Publications by authors named "Karen S Marder"

55 Publications

Plasma Glucosylsphingosine in GBA1 Mutation Carriers with and without Parkinson's Disease.

Mov Disord 2021 Nov 6. Epub 2021 Nov 6.

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Background: Biallelic mutations in the GBA1 gene encoding glucocerebrosidase cause Gaucher's disease, whereas heterozygous carriers are at risk for Parkinson's disease (PD). Glucosylsphingosine is a clinically meaningful biomarker of Gaucher's disease but could not be assayed previously in heterozygous GBA1 carriers.

Objective: The aim of this study was to assess plasma glucosylsphingosine levels in GBA1 N370S carriers with and without PD.

Methods: Glucosylsphingosine, glucosylceramide, and four other lipids were quantified in plasma from N370S heterozygotes with (n = 20) or without (n = 20) PD, healthy controls (n = 20), idiopathic PD (n = 20), and four N370S homozygotes (positive controls; Gaucher's/PD) using quantitative ultra-performance liquid chromatography tandem mass spectrometry.

Results: Plasma glucosylsphingosine was significantly higher in N370S heterozygotes compared with noncarriers, independent of disease status. As expected, Gaucher's/PD cases showed increases in both glucocerebrosidase substrates, glucosylsphingosine and glucosylceramide.

Conclusions: Plasma glucosylsphingosine accumulation in N370S heterozygotes shown in this study opens up its future assessment as a clinically meaningful biomarker of GBA1-PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28846DOI Listing
November 2021

The commercial genetic testing landscape for Parkinson's disease.

Parkinsonism Relat Disord 2021 Oct 19. Epub 2021 Oct 19.

Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.

Introduction: There have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing offered for PD as the first step of our gene curation.

Methods: The National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally.

Results: We identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial.

Conclusion: There is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD.
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http://dx.doi.org/10.1016/j.parkreldis.2021.10.001DOI Listing
October 2021

Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression.

JAMA Netw Open 2021 04 1;4(4):e215845. Epub 2021 Apr 1.

Department of Neurology, Mount Sinai Beth Israel, and Icahn School of Medicine, Mount Sinai, New York, New York.

Importance: Despite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone.

Objective: To evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD.

Design, Setting, And Participants: This longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020.

Main Outcomes And Measures: The associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale.

Results: Among 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004).

Conclusions And Relevance: These findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060834PMC
April 2021

The TCR repertoire of α-synuclein-specific T cells in Parkinson's disease is surprisingly diverse.

Sci Rep 2021 01 11;11(1):302. Epub 2021 Jan 11.

Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.

The self-antigen α-synuclein (α-syn) was recently shown to be associated with Parkinson's disease (PD). Here we mapped the T cell receptor (TCR) repertoire of α-syn-specific T cells from six PD patients. The self-antigen α-syn-specific repertoire was compared to the repertoire of T cells specific for pertussis (PT), as a representative foreign antigen that most individuals are exposed to, revealing that the repertoire for α-syn was as diverse as the repertoire for PT. The diversity of PT-specific clonotypes was similar between individuals with PD diagnosis and age-matched healthy controls. We found that the TCR repertoire was specific to each PD patient, and no shared TCRs among patients were defined, likely due to differences in HLA expression that select for different subsets of epitope-specific TCR rearrangements. This study provides the first characterization of α-syn-specific TCR clonotypes in individuals with PD. Antigen-specific TCRs can serve as immunotherapeutics and diagnostics, and means to track longitudinal changes in specific T cells, and disease progression.
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http://dx.doi.org/10.1038/s41598-020-79726-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801678PMC
January 2021

T Cell Responses to Neural Autoantigens Are Similar in Alzheimer's Disease Patients and Age-Matched Healthy Controls.

Front Neurosci 2020 27;14:874. Epub 2020 Aug 27.

Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States.

