Publications by authors named "Claire Henchcliffe"

52 Publications

Preclinical Efficacy and Safety of a Human Embryonic Stem Cell-Derived Midbrain Dopamine Progenitor Product, MSK-DA01.

Cell Stem Cell 2021 Feb;28(2):217-229.e7

Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra leading to disabling deficits. Dopamine neuron grafts may provide a significant therapeutic advance over current therapies. We have generated midbrain dopamine neurons from human embryonic stem cells and manufactured large-scale cryopreserved dopamine progenitors for clinical use. After optimizing cell survival and phenotypes in short-term studies, the cell product, MSK-DA01, was subjected to an extensive set of biodistribution, toxicity, and tumorigenicity assessments in mice under GLP conditions. A large-scale efficacy study was also performed in rats with the same lot of cells intended for potential human use and demonstrated survival of the grafted cells and behavioral amelioration in 6-hydroxydopamine lesioned rats. There were no adverse effects attributable to the grafted cells, no obvious distribution outside the brain, and no cell overgrowth or tumor formation, thus paving the way for a future clinical trial.
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http://dx.doi.org/10.1016/j.stem.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903922PMC
February 2021

Toward a Personalized Approach to Parkinson's Cell Therapy.

Mov Disord 2020 11;35(11):2119-2120

Department of Psychiatry, McLean Hospital, Belmont, Massachusetts, USA.

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http://dx.doi.org/10.1002/mds.28328DOI Listing
November 2020

Can google glass™ technology improve freezing of gait in parkinsonism? A pilot study.

Disabil Rehabil Assist Technol 2020 Nov 20:1-11. Epub 2020 Nov 20.

Weill Cornell Medical College, New York, NY, USA.

Purpose: Freezing of gait (FOG) is a disabling phenomenon defined by the periodic absence or reduction of forward progression of the feet despite the intention to walk. We sought to understand whether Google Glass (GG), a lightweight wearable device that provides simultaneous visual-auditory cues, might improve FOG in parkinsonism.

Methods: Patients with parkinsonism and FOG utilized GG custom-made auditory-visual cue applications: "Walk With Me" and "Unfreeze Me" in a single session intervention. We recorded ambulation time with and without GG under multiple conditions including 25 feet straight walk, dual task of performing serial 7's while straight walking, 180 degree turn after walking 25 feet, and walking through a doorway. FOG and patient experience questionnaires were administered.

Results: Using the GG "Walk With Me" program, improvements were noted in the following: average 25 feet straight walk by 0.32 s (SD 2.12); average dual task of serial 7's and 25 feet straight walk by 1.79 s (SD 2.91); and average walk through doorway by 0.59 s (SD 0.81). Average 180 degree turn after 25 feet walk worsened by 1.89 s (SD 10.66). Using the "Unfreeze Me" program, only the average dual task of serial 7's and 25 feet straight walk improved (better by 0.82 s (SD 3.08 sec). All other tasks had worse performance in terms of speed of completion.

Conclusion: This feasibility study provides preliminary data suggesting that some walking tasks may improve with GG, which uses various musical dance programs to provide visual and auditory cueing for patients with FOG. IMPLICATIONS FOR REHABILITATION Freezing of gait in parkinsonian syndromes is a disabling motor block described by patients as having their feet stuck to the floor leading to difficulty in initiation of gait and increased risk for falls. Wearable assistive devices such as Google Glass™ use visual and auditory cueing that may improve gait pattern in patients with freezing of gait. Augmented reality programs using wearable assistive devices are a home-based therapy, with the potential for reinforcing physical therapy techniques; this is especially meaningful during the COVID-19 pandemic when access to both medical and rehabilitative care has been curtailed.
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http://dx.doi.org/10.1080/17483107.2020.1849433DOI Listing
November 2020

Molecular Imaging of Striatal Dopaminergic Neuronal Loss and the Neurovascular Unit in Parkinson Disease.

Front Neurosci 2020 18;14:528809. Epub 2020 Sep 18.

Department of Radiology, Weill Cornell Medicine, Cornell University, New York, NY, United States.

Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by loss of nigrostriatal dopaminergic neurons. Impairment of the neurovascular unit (NVU) has been hypothesized to play a critical role in early PD pathophysiology, and to precede neurodegenerative mechanisms. [C-11]-PE2I (-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)nortropane) (PE2I) is a PET radiotracer targeting neuronal dopamine transporters (DaT) with high specificity, allowing for highly accurate and specific DaT quantification. We investigated NVU integrity using arterial spin labeling (ASL) MRI in a prospective cohort of 26 patients with PD, and correlated our findings with analysis of striatal DaT density using PE2I PET in a subcohort of 17 patients. Analysis was performed in FreeSurfer to obtain rCBF and mean standardized regional PET avidity. Pearson correlations and Mann-Whitney tests were performed. Significantly lower mean normalized striatal PE2I SUV values were seen in multiple regions in patients with greater disease duration ( < 0.05). PET uptake in the putamen correlated with disease duration independent of patient age. Stratifying patients based on Montreal Cognitive Assessment (MoCA) scores (stratified into ≥ 27 vs. < 27), there was statistically significantly lower PE2I PET avidity in the higher MoCA score group in both more and less affected sides of the caudate, putamen and pallidum ( < 0.05). A moderate negative correlation between MDS-UPDRS part 3 (motor) "off" and rCBF values was also seen in the L and R cerebellum WM ( = -0.43 and -0.47, < 0.05). A statistically significant negative correlation was found between dominant hand pegboard test results and rCBF in the less affected pallidum ( = -0.41; = 0.046). A statistically significant negative correlation of ASL MRI with [11C]-PE2I PET was also found ( = -0.53 to -0.58; -value 0.017-0.033) between left cerebral WM rCBF and more and less affected striatal PET regions. Our ROI-based analyses suggest that longer disease duration is associated with lower rCBF and lower PE2I mean SUV, implying greater NVU dysfunction and dopaminergic neuronal loss, respectively. Combined ASL MRI and PE2I PET imaging could inform future prospective clinical trials providing an improved mechanistic understanding of the disease, laying the foundation for the development of early disease biomarkers and potential therapeutic targets.
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http://dx.doi.org/10.3389/fnins.2020.528809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530280PMC
September 2020

A machine learning and network framework to discover new indications for small molecules.

PLoS Comput Biol 2020 08 7;16(8):e1008098. Epub 2020 Aug 7.

HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Dept. of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, United States of America.

Drug repurposing, identifying novel indications for drugs, bypasses common drug development pitfalls to ultimately deliver therapies to patients faster. However, most repurposing discoveries have been led by anecdotal observations (e.g. Viagra) or experimental-based repurposing screens, which are costly, time-consuming, and imprecise. Recently, more systematic computational approaches have been proposed, however these rely on utilizing the information from the diseases a drug is already approved to treat. This inherently limits the algorithms, making them unusable for investigational molecules. Here, we present a computational approach to drug repurposing, CATNIP, that requires only biological and chemical information of a molecule. CATNIP is trained with 2,576 diverse small molecules and uses 16 different drug similarity features, such as structural, target, or pathway based similarity. This model obtains significant predictive power (AUC = 0.841). Using our model, we created a repurposing network to identify broad scale repurposing opportunities between drug types. By exploiting this network, we identified literature-supported repurposing candidates, such as the use of systemic hormonal preparations for the treatment of respiratory illnesses. Furthermore, we demonstrated that we can use our approach to identify novel uses for defined drug classes. We found that adrenergic uptake inhibitors, specifically amitriptyline and trimipramine, could be potential therapies for Parkinson's disease. Additionally, using CATNIP, we predicted the kinase inhibitor, vandetanib, as a possible treatment for Type 2 Diabetes. Overall, this systematic approach to drug repurposing lays the groundwork to streamline future drug development efforts.
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http://dx.doi.org/10.1371/journal.pcbi.1008098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437923PMC
August 2020

Restoring Function to Dopaminergic Neurons: Progress in the Development of Cell-Based Therapies for Parkinson's Disease.

CNS Drugs 2020 06;34(6):559-577

Department of Neurology, Weill Medical College of Cornell University, 428 East 72nd Street, Suite 400, New York, NY, 10021, USA.

There is escalating interest in cell-based therapies to restore lost dopamine inputs in Parkinson's disease. This is based upon the rationale that implanting dopamine progenitors into the striatum can potentially improve dopamine-responsive motor symptoms. A rich body of data describing clinical trials of previous cell transplantation exists. These have included multiple cell sources for transplantation including allogeneic (human embryonic mesencephalic tissue, retinal pigment epithelial cells) and autologous (carotid body, adrenal medullary tissue) cells, as well as xenotransplantation. However, there are multiple limitations related to these cell sources, including availability of adequate numbers of cells for transplant, heterogeneity within cells transplanted, imprecisely defined mechanisms of action, and poor cell survival after transplantation in some cases. Nonetheless, evidence has accrued from a subset of trials to support the rationale for such a regenerative approach. Recent rapid advances in stem cell technology may now overcome these prior limitations. For example, dopamine neuron precursor cells for transplant can be generated from induced pluripotent cells and human embryonic stem cells. The benefits of these innovative approaches include: the possibility of scalability; a high degree of quality control; and improved understanding of mechanisms of action with rigorous preclinical testing. In this review, we focus on the potential for cell-based therapies in Parkinson's disease to restore the function of dopaminergic neurons, we critically review previous attempts to harness such strategies, we discuss potential benefits and predicted limitations, and we address how previous roadblocks may be overcome to bring a cell-based approach to the clinic.
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http://dx.doi.org/10.1007/s40263-020-00727-3DOI Listing
June 2020

