured by the ratio Aß1-42/1-40 in cerebrospinal fluid (CSF, n=126) and positron emission tomography (PET, n=194), and CSF markers for Aß production (BACE1, Aß1-40 and 1-38) and CSF tau. Associations amongst markers were tested with Generalized Estimating Equations including a random effect for twin status, adjusted for age, gender, and APOE ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. RESULTS: Twenty-seven individuals (14%) had an abnormal amyloid-PET, and 14 twin-pairs (15%) showed discordant amyloid-PET scans. Within twin-pairs, Aß production markers and total-tau (t-tau) levels strongly correlated (r range 0.73, 0.86; all p<0.0001), and Aß aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strong (r range 0.50, 0.64; all p<0.0001). Cross-twin cross-trait analysis showed that Aß1-38 in one twin correlated with Aß1-42/1-40 ratios, t-tau and p-tau levels in their co-twins (r range -0.28, 0.58; all p<.007). Within-pair differences in Aß production markers related to differences in tau levels (r range 0.49, 0.61; all p<0.0001). Twin discordance analyses suggest that Aß production and tau levels show coordinated increases in very early AD. INTERPRETATION: Our results suggest a substantial genetic/shared environmental background contributes to both Aß and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. This article is protected by copyright. All rights reserved.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33615397

RESUMO

PURPOSE: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR. METHODS: [18F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [18F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density. RESULTS: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERADSOT-based classification (i.e., any region mCERADSOT > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aß plaque was observed in all FP cases. Regional VR was also associated with regional plaque density. CONCLUSION: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.

6.
Alzheimers Res Ther ; 13(1): 14, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413634

RESUMO

BACKGROUND: We aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value. METHODS: MCI patients were selected from the Amsterdam Dementia Cohort (n = 402). Three-year progression probabilities to dementia were predicted using previously published models with and without CSF data (amyloid-beta1-42 (Abeta), phosphorylated tau (p-tau)). We incrementally augmented the proportion of patients undergoing CSF, starting with the 10% patients with prognostic probabilities based on clinical data around the median (percentile 45-55), until all patients received CSF. The optimal proportion was defined as the proportion where the stepwise algorithm showed similar prognostic discrimination (Harrell's C) and accuracy (three-year Brier scores) compared to CSF testing of all patients. We used the BioFINDER study (n = 221) for validation. RESULTS: The optimal proportion of MCI patients to receive CSF testing selected by the stepwise approach was 50%. CSF testing in only this proportion improved the performance of the model with clinical data only from Harrell's C = 0.60, Brier = 0.198 (Harrell's C = 0.61, Brier = 0.197 if the information on magnetic resonance imaging was available) to Harrell's C = 0.67 and Brier = 0.190, and performed similarly to a model in which all patients received CSF testing. Applying the stepwise approach in the BioFINDER study would again select half of the MCI patients and yielded robust results with respect to prognostic performance. INTERPRETATION: CSF biomarker testing adds prognostic value in half of the MCI patients. As such, we achieve a CSF saving recommendation while simultaneously retaining optimal prognostic accuracy.

7.
JAMA Netw Open ; 4(1): e2031654, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33449094

RESUMO

Importance: Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging. Objective: To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology. Design, Setting, and Participants: This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020. Exposures: Age, sex, APOE ε genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-ß, neurofibrillary tangles, and neuritic plaques). Main Outcomes and Measures: In annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology. Results: Of the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (ß, -0.10 SD per year; 95% CI, -0.14 to -0.05 SD; P < .001). Cognitive performance was associated with factors of physical health (eg, higher Barthel index: ß, 0.37 SD per year; 95% CI, 0.24-0.49; P < .001) and cognitive reserve (eg, higher education: ß, 0.41 SD per year; 95% CI, 0.29-0.53; P < .001), but none of these factors were associated with the rate of decline. Neuropathological reports were available for 44 participants. While centenarian brains revealed varying loads of postmortem neuropathological hallmarks of AD, this was not associated with cognitive performance or rate of decline. Conclusions and Relevance: While we observed a slight vulnerability for decline in memory function, centenarians maintained high levels of performance in all other investigated cognitive domains for up to 4 years despite the presence of risk factors of cognitive decline. These findings suggest that mechanisms of resilience may underlie the prolongation of cognitive health until exceptional ages.