Alzheimer's disease (AD), a chronic multifactorial and complex neurodegenerative disorder is a leading cause of dementia. Recently, neuroinflammation has been hypothesized as a contributing factor to AD pathogenesis. The role of adaptive immune responses against neuronal antigens, which can either confer protection or induce damage in AD, has not been fully characterized. Here, we measured T cell responses to several potential antigens of neural origin including amyloid precursor protein (APP), amyloid beta (Aβ), tau, α-synuclein, and transactive response DNA binding protein (TDP-43) in patients with AD and age-matched healthy controls (HC). Antigen-specific T cell reactivity was detected for all tested antigens, and response to tau-derived epitopes was particularly strong, but no significant differences between individuals with AD and age-matched HC were identified. We also did not observe any correlation between the antigen-specific T cell responses and clinical variables including age, gender, years since diagnosis and cognitive score. Additionally, further characterization did not reveal any differences in the relative frequency of major Peripheral Blood Mononuclear Cells (PBMC) subsets, or in the expression of genes between AD patients and HC. These observations have not identified a key role of neuronal antigen-specific T cell responses in AD.
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http://dx.doi.org/10.3389/fnins.2020.00874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481378PMC
August 2020

Quantifying Postural Control in Premanifest and Manifest Huntington Disease Using Wearable Sensors.

Neurorehabil Neural Repair 2020 09 16;34(9):771-783. Epub 2020 Jul 16.

G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

. Impairments in postural control in Huntington disease (HD) have important consequences for daily functioning. This observational study systematically examined baseline postural control and the effect of sensory attenuation and sensory enhancement on postural control across the spectrum of HD. . Participants (n = 39) included healthy controls and individuals in premanifest (pHD) and manifest stages (mHD) of HD. Using wearable sensors, postural control was assessed according to (1) postural set (sit vs stand), (2) sensory attenuation using clinical test of sensory integration, and (3) sensory enhancement with gaze fixation. Outcomes included sway smoothness, amplitude, and frequency. . Based on postural set, pHD reduced postural sway in sitting relative to standing, whereas mHD had pronounced sway in standing and sitting, highlighting a baseline postural deficit. During sensory attenuation, postural control in pHD deteriorated relative to controls when proprioceptive demands were high (eyes closed on foam), whereas mHD had significant deterioration of postural control when proprioception was attenuated (eyes open and closed on foam). Finally, gaze fixation improved sway smoothness, amplitude, and frequency in pHD; however, no benefit was observed in mHD. . Systematic examination of postural control revealed a fundamental postural deficit in mHD, which further deteriorates when proprioception is challenged. Meanwhile, postural deficits in pHD are detectable when proprioceptive challenge is high. Sensory enhancing strategies using gaze fixation to benefit posture may be useful when introduced well before motor diagnosis. These findings encourage further examination of wearable sensors as part of routine clinical assessments in HD.
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http://dx.doi.org/10.1177/1545968320939560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501191PMC
September 2020

α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson's disease.

Nat Commun 2020 04 20;11(1):1875. Epub 2020 Apr 20.

Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.

A diagnosis of motor Parkinson's disease (PD) is preceded by a prolonged premotor phase with accumulating neuronal damage. Here we examined the temporal relation between α-synuclein (α-syn) T cell reactivity and PD. A longitudinal case study revealed that elevated α-syn-specific T cell responses were detected prior to the diagnosis of motor PD, and declined after. The relationship between T cell reactivity and early PD in two independent cohorts showed that α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased. Additional analysis revealed significant association of α-syn-specific T cell responses with age and lower levodopa equivalent dose. These results confirm the presence of α-syn-reactive T cells in PD and show that they are most abundant immediately after diagnosis of motor PD. These cells may be present years before the diagnosis of motor PD, suggesting avenues of investigation into PD pathogenesis and potential early diagnosis.
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http://dx.doi.org/10.1038/s41467-020-15626-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171193PMC
April 2020

Research criteria for the diagnosis of prodromal dementia with Lewy bodies.

Neurology 2020 04 2;94(17):743-755. Epub 2020 Apr 2.

From the Newcastle University (I.G.M., A.J.T., P.D., J.P.T.); Mayo Clinic (T.J.F.), Jacksonville; University of Strasbourg (F.B.); Mayo Clinic (B.F.B., K.K.), Rochester; Nagoya University (H.F.), Kawasaki Memorial Hospital; Istituto Neurologico "Carlo Besta" (C.M., P.T.), Milan; Cambridge University (F.M.S.); McGill University (R.B.P.); King's College London and Stavanger University Hospital (D.A.); University of Exeter (C.B.); University of Chieti-Pescara (L.B.); Istanbul Faculty of Medicine (M.E.); University of Miami Miller School of Medicine (J.E.G.); University of California (D.G., D.P.S.), San Diego; Feinberg School of Medicine (J.G.G.); Massachusetts General Hospital (S.N.G.); Columbia University Irving Medical Center (L.S.H., K.S.M.); Osaka University (M.I.); Lou Ruvo Center of Brain Health (J.B.L.), Cleveland Clinic; University of Sydney (S.J.G.L.); Sunnybrook Health Sciences Centre (M.M.), University of Toronto; VA Puget Sound & University of Washington (D.W.T.); University College London (Z.W.).

