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1.
Alzheimers Dement ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31495604

RESUMO

INTRODUCTION: Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive. METHODS: A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty. RESULTS: Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10-4) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles. DISCUSSION: Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.

2.
Alzheimers Res Ther ; 11(1): 66, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366409

RESUMO

BACKGROUND: Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. METHODS: We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. RESULTS: Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. CONCLUSIONS: Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.

3.
Neuroimage Clin ; 24: 101949, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31398553

RESUMO

OBJECTIVES: Many predictive or influencing factors have emerged in investigations of the cognitive reserve model of patients with Alzheimer's disease (AD). For example, neuronal injury, which correlates with cognitive decline in AD, can be assessed by [18F]-fluorodeoxyglucose positron-emission-tomography (FDG-PET), structural magnetic resonance imaging (MRI) and total tau in cerebrospinal fluid (CSFt-tau), all according to the A/T/N-classification. The aim of this study was to calculate residual cognitive performance based on neuronal injury biomarkers as a surrogate of cognitive reserve, and to test the predictive value of this index for the individual clinical course. METHODS: 110 initially mild cognitive impaired and demented subjects (age 71 ±â€¯8 years) with a final diagnosis of AD dementia were assessed at baseline by clinical mini-mental-state-examination (MMSE), FDG-PET, MRI and CSFt-tau. All neuronal injury markers were tested for an association with clinical MMSE and the resulting residuals were correlated with years of education. We used multiple regression analysis to calculate the expected MMSE score based on neuronal injury biomarkers and covariates. The residuals of the partial correlation for each biomarker and the predicted residualized memory function were correlated with individual cognitive changes measured during clinical follow-up (27 ±â€¯13 months). RESULTS: FDG-PET correlated highly with clinical MMSE (R = -0.49, p < .01), whereas hippocampal atrophy to MRI (R = -0.15, p = .14) and CSFt-tau (R = -0.12, p = .22) showed only weak correlations. Residuals of all neuronal injury biomarker regressions correlated significantly with education level, indicating them to be surrogates of cognitive reserve. A positive residual was associated with faster cognitive deterioration at follow-up for the residuals of stand-alone FDG-PET (R = -0.36, p = .01) and the combined residualized memory function model (R = -0.35, p = .02). CONCLUSIONS: These findings suggest that subjects with higher cognitive reserve had accumulated more pathology, which subsequently caused a faster cognitive decline over time. Together with previous findings suggesting that higher reserve is associated with slower cognitive decline, we propose a biphasic reserve effect, with an initially protective phase followed by more rapid decompensation once the protection is overwhelmed.

4.
J Alzheimers Dis ; 70(2): 553-562, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256117

RESUMO

Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer's disease (AD), in conjunction with amyloid-ß (Aß) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aß and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and Aß42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aß42, reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal Aß42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aß/ reserve interaction for clinical progression was noted (adjusted HR = 0.15, p < 0.001), suggesting a moderating effect of reserve on the association between cortisol/Aß+ and clinical progression. Our findings indicate that cortisol hypersecretion accelerates clinical progression in CN individuals presenting with pathological Aß42. High reserve reduces the associated AD progression risk in these high-risk individuals.

5.
Neurodegener Dis ; 19(1): 43-50, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266021

RESUMO

BACKGROUND: Neprilysin (NEP) cleaves amyloid-ß 1-42 (Aß42) in the brain. Hence, we aimed to elucidate the effect of NEP on Aß42 in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [11C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. METHODS: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer's disease patients. RESULTS: CSF-NEP was significantly inversely associated with CSF-Aß42 and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. CONCLUSIONS: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer's pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

6.
Trends Mol Med ; 25(8): 662-672, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31221572

RESUMO

Despite the identification of several dozens of common genetic variants associated with Alzheimer's disease (AD) and Parkinson's disease (PD), most of the genetic risk remains uncharacterised. Therefore, it is important to understand the role of regulatory elements, such as miRNAs. Dysregulated miRNAs are implicated in AD and PD, with potential value in dissecting the shared pathophysiology between the two disorders. miRNAs relevant to both neurodegenerative diseases are related to axonal guidance, apoptosis, and inflammation, therefore, AD and PD likely arise from similar underlying biological pathway defects. Furthermore, pathways regulated by APP, L1CAM, and genes of the caspase family may represent promising therapeutic miRNA targets in AD and PD since they are targeted by dysregulated miRNAs in both disorders.

