Publications by authors named "Kathleen L Poston"

47 Publications

Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease.

Mov Disord 2021 May 4. Epub 2021 May 4.

Paracelsus-Elena-Klinik, Kassel, Germany.

Background: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).

Objective: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.

Methods: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.

Results: Baseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug-naive individuals, but some changed on starting levodopa treatment.

Conclusions: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28608DOI Listing
May 2021

Neuropathological correlation supports automated image-based differential diagnosis in parkinsonism.

Eur J Nucl Med Mol Imaging 2021 Apr 10. Epub 2021 Apr 10.

Center for Neurosciences, The Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.

Purpose: Up to 25% of patients diagnosed as idiopathic Parkinson's disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long-term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known.

Methods: Patients with an uncertain diagnosis of parkinsonism were referred for F-fluorodeoxyglucose (FDG) PET to classify patients as IPD or as APS based on the automated algorithm. Patients were followed by a movement disorder specialist and subsequently underwent neuropathological examination. The image-based classification was compared to the neuropathological diagnosis in 15 patients with parkinsonism.

Results: At the time of referral to PET, the clinical impression was only 66.7% accurate. The algorithm correctly identified 80% of the cases as IPD or APS (p = 0.02) and 87.5% of the APS cases as MSA or PSP (p = 0.03). The final clinical diagnosis was 93.3% accurate (p < 0.001), but needed several years of expert follow-up.

Conclusion: The image-based classifications agreed well with autopsy and can help to improve diagnostic accuracy during the period of clinical uncertainty.
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http://dx.doi.org/10.1007/s00259-021-05302-6DOI Listing
April 2021

Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology.

J Alzheimers Dis 2021 ;80(3):1243-1256

Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.

Background: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.

Objective: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.

Methods: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).

Results: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.

Conclusion: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.
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http://dx.doi.org/10.3233/JAD-201187DOI Listing
January 2021

Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aβ.

Parkinsonism Relat Disord 2021 Feb 12;83:71-78. Epub 2021 Jan 12.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA; Department of Neurosurgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. Electronic address:

Introduction: To identify clinically implementable biomarkers of cognitive impairment in Parkinson's Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis.

Methods: In this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aβ-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments.

Results: LHC-RHC (F = 3.41,p=0.023) and CSF Aβ-42:40 (χ(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment.

Conclusion: We used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940579PMC
February 2021

Dopamine transporter imaging predicts clinically-defined α-synucleinopathy in REM sleep behavior disorder.

Ann Clin Transl Neurol 2021 01 15;8(1):201-212. Epub 2020 Dec 15.

Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain.

Introduction: Individuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α-synucleinopathy (aSN). They could serve as a key population for disease-modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically-defined aSN in iRBD.

Methods: The sample included individuals with iRBD, early Parkinson's Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow-up versus those not diagnosed.

Results: The sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT-SPECT at baseline. Over 4.7 years of mean follow-up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79-83.3], P = 0.0003).

Conclusion: We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short-term risk of an aSN diagnosis.
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http://dx.doi.org/10.1002/acn3.51269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818144PMC
January 2021

Single-cell peripheral immunoprofiling of Alzheimer's and Parkinson's diseases.

Sci Adv 2020 Nov 25;6(48). Epub 2020 Nov 25.

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

Peripheral blood mononuclear cells (PBMCs) may provide insight into the pathogenesis of Alzheimer's disease (AD) or Parkinson's disease (PD). We investigated PBMC samples from 132 well-characterized research participants using seven canonical immune stimulants, mass cytometric identification of 35 PBMC subsets, and single-cell quantification of 15 intracellular signaling markers, followed by machine learning model development to increase predictive power. From these, three main intracellular signaling pathways were identified specifically in PBMC subsets from people with AD versus controls: reduced activation of PLCγ2 across many cell types and stimulations and selectively variable activation of STAT1 and STAT5, depending on stimulant and cell type. Our findings functionally buttress the now multiply-validated observation that a rare coding variant in is associated with a decreased risk of AD. Together, these data suggest enhanced PLCγ2 activity as a potential new therapeutic target for AD with a readily accessible pharmacodynamic biomarker.
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http://dx.doi.org/10.1126/sciadv.abd5575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688332PMC
November 2020

Quantitative Digitography Measures Fine Motor Disturbances in Chronically Treated HIV Similar to Parkinson's Disease.

