Weintraub, Daniel

AbstractBackgroundDementia with Lewy bodies (DLB) is a common neurodegenerative disorder; however, DLB can be difficult to differentiate from Alzheimer’s disease dementia (AD), particularly in the early stages. Research criteria for prodromal DLB were published in 2020 and further studies are needed to validate and refine future clinical criteria.MethodWe analyzed data from the Uniform Data Set from the National Alzheimer’s Coordinating Center (NACC database is funded by NIA/NIH U01‐AG016976). Annual visits occurred across 39 Alzheimer’s Disease Research Centers between September 2005 and September 2021. We identified non‐demented participants [i.e., normal cognition, impaired‐not mild cognitive impairment (MCI) or MCI] at baseline who subsequently received a clinical diagnosis of DLB or AD. Core clinical features (CCF) for DLB (i.e., motor features, visual hallucinations, probable REM sleep behavior disorder (pRBD), cognitive fluctuations), and supportive neuropsychiatric features (NPF; anxiety, apathy, and depression) were assessed through clinical exam and informant responses up to five years prior to dementia diagnosis.ResultThe sample consisted of 160 participants with DLB and 480 age/sex‐matched (1:3) participants with AD at first visit with dementia diagnosis. There was no significant difference in the number of visits prior to dementia diagnosis. The AD group was more racially and ethnically diverse than the DLB group. At the time of diagnosis, DLB participants demonstrated greater functional impairment. Descriptive results indicate CCF and NPF are common in DLB up to five years prior to conversion to dementia; however, motor slowing and NPF were reported in over 20% of the AD participants within the prodromal phase. The presence of 2 or more CCF yielded the greatest AUC (0.786; 95% CI: 0.743, 0.830) in distinguishing DLB from AD one year prior to dementia diagnosis. Combinations of 1 or more CCF with 1, 2, or 3 NPF resulted in significantly lower AUCs (0.725, 0.651, 0.547, respectively) due to decreased specificity.ConclusionCCF and supportive NPF are common in the prodromal phase of DLB; however, parkinsonism and NPF also occurred in the prodromal AD group. Parkinsonism may provide lower discrimination than cognitive fluctuations, visual hallucinations, or pRBD in differentiating DLB from AD in the prodromal phase.

Abstract Introduction Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. Methods Within 248 Aβ‐positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ‐positron emission tomography [PET] uptake, regional tau‐PET uptake, and regional magnetic resonance imaging–based atrophy) and risk‐factors (age, sex, education, apolipoprotein E [ APOE ], and white‐matter lesions) on cross‐sectional cognitive impairment and longitudinal cognitive decline. Results Sixteen percent of variance in cross‐sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aβ–tau–atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aβ, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively. Discussion These findings emphasize that treatments that remove Aβ and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.

AbstractBackgroundThe International Parkinson and Movement Disorders Society criteria for mild cognitive impairment in PD need validation. The objectives of this present study were to evaluate prognostic validity of level I (abbreviated) International Parkinson and Movement Disorders Society mild cognitive impairment in PD criteria for development of PD dementia and compared them with level II (comprehensive) criteria.MethodsWe analyzed data from 8 international studies (1045 patients) from our consortium that included baseline data on demographics, motor signs, depression, detailed neuropsychological testing, and longitudinal follow‐up for conversion to Parkinson's disease dementia. Survival analysis evaluated their contribution to the hazard of Parkinson's disease dementia.ResultsLevel I mild cognitive impairment in PD, increasing age, male sex, and severity of PD motor signs independently increased the hazard of Parkinson's disease dementia. Level I and level II mild cognitive impairment in PD classification had similar discriminative ability with respect to the time to Parkinson's disease dementia.ConclusionsLevel I mild cognitive impairment in PD classification independently contributes to the hazard of Parkinson's disease dementia. This finding supports the prognostic validity of the abbreviated mild cognitive impairment in PD criteria. © 2019 International Parkinson and Movement Disorder Society

AbstractBackground: Numerous neuropsychological tests and test versions are used in Parkinson's disease research, but their relative capacity to detect mild cognitive deficits and their comparability across studies are unknown. The objective of this study was to identify neuropsychological tests that consistently detect cognitive decline in PD across studies.Methods: Data from 30 normed neuropsychological tests across 20 international studies in up to 2908 nondemented PD patients were analyzed. A subset of 17 tests was administered to up to 1247 healthy controls. A 2‐step meta‐analytic approach using standardized scores compared performance in PD with normative data.Results: Pooled estimates of the differences between PD and site‐specific healthy controls identified significant cognitive deficits in PD patients on 14 test scores across 5 commonly assessed cognitive domains (attention or working memory, executive, language, memory, and visuospatial abilities), but healthy control performance was statistically above average on 7 of these tests. Analyses based on published norms only, as opposed to direct assessment of healthy controls, showed high between‐study variability that could not be accounted for and led to inconclusive results.Conclusions: Normed neuropsychological tests across multiple cognitive domains consistently detect cognitive deficits in PD when compared with site‐specific healthy control performance, but relative PD performance was significantly affected by the inclusion and type of healthy controls versus the use of published norms only. Additional research is needed to identify a cognitive battery that can be administered in multisite international studies and that is sensitive to cognitive decline, responsive to therapeutic interventions, and superior to individual cognitive tests. © 2018 International Parkinson and Movement Disorder Society

ABSTRACT As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled “Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease.” In particular, we suggest that the 1‐year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, “PD (dementia with Lewy bodies subtype),” will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

AbstractBackgroundIncreasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2‐related PD is not well‐characterized.MethodsA cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models.ResultsLRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter‐Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03).ConclusionsOur cross‐sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2‐related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline. © 2015 International Parkinson and Movement Disorder Society