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

N Engl J Med 2020 05;382(20):1926-1932

From the Departments of Neurosurgery (J.S.S., B.S.C.), Neurology (T.M.H.), and Radiology (K.K., Q.L.), the Gordon Center for Medical Imaging (K.K., Q.L.), and the Division of Neuroradiology (O.R.), Massachusetts General Hospital, the Department of Pediatrics, Computational Health Informatics Program, Boston Children's Hospital (I.-H.L., S.-W.K.), and the Connell and O'Reilly Families Cell Manipulation Core Facility, Dana-Farber/Harvard Cancer Center (J.R.), Boston, and the Department of Psychiatry (B.M.C.) and the Molecular Neurobiology Laboratory (B.S., T.-Y.P., N.L., S.K., J.J., Y.C., H.S., J.K., T.K., P.L., K.-S.K.), McLean Hospital, Belmont - all in Massachusetts; the Departments of Neurology (C.H.) and Neurosurgery (M.K.) and the Brain and Mind Research Institute (G.A.P.), Weill Cornell Medical College, New York; the Department of Neurology, Kaiser Permanente, Irvine, CA (C.N.); and the Department of Molecular and Life Sciences, Hanyang University, Seoul, South Korea (H.S.).

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1915872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288982PMC
May 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

University of Rochester, Rochester, 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

Neurophysiological Biomarkers of Parkinson's Disease.

J Parkinsons Dis 2020 ;10(2):471-480

Codiak BioSciences, Cambridge, MA, USA.

Background: There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.

Objective: To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease.

Methods: A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls.

Results: Qualitative and test/retest analysis of the EEG data demonstrated the reliability of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson's patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson's disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson's disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET.

Conclusion: Our results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson's disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson's disease modification therapy.
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http://dx.doi.org/10.3233/JPD-191844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242849PMC
January 2020

The future of stem cell therapies for Parkinson disease.

Nat Rev Neurosci 2020 02 6;21(2):103-115. Epub 2020 Jan 6.

Department of Neurology, Weill Cornell Medical College, New York, NY, USA.

Cell-replacement therapies have long been an attractive prospect for treating Parkinson disease. However, the outcomes of fetal tissue-derived cell transplants in individuals with Parkinson disease have been variable, in part owing to the limitations of fetal tissue as a cell source, relating to its availability and the lack of possibility for standardization and to variation in methods. Advances in developmental and stem cell biology have allowed the development of cell-replacement therapies that comprise dopamine neurons derived from human pluripotent stem cells, which have several advantages over fetal cell-derived therapies. In this Review, we critically assess the potential trajectory of this line of translational and clinical research and address its possibilities and current limitations and the broader range of Parkinson disease features that dopamine cell replacement based on generating neurons from human pluripotent stem cells could effectively treat in the future.
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http://dx.doi.org/10.1038/s41583-019-0257-7DOI Listing
February 2020

Sex and Gender Driven Modifiers of Alzheimer's: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks.

Front Aging Neurosci 2019 15;11:315. Epub 2019 Nov 15.

Department of Neurology, Weill Cornell Medicine, Cornell University, New York, NY, United States.

Research indicates that after advanced age, the major risk factor for late-onset Alzheimer's disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex- and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the "estrogen hypothesis." This posits that sex hormones, 17β-estradiol in particular, exert a neuroprotective effect by shielding females' brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17β-estradiol during the menopause transition (MT) as key underlying mechanisms.
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http://dx.doi.org/10.3389/fnagi.2019.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872493PMC
November 2019

Motor phenotype classification in moderate to advanced PD in BioFIND study.

Parkinsonism Relat Disord 2019 08 23;65:178-183. Epub 2019 Jun 23.

Fresco Institute for Parkinson's and Movement Disorders, Department of Neurology, NYU Langone Health, New York, NY, USA. Electronic address:

Background: Three motor phenotypes have been described in PD: postural instability and gait difficulty (PIGD) dominant, tremor-dominant (TD), and indeterminate (IND) subtype. These phenotypes have been associated with different cognitive trajectories, motor outcomes, and biomarkers profiles. However, whether motor subtype classifications change with treatment and disease progression is not well established.