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.
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http://dx.doi.org/10.1212/WNL.0000000000009323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274845PMC
April 2020

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

JAMA Neurol 2020 06;77(6):755-763

Columbia University Irving Medical Center, New York, New York.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings.

Conclusions And Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.
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http://dx.doi.org/10.1001/jamaneurol.2020.0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483960PMC
June 2020

The choice not to undergo genetic testing for Huntington disease: Results from the PHAROS study.

Clin Genet 2019 07 15;96(1):28-34. Epub 2019 May 15.

Department of Neurology, University of Rochester, Rochester, NY.

Rates of genetic testing in Huntington disease (HD) are lower than was predicted before direct DNA testing became available. Clinicians often do not have in-depth conversations with people at risk who chose not to test. We queried 733 research subjects who chose not to learn their HD gene status when enrolling in the Prospective Huntington At-Risk Observational Study, carried out between 1999 and 2008. Lack of an effective cure or treatment (66% of subjects) and inability to undo knowledge (66%) were the major reasons cited for choosing not to undergo HD DNA testing. Most subjects were not concerned about the length or burden of the testing process (61% and 59%, respectively). Subjects were optimistic that a treatment to improve symptoms or postpone onset would be developed within the next 10 years (56% and 53%, respectively), but they had less certainty about the prospects to prevent HD onset (36%). This is the first large, systematic study of why people at risk for HD choose not to undergo genetic testing. Attitudes about how people at risk for HD approach this life-altering choice should be reassessed as new treatments develop, and as clinical trials now require genetic testing at entry.
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http://dx.doi.org/10.1111/cge.13529DOI Listing
July 2019

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

Mov Disord 2019 04 20;34(4):526-535. Epub 2019 Feb 20.

Montreal Neurological Institute, McGill University, Montréal, QC, Canada.

Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD.

Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed.

Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome.

Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469643PMC
April 2019

Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease.

Eur J Med Genet 2019 Jan 26;62(1):65-69. Epub 2018 May 26.

Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address:

Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.

Methods: GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used.

Results: Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001).

Conclusion: Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.
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http://dx.doi.org/10.1016/j.ejmg.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261782PMC
January 2019

Progression in the LRRK2-Asssociated Parkinson Disease Population.

JAMA Neurol 2018 03;75(3):312-319

Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, New York.

Importance: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials.

Objective: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.

Design, Setting, And Participants: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis.

Main Outcomes And Measures: Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores.

Results: Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08).

Conclusions And Relevance: Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.
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http://dx.doi.org/10.1001/jamaneurol.2017.4019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885854PMC
March 2018

Clinical and neuropathological features of progressive supranuclear palsy in Leucine rich repeat kinase (LRRK2) G2019S mutation carriers.

Mov Disord 2018 02 9;33(2):335-338. Epub 2017 Nov 9.

Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA.

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http://dx.doi.org/10.1002/mds.27225DOI Listing
February 2018

Alzheimer's Disease-Related Dementias Summit 2016: National research priorities.

Neurology 2017 Dec 8;89(23):2381-2391. Epub 2017 Nov 8.

