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  • Babulal, Ganesh M, et al. (författare)
  • Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.
  • 2019
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 15:2, s. 292-312
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
  • Bell, Joanne, et al. (författare)
  • A novel BACE inhibitor (PF-05297909): : A two-part adaptive design to evaluate safety, pharmacokinetics and pharmacodynamics for modifying beta-amyloid in a first-in-human study
  • 2013
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 9:4, s. P287
  • Tidskriftsartikel (refereegranskat)abstract
    • <h2>Background</h2><p>The accumulation of amyloid beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration seen in the Alzheimer's disease (AD) brain. Given the central role of Aβ42 in AD pathogenesis, a therapeutic strategy to lower central Aβ42 (and Aβ40) levels via inhibition of BACE was adopted in a first in human trial in a 2-part adaptive design.</p><h2>Methods</h2><p>Part 1 evaluated PF-05297909 plasma PK and the PK/PD relationship for the reduction of plasma Aβ40, Aβ42 and AβX levels; Part 2 evaluated the exposure-response relationship between PF-05297909 and CSF levels of Aβ40, Aβ42 and AβX. Sufficient safety and tolerability, plasma exposure and reduction in plasma Aβ were necessary to initiate Part 2. Part 1 was a sequential parallel group dose escalation (25, 100, 250 and 325 mg) with n=8 (6:2, active:placebo) healthy volunteers (HV) in each cohort. Part 2 consisted of 3 cohorts of n=8 (6:2, active:placebo) HV. Doses selected for Part 2 started with the highest safe dose in Part 1 and then adapted for subsequent cohorts. The PK/PD relationship between PF-05297909 and Aβ42 was determined using a non-linear mixed effects (NLME) analysis. The doses for Part 2 - cohort 2 and 3 were to be chosen to improve the relative standard error in the estimate of the BACE IC50 as quantified by evaluating the determinant of the Fisher information matrix for the NLME model.</p><h2>Results</h2><p>PF-05297909 was well-tolerated. Reduction in plasma Aβ (Aβ40 and Aβ42) was exposure related with an apparent maximum at the 250 mg dose with a greater duration of activity at the 325 mg dose of PF-05297909. A 325 mg dose was selected for Part 2 - cohorts 1 and 2 without further cohorts being run, as stopping criteria for futility were met following analysis of cohort 2. A PK/PD relationship in CSF was not observed.</p><h2>Conclusions</h2><p>The adaptive designed PF-05297909 FIH study allowed efficient testing of safety and of the PK/PD relationship between PF-05297909 exposure and Aβ (Aβ40 and Aβ42). PF-05297909 was safe and well tolerated in HV at exposures tested. A robust effect on plasma Aβ did not translate to CSF pharmacodynamic effects.</p>
  • Benedict, Christian, et al. (författare)
  • Self-reported sleep disturbance is associated with Alzheimer's disease risk in men
  • 2015
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 11:9, s. 1090-1097
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>OBJECTIVE:</strong> To study the association between self-reported sleep disturbances and dementia risk.</p><p><strong>METHODS:</strong> Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years.</p><p><strong>RESULTS:</strong> Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P &lt; .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P &lt; .001). No group differences were found in Aβ levels.</p><p><strong>CONCLUSION:</strong> Improving sleep quality may help reduce the neurodegenerative risk in older men.</p>
  • Bereczki, E., et al. (författare)
  • Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia
  • 2016
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 12:11, s. 1149-1158
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. Methods A total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. Results We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. Discussion Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases. © 2016 The Alzheimer's Association
  • Bos, Isabelle, et al. (författare)
  • Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum
  • 2019
  • Ingår i: Alzheimer's & Dementia. - Elsevier. - 1552-5260 .- 1552-5279. ; 15:5, s. 644-654
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>INTRODUCTION:</strong> We investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).</p><p><strong>METHODS:</strong> We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ- vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.</p><p><strong>RESULTS:</strong> Ng and T-tau distinguished between Aβ+ from Aβ- individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.</p><p><strong>DISCUSSION:</strong> Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.</p>
  • Duits, Flora H., et al. (författare)
  • The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
  • 2014
  • Ingår i: Alzheimer's & Dementia. - Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.</p>
  • Eckerström, Marie, 1981-, et al. (författare)
  • Longitudinal evaluation of criteria for subjective cognitive decline and preclinical Alzheimer's disease in a memory clinic sample.
  • 2017
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 16:8, s. 96-107
  • Tidskriftsartikel (refereegranskat)abstract
    • Subjective cognitive decline (SCD) and biomarker-based "at-risk" concepts such as "preclinical" Alzheimer's disease (AD) have been developed to predict AD dementia before objective cognitive impairment is detectable. We longitudinally evaluated cognitive outcome when using these classifications.Memory clinic patients (n = 235) were classified as SCD (n = 122): subtle cognitive decline (n = 36) and mild cognitive impairment (n = 77) and subsequently subclassified into SCDplus and National Institute on Aging-Alzheimer's Association (NIA-AA) stages 0 to 3. Mean (standard deviation) follow-up time was 48 (35) months. Proportion declining cognitively and prognostic accuracy for cognitive decline was calculated for all classifications.Among SCDplus patients, 43% to 48% declined cognitively. Among NIA-AA stage 1 to 3 patients, 50% to 100% declined cognitively. The highest positive likelihood ratios (+LRs) for subsequent cognitive decline (+LR 6.3), dementia (+LR 3.4), and AD dementia (+LR 6.5) were found for NIA-AA stage 2.In a memory clinic setting, NIA-AA stage 2 seems to be the most successful classification in predicting objective cognitive decline, dementia, and AD dementia.