7.
Int J Geriatr Psychiatry ; 34(10): 1378-1385, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31025764

RESUMO

OBJECTIVE: We aimed to investigate factors associated with self- and carer-rated quality of life (QoL) and caregiver burden related to very mild to severe clinical Alzheimer disease (AD). METHODS: One hundred patient-carer dyads were recruited, and assessments of relevant outcomes were performed, including sociodemographic characteristics, QoL, activities of daily living (ADL), cognitive performance, behavioural and psychological symptoms of dementia (BPSD), caregiver burden, and health resource utilisation. RESULTS: There was a strong correlation between carer- and self-rated QoL, with patients consistently rating their QoL higher than caregivers. Duration of illness did not affect the QoL ratings. There was an inverse association between both self- and carer-rated QoL with age, age at symptom onset, impairment of ADL, time spent on assisting the patient, and depression. Both self- and carer-rated QoL ratings were higher if the caregiver was a spouse vs a child. Carer-rated QoL was inversely associated with severity of dementia, BPSD, caregiver burden, and requirement to supervise the patient. The variables age at symptom onset, ADL, and living together with the primary caregiver explained 34.50% of the variance in self-rated QoL, whereas age at symptom onset, ADL, and BPSD explained 48.20% of the variance in carer-rated QoL. For caregiver burden, 26% of the variance was explained by the variables ADL, living together with the primary caregiver, and agitation. CONCLUSION: Our study highlights the need for a stronger focus on QoL in clinical AD research by providing further pieces of evidence on the key determinants, including the important aspect of caregiver burden.

8.
Ann Neurol ; 85(6): 835-851, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30990912

RESUMO

OBJECTIVE: MicroRNA (miRNA)-mediated (dys)regulation of gene expression has been implicated in Parkinson's disease (PD), although results of miRNA expression studies remain inconclusive. We aimed to identify miRNAs that show consistent differential expression across all published expression studies in PD. METHODS: We performed a systematic literature search on miRNA expression studies in PD and extracted data from eligible publications. After stratification for brain, blood, and cerebrospinal fluid (CSF)-derived specimen, we performed meta-analyses across miRNAs assessed in three or more independent data sets. Meta-analyses were performed using effect-size- and p-value-based methods, as applicable. RESULTS: After screening 599 publications, we identified 47 data sets eligible for meta-analysis. On these, we performed 160 meta-analyses on miRNAs quantified in brain (n = 125), blood (n = 31), or CSF (n = 4). Twenty-one meta-analyses were performed using effect sizes. We identified 13 significantly (Bonferroni-adjusted α = 3.13 × 10-4 ) differentially expressed miRNAs in brain (n = 3) and blood (n = 10) with consistent effect directions across studies. The most compelling findings were with hsa-miR-132-3p (p = 6.37 × 10-5 ), hsa-miR-497-5p (p = 1.35 × 10-4 ), and hsa-miR-133b (p = 1.90 × 10-4 ) in brain and with hsa-miR-221-3p (p = 4.49 × 10-35 ), hsa-miR-214-3p (p = 2.00 × 10-34 ), and hsa-miR-29c-3p (p = 3.00 × 10-12 ) in blood. No significant signals were found in CSF. Analyses of genome-wide association study data for target genes of brain miRNAs showed significant association (α = 9.40 × 10-5 ) of genetic variants in nine loci. INTERPRETATION: We identified several miRNAs that showed highly significant differential expression in PD. Future studies may assess the possible role of the identified brain miRNAs in pathogenesis and disease progression as well as the potential of the top blood miRNAs as biomarkers for diagnosis, progression, or prediction of PD. ANN NEUROL 2019;85:835-851.

9.
Mol Psychiatry ; 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30899092

RESUMO

In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aß) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aß, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aß-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

10.
J Alzheimers Dis ; 69(1): 83-90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909232

RESUMO

Cost- and time-effective markers of Alzheimer's disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-ß protein precursor ß (sAßPPß) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAßPPß levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N = 33) are significantly lower (p < 0.01) than those of cognitively healthy elderly individuals without AD (N = 39), while CSF sAßPPß levels did not differ between the studied groups. This provides further evidence for the potential of sAßPPß in plasma as an AD biomarker candidate.

11.
BMC Med ; 17(1): 47, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30808345

RESUMO

BACKGROUND: The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies. DISCUSSION: This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24-25 November 2017, Munich, Germany) and the Alzheimer's Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer's disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models. CONCLUSION: There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.

12.
Parkinsonism Relat Disord ; 62: 98-104, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30772279

RESUMO

INTRODUCTION: Due to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD. METHODS: In 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking. RESULTS: We found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD. CONCLUSION: Our data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.

13.
J Alzheimers Dis ; 68(1): 383-394, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30776000

RESUMO

BACKGROUND: Several automatic tools have been implemented for semi-quantitative assessment of brain [18]F-FDG-PET. OBJECTIVE: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer's disease (pAD) from controls. METHODS: Sixty-two pAD patients (MMSE score = 27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score = 29.2±1.2) were enrolled in five centers of the European Alzheimer's Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between [18]F-FDG-PET and a verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). RESULTS: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p < 0.005) better than any of the other methods. CONCLUSION: The study confirms the good accuracy of [18]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods.