From the National Institute of Neurological Disorders and Stroke (R.A.C., W.J.K., J.T.G., S.J., D.B., M.E., C.S.M., P.A.S., B.-A.S., M.L.S., C.L.T., A.K.G.), Bethesda, MD; Rush Alzheimer's Disease Center (D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (S.T.C.), David Geffen School of Medicine, University of California, Los Angeles; The Association for Frontotemporal Degeneration (S.L.-J.D.), Radnor, PA; Department of Neuroscience (D.W.D.), Mayo Clinic, Jacksonville, FL; The Alzheimer's Drug Discovery Foundation (H.F.); Icahn School of Medicine at Mount Sinai (H.F.), New York, NY; Department of Neurology (S.M.G.), Massachusetts General Hospital, Harvard Medical School, Boston; Eli Lilly and Company (M.L.H.), Lilly Research Centre, Erl Wood Manor, Windlesham, UK; Department of Neurology (D.S.K.), Mayo Clinic Rochester, MN; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (J.J.M., K.S.M.) and College of Physicians and Surgeons (K.S.M.), Columbia University, New York, NY; National Institute on Aging (C.H.P., N.B.S.), Bethesda, MD; Memory and Aging Center, Department of Neurology (W.W.S.), and Department of Pathology (W.W.S.), University of California San Francisco; Lewy Body Dementia Association (A.T.), Lilburn, GA; National Institute of Diabetes and Digestive and Kidney Diseases (S.P.W.), Bethesda, MD; and Knight Alzheimer's Disease Research Center (D.M.H.), Hope Center for Neurological Disorders (D.M.H.), and Department of Neurology (D.M.H.), Washington University in St. Louis, MO.

Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature.
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http://dx.doi.org/10.1212/WNL.0000000000004717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719928PMC
December 2017

Elevated GM3 plasma concentration in idiopathic Parkinson's disease: A lipidomic analysis.

PLoS One 2017 17;12(2):e0172348. Epub 2017 Feb 17.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, United States of America.

Parkinson's disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the 'Spot' study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols. Each lipid species was analyzed using a logistic regression model. The plasma concentrations of two lipid subclasses, triglycerides and monosialodihexosylganglioside (GM3), were different between PD and control participants. GM3 ganglioside concentration had the most significant difference between PD and controls (1.531±0.037 pmol/μl versus 1.337±0.040 pmol/μl respectively; p-value = 5.96E-04; q-value = 0.048; when normalized to total lipid: p-value = 2.890E-05; q-value = 2.933E-03). Next, we used a collection of 20 GM3 and glucosylceramide (GlcCer) species concentrations normalized to total lipid to perform a ROC curve analysis, and found that these lipids compare favorably with biomarkers reported in previous studies (AUC = 0.742 for males, AUC = 0.644 for females). Our results suggest that higher plasma GM3 levels are associated with PD. GM3 lies in the same glycosphingolipid metabolic pathway as GlcCer, a substrate of the enzyme glucocerebrosidase, which has been associated with PD. These findings are consistent with previous reports implicating lower glucocerebrosidase activity with PD risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172348PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315374PMC
August 2017

Arm swing as a potential new prodromal marker of Parkinson's disease.

Mov Disord 2016 10;31(10):1527-1534

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Reduced arm swing is a well-known clinical feature of Parkinson's disease (PD), often observed early in the course of the disease. We hypothesized that subtle changes in arm swing and axial rotation may also be detectable in the prodromal phase.

Objective: The purpose of this study was to evaluate the relationship between the LRRK2-G2019S mutation, arm swing, and axial rotation in healthy nonmanifesting carriers and noncarriers of the G2019S mutation and in patients with PD.

Methods: A total of 380 participants (186 healthy nonmanifesting controls and 194 PD patients) from 6 clinical sites underwent gait analysis while wearing synchronized 3-axis body-fixed sensors on the lower back and bilateral wrists. Participants walked for 1 minute under the following 2 conditions: (1) usual walking and (2) dual-task walking. Arm swing amplitudes, asymmetry, variability, and smoothness were calculated for both arms along with measures of axial rotation.

Results: A total of 122 nonmanifesting participants and 67 PD patients were carriers of the G2019S mutation. Nonmanifesting mutation carriers walked with greater arm swing asymmetry and variability and lower axial rotation smoothness under the dual task condition when compared with noncarriers (P < .04). In the nonmanifesting mutation carriers, arm swing asymmetry was associated with gait variability under dual task (P = .003). PD carriers showed greater asymmetry and variability of movement than PD noncarriers, even after controlling for disease severity (P < .009).

Conclusions: The G2019S mutation is associated with increased asymmetry and variability among nonmanifesting participants and patients with PD. Prospective studies should determine if arm swing asymmetry and axial rotation smoothness may be used as motor markers of prodromal PD. © 2016 International Parkinson and Movement Disorder Society.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053872PMC
http://dx.doi.org/10.1002/mds.26720DOI Listing
October 2016

variants and glucocerebrosidase activity in Parkinson's disease.

