Publications by authors named "Brenna Cholerton"

67 Publications

Resting-State Cerebello-Cortical Dysfunction in Parkinson's Disease.

Front Neurol 2020 28;11:594213. Epub 2021 Jan 28.

Department of Radiology, University of Washington Medical Center, Seattle, WA, United States.

Recently, the cerebellum's role in Parkinson's disease (PD) has been highlighted. Therefore, this study sought to test the hypothesis that functional connectivity (FC) between cerebellar and cortical nodes of the resting-state networks differentiates PD patients from controls by scanning participants at rest using functional magnetic resonance imaging (fMRI) and investigating connectivity of the cerebellar nodes of the resting-state networks. Sixty-two PD participants off medication for at least 12 h and 33 normal controls (NCs) were scanned at rest using blood oxygenation level-dependent fMRI scans. Motor and cognitive functions were assessed with the Movement Disorder Society's Revision of the Unified Parkinson's Disease Rating Scale III and Montreal Cognitive Assessment, respectively. Connectivity was investigated with cerebellar seeds defined by Buckner's 7-network atlas. PD participants had significant differences in FC when compared to NC participants. Most notably, PD patients had higher FC between cerebellar nodes of the somatomotor network (SMN) and the corresponding cortical nodes. Cognitive functioning was differentially associated with connectivity of the cerebellar SMN and dorsal attention network. Further, cerebellar connectivity of frontoparietal and default mode networks correlated with the severity of motor function. Our study demonstrates altered cerebello-cortical FC in PD, as well as an association of this FC with PD-related motor and cognitive disruptions, thus providing additional evidence for the cerebellum's role in PD.
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http://dx.doi.org/10.3389/fneur.2020.594213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876057PMC
January 2021

Genetic Insights into Alzheimer's Disease.

Annu Rev Pathol 2021 01;16:351-376

Department of Pathology, Stanford University, Stanford, California 94304, USA; email:

Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying neuropathologic changes and neuropsychological manifestations. While a clinical diagnosis is often made on the basis of initial memory dysfunction that progresses to involve multiple cognitive domains, definitive diagnosis requires autopsy examination of the brain to identify amyloid plaques and neurofibrillary degeneration. Over the past 100 years, there has been remarkable progress in our understanding of the underlying pathophysiologic processes, pathologic changes, and clinical phenotypes of AD, largely because genetic pathways that include but expand beyond amyloid processing have been uncovered. This review discusses the current state of understanding of the genetics of AD with a focus on how these advances are both shaping our understanding of the disease and informing novel avenues and approaches for development of potential therapeutic targets.
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http://dx.doi.org/10.1146/annurev-pathmechdis-012419-032551DOI Listing
January 2021

Relationships Between Sensorimotor Inhibition and Mobility in Older Adults With and Without Parkinson's Disease.

J Gerontol A Biol Sci Med Sci 2021 Mar;76(4):630-637

Department of Neurology, Oregon Health and Science University, Portland.

Background: Reduced cortical sensorimotor inhibition is associated with mobility and cognitive impairments in people with Parkinson's disease (PD) and older adults (OAs). However, there is a lack of clarity regarding the relationships among sensorimotor, cognitive, and mobility impairments. The purpose of this study was to determine how cortical sensorimotor inhibition relates to impairments in mobility and cognition in people with PD and OAs.

Method: Cortical sensorimotor inhibition was characterized with short-latency afferent inhibition (SAI) in 81 people with PD and 69 OAs. Six inertial sensors recorded single- and dual-task gait and postural sway characteristics during a 2-minute walk and a 1-minute quiet stance. Cognition was assessed across the memory, visuospatial, executive function, attention, and language domains.

Results: SAI was significantly impaired in the PD compared to the OA group. The PD group preformed significantly worse across all gait and postural sway tasks. In PD, SAI significantly correlated with single-task foot strike angle and stride length variability, sway area, and jerkiness of sway in the coronal and sagittal planes. In OAs, SAI significantly related to single-task gait speed and stride length, dual-task stride length, and immediate recall (memory domain). No relationship among mobility, cognition, and SAI was observed.

Conclusions: Impaired SAI related to slower gait in OA and to increased gait variability and postural sway in people with PD, all of which have been shown to be related to increased fall risk.
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http://dx.doi.org/10.1093/gerona/glaa300DOI Listing
March 2021

White Matter Lesions in Mild Cognitive Impairment and Idiopathic Parkinson's Disease: Multimodal Advanced MRI and Cognitive Associations.