  • Elobeid, Adila, et al. (författare)
  • Alzheimer's disease-related plaques in nondemented subjects
  • 2014
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 10:5, s. 522-529
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Alzheimer's disease (AD) pathology was assessed in 587 nondemented subjects, with age at death at or more than 50 years. In 307 subjects, amyloid-beta (A beta) immunoreactive (IR) plaques were seen; in 192 subjects, neuritic plaques (NPs) stained with modified Bielschowsky silver stain (mBky) were observed. In 20% of the whole cohort and in 62% of the 192 subjects with NPs in mBky, hyperphosphorylated tau (HPtau) IR NPs were seen. In most cases in this nondemented cohort, the HPtau IR NPs were observed either sparsely or to a moderate extent. The correlation between the NP score and Braak stage was best (r = 0.6, P &lt; .001) when HPtau immunohistochemistry was used. Eighty-three percent of the subjects could not be categorized following the 1997 National Institute on Aging and the Reagan Institute (NIA-RI) recommendations, whereas the 2012 National Institute on Aging Alzheimer's Association (NIA-AA) guidelines were applicable for all study subjects. Twenty-eight subjects had an intermediate level of AD neuropathological change according to the 2012 NIA-AA guidelines, and 25 of these 28 subjects displayed HPtau IR NPs in the temporal cortex. It is noteworthy, however, that as many as 119 out of the 192 subjects with NPs in mBky displayed HPtau IR NPs in the temporal cortex. Ninety-four of these 119 subjects with neocortical HPtau IR NPs had a low level of neuropathological AD change according to the 2012 NIA-AA guidelines because they were in Braak stages I and II. Thus, 94 subjects were not acknowledged as being at risk for AD when applying the 2012 NIA-AA guidelines. We suggest that to identify all subjects with cortical HPtau pathology and, consequently, probably being at risk for developing AD, in addition to the level of AD neuropathological change as recommended by the 2012 NIA-AA guidelines, assessment of HPtau IR NPs in the neocortex should be carried out.</p>
  • Exalto, Lieza G, et al. (författare)
  • Midlife risk score for the prediction of dementia four decades later
  • 2013
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 10:5, s. 562-570
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Objective</p><p>The objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors , aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population. Our second aim was to improve the CAIDE risk score by additional midlife risk factors.</p><p>Methods</p><p>This retrospective cohort study was conducted in an integrated health care delivery system. A total of 9480 Kaiser Permanente members who participated in a health survey study (age range, 40–55 years) from 1964 to 1973 were included in this study. Dementia diagnoses from primary care and medical specialist visits were collected from January 1, 1994 to January 16, 2006, using International Classification of Diseases 9 codes 290.0, 290.1 for “possible dementia,” and 331.0 and 290.4 for “specialist confirmed dementia.” Risk model prediction and validation were examined with the C statistic, net reclassification improvement, and integrated discrimination improvement. Dementia risk per sum score was calculated with Kaplan-Meier estimates.</p><p>Results</p><p>A total of 2767 participants (25%) were diagnosed with any type of dementia, of which 1011 diagnoses (10.7%) were specialist-confirmed diagnoses. Average time between midlife examination and end of follow-up was 36.1 years. The CAIDE risk score replicated well with a C statistic of 0.75, quite similar to the original CAIDE C statistic of 0.78. The CAIDE score also predicted well within different race strata. Other midlife risk factors (central obesity, depressed mood, diabetes mellitus, head trauma, lung function, and smoking) did not improve predictability. The risk score allowed stratification of participants into those with 40-year low (9%) and high (29%) dementia risk.</p><p>Conclusions</p><p>A combination of modifiable vascular risk factors in midlife is highly predictive of the likelihood of dementia decades later. Possible dementia prevention strategies should point to a life course perspective on maintaining vascular health.</p>
  • Forlenza, O. V., et al. (författare)
  • Cerebrospinal fluid biomarkers in Alzheimer's disease: Diagnostic accuracy and prediction of dementia
  • 2015
  • Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 1:4, s. 455-463
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Guidelines for the use of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer's disease (AD) establish that each laboratory must use internally qualified cutoff values. We determined the concentrations of biomarkers that discriminate cases from controls and combinations that predict the progression to dementia in a Brazilian cohort. Methods: Concentrations of amyloid-beta peptide (Aβ1-42), total tau (T-tau), and 181Thr-phosphorylated-tau (P-tau) were determined in CSF samples from 184 older adults (68 mild cognitive impairment, 41 AD, 34 non-AD cognitive impairment, and 41 controls) by the INNO-BIA AlzBio3 assay. Results: Cutoff values discriminating AD from controls are as follows: Aβ1-42: 416.0 pg/mL (sensitivity [SE]: 83%, specificity (SP): 70%); T-tau: 76.7 pg/mL (SE: 82%, SP: 67%); P-tau: 36.1 pg/mL (SE: 83%, SP: 49%); Aβ1-42/P-tau &lt;9.53 (SE: 88%, SP: 78%); and Aβ1-42/T-tau &lt;4.13 (SE: 80%; SP: 80%). Combining values Aβ1-42 &lt;416.5 pg/mL and Aβ1-42/P-tau &lt;9.5 best predicted the conversion in 2 years (Cox regression: hazard ratio 7.24 [2.09-25.06], P =.002, SE: 74%, Sp: 73%). Discussion: Our findings are in line with most of the available evidence in this field; yet, our cutoff values are different from those derived from other laboratories. © 2015 The Authors.
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