NPJ Parkinsons Dis 2016;2. Epub 2016 Mar 10.

Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Montréal Neurological Institute & Hospital, and the Department of Human Genetics, McGill University, Montreal, QC, Canada.

Mutations in glucocerebrosidase () are a common risk factor for Parkinson's disease (PD). The scavenger receptor class B member 2 () gene encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome. Two common SNPs in linkage disequilibrium with , rs6812193 and rs6825004, have been associated with PD and Lewy Body Disease in genome wide association studies. Whether these SNPs are associated with altered glucocerebrosidase enzymatic activity is unknown. Our objective was to determine whether SNPs are associated with PD and with reduced GCase activity. The gene was fully sequenced, and the G2019S and rs6812193 and rs6825004 SNPs were genotyped in 548 PD patients and 272 controls. GCase activity in dried blood spots was measured by tandem mass spectrometry. We tested the association between genotypes and PD risk in regression models adjusted for gender, age, and G2019S and mutation status. We compared GCase activity between participants with different genotypes at rs6812193 and rs6825004. Genotype at rs6812193 was associated with PD status. PD cases were less likely to carry the T allele than the C allele (OR=0.71; p=0.004), but GCase enzymatic activity was similar across rs6812193 genotypes (C/C: 11.88 μmol/l/h; C/T: 11.80 μmol/l/h; T/T: 12.02 μmol/l/h; p=0.867). Genotype at rs6825004 was not associated with either PD status or GCase activity. In conclusion, our results support an association between genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity.
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http://dx.doi.org/10.1038/npjparkd.2016.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838276PMC
March 2016

CSF β-Amyloid 1-42 Predicts Progression to Cognitive Impairment in Newly Diagnosed Parkinson Disease.

J Mol Neurosci 2016 Jan 2;58(1):88-92. Epub 2015 Sep 2.

Department of Neurology, Columbia University, 710 W 168th St, New York, NY, 10032, USA.

Low CSF β-amyloid 1-42 has been associated with cognitive decline in advanced Parkinson's disease; data from a single cohort suggest β-amyloid 1-42 may be an early marker of cognitive impairment. Newly diagnosed Parkinson's participants (mean duration, 6.9 months) in the Parkinson's Progression Markers Initiative (n = 341) were assessed at baseline (untreated state) and followed for 2 years. CSF β-amyloid 1-42, α-synuclein, total tau, and tau phosphorylated at threonine 181 were collected at baseline. Participants were classified as having cognitive impairment (CI) if scores on two of six cognitive tests were 1.5 standard deviations below the standardized mean based on published norms in healthy controls. Multivariable regression analyses were used to determine the association between baseline CSF markers with cognitive impairment, defined by neuropsychological testing performance at 2-year follow-up. Fifty-five participants (16.1 %) had CI at baseline and were not included in further analyses. Thirty-seven of the 286 participants without CI at baseline (12.9 %) developed CI at 2 years. Participants with CI at 2 years had significantly lower mean baseline CSF β-amyloid 1-42 levels than non-CI participants (343.8 vs. 380.4 pg/mL, p < 0.01); no significant difference was seen for α-synuclein, T-tau, or P-tau 181. In a regression model of 286 participants without baseline CI adjusted for age, gender, disease duration, education, motor severity, and depression status, lower baseline β-amyloid 1-42 levels were associated with higher odds of CI at 2 years. (OR(10pg/mL) = 1.04, 95 % CI 1.01-1.08, p < 0.05). CSF β-amyloid 1-42 level at disease onset is an independent predictor of cognitive impairment in early Parkinson's disease.
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http://dx.doi.org/10.1007/s12031-015-0647-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738011PMC
January 2016

Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers.

Neurology 2015 Jan 24;84(4):399-406. Epub 2014 Dec 24.

From the Centre for Cognitive Neuroimaging (R.C.H., I.T.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen; Department of Neurology (R.C.H., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Movement Disorders Unit, Department of Neurology (A.T., T.G., A.M., N.G.), and Genetic Institute (A.O.-U.), Tel Aviv Sourasky Medical Center; Sackler School of Medicine (A.T., T.G., A.O.-U., N.G.), Tel Aviv University, Israel; Department of Neurology (B.F.L.v.N.), Catharina Hospital, Eindhoven, the Netherlands; Columbia University (K.S.M.), Columbia University Medical Center, New York; and Beth Israel Medical Center (S.B.), New York, NY.