Methods: To evaluate motor subtype ratio changes, we used the chi-square test for the off and on state motor subtypes for 115 PD participants in the BioFIND study and used repeated-measures analyses to evaluate longitudinal changes in 162 PD participants with five-year follow-up in the PPMI study.

Results: PIGD and TD subtypes in moderate to advanced PD participants change with dopaminergic agents. For those who shifted subtypes, improvement in tremor accounted for the transition of 15 (25.4%) TD participants, while the lack of tremor improvement along with minimal changes in PIGD score resulted in changes for eight (19.0%) PIGD individuals. Analyses of PPMI data revealed that all three subgroups had a significant decrease in subtype ratio with disease progression and a significant decline in subtype ratio occurred only in the TD subgroup with dopaminergic agents. The impact of dopaminergic medication effect on subtype shift for each visit was also more notable with disease advancement.

Conclusions: Motor subtypes are not fixed but change with progression of the disease and with treatment. Improvement in tremor was the main contributor to motor phenotype transitions in the BioFIND cohort. A more stable classification system for subtypes based on underlying biological differences is desirable.
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http://dx.doi.org/10.1016/j.parkreldis.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774826PMC
August 2019

Data-Driven Subtyping of Parkinson's Disease Using Longitudinal Clinical Records: A Cohort Study.

Sci Rep 2019 01 28;9(1):797. Epub 2019 Jan 28.

Department of Healthcare Policy and Research, Weill Cornell Medical College, Cornell University, New York, USA.

Parkinson's disease (PD) is associated with diverse clinical manifestations including motor and non-motor signs and symptoms, and emerging biomarkers. We aimed to reveal the heterogeneity of PD to define subtypes and their progression rates using an automated deep learning algorithm on the top of longitudinal clinical records. This study utilizes the data collected from the Parkinson's Progression Markers Initiative (PPMI), which is a longitudinal cohort study of patients with newly diagnosed Parkinson's disease. Clinical information including motor and non-motor assessments, biospecimen examinations, and neuroimaging results were used for identification of PD subtypes. A deep learning algorithm, Long-Short Term Memory (LSTM), was used to represent each patient as a multi-dimensional time series for subtype identification. Both visualization and statistical analysis were performed for analyzing the obtained PD subtypes. As a result, 466 patients with idiopathic PD were investigated and three subtypes were identified. Subtype I (Mild Baseline, Moderate Motor Progression) is comprised of 43.1% of the participants, with average age 58.79 ± 9.53 years, and was characterized by moderate functional decay in motor ability but stable cognitive ability. Subtype II (Moderate Baseline, Mild Progression) is comprised of 22.9% of the participants, with average age 61.93 ± 6.56 years, and was characterized by mild functional decay in both motor and non-motor symptoms. Subtype III (Severe Baseline, Rapid Progression) is comprised 33.9% of the patients, with average age 65.32 ± 8.86 years, and was characterized by rapid progression of both motor and non-motor symptoms. These subtypes suggest that when comprehensive clinical and biomarker data are incorporated into a deep learning algorithm, the disease progression rates do not necessarily associate with baseline severities, and the progression rate of non-motor symptoms is not necessarily correlated with the progression rate of motor symptoms.
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http://dx.doi.org/10.1038/s41598-018-37545-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349906PMC
January 2019

Repairing the Brain: Cell Replacement Using Stem Cell-Based Technologies.

J Parkinsons Dis 2018 ;8(s1):S131-S137

Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, BMC, Lund, Sweden.

Current approaches to cell replacement therapy in Parkinson's disease are strongly focused on the dopamine system, with the view that restoring dopaminergic inputs in a localized and physiologic manner will provide superior benefits in terms of effect and longevity compared with oral medication. Experience using transplants of fetal tissue containing dopaminergic cell precursors has provided valuable proof that the approach is feasible, and that engrafted cells can survive and function over many years. However, multiple drawbacks and procedural complications are recognized in using fetal cells. Recent strides in stem cell technology now make it possible to overcome some of the barriers associated with fetal tissue. In particular the generation of high numbers of specific cell types, such as dopaminergic neurons, from stem cells means that quality, consistency, activity, and safety can be more thoroughly determined prior to transplantation, thus providing hope for more robust outcomes. These cells are also predicted to provide benefit without leading to the graft-induced dyskinesia that led to morbidity in a subset of individuals who underwent fetal mesencephalic cell and tissue grafting in the 1990s. In thinking about developing such novel therapeutics, the choice of starting material has also expanded, with the availability of multiple human embryonic stem cell lines, as well as the possibilities for producing induced pluripotent cells, or neuronal cells from a patient's own tissue. In this article, we speculate on how rapidly expanding knowledge and technical possibilities may impact on stem cell-based therapies for cell replacement in Parkinson's disease over the next two decades.
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http://dx.doi.org/10.3233/JPD-181488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311366PMC
October 2019

18F-FPEB PET/CT Shows mGluR5 Upregulation in Parkinson's Disease.

