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1.
Artigo em Inglês | MEDLINE | ID: mdl-33594474

RESUMO

PURPOSE: To review how outcomes of clinical utility are operationalized in current amyloid-PET validation studies, to prepare for formal assessment of clinical utility of amyloid-PET-based diagnosis. METHODS: Systematic review of amyloid-PET research studies published up to April 2020 that included outcomes of clinical utility. We extracted and analyzed (a) outcome categories, (b) their definition, and (c) their methods of assessment. RESULTS: Thirty-two studies were eligible. (a) Outcome categories were clinician-centered (found in 25/32 studies, 78%), patient-/caregiver-centered (in 9/32 studies, 28%), and health economics-centered (5/32, 16%). (b) Definition: Outcomes were mainly defined by clinical researchers; only the ABIDE study expressly included stakeholders in group discussions. Clinician-centered outcomes mainly consisted of incremental diagnostic value (25/32, 78%) and change in patient management (17/32, 53%); patient-/caregiver-centered outcomes considered distress after amyloid-pet-based diagnosis disclosure (8/32, 25%), including quantified burden of procedure for patients' outcomes (n = 8) (1/8, 12.5%), impact of disclosure of results (6/8, 75%), and psychological implications of biomarker-based diagnosis (75%); and health economics outcomes focused on costs to achieve a high-confidence etiological diagnosis (5/32, 16%) and impact on quality of life (1/32, 3%). (c) Assessment: all outcome categories were operationalized inconsistently across studies, employing 26 different tools without formal rationale for selection. CONCLUSION: Current studies validating amyloid-PET already assessed outcomes for clinical utility, although non-clinician-based outcomes were inconsistent. A wider participation of stakeholders may help produce a more thorough and systematic definition and assessment of outcomes of clinical utility and help collect evidence informing decisions on reimbursement of amyloid-PET.

3.
Mol Imaging Biol ; 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33496930

RESUMO

PURPOSE: Dynamic positron emission tomography (PET) protocols allow for accurate quantification of [18F]flortaucipir-specific binding. However, dynamic acquisitions can be challenging given the long required scan duration of 130 min. The current study assessed the effect of shorter scan protocols for [18F]flortaucipir on its quantitative accuracy. PROCEDURES: Two study cohorts with Alzheimer's disease (AD) patients and healthy controls (HC) were included. All subjects underwent a 130-min dynamic [18F]flortaucipir PET scan consisting of two parts (0-60/80-130 min) post-injection. Arterial sampling was acquired during scanning of the first cohort only. For the second cohort, a second PET scan was acquired within 1-4 weeks of the first PET scan to assess test-retest repeatability (TRT). Three alternative time intervals were explored for the second part of the scan: 80-120, 80-110 and 80-100 min. Furthermore, the first part of the scan was also varied: 0-50, 0-40 and 0-30 min time intervals were assessed. The gap in the reference TACs was interpolated using four different interpolation methods: population-based input function 2T4k_VB (POP-IP_2T4k_VB), cubic, linear and exponential. Regional binding potential (BPND) and relative tracer delivery (R1) values estimated using simplified reference tissue model (SRTM) and/or receptor parametric mapping (RPM). The different scan protocols were compared to the respective values estimated using the original scan acquisition. In addition, TRT of the RPM BPND and R1 values estimated using the optimal shortest scan duration was also assessed. RESULTS: RPM BPND and R1 obtained using 0-30/80-100 min scan and POP-IP_2T4k_VB reference region interpolation had an excellent correlation with the respective parametric values estimated using the original scan duration (r2 > 0.95). The TRT of RPM BPND and R1 using the shortest scan duration was - 1 ± 5 % and - 1 ± 6 % respectively. CONCLUSIONS: This study demonstrated that [18F]flortaucipir PET scan can be acquired with sufficient quantitative accuracy using only 50 min of dual-time-window scanning time.

4.
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.

5.
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.

6.
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.

7.
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.

8.
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.

9.
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.

10.
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.

11.
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.

12.
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.