Objective: We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD.

Methods: We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen.

Results: The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers.

Conclusions: Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes.
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http://dx.doi.org/10.1212/WNL.0000000000001189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336002PMC
January 2015

Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease.

JAMA Neurol 2015 Jan;72(1):100-5

Sagamihara National Hospital, Kanagawa, Japan.

Importance: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD.

Observations: We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs.

Conclusions And Relevance: To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.
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http://dx.doi.org/10.1001/jamaneurol.2014.2704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399368PMC
January 2015

The relationship between obsessive-compulsive symptoms and PARKIN genotype: The CORE-PD study.

Mov Disord 2015 Feb 12;30(2):278-83. Epub 2014 Nov 12.

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Background: Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS).

Methods: The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers.

Results: Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13).

Conclusions: First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318772PMC
February 2015

Variability in interval production is due to timing-dependent deficits in Huntington's disease.

Mov Disord 2014 Oct 22;29(12):1516-22. Epub 2014 Aug 22.

Department of Rehabilitation & Regenerative Medicine (Program in Physical Therapy), and G.H. Sergievsky Center, College of Physicians & Surgeons, Columbia University, New York, New York, USA.

In Huntington's disease (HD), increased variability is seen in performance of motor tasks that require implicit control of timing. We examined whether timing variability was also evident in an explicit interval-timing task. Sixty subjects (21 controls, 19 manifest HD, and 20 pre-manifest HD) performed a single-interval production task with three target intervals (1.1 s, 2.2 s, 3.3 s). We analyzed accuracy (proportional error) and precision (standard deviation) across groups and intervals. No differences were seen in accuracy across groups or intervals. Precision was significantly lower in manifest (P = 0.0001) and pre-manifest HD (P = 0.04) compared with controls. This was particularly true for pre-manifest subjects close to diagnosis (based on probability of diagnosis in 5 years). Precision was correlated with proximity to diagnosis (r2  = 0.3, P < 0.01). To examine the source of reduced precision, we conducted linear regression of standard deviation with interval duration. Slope of the regression was significantly higher in manifest HD (P = 0.02) and in pre-manifest HD close to diagnosis (P = 0.04) compared with controls and pre-manifest participants far from diagnosis. Timing precision is impaired before clinical diagnosis in Huntington's disease. Slope analysis suggests that timing variability (decreased precision) was attributable to deficits in timing-dependent processes. Our results provide additional support for the proposal that the basal ganglia are implicated in central timekeeping functions. Because the single interval production task was sensitive to deficits in pre-manifest HD, temporal precision may be a useful outcome measure in future clinical trials.
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http://dx.doi.org/10.1002/mds.25998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188696PMC
October 2014

Recommendations of the Alzheimer's disease-related dementias conference.

Neurology 2014 Aug 30;83(9):851-60. Epub 2014 Jul 30.

From the Department of Pathology (T.J.M.), University of Washington, Seattle; National Institute of Neurological Disorders and Stroke (W.J.K., D.B., W.R.G., A.N.K., B.-A.S., M.S., C.L.T., S.P.W., R.A.C.), Bethesda, MD; Neuropathology Lab (D.W.D.), Mayo Clinic, Jacksonville, FL; Department of Epidemiology & Biostatistics (M.M.G.), University of California San Francisco; Hemorrhagic Stroke Research Program (S.M.G.), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Neurodegenerative Diseases DHT at Eli Lilly and Company (M.L.H.), Lilly Research Center, Windlesham, UK; Department of Neurology (D.S.K.), Mayo Clinic Rochester, MN; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (J.J.M., K.S.M.), Columbia University Medical Center, New York; Columbia University (J.J.M., K.S.M.), College of Physicians and Surgeons, New York, NY; University of California San Francisco Memory and Aging Center (B.L.M., W.W.S.); National Institute on Aging (C.H.P., N.B.S.), Bethesda, MD; and Zilhka Neurogenetic Institute (B.V.Z.), Center for Neurodegeneration and Regeneration and Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, Los Angeles, CA.