J Neuroimaging 2019 01 19;29(1):97-103. Epub 2018 Sep 19.

Department of Radiology, Weill Cornell Medicine, New York, NY.

Background And Purpose: Dopamine and glutamate reciprocally regulate each other in some of the neurocircuits affected by Parkinson's disease (PD). The objective of this pilot study was to explore relationships between these neurotransmitter systems with positron emission tomography.

Methods: The sample consisted of nine patients with PD and eight healthy volunteers (HVs). Dynamic images of the brain were acquired after the IV administration of ∼370 MBq (10 mCi) of [ C]PE2i, a dopamine transporter (DaT) imaging agent, and ∼185 MBq (∼5 mCi) of [ F]FPEB, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist. Multiple volumes of interest were semiautomatically placed on contemporaneously acquired MRI scans. Nondisplaceable binding potentials (BP ) were calculated with the Logan reference tissue model using cerebellar white matter as the reference region.

Results: The findings showed that average [ F]FPEB BP values were slightly more than 20% higher in PD than HVs in several mesocortical regions, including the bilateral putamen (P = .01), hippocampus (P = .02), and amygdala (P = .05). Average [ C]PE2i BP was significantly reduced by about half or more in patients with PD in the bilateral caudate (P < .001) and putamen (P < .001).

Conclusions: mGluR5 seems upregulated in strategic dopaminergic brain regions adversely affected by PD. The findings seem to confirm that DaT tracers are better discriminatory biomarkers for diagnosing PD; however, mGluR5 tracers might deserve further exploration as potential biomarkers of response in clinical trials.
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http://dx.doi.org/10.1111/jon.12563DOI Listing
January 2019

Rapid eye movement sleep behavior disorder and the link to alpha-synucleinopathies.

Clin Neurophysiol 2018 08 29;129(8):1551-1564. Epub 2018 May 29.

Weill Cornell Medical College, New York, NY, USA.

Rapid eye movement (REM) sleep behavior disorder (RBD) involves REM sleep without atonia in conjunction with a recurrent nocturnal dream enactment behavior, with vocalizations such as shouting and screaming, and motor behaviors such as punching and kicking. Secondary RBD is well described in association with neurological disorders including Parkinson's disease (PD), multiple system atrophy (MSA), and other conditions involving brainstem structures such as tumors. However, RBD alone is now considered to be a potential harbinger of later development of neurodegenerative disorders, in particular PD, MSA, dementia with Lewy bodies (DLB), and pure autonomic failure. These conditions are linked by their underpinning pathology of alpha-synuclein protein aggregation. In RBD, it is therefore important to recognize the potential risk for later development of an alpha-synucleinopathy, and to investigate for other potential causes such as medications. Other signs and symptoms have been described in RBD, such as orthostatic hypotension, or depression. While it is important to recognize these features to improve patient management, they may ultimately provide clinical clues that will lead to risk stratification for phenoconversion. A critical need is to improve our ability to counsel patients, particularly with regard to prognosis. The ability to identify who, of those with RBD, is at high risk for later neurodegenerative disorders will be paramount, and would in addition advance our understanding of the prodromal stages of the alpha-synucleinopathies. Moreover, recognition of at-risk individuals for neurodegenerative disorders may ultimately provide a platform for the testing of possible neuroprotective agents for these neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.clinph.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495539PMC
August 2018

Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.

J Neuroimaging 2018 09 4;28(5):496-505. Epub 2018 May 4.

Weill Cornell Medicine, New York, NY.

Background And Purpose: Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [ C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials.

Methods: The sample consisted of 20 participants with PD and 19 HVs. Two independent teams analyzed the data to compare the volume of distribution calculated using image-derived input functions (IDIFs), and binding potentials calculated using the Logan reference region model.

Results: With all methods, the higher signal-to-background in patients resulted in lower variability and better repeatability than in controls. We were able to use noninvasive techniques showing significantly increased uptake of PK in multiple brain regions of participants with PD compared to HVs.