J Neuroimaging 2020 11 16;30(6):843-850. Epub 2020 Sep 16.

Department of Radiology, Integrated Brain Imaging Center, University of Washington Medical Center, Seattle, WA.

Cerebrovascular disease is a common comorbidity in older adults, typically assessed in terms of white matter hyperintensities (WMHs) on MRI. While it is well known that WMHs exacerbate cognitive symptoms, the exact relation of WMHs with cognitive performance and other degenerative diseases is unknown. Furthermore, based on location, WMHs are often classified into periventricular and deep WMHs and are believed to have different pathological origins. Whether the two types of WMHs influence cognition differently is unclear. Using regression models, we assessed the independent association of these two types of WMHs with cognitive performance in two separate studies focused on distinct degenerative diseases, early Alzheimer's (mild cognitive impairment), and Parkinson's disease. We further tested if the two types of WMHs were differentially associated with reduced cortical cerebral blood flow (CBF) as measured by arterial spin labeling and increased mean diffusivity (MD, a marker of tissue injury) as measured by diffusion imaging. Our approach revealed that both deep and periventricular WMHs were associated with poor performance on tests of global cognition (Montreal cognitive Assessment, MoCA), task processing (Trail making test), and category fluency in the study of mild cognitive impairment. They were associated with poor performance in global cognition (MoCA) and category fluency in the Parkinson's disease study. Of note, more associations were detected between cognitive performance and deep WMHs than between cognitive performance and periventricular WMHs. Mechanistically, both deep and periventricular WMHs were associated with increased MD. Both deep and periventricular WMHs were also associated with reduced CBF in the gray matter.
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http://dx.doi.org/10.1111/jon.12778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722040PMC
November 2020

Multivariate prediction of dementia in Parkinson's disease.

NPJ Parkinsons Dis 2020 25;6:20. Epub 2020 Aug 25.

Department of Pathology, Stanford University School of Medicine, Palo Alto, CA USA.

Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort ( = 827). Age, disease duration, sex, and status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.
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http://dx.doi.org/10.1038/s41531-020-00121-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447766PMC
August 2020

White Matter Hyperintensities Related to Parkinson's Disease Executive Function.

Mov Disord Clin Pract 2020 Aug 30;7(6):629-638. Epub 2020 Apr 30.

Department of Neurology and Neurological Sciences Stanford University Palo Alto California USA.

Background: People with Parkinson's disease (PD) can develop multidomain cognitive impairments; however, it is unclear whether different pathologies underlie domain-specific cognitive dysfunction.

Objectives: We investigated the contribution of vascular copathology severity and location, as measured by MRI white matter hyperintensities (WMHs), to domain-specific cognitive impairment in PD.

Methods: We studied 85 PD (66.6 ± 9.2 years) and 18 control (65.9 ± 6.6) participants. Using the Fazekas scale for rating the severity of WMH, we subdivided PD into 14 PDWMH and 71 PDWMH. Participants underwent global, executive, visuospatial, episodic memory, and language testing. We performed nonparametric permutation testing to create WMH probability maps based on PD-WMH group and cognitive test performance.

Results: The PDWMH group showed worse global and executive cognitive performance than the PDWMH group. On individual tests, the PDWMH group showed worse Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities Test (SDMT), and Digit Span scores. WMH probability maps showed that in the PDWMH group, worse Stroop was associated with lesions centered around the corticospinal tract (CST), forceps major, inferior-fronto-occipital fasciculus, and superior longitudinal fasciculus; worse SDMT with lesions around the CST, forceps major, and posterior corona radiata; worse Digit Span with lesions around the posterior corona radiata; and worse MoCA with lesions around the CST.

Conclusions: We found that WMH severity was associated with PD executive dysfunction, including worse attention, working memory, and processing speed. Disruption of key white matter tracts in proximity to vascular lesions could contribute to these specific cognitive impairments. Early treatment of vascular disease might mitigate some executive dysfunction in a subset of patients with PD.
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http://dx.doi.org/10.1002/mdc3.12956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396844PMC
August 2020

Hallucinations and Development of Dementia in Parkinson's Disease.

J Parkinsons Dis 2020 ;10(4):1643-1648

Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA.