8.
Mol Imaging Biol ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33443720

RESUMO

PURPOSE: The simplified reference tissue model (SRTM) is commonly applied for the quantification of brain positron emission tomography (PET) studies, particularly because it avoids arterial cannulation. SRTM requires a validated reference region which is obtained by baseline-blocking or displacement studies. Once a reference region is validated, the use should be verified for each new subject. This verification normally requires volume of distribution (VT) of a reference region. However, performing dynamic scanning and arterial sampling is not always possible, specifically in elderly subjects and in advanced disease stages. The aim of this study was to investigate the use of non-invasive standardised uptake value (SUV) approaches, in comparison to VT, as a verification of the previously validated grey matter cerebellum reference region for [18F]flortaucipir and [18F]florbetapir PET imaging in Alzheimer's disease (AD) patients and controls. PROCEDURES: Dynamic 130-min [18F]flortaucipir PET scans obtained from nineteen subjects (10 AD patients) and 90-min [18F]florbetapir dynamic scans obtained from fourteen subjects (8 AD patients) were included. Regional VT's were estimated for both tracers and were considered the standard verification of the previously validated reference region. Non-invasive SUVs corrected for body weight (SUVBW), lean body mass (SUL), and body surface area (SUVBSA) were obtained by using later time intervals of the dynamic scans. Simulations were also performed to assess the effect of flow and specific binding (BPND) on the SUVs. RESULTS: A low SUV corresponded well with a low VT for both [18F]flortaucipir and [18F]florbetapir. Simulation confirmed that SUVs were only slightly affected by flow changes and that increases in SUV were predominantly determined by the presence of specific binding. CONCLUSIONS: In situations where dynamic scanning and arterial sampling is not possible, a low SUV(80-100 min) for [18F]flortaucipir and a low SUV(50-70 min) for [18F]florbetapir may be used as indication for absence of specific binding in the grey matter cerebellum reference region.

9.
Brain Cogn ; 148: 105660, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33421942

RESUMO

Frontotemporal dementia (FTD) is a neurodegenerative disease that presents with profound changes in social cognition. Music might be a sensitive probe for social cognition abilities, but underlying neurobiological substrates are unclear. We performed a meta-analysis of voxel-based morphometry studies in FTD patients and functional MRI studies for music perception and social cognition tasks in cognitively normal controls to identify robust patterns of atrophy (FTD) or activation (music perception or social cognition). Conjunction analyses were performed to identify overlapping brain regions. In total 303 articles were included: 53 for FTD (n = 1153 patients, 42.5% female; 1337 controls, 53.8% female), 28 for music perception (n = 540, 51.8% female) and 222 for social cognition in controls (n = 5664, 50.2% female). We observed considerable overlap in atrophy patterns associated with FTD, and functional activation associated with music perception and social cognition, mostly encompassing the ventral language network. We further observed overlap across all three modalities in mesolimbic, basal forebrain and striatal regions. The results of our meta-analysis suggest that music perception and social cognition share neurobiological circuits that are affected in FTD. This supports the idea that music might be a sensitive probe for social cognition abilities with implications for diagnosis and monitoring.

10.
J Alzheimers Dis ; 79(3): 1195-1201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427744

RESUMO

BACKGROUND: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia. OBJECTIVE: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD. METHODS: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n = 284) and subsequently who had a genetic variant (n = 48) with a diagnosis of rtvFTD (n = 6) in 2 specialized memory clinics. RESULTS: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia. CONCLUSION: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD.

11.
Ann Clin Transl Neurol ; 8(2): 348-358, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421355

RESUMO

OBJECTIVE: To investigate the relationship between amyloid-ß (Aß) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition. METHODS: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aß status determined by [18 F]-flutemetamol PET (normal = Aß - vs. abnormal = Aß+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aß on cognitive decline were mediated by atrophy of specific anatomical brain areas. RESULTS: Subjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aß+. Compared to Aß-, Aß+ individuals showed steeper decline on memory (ß ± SE = -0.26 ± 0.09), and processing speed (ß ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aß+ individuals was mediated through parahippocampal atrophy. INTERPRETATION: These results show that Aß abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aß pathology.

12.
Alzheimers Res Ther ; 13(1): 2, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397464

RESUMO

BACKGROUND: As Alzheimer's disease (AD) pathology presents decades before dementia manifests, unbiased biomarker cut-points may more closely reflect presence of pathology than clinically defined cut-points. Currently, unbiased cerebrospinal fluid (CSF) tau cut-points are lacking. METHODS: We investigated CSF t-tau and p-tau cut-points across the clinical spectrum using Gaussian mixture modelling, in two independent cohorts (Amsterdam Dementia Cohort and ADNI). RESULTS: Individuals with normal cognition (NC) (total n = 1111), mild cognitive impairment (MCI) (total n = 1213) and Alzheimer's disease dementia (AD) (total n = 1524) were included. In both cohorts, four CSF t- and p-tau distributions and three corresponding cut-points were identified. Increasingly high tau subgroups were characterized by steeper MMSE decline and higher progression risk to AD (cohort/platform-dependent HR, t-tau 1.9-21.3; p-tau 2.2-9.5). LIMITATIONS: The number of subjects in some subgroups and subanalyses was small, especially in the highest tau subgroup and in tau PET analyses. CONCLUSIONS: In two independent cohorts, t-tau and p-tau levels showed four subgroups. Increasingly high tau subgroups were associated with faster clinical decline, suggesting our approach may aid in more precise prognoses.