Conclusion: Although not necessarily reflecting absolute values, these noninvasive image analysis methods can discriminate between PD patients and HVs. We see a difference of 24% in the substantia nigra between PD and HV with a repeatability coefficient of 13%, showing that it will be possible to estimate responses in longitudinal, within subject trials of novel neuroprotective drugs.
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http://dx.doi.org/10.1111/jon.12519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174975PMC
September 2018

Valbenazine as the first and only approved treatment for adults with tardive dyskinesia.

Expert Rev Clin Pharmacol 2018 Mar 23;11(3):209-217. Epub 2018 Jan 23.

a Parkinson's Disease and Movement Disorders Institute , Weill Cornell Medicine/New York Presbyterian Hospital , New York , NY , USA.

Introduction: Valbenazine is a selective VMAT2 inhibitor that the FDA approved in April 2017 for the specific treatment of tardive dyskinesia (TD), a movement disorder commonly caused by dopamine blocking agents. Valbenazine acts to decrease dopamine release, reducing excessive movement found in TD. Areas covered: This drug profile reviews the development of valbenazine and the clinical trials that led to its approval as the first treatment specific to TD. The literature search was performed with the PubMed online database. Expert commentary: Two clinical trials assessing the efficacy of valbenazine have shown the reduction of antipsychotic-induced involuntary movement. No life threatening adverse effects were found. Data from a 42-week extension study demonstrated sustained response.
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http://dx.doi.org/10.1080/17512433.2018.1429264DOI Listing
March 2018

Kufor-Rakeb Syndrome Due to a Novel ATP13A2 Mutation in 2 Chinese-American Brothers.

Mov Disord Clin Pract 2018 Jan-Feb;5(1):92-95. Epub 2017 Dec 21.

Department of Neurology Weill Cornell Medicine New York-Presbyterian Hospital New York New York USA.

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http://dx.doi.org/10.1002/mdc3.12567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336435PMC
December 2017

Cerebrospinal fluid, plasma, and saliva in the BioFIND study: Relationships among biomarkers and Parkinson's disease Features.

Mov Disord 2018 02 4;33(2):282-288. Epub 2017 Dec 4.

Division of Movement Disorders, Department of Neurology, Columbia University Medical Center, New York, New York, USA.

Objective: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms.

Background: CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear.

Methods: BioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined.

Results: CSF alpha-synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha-synuclein did not differ between PD and controls, and alpha-synuclein did not significantly correlate among biofluids. CSF beta-amyloid was lower in PD versus controls (P < .01), and correlated weakly with MoCA recall scores (r = 0.23, P = .02). CSF alpha-synuclein was lower in the postural instability/gait difficulty phenotype than other motor phenotypes (P < .01). No CSF biomarkers predicted or correlated with total motor or rapid eye movement sleep behavior disorder scores. CSF alpha-synuclein correlated with beta-amyloid , total-tau, and phosphorylated-tau (r = 0.41, 0.81, 0.43, respectively; Ps < .001).

Conclusion: Lower CSF alpha-synuclein is associated with diagnosis and motor phenotype in moderate-advanced PD. Plasma and saliva alpha-synuclein neither correlate with CSF alpha-synuclein, nor distinguish PD from controls. CSF beta-amyloid remains a potential biomarker for cognitive impairment in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836918PMC
February 2018

Evidence for the use of pimavanserin in the treatment of Parkinson's disease psychosis.

Ther Adv Neurol Disord 2016 Nov 3;9(6):462-473. Epub 2016 Oct 3.

Department of Neurology, Weill Cornell Medical Center, New York, NY USA.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with both motor and nonmotor symptoms (NMS), leading to significant morbidity and caregiver burden. Psychosis is common but is under recognized by physicians. When present, it increases the patient's risk of hospitalization and nursing home placement and caregiver burden. Although the atypical antipsychotic agent, clozapine, has been considered the gold standard treatment, severe agranulocytosis in 0.38% of patients and more commonly milder leukopenia, resulting in frequent blood testing, limit its use. Pimavanserin, a 5HT2A receptor inverse agonist, has been shown to reduce psychosis in PD without worsening motor symptoms. It is therefore a welcome therapeutic option for this devastating NMS.
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http://dx.doi.org/10.1177/1756285616664300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066530PMC
November 2016

The BioFIND study: Characteristics of a clinically typical Parkinson's disease biomarker cohort.

Mov Disord 2016 06 26;31(6):924-32. Epub 2016 Apr 26.

The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.

Background: Identifying PD-specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well-characterized, clinically typical, moderate to advanced PD cohorts is critically needed.

Methods: BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross-sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites.