Neuropsychiatric symptoms are common in Parkinson's disease (PD). We investigated the relationship between neuropsychiatric symptoms and current and future diagnosis of PD dementia (PDD). Individuals with PD who had a study partner were enrolled (n = 696). Study partners were administered the Neuropsychiatric Inventory or Neuropsychiatric Inventory Questionnaire at baseline. Participants were assigned a cognitive diagnosis at baseline and follow up visits. Hallucinations were significantly associated with a diagnosis of PDD cross-sectionally (p < 0.001) and with shortened time to dementia longitudinally among initially nondemented participants (n = 444; p = 0.005). Screening for hallucinations may be useful for assessing risk of dementia in participants with PD.
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http://dx.doi.org/10.3233/JPD-202116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609584PMC
January 2020

Arterial spin labeling detects perfusion patterns related to motor symptoms in Parkinson's disease.

Parkinsonism Relat Disord 2020 07 11;76:21-28. Epub 2020 May 11.

Integrated Brain Imaging Center, Radiology, University of Washington Medical Center, Seattle, WA, USA.

Introduction: Imaging neurovascular disturbances in Parkinson's disease (PD) is an excellent measure of disease severity. Indeed, a disease-specific regional pattern of abnormal metabolism has been identified using positron emission tomography. Only a handful of studies, however, have applied perfusion MRI to detect this disease pattern. Our goal was to replicate the evaluation of a PD-related perfusion pattern using scaled subprofile modeling/principal component analysis (SSM-PCA).

Methods: We applied arterial spin labeling (ASL) MRI for this purpose. Uniquely, we assessed this pattern separately in PD individuals ON and OFF dopamine medications. We further compared the existence of these patterns and their strength in each individual with their Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor (MDS-UPDRS) scores, cholinergic tone as indexed by short-term afferent inhibition (SAI), and other neuropsychiatric tests.

Results: We observed a PD-related perfusion pattern that was similar to previous studies. The patterns were observed in both ON and OFF states but only the pattern in the OFF condition could significantly (AUC=0.72) differentiate between PD and healthy subjects. In the ON condition, PD subjects were similar to controls from a CBF standpoint (AUC=0.45). The OFF pattern prominently included the posterior cingulate, precentral region, precuneus, and the subcallosal cortex. Individual principal components from the ON and OFF states were strongly associated with MDS-UPDRS scores, SAI amplitude and latency.

Conclusion: Using ASL, our study identified patterns of abnormal perfusion in PD and were associated with disease symptoms.
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http://dx.doi.org/10.1016/j.parkreldis.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554132PMC
July 2020

Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau.

Brain 2020 03;143(3):932-943

Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089668PMC
March 2020

Participant and Study Partner Reported Impact of Cognition on Functional Activities in Parkinson's Disease.

Mov Disord Clin Pract 2020 Jan 14;7(1):61-69. Epub 2019 Dec 14.

Geriatric Research, Education, and Clinical Center Veterans Affairs Puget Sound Health Care System Seattle Washington USA.

Introduction: Cognitive dysfunction is common in Parkinson's disease (PD) and associated with reduced functional abilities and increased dependence. To date, however, little is known about the relationship between performance of instrumental activities of daily living (IADLs) and cognitive stages in PD, and there are conflicting reports as to whether declines in specific cognitive domains predict IADL impairment.

Methods: Participants with PD were drawn from the Pacific Udall Center and included in the study if both participant and study partner IADL ratings and cognitive tests were completed (n = 192). Logistic regression analyses were performed to determine whether participant and/or study partner rating predicted mild cognitive impairment or dementia. Correlations are reported for the relationship between participant/study partner IADL reports as well as for specific cognitive tests.

Results: Although both participant and study partner ratings of IADL performance were associated with a diagnosis of PD with dementia, only participant self-rating of functional ability was significantly associated with a diagnosis of PD with mild cognitive impairment. Functional ability correlated most strongly with measures of processing speed, auditory working memory, and immediate verbal recall for both the participant and study partner ratings.

Conclusion: For participants with PD in the early stages of cognitive decline, self-rating may be more sensitive to the impact of cognitive changes on IADL function than ratings made by a knowledgeable study partner. Changes in executive function, processing speed, and learning may indicate a higher likelihood of IADL impairment. Careful assessment of cognition and IADL performance is recommended to permit individualized interventions prior to significant disability.
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http://dx.doi.org/10.1002/mdc3.12870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962683PMC
January 2020

Cognitive Correlates of MRI-defined Cerebral Vascular Injury and Atrophy in Elderly American Indians: The Strong Heart Study.