Front Aging Neurosci 2020 7;12:539598. Epub 2020 Oct 7.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States.

: Motor and cognitive deficits were compared in aging, chronically treated human immunodeficiency virus (HIV) people, people with mild-to-moderate stage Parkinson's disease (PD), and healthy controls. : Groups consisted of 36 people with PD, 28 with HIV infection, and 28 healthy controls. Motor function was assessed with the Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) and a rapid alternating finger tapping (RAFT) task on an engineered keyboard known as Quantitative Digitography (QDG). Executive function, verbal memory, and visuospatial processing were assessed using standard neuropsychological tests. : HIV demonstrated RAFT deficits similar to PD such as reduced amplitude ( = 0.023) and greater amplitude variability ( = 0.019) in the index finger when compared to controls. This fine motor disturbance correlated with HIV's immune health, measured by their CD4 T cell count ( < 0.01). The UPDRS did not yield motor differences between HIV and controls. Executive function and verbal memory were impaired in HIV ( = 0.006, = 0.016, respectively), but not in PD; visuospatial processing was similarly impaired in HIV and PD ( < 0.05) although motor deficits predominated in PD. : Fine motor bradykinesia measured quantitatively by QDG RAFT holds promise as a marker of motor decline related to current immune health in aging HIV patients and may be useful in longitudinal studies regarding mechanisms of immunosenescence vs. potential toxicity of combination antiretroviral therapy (cART) in this population. Additionally, motor and cognitive networks in HIV may be affected differently as the disease progresses as observed in the differential patterns of impairment between HIV and PD, providing insight into the mechanisms of brain deterioration in HIV.
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http://dx.doi.org/10.3389/fnagi.2020.539598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575770PMC
October 2020

Cognitive and motor deficits in older adults with HIV infection: Comparison with normal ageing and Parkinson's disease.

J Neuropsychol 2020 Oct 8. Epub 2020 Oct 8.

Neuroscience Program, Bioscience Division, Center for Health Sciences, SRI International, Menlo Park, California, USA.

Despite the life-extending success of antiretroviral pharmacotherapy in HIV infection (HIV), the prevalence of mild cognitive impairment in HIV remains high. Near-normal life expectancy invokes an emerging role for age-infection interaction and a potential synergy between immunosenescence and HIV-related health factors, increasing risk of cognitive and motor impairment associated with degradation in corticostriatal circuits. These neural systems are also compromised in Parkinson's disease (PD), which could help model the cognitive deficit pattern in HIV. This cross-sectional study examined three groups, age 45-79 years: 42 HIV, 41 PD, and 37 control (CTRL) participants, tested at Stanford University Medical School and SRI International. Neuropsychological tests assessed executive function (EF), information processing speed (IPS), episodic memory (MEM), visuospatial processing (VSP), and upper motor (MOT) speed and dexterity. The HIV and PD deficit profiles were similar for EF, MEM, and VSP. Although only the PD group was impaired on MOT compared with CTRL, MOT scores were related to cognitive scores in HIV but not PD. Performance was not related to depressive symptoms, socioeconomic status, or CD4 T-cell counts. The overlap of HIV-PD cognitive deficits implicates frontostriatal disruption in both conditions. The motor-cognitive score relation in HIV provides further support for the hypothesis that these processes share similar underlying mechanisms in HIV infection possibly expressed with or exacerbated by ageing.
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http://dx.doi.org/10.1111/jnp.12227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026757PMC
October 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

Alterations of Brain Signal Oscillations in Older Individuals with HIV Infection and Parkinson's Disease.

J Neuroimmune Pharmacol 2021 Jun 14;16(2):289-305. Epub 2020 Apr 14.

Neuroscience Program, Biosciences Division, Center for Health Sciences, SRI International, Menlo Park, CA, USA.