Results: We present the study methodology and data on the cohort's clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined off and on states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from off state PD assessments and from controls.

Conclusion: Our cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson's Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD's broad and heterogeneous spectrum. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021110PMC
http://dx.doi.org/10.1002/mds.26613DOI Listing
June 2016

Future needs for informed consent in stem cell clinical trials in neurodegenerative diseases.

Neural Regen Res 2016 Jan;11(1):83-5

Weill Cornell Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medical College, New York, NY, USA.

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http://dx.doi.org/10.4103/1673-5374.169632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774238PMC
January 2016

First-in-human cell transplant trials in Parkinson's disease: The need for an improved informed consent process.

Parkinsonism Relat Disord 2015 Aug 19;21(8):829-32. Epub 2015 May 19.

Weill Cornell Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medical College, 428 East 72nd Street, Suite 400, New York, NY 10021, USA. Electronic address:

First-in-human clinical trials of innovative medical procedures, such as cell transplantation for Parkinson's disease, present a variety of ethical challenges. In an era of rapidly developing stem cell technologies likely to be translated into clinical trials over the next few years, it is critical that ethical concerns be fully considered. One important undertaking is ensuring that research participants give free and truly informed consent. This will necessitate adequate disclosure of risks and benefits at a time when these are incompletely defined; ensuring understanding of a complex research protocol when there is significant possibility of therapeutic misconception; and careful determination of capacity for informed consent in patients with a neurodegenerative disorder that is known to affect cognition. Here we call attention to the ethical issues that researchers conducting these types of trials will face when trying to obtain a genuinely informed consent, and we suggest possible solutions.
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http://dx.doi.org/10.1016/j.parkreldis.2015.05.011DOI Listing
August 2015

Dance for PD: a preliminary investigation of effects on motor function and quality of life among persons with Parkinson's disease (PD).

J Neural Transm (Vienna) 2015 Sep 3;122(9):1263-70. Epub 2015 Apr 3.

Brooklyn Parkinson Group, Brooklyn, NY, USA,

In 2001, Dance for Parkinson's disease (DfPD(®)) classes for persons with Parkinson's disease and care partners were developed by Brooklyn Parkinson Group and Mark Morris Dance Group. A previous assessment suggested that individuals experience positive benefits from DfPD(®). The current preliminary uncontrolled study investigated the effects of a dance intervention on several motor and quality of life aspects of PD following 16 sessions (8 weeks; 20 h) taught by professional dancers/teachers. A mixed methods design was used to determine the effects of the class. Assessment instruments administered at baseline and post-intervention included the Hoehn and Yahr, UPDRS (part III), Berg Balance Scale, Beck Depression Inventory, and PDQ-39 and individual interviews after the last class. Hoehn and Yahr scores ranged from 1 to 4. UPDRS III total scores and sub scores of gait and tremor improved following the intervention (P < 0.05). During interviews participants reported physical, emotional, and social benefits. Despite the diversity of baseline measures post-class interview results were consistently positive across the sample. Twelve of 14 subjects (mean age 66.2) with idiopathic PD completed the sessions. After 4 years, four participants regularly attended DfPD(®) classes. The low attrition rate and continued attendance suggest notable adherence to the DfPD(®) class. The importance of the results is both clinical and conceptual, highlighting the value of using both quantitative and qualitative data to evaluate the benefits of dance with PD.
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http://dx.doi.org/10.1007/s00702-015-1380-xDOI Listing
September 2015