13.
Alzheimers Res Ther ; 12(1): 138, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33121534

RESUMO

BACKGROUND: Impairment in daily functioning is a clinical hallmark of dementia. Difficulties with "instrumental activities of daily living" (IADL) seem to increase gradually over the course of Alzheimer's disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD. METHODS: In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging-Alzheimer's Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized. RESULTS: The rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = - 0.32 [- 0.55, - 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (- 1.06 [- 1.27, - 0.85], p < .001) and nearly two SD units per year in stage 4+ (1.93 [- 2.19, - 1.67], p < .001). Overall, results were similar between community-based and memory clinic study cohorts. CONCLUSIONS: Our results suggest that the rate of functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive NIA-AA clinical stage. These results imply that incremental changes in function are a meaningful measure for early disease monitoring. Combined with the low-cost assessment, this advocates the use of these functional questionnaires for capturing the effects of early AD-related cognitive decline on daily life.

14.
J Int Neuropsychol Soc ; : 1-13, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33046162

RESUMO

OBJECTIVE: Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging - Alzheimer's Association (NIA-AA) research framework. METHOD: Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models. RESULTS: 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (ß = -.58, p < .001). Word List Delayed Recall (ß = -.22, p < .05) and Trail Making Test (ß = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (ß = -1.13, p < .001) and 4 (ß = -2.23, p < .001). CONCLUSIONS: We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.

15.
Neurology ; 95(21): e2845-e2853, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33046617

RESUMO

OBJECTIVE: To evaluate the association between brain amyloid ß (Aß) and cerebral small vessel disease (CSVD) markers, as well as their joint effect on cognition, in a memory clinic study. METHODS: A total of 186 individuals visiting a memory clinic, diagnosed with no cognitive impairment, cognitive impairment no dementia (CIND), Alzheimer dementia (AD), or vascular dementia were included. Brain Aß was measured by [11C] Pittsburgh compound B-PET global standardized uptake value ratio (SUVR). CSVD markers including white matter hyperintensities (WMH), lacunes, and cerebral microbleeds (CMBs) were graded on MRI. Cognition was assessed by neuropsychological testing. RESULTS: An increase in global SUVR is associated with a decrease in Mini-Mental State Examination (MMSE) in CIND and AD, as well as a decrease in global cognition Z score in AD, independent of age, education, hippocampal volume, and markers of CSVD. A significant interaction between global SUVR and WMH was found in relation to MMSE in CIND (P for interaction: 0.009), with an increase of the effect size of Aß (ß = -6.57 [-9.62 to -3.54], p < 0.001) compared to the model without the interaction term (ß = -2.91 [-4.54 to -1.29], p = 0.001). CONCLUSION: Higher global SUVR was associated with worse cognition in CIND and AD, but was augmented by an interaction between global SUVR and WMH only in CIND. This suggests that Aß and CSVD are independent processes with a possible synergistic effect between Aß and WMH in individuals with CIND. There was no interaction effect between Aß and lacunes or CMBs. Therefore, in preclinical phases of AD, WMH should be targeted as a potentially modifiable factor to prevent worsening of cognitive dysfunction.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33011127

RESUMO

OBJECTIVES: This study sought to investigate the extent of hypertensive exposure as assessed by cardiovascular magnetic resonance imaging (MRI) in relation to cerebral small vessel disease (CSVD) and cognitive impairment, with the aim of understanding the role of hypertension in the early stages of deteriorating brain health. BACKGROUND: Preserving brain health into advanced age is one of the great challenges of modern medicine. Hypertension is thought to induce vascular brain injury through exposure of the cerebral microcirculation to increased pressure/pulsatility. Cardiovascular MRI provides markers of (subclinical) hypertensive exposure, such as aortic stiffness by pulse wave velocity (PWV), left ventricular (LV) mass index (LVMi), and concentricity by mass-to-volume ratio. METHODS: A total of 559 participants from the Heart-Brain Connection Study (431 patients with manifest cardiovascular disease and 128 control participants), age 67.8 ± 8.8 years, underwent 3.0-T heart-brain MRI and extensive neuropsychological testing. Aortic PWV, LVMi, and LV mass-to-volume ratio were evaluated in relation to presence of CSVD and cognitive impairment. Effect modification by patient group was investigated by interaction terms; results are reported pooled or stratified accordingly. RESULTS: Aortic PWV (odds ratio [OR]: 1.17; 95% confidence interval [CI]: 1.05 to 1.30 in patient groups only), LVMi (in carotid occlusive disease, OR: 5.69; 95% CI: 1.63 to 19.87; in other groups, OR: 1.30; 95% CI: 1.05 to 1.62]) and LV mass-to-volume ratio (OR: 1.81; 95% CI: 1.46 to 2.24) were associated with CSVD. Aortic PWV (OR: 1.07; 95% CI: 1.02 to 1.13) and LV mass-to-volume ratio (OR: 1.27; 95% CI: 1.07 to 1.51) were also associated with cognitive impairment. Relations were independent of sociodemographic and cardiac index and mostly persisted after correction for systolic blood pressure or medical history of hypertension. Causal mediation analysis showed significant mediation by presence of CSVD in the relation between hypertensive exposure markers and cognitive impairment. CONCLUSIONS: The extent of hypertensive exposure is associated with CSVD and cognitive impairment beyond clinical blood pressure or medical history. The mediating role of CSVD suggests that hypertension may lead to cognitive impairment through the occurrence of CSVD.