J Int Neuropsychol Soc 2020 03 3;26(3):263-275. Epub 2019 Dec 3.

Department of Psychology and Psychology Clinical Neuroscience Center, University of New Mexico, Albuquerque, NM, USA.

Objective: American Indians experience substantial health disparities relative to the US population, including vascular brain aging. Poorer cognitive test performance has been associated with cranial magnetic resonance imaging findings in aging community populations, but no study has investigated these associations in elderly American Indians.

Methods: We examined 786 American Indians aged 64 years and older from the Cerebrovascular Disease and its Consequences in American Indians study (2010-2013). Cranial magnetic resonance images were scored for cortical and subcortical infarcts, hemorrhages, severity of white matter disease, sulcal widening, ventricle enlargement, and volumetric estimates for white matter hyperintensities (WMHs), hippocampus, and brain. Participants completed demographic, medical history, and neuropsychological assessments including testing for general cognitive functioning, verbal learning and memory, processing speed, phonemic fluency, and executive function.

Results: Processing speed was independently associated with the presence of any infarcts, white matter disease, and hippocampal and brain volumes, independent of socioeconomic, language, education, and clinical factors. Other significant associations included general cognitive functioning with hippocampal volume. Nonsignificant, marginal associations included general cognition with WMH and brain volume; verbal memory with hippocampal volume; verbal fluency and executive function with brain volume; and processing speed with ventricle enlargement.

Conclusions: Brain-cognition associations found in this study of elderly American Indians are similar to those found in other racial/ethnic populations, with processing speed comprising an especially strong correlate of cerebrovascular disease. These findings may assist future efforts to define opportunities for disease prevention, to conduct research on diagnostic and normative standards, and to guide clinical evaluation of this underserved and overburdened population.
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http://dx.doi.org/10.1017/S1355617719001073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083690PMC
March 2020

Cognitive associations with comprehensive gait and static balance measures in Parkinson's disease.

Parkinsonism Relat Disord 2019 12 4;69:104-110. Epub 2019 Jul 4.

Department of Neurology, Oregon Health and Science University, Portland, OR, USA; Portland Veterans Affairs Health Care System, Portland, OR, USA. Electronic address:

Introduction: Gait and balance impairments are cardinal features of Parkinson's disease (PD) that require cognitive input. However, the extent to which specific gait and balance characteristics relate to cognition in PD is unclear. In addition, independent models of gait and balance have not been developed from the same cohort. We aimed to i) develop models of gait and balance in a large PD cohort and ii) determine which gait and balance characteristics best related to cognition.

Methods: One hundred and ninety-eight people with PD were recruited to the Pacific Udall Center. Using six inertial sensors (APDM, Inc.), comprehensive gait measurements were collected over a 2-min continuous walk and comprehensive static balance measures were collected during a 60-second standing task. Six domains of cognition were assessed: global cognition, attention, executive function, language, memory, and visuospatial function. Correlations and hierarchical linear regression determined independent associations.

Results: Principal components analysis identified a gait model containing four domains accounting for 80.1% of total variance: pace/turning, rhythm, variability, and trunk. The balance model contained four independent domains accounting for 84.5% of total variance: sway area/jerkiness, sway velocity, sway frequency anteroposterior, and sway frequency mediolateral. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function.

Conclusions: Gait and balance characteristics were associated with specific types of cognition. The specific relationships between gait or balance with cognitive functions suggests shared cerebral cortical circuitry for mobility and cognitive functions.
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http://dx.doi.org/10.1016/j.parkreldis.2019.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900452PMC
December 2019

The associations among sociocultural factors and neuropsychological functioning in older American Indians: The Strong Heart Study.

Neuropsychology 2019 Nov 25;33(8):1078-1088. Epub 2019 Jul 25.

Institute for Education and Research to Advance Community Health.

Objective: Valid neuropsychological assessment is critical to the accurate diagnosis and effective treatment of diverse populations. American Indians and Alaska Natives experience substantial health disparities relative to the general U.S.

Population: Given the dearth of studies on neuropsychological health in this population, we aimed to characterize neuropsychological performance among older American Indians with respect to age, sex, education, income, and language use.