More than 30 years after the human immunodeficiency virus (HIV) epidemic, HIV patients are now aging due to the advances of antiretroviral therapy. With immunosenescence and the susceptibility of dopamine-rich basal ganglia regions to HIV-related injury, older HIV patients may show neurofunctional deficits similar to patients with Parkinson's disease (PD). We examined the amplitudes of low frequency fluctuations (ALFF) across different frequency bands of the BOLD signal in 30 older HIV-infected individuals, 33 older healthy controls, and 36 PD patients. Participants underwent resting-state fMRI, neuropsychological testing, and a clinical motor exam. HIV patients mainly showed abnormalities in cortical ALFF with reduced prefrontal amplitudes and enhanced sensorimotor and inferior temporal amplitudes. Frontal hypoactivation was overlapping for HIV and PD groups and different from controls. PD patients further exhibited reduced pallidum amplitudes compared to the other groups. In the HIV group, lower pallidum amplitudes were associated with lower CD4 nadir and CD4 T cell counts. Abnormalities in ALFF dynamics were largely associated with cognitive and motor functioning in HIV and PD groups. The disruption of neurofunctional frequency dynamics in subcortical-cortical circuits could contribute to the development of cognitive and motor dysfunction and serve as a biomarker for monitoring disease progression with immunosenescence. Graphical Abstract.
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http://dx.doi.org/10.1007/s11481-020-09914-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554056PMC
June 2021

Substantia Nigra Volume Dissociates Bradykinesia and Rigidity from Tremor in Parkinson's Disease: A 7 Tesla Imaging Study.

J Parkinsons Dis 2020 ;10(2):591-604

Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.

Background: In postmortem analysis of late stage Parkinson's disease (PD) neuronal loss in the substantial nigra (SN) correlates with the antemortem severity of bradykinesia and rigidity, but not tremor.

Objective: To investigate the relationship between midbrain nuclei volume as an in vivo biomarker for surviving neurons in mild-to-moderate patients using 7.0 Tesla MRI.

Methods: We performed ultra-high resolution quantitative susceptibility mapping (QSM) on the midbrain in 32 PD participants with less than 10 years duration and 8 healthy controls. Following blinded manual segmentation, the individual volumes of the SN, subthalamic nucleus, and red nucleus were measured. We then determined the associations between the midbrain nuclei and clinical metrics (age, disease duration, MDS-UPDRS motor score, and subscores for bradykinesia/rigidity, tremor, and postural instability/gait difficulty).

Results: We found that smaller SN correlated with longer disease duration (r = -0.49, p = 0.004), more severe MDS-UPDRS motor score (r = -0.42, p = 0.016), and more severe bradykinesia-rigidity subscore (r = -0.47, p = 0.007), but not tremor or postural instability/gait difficulty subscores. In a hemi-body analysis, bradykinesia-rigidity severity only correlated with SN contralateral to the less-affected hemi-body, and not contralateral to the more-affected hemi-body, possibly reflecting the greatest change in dopamine neuron loss early in disease. Multivariate generalized estimating equation model confirmed that bradykinesia-rigidity severity, age, and disease duration, but not tremor severity, predicted SN volume.

Conclusions: In mild-to-moderate PD, SN volume relates to motor manifestations in a motor domain-specific and laterality-dependent manner. Non-invasive in vivo 7.0 Tesla QSM may serve as a biomarker in longitudinal studies of SN atrophy and in studies of people at risk for developing PD.
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http://dx.doi.org/10.3233/JPD-191890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242837PMC
January 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

MRI biomarkers of motor and non-motor symptoms in Parkinson's disease.

Parkinsonism Relat Disord 2020 04 10;73:85-93. Epub 2019 Oct 10.

Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, 300 Pasteur Dr. Room A343. MC-5235, Stanford, CA, 94305, USA. Electronic address:

Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. There is emerging evidence that iron sensitive, neuromelanin sensitive, diffusion sensitive, and resting state functional magnetic imaging measures can capture changes within the nigrostriatal system. Iron, neuromelanin, and diffusion sensitive measures demonstrate high specificity and sensitivity in distinguishing Parkinson's disease relative to controls, with inconsistent results differentiating Parkinson's disease relative to atypical parkinsonian disorders. They may also serve as useful monitoring biomarkers, with each possibly detecting different aspects of the disease course (early nigrosome changes versus broader substantia nigra changes). Investigations of non-motor symptoms, such as cognitive impairment, require careful consideration of the nature of cognitive deficits to characterize regional and network specific impairment. While the early, executive dysfunction observed is consistent with nigrostriatal degeneration, the memory and visuospatial impairments, the harbingers of a dementia process reflect dopaminergic independent dysfunction involving broader regions of the brain.
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http://dx.doi.org/10.1016/j.parkreldis.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145760PMC
April 2020

Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson's disease.

Neurosci Biobehav Rev 2019 08 24;103:305-315. Epub 2019 May 24.