13.
Alzheimers Res Ther ; 12(1): 169, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33357241

RESUMO

BACKGROUND: We evaluated Aß misfolding in combination with Aß42/40 ratio as a prognostic tool for future clinical progression to mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD) in individuals with subjective cognitive decline (SCD). METHODS: Baseline plasma samples (n = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 ± 9 years; 57% male, mean follow-up time 2.7 years) were analyzed using immuno-infrared-sensor technology. Within 6 years of follow-up, 22 (11%) individuals progressed to MCI or dementia due to AD. Sensor readout values > 1646 cm- 1 reflected normal Aß folding; readouts at ≤ 1646 cm- 1 reflected low and at < 1644 cm- 1 high misfolding. We used Cox proportional hazard models to quantify Aß misfolding as a prognostic biomarker for progression to MCI and dementia due to AD. The accuracy of the predicted development of MCI/AD was determined by time-dependent receiver operating characteristic (t-ROC) curve analyses that take individual follow-up and conversion times into account. Statistical models were adjusted for age, sex, and APOEε4 status. Additionally, plasma Aß42/40 data measured by SIMOA were statistically analyzed and compared. RESULTS: All 22 patients who converted to MCI or AD-dementia within 6 years exhibited Aß misfolding at baseline. Cox analyses revealed a hazard ratio (HR) of 19 (95% confidence interval [CI] 2.2-157.8) for future conversion of SCD subjects with high misfolding and of 11 (95% CI 1.0-110.1) for those with low misfolding. T-ROC curve analyses yielded an area under the curve (AUC) of 0.94 (95% CI 0.86-1.00; 6-year follow-up) for Aß misfolding in an age, sex, and APOEε4 model. A similar model with plasma Aß42/40 ratio yielded an AUC of 0.92 (95% CI, 0.82-1.00). The AUC increased to 0.99 (95% CI, 0.99-1.00) after inclusion of both Aß misfolding and the Aß42/40 ratio. CONCLUSIONS: A panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical MCI and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes. Follow-up studies and external validation in larger cohorts are in progress for further validation of our findings.

14.
Transl Psychiatry ; 10(1): 403, 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33223526

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aß) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aß42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aß38 and CSF-Aß40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aß and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

15.
J Alzheimers Dis ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33185612

RESUMO

BACKGROUND: Epidemiologic studies have provided inconclusive evidence for a protective effect of caffeine consumption on risk of dementia and cognitive decline. OBJECTIVE: To summarize literature on the association between caffeine and 1) the risk of dementia and/or cognitive decline, and 2) cognitive performance in individuals with mild cognitive impairment (MCI) or dementia, and 3) to examine the effect of study characteristics by categorizing studies based on caffeine source, quantity and other possible confounders. METHODS: We performed a systematic review of caffeine effects by assessing overall study outcomes; positive, negative or no effect. Our literature search identified 61 eligible studies performed between 1990 and 2020. RESULTS: For studies analyzing the association between caffeine and the risk of dementia and/or cognitive decline, 16/57 (28%) studies including a total of 40,707/153,070 (27%) subjects reported positive study outcomes, and 30/57 (53%) studies including 71,219/153,070 (47%) subjects showed positive results that were dependent on study characteristics. Caffeine effects were more often positive when consumed in moderate quantities (100-400 mg/d), consumed in coffee or green tea, and in women. Furthermore, four studies evaluated the relationship between caffeine consumption and cognitive function in cognitively impaired individuals and the majority (3/4 [75% ]) of studies including 272/289 subjects (94%) reported positive outcomes. CONCLUSION: This review suggests that caffeine consumption, especially moderate quantities consumed through coffee or green tea and in women, may reduce the risk of dementia and cognitive decline, and may ameliorate cognitive decline in cognitively impaired individuals.