17.
Alzheimers Dement (Amst) ; 12(1): e12083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32864411

RESUMO

Introduction: Web-based cognitive tests have potential for standardized screening in neurodegenerative disorders. We examined accuracy and consistency of cCOG, a computerized cognitive tool, in detecting mild cognitive impairment (MCI) and dementia. Methods: Clinical data of 306 cognitively normal, 120 mild cognitive impairment (MCI), and 69 dementia subjects from three European cohorts were analyzed. Global cognitive score was defined from standard neuropsychological tests and compared to the corresponding estimated score from the cCOG tool containing seven subtasks. The consistency of cCOG was assessed comparing measurements administered in clinical settings and in the home environment. Results: cCOG produced accuracies (receiver operating characteristic-area under the curve [ROC-AUC]) between 0.71 and 0.84 in detecting MCI and 0.86 and 0.94 in detecting dementia when administered at the clinic and at home. The accuracy was comparable to the results of standard neuropsychological tests (AUC 0.69-0.77 MCI/0.91-0.92 dementia). Discussion: cCOG provides a promising tool for detecting MCI and dementia with potential for a cost-effective approach including home-based cognitive assessments.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32875431

RESUMO

PURPOSE: Visual reading of 18F-florbetapir positron emission tomography (PET) scans is used in the diagnostic process of patients with cognitive disorders for assessment of amyloid-ß (Aß) depositions. However, this can be time-consuming, and difficult in case of borderline amyloid pathology. Computer-aided pattern recognition can be helpful in this process but needs to be validated. The aim of this work was to develop, train, validate and test a convolutional neural network (CNN) for discriminating between Aß negative and positive 18F-florbetapir PET scans in patients with subjective cognitive decline (SCD). METHODS: 18F-florbetapir PET images were acquired and visually assessed. The SCD cohort consisted of 133 patients from the SCIENCe cohort and 22 patients from the ADNI database. From the SCIENCe cohort, standardized uptake value ratio (SUVR) images were computed. From the ADNI database, SUVR images were extracted. 2D CNNs (axial, coronal and sagittal) were built to capture features of the scans. The SCIENCe scans were randomly divided into training and validation set (5-fold cross-validation), and the ADNI scans were used as test set. Performance was evaluated based on average accuracy, sensitivity and specificity from the cross-validation. Next, the best performing CNN was evaluated on the test set. RESULTS: The sagittal 2D-CNN classified the SCIENCe scans with the highest average accuracy of 99% ± 2 (SD), sensitivity of 97% ± 7 and specificity of 100%. The ADNI scans were classified with a 95% accuracy, 100% sensitivity and 92.3% specificity. CONCLUSION: The 2D-CNN algorithm can classify Aß negative and positive 18F-florbetapir PET scans with high performance in SCD patients.

19.
Transl Psychiatry ; 10(1): 332, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994401

RESUMO

Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was ß-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to ß-amyloid metabolism.

20.
Alzheimers Dement (N Y) ; 6(1): e12034, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32995468

RESUMO

Introduction: We examined the role of hemodynamic dysfunction in cognition by relating cerebral blood flow (CBF), measured with arterial spin labeling (ASL), to cognitive functioning, in patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (MRI; ie, possible vascular cognitive impairment [VCI]). Methods: We included 439 participants (124 HF; 75 COD; 127 possible VCI; 113 reference participants) from the Dutch multi-center Heart-Brain Study. We used pseudo-continuous ASL to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and four cognitive domains. Results: CBF values were lowest in COD, followed by VCI and HF, compared to reference participants. This did not explain cognitive impairment, as we did not find an association between CBF and cognitive functioning. Discussion: We found that reduced CBF is not the major explanatory factor underlying cognitive impairment in patients with hemodynamic dysfunction along the heart-brain axis.

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