Method: From 2010 to 2014, we recruited 818 American Indians aged 60 and older from the Cerebrovascular Disease and Its Consequences in American Indians Study, who comprised all of the surviving members of a cardiovascular study (Strong Heart Study). This cohort from 11 tribes resided on or near their home reservations in three geographic regions (Northern Plains, Southern Plains, and Southwest). Using a cross-sectional design investigating potential vascular brain injury, we administered a brief, targeted neuropsychological and motor function assessments.

Results: Higher scores on neuropsychological tests were associated with younger age, female sex, more education, higher income, and less Native American language use. Similar associations were found for the motor tests, although men had higher scores on both motor function tests. After accounting for other sociocultural and health factors, age, sex, education, income, and Native American language use all had significant associations to the test scores.

Conclusions: Our findings may be used to guide research and inform clinical practice. The development of future normative studies for older American Indians will be more culturally appropriate when sociocultural factors are included. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048411PMC
November 2019

Visuospatial functioning is associated with sleep disturbance and hallucinations in nondemented patients with Parkinson's disease.

J Clin Exp Neuropsychol 2019 10 10;41(8):803-813. Epub 2019 Jun 10.

g Department of Pathology, Stanford University School of Medicine , Palo Alto , CA , USA.

: Cognitive impairment is a common symptom of Parkinson's disease (PD) associated with reduced quality of life and a more severe disease state. Previous research has shown an association between visuospatial dysfunction and worse disease course; however, it is not clear whether this is separable from executive dysfunction and/or dementia. This study sought to determine whether distinct cognitive factors could be measured in a large PD cohort, and if those factors were differentially associated with other PD-related features, specifically to provide insight into visuospatial dysfunction. : Non-demented participants with PD from the Pacific Udall Center were enrolled (n = 197). Co-participants (n = 104) completed questionnaires when available. Principal components factor analysis (PCFA) was utilized to group the neuropsychological test scores into independent factors by considering those with big factor loading (≥.40). Linear and logistic regression analyses were performed to examine the relationship between the cognitive factors identified in the PCFA and other clinical features of PD. : Six factors were extracted from the PCFA: 1) executive/processing speed, 2) visual learning & memory/visuospatial, 3) auditory working memory, 4) contextual verbal memory, 5) semantic learning & memory, and 6) visuospatial. Motor severity (p = 0.001), mood (p < 0.001), and performance on activities of daily living scores (informant: p < 0.001, patient: p = 0.009) were primarily associated with frontal and executive factors. General sleep disturbance (p < 0.006) and hallucinations (p = 0.002) were primarily associated with visuospatial functioning and visual learning/memory. : Motor symptoms, mood, and performance on activities of daily living were primarily associated with frontal/executive factors. Sleep disturbance and hallucinations were associated with visuospatial functioning and visual learning/memory only, over and above executive functioning and regardless of cognitive disease severity. These findings support that visuospatial function in PD may indicate a more severe disease course, and that symptom management should be guided accordingly.
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http://dx.doi.org/10.1080/13803395.2019.1623180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681669PMC
October 2019

Type 2 diabetes and later cognitive function in older American Indians: The Strong Heart Study.

Int J Geriatr Psychiatry 2019 07 15;34(7):1050-1057. Epub 2019 Apr 15.

Department of Community Health, Washington State University, Seattle, WA, USA.

Objectives: Insulin resistance is a substantial health issue for American Indians, with type 2 diabetes overrepresented in this population as compared with non-Hispanic whites. Insulin resistance and its related conditions in turn increase risk for dementia and cognitive impairment. The aim of the current study was to determine whether type 2 diabetes and insulin resistance at midlife was associated with later-life cognitive testing in a large sample of older American Indians, aged 65 and older.

Methods: American Indian participants who underwent both fasting blood draw as part of the Strong Heart Study and had subsequent cognitive testing as part of the later adjunct Cerebrovascular Disease and its Consequences in American Indians study were included (n = 790). Regression models examined type 2 diabetes and impaired fasting glucose and subsequent cognitive test performance as part of a longitudinal study design. The relationship between a continuous measure of insulin resistance and later cognitive test performance was assessed using generalized estimating equations.

Results: Controlling for demographic and clinical factors, verbal fluency and processing speed/working memory were significantly negatively associated with having type 2 diabetes and with insulin resistance, but not with impaired fasting glucose.