16.
Alzheimers Res Ther ; 12(1): 148, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33189136

RESUMO

BACKGROUND: We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer's disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. METHODS: We retrospectively included 150 participants, including 29 bvAD, 28 "typical" amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. RESULTS: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85-0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD

17.
Artigo em Inglês | MEDLINE | ID: mdl-33216869

RESUMO

Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic-risk-scores (PRS) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N=343), a population-matched cohort of older-adults from five cohorts (N=2905), and summary statistics data from a GWAS on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older-adults. This PRS was also associated with longer survival in an independent sample of younger individuals, (p=0.02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human lifespan is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

18.
Front Psychiatry ; 11: 585686, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192733

RESUMO

Background: The recent COVID-19 pandemic is not only a major healthcare problem in itself, but also poses enormous social challenges. Though nursing homes increasingly receive attention, the majority of people with cognitive decline and dementia live at home. We aimed to explore the psychosocial effects of corona measures in memory clinic (pre-)dementia patients and their caregivers. Methods: Between April 28th and July 13th 2020, n = 389 patients of Alzheimer center Amsterdam [n = 121 symptomatic (age = 69 ± 6, 33%F, MMSE = 23 ± 5), n = 268 cognitively normal (age = 66 ± 8, 40% F, MMSE = 29 ± 1)] completed a survey on psychosocial effects of the corona measures. Questions related to social isolation, worries for faster cognitive decline, behavioral problems and discontinuation of care. In addition, n = 147 caregivers of symptomatic patients completed a similar survey with additional questions on caregiver burden. Results: Social isolation was experienced by n = 42 (35%) symptomatic and n = 67 (25%) cognitively normal patients and two third of patients [n = 129 (66%); n = 58 (75%) symptomatic, n = 71 (61%) cognitively normal] reported that care was discontinued. Worries for faster cognitive decline were existed in symptomatic patients [n = 44 (44%)] and caregivers [n = 73 (53%)], but were also reported by a subgroup of cognitively normal patients [n = 27 (14%)]. Both patients [n = 56 (46%) symptomatic, n = 102 (38%) cognitively normal] and caregivers [n = 72 (48%)] reported an increase in psychological symptoms. More than three quarter of caregivers [n = 111(76%)] reported an increase in patients' behavioral problems. A higher caregiver burden was experienced by n = 69 (56%) of caregivers and n = 43 (29%) of them reported that a need for more support. Discontinuation of care (OR = 3.3 [1.3-7.9]), psychological (OR = 4.0 [1.6-9.9]) and behavioral problems (OR = 3.0 [1.0-9.0]) strongly related to experiencing a higher caregiver burden. Lastly, social isolation (OR = 3.2 [1.2-8.1]) and psychological symptoms (OR = 8.1 [2.8-23.7]) were red flags for worries for faster cognitive decline. Conclusion: Not only symptomatic patients, but also cognitively normal patients express worries for faster cognitive decline and psychological symptoms. Moreover, we identified patients who are at risk of adverse outcomes of the corona measures, i.e., discontinued care, social isolation, psychological and behavioral problems. This underlines the need for health care professionals to provide ways to warrant the continuation of care and support (informal) networks surrounding patients and caregivers to mitigate the higher risk of negative psychosocial effects.

19.
medRxiv ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33173883

RESUMO

Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.

20.
J Am Med Dir Assoc ; 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33239240

RESUMO

OBJECTIVE: In cognitively normal adults, nutritional parameters are related to cognitive decline and incidence of dementia. Studies on the role of nutrition in predementia stages subjective cognitive decline and mild cognitive impairment, and mild stages of Alzheimer's disease (AD) dementia in a clinical setting are lacking. In the absence of a curative treatment, this evidence is important for targeting nutritional factors to potentially prevent or delay further cognitive decline. Our aim is to investigate associations of nutritional parameters with clinical progression in patients ranging from those who are cognitively normal to those who have AD dementia. DESIGN: Longitudinal. SETTING AND PARTICIPANTS: Memory clinic, 551 patients (219 with subjective cognitive decline, 135 with mild cognitive impairment, and 197 with AD dementia), mean age 64 ± 8 years. MEASUREMENTS: We assessed body mass index, fat-free mass, Mini-Nutritional Assessment, and dietary intake with the Dutch Healthy Diet food frequency questionnaire and the 238-item healthy life in an urban setting (HELIUS) food frequency questionnaire at baseline. Cox proportional hazard models were used to evaluate associations of nutritional parameters with clinical progression. Additional analyses were restricted to patients who were amyloid positive. RESULTS: We observed clinical progression in 170 patients (31%) over 2.2 ± 0.9 years. Poorer Mini-Nutritional Assessment score [hazard ratio (95% confidence interval) 1.39 (1.18-1.64)], lower body mass index [1.15 (0.96-1.38)], lower fat-free mass [1.40 (0.93-2.10)], and a less healthy dietary pattern [1.22 (1.01-1.48)] were associated with a higher risk of clinical progression. Similar effect sizes were found in patients who were amyloid positive. CONCLUSIONS AND IMPLICATIONS: Poorer nutritional status and a less healthy dietary pattern are associated with a higher risk of clinical progression. This study provides support for investigating whether improving nutritional status can alter the clinical trajectory of AD.

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