Department of Psychology, Palo Alto University, 1791 Arastradero Rd, Palo Alto, CA, 94304, USA; Neuroscience Program, Center for Health Sciences, Bioscience Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025, USA. Electronic address:

Recent evidence has advanced our understanding of the function of sleep to include removal of neurotoxic protein aggregates via the glymphatic system. However, most research on the glymphatic system utilizes animal models, and the function of waste clearance processes in humans remains unclear. Understanding glymphatic function offers new insight into the development of neurodegenerative diseases that result from toxic protein inclusions, particularly those characterized by neuropathological sleep dysfunction, like Parkinson's disease (PD). In PD, we propose that glymphatic flow may be compromised due to the combined neurotoxic effects of alpha-synuclein protein aggregates and deteriorated dopaminergic neurons that are linked to altered REM sleep, circadian rhythms, and clock gene dysfunction. This review highlights the importance of understanding the functional role of glymphatic system disturbance in neurodegenerative disorders and the subsequent clinical and neuropathological effects on disease progression. Future research initiatives utilizing noninvasive brain imaging methods in human subjects with PD are warranted, as in vivo identification of functional biomarkers in glymphatic system functioning may improve clinical diagnosis and treatment of PD.
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http://dx.doi.org/10.1016/j.neubiorev.2019.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692229PMC
August 2019

Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease.

Neuroimage Clin 2019 18;23:101824. Epub 2019 Apr 18.

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

Objective: Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life.

Methods: We studied 29 participants with PD (age 65.5 ± 7.8 years; disease duration 4.5 ± 3.0 years) and 8 matched-healthy controls (age 67.9 ± 6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD.

Results: In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05).

Conclusions: In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.
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http://dx.doi.org/10.1016/j.nicl.2019.101824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500913PMC
April 2020

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

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

Episodic recognition memory and the hippocampus in Parkinson's disease: A review.

Cortex 2019 04 4;113:191-209. Epub 2018 Dec 4.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Parkinson's disease is a progressive neurodegenerative disorder of aging. The hallmark pathophysiology includes the development of neuronal Lewy bodies in the substantia nigra of the midbrain with subsequent loss of dopaminergic neurons. These neuronal losses lead to the characteristic motor symptoms of bradykinesia, rigidity, and rest tremor. In addition to these cardinal motor symptoms patients with PD experience a wide range of non-motor symptoms, the most important being cognitive impairments that in many circumstances lead to dementia. People with PD experience a wide range of cognitive impairments; in this review we will focus on memory impairment in PD and specifically episodic memory, which are memories of day-to-day events of life. Importantly, these memory impairments severely impact the lives of patients and caregivers alike. Traditionally episodic memory is considered to be markedly dependent on the hippocampus; therefore, it is important to understand the exact nature of PD episodic memory deficits in relation to hippocampal function and dysfunction. In this review, we discuss an aspect of episodic memory called recognition memory and its subcomponents called recollection and familiarity. Recognition memory is believed to be impaired in PD; thus, we discuss what aspects of the hippocampus are expected to be deficient in function as they relate to these recognition memory impairments. In addition to the hippocampus as a whole, we will discuss the role of hippocampal subfields in recognition memory impairments.
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http://dx.doi.org/10.1016/j.cortex.2018.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445686PMC
April 2019

Ultra-Low-Dose F-Florbetaben Amyloid PET Imaging Using Deep Learning with Multi-Contrast MRI Inputs.

Radiology 2019 03 11;290(3):649-656. Epub 2018 Dec 11.

From the Departments of Radiology (K.T.C., F.B.d.C.M., S.S., G.Z.), Electrical Engineering (E.G., J.M.P.), and Neurology and Neurological Sciences (A.B., K.L.P., S.J.S., M.D.G., E.M.), Stanford University, 1201 Welch Rd, Stanford, CA 94305; Department of Engineering Physics, Tsinghua University, Beijing, PR China (J.X.); GE Healthcare, Menlo Park, Calif (M.K.); and Subtle Medical, Menlo Park, CA (E.G.).