Conclusion: In this sample of American Indians, type 2 diabetes at midlife was associated with subsequent lower performance on measures of executive function. These results may have important implications for future implementation of diagnostic and intervention services in this population.
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http://dx.doi.org/10.1002/gps.5108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579638PMC
July 2019

Cognitive Performance in Parkinson's Disease in the Brain Health Registry.

J Alzheimers Dis 2019 ;68(3):1029-1038

Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA.

The study of cognition in Parkinson's disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer's disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥50) with self-reported PD data and online cognitive testing available were included (n = 11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values < 0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies.
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http://dx.doi.org/10.3233/JAD-181009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497062PMC
August 2020

Using Varying Diagnostic Criteria to Examine Mild Cognitive Impairment Prevalence and Predict Dementia Incidence in a Community-Based Sample.

J Alzheimers Dis 2019 ;68(4):1439-1451

Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.

Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed = 5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant's mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI prevalence ranged from 56-92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk.
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http://dx.doi.org/10.3233/JAD-180746DOI Listing
August 2020

Concepts for brain aging: resistance, resilience, reserve, and compensation.

Alzheimers Res Ther 2019 03 11;11(1):22. Epub 2019 Mar 11.

Pacific Health Research and Education Institute, Honolulu, HI, USA.

A primary goal of research in cognitive impairment and dementia is to understand how some individuals retain sufficient cognitive function for a fulfilling life while many others are robbed of their independence, sometimes their essence, in the last years and decades of life. In this commentary, we propose operational definitions of the types of factors that may help individuals retain cognitive function with aging. We propose operational definitions of resistance, resilience, reserve, with an eye toward how these may be measured and interpreted, and how they may enable research aimed at prevention. With operational definitions and quantification of resistance, resilience, and reserve, a focused analytic search for their determinants and correlates can be undertaken. This approach, essentially a search to identify protective risk factors and their mechanisms, represents a relatively unexplored pathway toward the identification of candidate preventive interventions.
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http://dx.doi.org/10.1186/s13195-019-0479-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410486PMC
March 2019

An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ε4 allele.

Neurobiol Dis 2019 07 28;127:278-286. Epub 2019 Feb 28.

Stanford University, Department of Neurology and Neurological Sciences, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America; Stanford University, Department of Neurosurgery, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America. Electronic address:

Objective: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aβ-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aβ-42 compared to patients with normal levels.

Methods: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aβ-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Aβ at baseline, PD participants with normal CSF Aβ, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education.

Results: 423 de novo PD participants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Aβ-42 (39 APOE ε4+, 64 APOE ε4-). Compared to participants with normal CSF Aβ-42, those with low CSF Aβ-42 declined faster on most cognitive tests. Within the low CSF Aβ-42 group, APOE ε4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72).

Discussion: PD patients with low CSF Aβ-42 and APOE ε4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Aβ-42 and APOE ε4 might interact to promote early cognitive changes in PD patients.
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http://dx.doi.org/10.1016/j.nbd.2019.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588475PMC
July 2019

Comparative sensitivity of the MoCA and Mattis Dementia Rating Scale-2 in Parkinson's disease.

Mov Disord 2019 02 10;34(2):285-291. Epub 2018 Dec 10.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.

Background: Clinicians and researchers commonly use global cognitive assessments to screen for impairment. Currently there are no published studies directly comparing the sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD. The objective of this study was to identify the relative sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD.

Methods: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 were administered to training and validation cohorts. Cutoff scores were determined within the training cohort (n = 85) to optimize sensitivity and specificity for cognitive impairment and were applied to an independent validation cohort (n = 521).

Results: The Montreal Cognitive Assessment was consistently sensitive across training and validation cohorts (90.0% and 80.3%, respectively), whereas the Mattis Dementia Rating Scale-2 was not (87.5% and 60.3%, respectively). In individual domains, the Montreal Cognitive Assessment remained sensitive to memory and visuospatial impairments (91.9% and 87.8%, respectively), whereas the Mattis Dementia Rating Scale-2 was sensitive to executive impairments (86.2%).

Conclusion: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 demonstrated individual strengths. Future work should focus on developing domain-specific cognitive screening tools for PD. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532623PMC
February 2019

Prediction of cognitive progression in Parkinson's disease using three cognitive screening measures.

Clin Park Relat Disord 2019 20;1:91-97. Epub 2019 Oct 20.