14.
Neurobiol Aging ; 74: 182-190, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30458365

RESUMO

TREM2 was suggested to be an important regulator of microglia during neurodegeneration, but previous studies report conflicting results in relation to soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) when using clinical criteria to classify Alzheimer's disease (AD). The present study explores sTREM2 CSF levels and their associations with other biomarkers and cognitive measures in a prospective AD cohort. Based on the available CSF biomarker information, 497 subjects were classified according to the 2018 National Institute on Aging-Alzheimer's Association research framework guidelines, which group biomarkers into those of amyloid-ß deposition, tau pathology, and neurodegeneration. CSF sTREM2 concentrations were associated with markers of neurodegeneration and fibrillar tau pathology, but not amyloidosis; sTREM2 concentrations were increased in total tau-positive versus -negative individuals; sTREM2 was not related to cognitive and other biomarker changes over time; and sTREM2 concentrations increased over time in total tau-positive versus -negative individuals with AD pathophysiology. The present study provides evidence in support of sTREM2 in CSF as a marker of neuroinflammation across the spectrum of early clinical AD. sTREM2 is linked to neuronal injury and may therefore offer complementary information relevant for diagnostic purposes and novel treatment approaches targeting the immune system in AD.

15.
Int J Epidemiol ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30462234

RESUMO

Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding. Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.

17.
Front Neurol ; 9: 483, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29973914

RESUMO

Background: F-18-fluordeoxyglucose positron emission tomography (FDG-PET) is widely used for discriminative diagnosis of tau-positive atypical parkinsonian syndromes (T+APS). This approach now stands to be augmented with more specific tau tracers. Therefore, we retrospectively analyzed a large clinical routine dataset of FDG-PET images for evaluation of the strengths and limitations of stand-alone FDG-PET. Methods: A total of 117 patients (age 68.4 ± 11.1 y) underwent an FDG-PET exam. Patients were followed clinically for a minimum of one year and their final clinical diagnosis was recorded. FDG-PET was rated visually (positive/negative) and categorized as high, moderate or low likelihood of T+APS and other neurodegenerative disorders. We then calculated positive and negative predictive values (PPV/NPV) of FDG-PET readings for the different subgroups relative to their final clinical diagnosis. Results: Suspected diagnoses were confirmed by clinical follow-up (≥1 y) for 62 out of 117 (53%) patients. PPV was excellent when FDG-PET indicated a high likelihood of T+APS in combination with low to moderate likelihood of another neurodegenerative disorder. PPV was distinctly lower when FDG-PET indicated only a moderate likelihood of T+APS or when there was deemed equal likelihood of other neurodegenerative disorder. NPV of FDG-PET with a low likelihood for T+APS was high. Conclusions: FDG-PET has high value in clinical routine evaluation of suspected T+APS, gaining satisfactory differential diagnosis in two thirds of the patients. One third of patients would potentially profit from further evaluation by more specific radioligands, with FDG-PET serving gatekeeper function for the more expensive methods.

18.
Dement Geriatr Cogn Disord ; 45(3-4): 152-161, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29788013

RESUMO

BACKGROUND/AIMS: The utility of ß-site amyloid-ß precursor protein (AßPP) cleaving enzyme 1 (BACE1) activity and soluble AßPP ß (sAßPPß) levels in cerebrospinal fluid (CSF) in detecting Alzheimer's disease (AD) is still elusive. METHODS: BACE1 activity and sAßPPß concentration were measured in patients with AD dementia (n = 56) and mild cognitive impairment (MCI) due to AD (n = 76) with abnormal routine AD CSF markers, in patients with MCI with normal CSF markers (n = 39), and in controls without preclinical AD (n = 48). In a subsample with available 18F-fluorodeoxyglucose positron emission tomography (FDG PET) data, ordinal regression models were employed to compare the contribution of BACE1 and sAßPPß to correct diagnostic classification to that of FDG PET. RESULTS: BACE1 activity was significantly higher in patients with MCI due to AD compared to both controls and patients with MCI with normal CSF markers. sAßPPß did not differ between any of the studied groups. Interestingly, BACE1 activity was not found to be inferior to FDG PET as predictive covariate in differentiating between the diagnostic groups. CONCLUSIONS: Further studies using biomarker-underpinned diagnoses are warranted to shed more light on the potential diagnostic utility of BACE1 activity as AD biomarker candidate in MCI.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Ácido Aspártico Endopeptidases/líquido cefalorraquidiano , Disfunção Cognitiva , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Diagnóstico Diferencial , Feminino , Fluordesoxiglucose F18/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacologia
19.
Methods Mol Biol ; 1750: 15-29, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29512063

RESUMO

Progress in prevention and treatment of Alzheimer's disease (AD) and dementia is hampered by the restricted understanding of the biological and environmental causes underlying pathophysiology. It is widely accepted that certain genetic factors are associated with AD and a number of lifestyle and other environmental characteristics have also been linked to dementia risk. However, interactions between genes and the environment are not yet well understood, and coordinated global action is required to utilize existing cohorts and other resources effectively and efficiently to identify new avenues for dementia prevention. This chapter provides a brief summary of current research on risk and protective factors and opportunities and challenges in relation to population-based approaches are discussed.

20.
Brain ; 141(4): 1186-1200, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29462334

RESUMO

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

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