Purpose To reduce radiotracer requirements for amyloid PET/MRI without sacrificing diagnostic quality by using deep learning methods. Materials and Methods Forty data sets from 39 patients (mean age ± standard deviation [SD], 67 years ± 8), including 16 male patients and 23 female patients (mean age, 66 years ± 6 and 68 years ± 9, respectively), who underwent simultaneous amyloid (fluorine 18 [F]-florbetaben) PET/MRI examinations were acquired from March 2016 through October 2017 and retrospectively analyzed. One hundredth of the raw list-mode PET data were randomly chosen to simulate a low-dose (1%) acquisition. Convolutional neural networks were implemented with low-dose PET and multiple MR images (PET-plus-MR model) or with low-dose PET alone (PET-only) as inputs to predict full-dose PET images. Quality of the synthesized images was evaluated while Bland-Altman plots assessed the agreement of regional standard uptake value ratios (SUVRs) between image types. Two readers scored image quality on a five-point scale (5 = excellent) and determined amyloid status (positive or negative). Statistical analyses were carried out to assess the difference of image quality metrics and reader agreement and to determine confidence intervals (CIs) for reading results. Results The synthesized images (especially from the PET-plus-MR model) showed marked improvement on all quality metrics compared with the low-dose image. All PET-plus-MR images scored 3 or higher, with proportions of images rated greater than 3 similar to those for the full-dose images (-10% difference [eight of 80 readings], 95% CI: -15%, -5%). Accuracy for amyloid status was high (71 of 80 readings [89%]) and similar to intrareader reproducibility of full-dose images (73 of 80 [91%]). The PET-plus-MR model also had the smallest mean and variance for SUVR difference to full-dose images. Conclusion Simultaneously acquired MRI and ultra-low-dose PET data can be used to synthesize full-dose-like amyloid PET images. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Catana in this issue.
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http://dx.doi.org/10.1148/radiol.2018180940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394782PMC
March 2019

Information processing deficit in older adults with HIV infection: A comparison with Parkinson's disease.

Neuropsychology 2019 Feb 26;33(2):157-168. Epub 2018 Nov 26.

Neuroscience Program, Center for Health Sciences, Bioscience Division, SRI International.

Objective: Individuals with HIV treated with antiretroviral therapy can expect to reach average life span, making them susceptible to combined disease and aging effects on cognitive and motor functions. Slowed processing speed in HIV is a concern for cognitive and everyday functioning and is sensitive to declines in aging. We hypothesized that information processing (IP) deficits, over and above that expected with normal aging, would occur in older HIV patients similar to those observed in Parkinson's disease (PD) patients, with both conditions affecting frontostriatal pathways.

Method: Groups comprised 26 individuals with HIV infection, 29 with mild-to-moderate PD, and 21 healthy controls (C). Speed of IP was assessed with the oral version of the Symbol Digit Modalities Test and the color naming condition of the Golden Stroop Task.

Results: The HIV group was impaired on speed of IP tasks compared with both the C and PD groups. Even after controlling for normal aging effects, older age in the HIV group correlated with IP slowing. Slower IP speed was associated with poorer general cognitive ability and more extrapyramidal motor signs in older HIV-infected individuals.

Conclusions: The notable effects of impaired IP speed, over and above neurotypical age-related declines, indicate that older HIV-infected individuals may have an enhanced vulnerability for developing nonmotor and motor symptoms despite antiretroviral therapy. Assessing for oral IP speed may provide the unique opportunity to identify early signs of progressive clinical declines in HIV. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372910PMC
February 2019

Dopamine-related dissociation of cortical and subcortical brain activations in cognitively unimpaired Parkinson's disease patients OFF and ON medications.

Neuropsychologia 2018 10 21;119:24-33. Epub 2018 Jul 21.

Stanford University Medical Center, Department of Neurology & Neurological Sciences, Stanford, CA 94305, USA; Stanford University Medical Center, Department of Neurosurgery, Stanford, CA 94305, USA. Electronic address:

Background: Despite dopaminergic depletion that is severe enough to cause the motor symptoms of Parkinson's disease (PD), many patients remain cognitively unimpaired. Little is known about brain mechanisms underlying such preserved cognitive abilities and their alteration by dopaminergic medications.

Objectives: We investigated brain activations underlying dopamine-related differences in cognitive function using a unique experimental design with PD patients off and on dopaminergic medications. We tested the dopamine overdose hypothesis, which posits that the excess of exogenous dopamine in the frontal cortical regions can impair cognition.

Methods: We used a two-choice forced response Choice Reaction Time (CRT) task to probe cognitive processes underlying response selection and execution. Functional magnetic resonance imaging data were acquired from 16 cognitively unimpaired (Level-II) PD participants and 15 well-matched healthy controls (HC). We compared task performance (i.e. reaction time and accuracy) and brain activation of PD participants off dopaminergic medications (PD_OFF) in comparison with HC, and PD_OFF participants with those on dopaminergic medications (PD_ON).