Department of Pathology, Stanford University School of Medicine, Palo Alto, California.

Introduction: Cognitive impairment is a common complication of Parkinson's disease (PD) and identifying risk factors for progression to Parkinson's disease dementia (PDD) is important. However, little research has been done comparing the utility of commonly used cognitive screening tests in predicting cognitive progression in PD.

Methods: We retrospectively reviewed data from patients with PD enrolled in the Pacific Udall Center who had baseline and longitudinal neuropsychological and global cognitive screening tests. The diagnostic accuracies of 3 common screening tests were compared: Montreal Cognitive Assessment (MoCA), Mattis Dementia Rating Scale (DRS-2), and Mini Mental Status Examination (MMSE). Cognitive diagnoses of PD with mild cognitive impairment (PD-MCI) and PDD were based on full neuropsychological testing and established Movement Disorder Society criteria. Logistic regression and Cox proportional hazards regression models were used to examine predictors of cognitive decline.

Results: Four hundred seventy patients for whom scores on all 3 screening tests were available from the same assessment were included in a cross-sectional analysis. The MoCA demonstrated the best overall diagnostic accuracy for PD-MCI (AUC= 0.79, sensitivity= 76.4%) and for PDD (AUC= 0.89, sensitivity= 81.0%) compared to the DRS-2 and MMSE. A longitudinal analysis was performed on the subset of patients (316/470; 67.2%) who were nondemented at baseline and had undergone two or more assessments. After controlling for covariates, the MoCA was the only test associated with progression to PDD (OR= 1.27 95% CI 1.1 - 1.5, p=0.001) and faster time to dementia (HR = 1.3, 95% CI 1.1 - 1.4, p<0.0001).

Conclusions: This study provides additional support for the use of the MoCA as a primary screening tool for cognitive impairment in PD and is the first to show that the MoCA is a predictor of conversion to PDD.
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http://dx.doi.org/10.1016/j.prdoa.2019.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197868PMC
October 2019

TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study.

J Alzheimers Dis 2018 ;66(4):1549-1558

Department of Pathology, Stanford University, Stanford, CA, USA.

Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57-34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features.
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http://dx.doi.org/10.3233/JAD-180162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382067PMC
November 2019

Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease.

Parkinsonism Relat Disord 2018 05 9;50:29-36. Epub 2018 Feb 9.

Department of Epidemiology, University of California, Irvine, School of Medicine, Irvine, CA, USA.

Introduction: Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease.

Methods: Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD.

Results: Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males.

Conclusions: This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.
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http://dx.doi.org/10.1016/j.parkreldis.2018.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943177PMC
May 2018

Quantitative cerebrovascular pathology in a community-based cohort of older adults.

Neurobiol Aging 2018 05 31;65:77-85. Epub 2018 Jan 31.

Radiology, University of Washington Medical Center, Seattle, WA, USA.

Cerebrovascular disease, especially small vessel pathology, is the leading comorbidity in degenerative disorders. We applied arterial spin labeling and cerebrovascular reserve (CVR) imaging to quantify small vessel disease and study its effect on cognitive symptoms in nondemented older adults from a community-based cohort. We evaluated baseline cerebral blood flow (CBF) using arterial spin labeling and percent signal change as a marker of CVR using blood-oxygen level-dependent imaging following a breath-hold stimulus. Measurements were performed in and near white matter hyperintensities, which are currently the standard to assess severity of vascular pathology. We show that similar to other studies (1) CBF and CVR are markedly reduced in the hyperintensities as well as in the tissue surrounding them, indicating susceptibility to infarction; (2) low CBF and CVR are significantly correlated with poor cognitive performance; and (3) in addition, compared to a 58.4% reduction in CBF, larger exhaustion (79.3%) of CVR was observed in the hyperintensities with a faster, nonlinear rate of decline. We conclude that CVR may be a more sensitive biomarker of small vessel disease than CBF.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871567PMC
May 2018

Associations between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex.

J Alzheimers Dis 2018 ;61(2):653-662

Department of Pathology, Stanford University, Stanford, CA, USA.

Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer's disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex.
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http://dx.doi.org/10.3233/JAD-170414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745256PMC
January 2019

Homocysteine and cognitive function in Parkinson's disease.

Parkinsonism Relat Disord 2017 Nov 9;44:1-5. Epub 2017 Aug 9.