The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease-related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.
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http://dx.doi.org/10.1212/WNL.0000000000000733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155046PMC
August 2014

Hippocampal laminar distribution of tau relates to Alzheimer's disease and age of onset.

J Alzheimers Dis 2015 ;43(1):315-24

Department of Neurology, Columbia University, New York, NY, USA Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.

Background: Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways.

Objective: To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates.

Methods: 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High OML Only (n = 35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared.

Results: High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI -6.7 to -0.7, p < 0.01), after adjustment for demographics and symptom duration.

Conclusions: Phospho-tau pathology, when prominent within both IML and OML, is associated with CERAD diagnosis of Definite AD and earlier age of onset in AD. Laminar patterns of tau deposition reflect regional involvements during disease course.
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http://dx.doi.org/10.3233/JAD-140279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293261PMC
January 2016

Parkinson's disease with Lewy bodies associated with a heterozygous PARKIN dosage mutation.

Mov Disord 2014 Apr 27;29(4):566-8. Epub 2013 Dec 27.

Department of Neurology, Columbia University, New York, New York, USA.

Background: PARKIN-related disease remains incompletely understood. First, the pathogenicity of heterozygous PARKIN mutations is unclear, although some evidence supports causality. Second, unlike sporadic Parkinson's disease (PD), Lewy bodies are present only in a minority of cases. Only one other heterozygote PARKIN carrier with autopsy findings has been described. Our case adds to the broadening pathological and clinical phenotype of PARKIN-related disease.

Methods: Clinical chart, genetic analysis, and pathological findings of a patient with familial PD are reviewed.

Results: A 44-year-old man developed slowly progressive tremor-predominant PD with excellent response to levodopa. Genetic analysis revealed a heterozygous PARKIN exon 3-4 deletion, also present in 2 family members with early-onset PD. Postmortem examination showed severe neuronal loss in the substantia nigra and nucleus coeruleus with the presence of diffuse Lewy bodies.

Conclusions: The deletion is unlikely an incidental finding considering family history, age at onset, and the presence of clinical and pathological features not typical of sporadic PD.
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http://dx.doi.org/10.1002/mds.25792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281030PMC
April 2014

Learning fast accurate movements requires intact frontostriatal circuits.

Front Hum Neurosci 2013 13;7:752. Epub 2013 Nov 13.

Motor Performance Lab, Department of Neurology, The Neurological Institute, Columbia University New York, NY, USA.

The basal ganglia are known to play a crucial role in movement execution, but their importance for motor skill learning remains unclear. Obstacles to our understanding include the lack of a universally accepted definition of motor skill learning (definition confound), and difficulties in distinguishing learning deficits from execution impairments (performance confound). We studied how healthy subjects and subjects with a basal ganglia disorder learn fast accurate reaching movements. We addressed the definition and performance confounds by: (1) focusing on an operationally defined core element of motor skill learning (speed-accuracy learning), and (2) using normal variation in initial performance to separate movement execution impairment from motor learning abnormalities. We measured motor skill learning as performance improvement in a reaching task with a speed-accuracy trade-off. We compared the performance of subjects with Huntington's disease (HD), a neurodegenerative basal ganglia disorder, to that of premanifest carriers of the HD mutation and of control subjects. The initial movements of HD subjects were less skilled (slower and/or less accurate) than those of control subjects. To factor out these differences in initial execution, we modeled the relationship between learning and baseline performance in control subjects. Subjects with HD exhibited a clear learning impairment that was not explained by differences in initial performance. These results support a role for the basal ganglia in both movement execution and motor skill learning.
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http://dx.doi.org/10.3389/fnhum.2013.00752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826079PMC
December 2013

Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

Mov Disord 2013 Dec 15;28(14):1966-71. Epub 2013 Oct 15.

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.
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http://dx.doi.org/10.1002/mds.25647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859844PMC
December 2013

Cognitive and motor function in long-duration PARKIN-associated Parkinson disease.

JAMA Neurol 2014 Jan;71(1):62-7

Department of Neurology, University of Puerto Rico, San Juan.

Importance: Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients.

Objective: Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers.

Design, Setting, And Participants: Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers.

Main Outcomes And Measures: Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose.

Results: Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains.

Conclusions And Relevance: In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.
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http://dx.doi.org/10.1001/jamaneurol.2013.4498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947132PMC
January 2014
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