Results: PD_OFF and PD_ON groups did not differ from each other, or from the HC group, in reaction time or accuracy. Compared to HC, PD_OFF activated the bilateral putamen less, and this was compensated by higher activation of the anterior insula. No such differences were observed in the PD_ON group, compared to HC. Compared to both HC and PD_OFF, PD_ON participants showed dopamine-related hyperactivation in the frontal cortical regions and hypoactivation in the amygdala.

Conclusion: Our data provide further evidence that PD_OFF and PD_ON participants engage different cortical and subcortical systems to achieve similar levels of cognitive performance as HC. Crucially, our findings demonstrate dopamine-related dissociation in brain activation between cortical and subcortical regions, and provide novel support for the dopamine overdose hypothesis.
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http://dx.doi.org/10.1016/j.neuropsychologia.2018.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191343PMC
October 2018

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

Further study of the Montreal Cognitive Assessment's domain-specific metrics could allow for international data comparison and collaboration.

Parkinsonism Relat Disord 2018 03 21;48:101. Epub 2017 Nov 21.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2017.11.336DOI Listing
March 2018

Distinct alterations in Parkinson's medication-state and disease-state connectivity.

Neuroimage Clin 2017 6;16:575-585. Epub 2017 Sep 6.

Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States.

Altered brain connectivity has been described in people with Parkinson's disease and in response to dopaminergic medications. However, it is unclear whether dopaminergic medications primarily 'normalize' disease related connectivity changes or if they induce unique alterations in brain connectivity. Further, it is unclear how these disease- and medication-associated changes in brain connectivity relate differently to specific motor manifestations of disease, such as bradykinesia/rigidity and tremor. In this study, we applied a novel covariance projection approach in combination with a bootstrapped permutation test to resting state functional MRI data from 57 Parkinson's disease and 20 healthy control participants to determine the Parkinson's medication-state and disease-state connectivity changes associated with different motor manifestations of disease. First, we identified brain connections that best classified Parkinson's disease ON versus OFF dopamine and Parkinson's disease versus healthy controls, achieving 96.9 ± 5.9% and 72.7 ± 12.4% classification accuracy, respectively. Second, we investigated the connections that significantly contribute to the classifications. We found that the connections greater in Parkinson's disease OFF compared to ON dopamine are primarily between motor (cerebellum and putamen) and posterior cortical regions, such as the posterior cingulate cortex. By contrast, connections that are greater in ON compared to OFF dopamine are between the right and left medial prefrontal cortex. We also identified the connections that are greater in healthy control compared to Parkinson's disease and found the most significant connections are associated with primary motor regions, such as the striatum and the supplementary motor area. Notably, these are different connections than those identified in Parkinson's disease OFF compared to ON. Third, we determined which of the Parkinson's medication-state and disease-state connections are associated with the severity of different motor symptoms. We found two connections correlate with both bradykinesia/rigidity severity and tremor severity, whereas four connections correlate with only bradykinesia/rigidity severity, and five connections correlate with only tremor severity. Connections that correlate with only tremor severity are anchored by the cerebellum and the supplemental motor area, but only those connections that include the supplemental motor area predict dopaminergic improvement in tremor. Our results suggest that dopaminergic medications do not simply 'normalize' abnormal brain connectivity associated with Parkinson's disease, but rather dopamine drives distinct connectivity changes, only some of which are associated with improved motor symptoms. In addition, the dissociation between of connections related to severity of bradykinesia/rigidity versus tremor highlights the distinct abnormalities in brain circuitry underlying these specific motor symptoms.
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http://dx.doi.org/10.1016/j.nicl.2017.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608603PMC
June 2018

Long-term follow-up of a randomized AAV2- gene therapy trial for Parkinson's disease.

JCI Insight 2017 04 6;2(7):e90133. Epub 2017 Apr 6.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2- delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and F-fluorodeoxyglucose (FDG) PET imaging. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2- group compared with the sham group continued at 12 months [time effect: (4,138) = 11.55, < 0.001; group effect: (1,35) = 5.45, < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2- group ( = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines ( < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2- group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2- group ( < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. These findings show that clinical benefits after gene therapy with STN AAV2- in PD patients persist at 12 months. ClinicalTrials.gov NCT00643890. Neurologix Inc.
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http://dx.doi.org/10.1172/jci.insight.90133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374069PMC
April 2017