Department of Neurology, Oregon Health and Science University, Portland, OR, United States; Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, United States. Electronic address:

Introduction: Increased plasma homocysteine (HC) is a risk factor for dementia in the general population. Levodopa therapy causes increased plasma HC, but it remains unclear whether elevated plasma HC is associated with cognitive impairment in Parkinson's disease (PD).

Methods: The study population includes all participants in the Pacific Northwest Udall Center (PANUC) Clinical cohort at the time of the study, consisting of 294 individuals with PD who had a standardized neuropsychological assessment and plasma collection for HC measurement. We tested the hypothesis that elevated plasma HC is inversely related to cognitive function in patients with PD.

Results: As expected, plasma HC was positively associated with age, disease duration, disease severity, and levodopa usage, while cognitive function was associated with age, education, gender, and APOE genotype, so subsequent analyses controlled for these covariates. When plasma HC was dichotomized as normal (<14 μmol/L) or elevated (≥14 μmol/L), subjects with hyper-homocysteinemia had lower scores on Digit Symbol (p = 0.031), Hopkins Verbal Learning Task (HVLT) Delayed Recall (p = 0.004), and semantic verbal fluency (p = 0.049). When examined as a continuous variable, plasma HC was inversely associated with HVLT Delayed Recall (p = 0.009)) and semantic verbal fluency (p = 0.004), but was not significantly related to Digit symbol, Trail-making test, Judgment of Line Orientation, phonemic verbal fluency, MMSE, or MOCA. When analysis was restricted to non-demented subjects (n = 231), the findings were unchanged.

Conclusions: We conclude that plasma HC is significantly associated with some aspects of cognitive function in PD, and may represent a treatable risk factor for cognitive decline in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858907PMC
November 2017

Total Brain and Hippocampal Volumes and Cognition in Older American Indians: The Strong Heart Study.

Alzheimer Dis Assoc Disord 2017 Apr-Jun;31(2):94-100

*Department of Pathology, Stanford University, Palo Alto, CA †Institute for Research and Education to Advance Community Health, Washington State University, Seattle, WA ∥College of Nursing, Washington State University, Seattle, WA Departments of ‡Radiology §Neurology, School of Medicine **Epidemiology, School of Public Health, University of Washington, Seattle, WA ††College of Medicine, Washington State University, Seattle, WA ¶Department of Psychology, University of New Mexico, Albuquerque, NM #MedStar Health Research Institute, Hyattsville, MD.

Background: Estimates of hippocampal volume by magnetic resonance imaging have clinical and cognitive correlations and can assist in early Alzheimer disease diagnosis. However, little is known about the relationship between global or regional brain volumes and cognitive test performance in American Indians.

Materials And Methods: American Indian participants (N=698; median age, 72 y) recruited for the Cerebrovascular Disease and its Consequences in American Indians study, an ancillary study of the Strong Heart Study cohort, were enrolled. Linear regression models assessed the relationship between magnetic resonance imaging brain volumes (total brain and hippocampi) and cognitive measures of verbal learning and recall, processing speed, verbal fluency, and global cognition.

Results: After controlling for demographic and clinical factors, all volumetric measurements were positively associated with processing speed. Total brain volume was also positively associated with verbal learning, but not with verbal recall. Conversely, left hippocampal volume was associated with both verbal learning and recall. The relationship between hippocampal volume and recall performance was more pronounced among those with lower scores on a global cognitive measure. Controlling for APOE ε4 did not substantively affect the associations.

Conclusions: These results support further investigation into the relationship between structural Alzheimer disease biomarkers, cognition, genetics, and vascular risk factors in aging American Indians.
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http://dx.doi.org/10.1097/WAD.0000000000000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492994PMC
December 2017

Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease.

Neurobiol Aging 2017 08 20;56:211.e1-211.e7. Epub 2017 Apr 20.

Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. Electronic address:

Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (P) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; P = 2.7 × 10) for JoLO, PARP4 rs9318600 (P = 0.006), and rs9581094 (P = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (P = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536182PMC
August 2017

Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial.

J Alzheimers Dis 2017 ;57(4):1325-1334

Seattle Children's Hospital, Seattle, WA, USA.

Background: Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.

Objective: The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.

Methods: This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.

Results: The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio.

Conclusion: Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.
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http://dx.doi.org/10.3233/JAD-161256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409050PMC
February 2018