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

Authors:
M Flint Beal David Oakes Ira Shoulson Claire Henchcliffe Wendy R Galpern Richard Haas Jorge L Juncos John G Nutt Tiffini Smith Voss Bernard Ravina Clifford M Shults Karen Helles Victoria Snively Mark F Lew Brian Griebner Arthur Watts Shan Gao Emmanuelle Pourcher Louisette Bond Katie Kompoliti Pinky Agarwal Cherissa Sia Mandar Jog Linda Cole Munira Sultana Roger Kurlan Irene Richard Cheryl Deeley Cheryl H Waters Angel Figueroa Ani Arkun Matthew Brodsky William G Ondo Christine B Hunter Joohi Jimenez-Shahed Alicia Palao Janis M Miyasaki Julie So James Tetrud Liza Reys Katharine Smith Carlos Singer Anita Blenke David S Russell Candace Cotto Joseph H Friedman Margaret Lannon Lin Zhang Edward Drasby Rajeev Kumar Thyagarajan Subramanian Donna Stuppy Ford David A Grimes Diane Cote Jennifer Conway Andrew D Siderowf Marian Leslie Evatt Barbara Sommerfeld Abraham N Lieberman Michael S Okun Ramon L Rodriguez Stacy Merritt Camille Louise Swartz W R Wayne Martin Pamela King Natividad Stover Stephanie Guthrie Ray L Watts Anwar Ahmed Hubert H Fernandez Adrienna Winters Zoltan Mari Ted M Dawson Becky Dunlop Andrew S Feigin Barbara Shannon Melissa Jill Nirenberg Mattson Ogg Samuel A Ellias Cathi-Ann Thomas Karen Frei Ivan Bodis-Wollner Sofya Glazman Thomas Mayer Robert A Hauser Rajesh Pahwa April Langhammer Ranjit Ranawaya Lorelei Derwent Kapil D Sethi Buff Farrow Rajan Prakash Irene Litvan Annette Robinson Alok Sahay Maureen Gartner Vanessa K Hinson Samuel Markind Melisa Pelikan Joel S Perlmutter Johanna Hartlein Eric Molho Sharon Evans Charles H Adler Amy Duffy Marlene Lind Lawrence Elmer Kathy Davis Julia Spears Stephanie Wilson Maureen A Leehey Neal Hermanowicz Shari Niswonger Holly A Shill Sanja Obradov Alex Rajput Marilyn Cowper Stephanie Lessig David Song Deborah Fontaine Cindy Zadikoff Karen Williams Karen A Blindauer Jo Bergholte Clara Schindler Propsom Mark A Stacy Joanne Field Dragos Mihaila Mark Chilton Ergun Y Uc Jeri Sieren David K Simon Lauren Kraics Althea Silver James T Boyd Robert W Hamill Christopher Ingvoldstad Jennifer Young Karen Thomas Sandra K Kostyk Joanne Wojcieszek Ronald F Pfeiffer Michel Panisset Monica Beland Stephen G Reich Michelle Cines Nancy Zappala Jean Rivest Richard Zweig L Pepper Lumina Colette Lynn Hilliard Stephen Grill Marye Kellermann Paul Tuite Susan Rolandelli Un Jung Kang Joan Young Jayaraman Rao Maureen M Cook Lawrence Severt Karyn Boyar

JAMA Neurol 2014 May;71(5):543-52

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

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective: To examine whether CoQ10 could slow disease progression in early PD.

Design, Setting, And Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation.

Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E.

Main Outcomes And Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo.

Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo).

Conclusions And Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit.

Trial Registration: clinicaltrials.gov Identifier: NCT00740714.
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http://dx.doi.org/10.1001/jamaneurol.2014.131DOI Listing
May 2014

Sex differences in cerebral energy metabolism in Parkinson's disease: a phosphorus magnetic resonance spectroscopic imaging study.

Parkinsonism Relat Disord 2014 May 13;20(5):545-8. Epub 2014 Feb 13.

Neurology, Weill Cornell Medical College, New York, NY 10021, United States. Electronic address:

Objective: To test the hypothesis that there are sex differences in cerebral energy metabolism in Parkinson's disease (PD).

Methods: Phosphorus magnetic resonance spectroscopy ((31)P MRS) was used to determine high-energy phosphate (phosphocreatine and ATP) and low-energy phosphate (free phosphate) levels in the striatum and temporoparietal cortical gray matter (GM) in 10 men and 10 women with PD, matched for age at onset, disease duration, and UPDRS scores.

Results: In the hemisphere more affected by PD, both ATP and high energy phosphate (HEP: phosphocreatine + ATP) content in striatum was 15% lower in men versus women with PD (p = .050 and p = .048, respectively). Similar decreases by 16% in ATP (p = .023) and 12% in HEP (p = .046) were observed in GM in men versus women with PD. In contrast, there were no detectable sex differences in ATP or HEP in healthy age-matched controls.

Conclusions: Men with PD have lower levels of ATP and high energy phosphate than women in brain regions affected by PD. These findings suggest that there may be a greater burden of mitochondrial dysfunction in PD in men versus women with PD.
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http://dx.doi.org/10.1016/j.parkreldis.2014.02.003DOI Listing
May 2014

Usefulness of proton and phosphorus MR spectroscopic imaging for early diagnosis of Parkinson's disease.

J Neuroimaging 2015 Jan-Feb;25(1):105-10. Epub 2013 Dec 10.

Department of Radiology, Weill Cornell Medical College, New York, NY.

Background And Purpose: Cerebral mitochondrial dysfunction has been observed in Parkinson's disease (PD). If mitochondrial dysfunction is an early event contributing to PD development, then noninvasive techniques that detect disturbed energy metabolism in vivo might be useful tools for early diagnosis and treatment monitoring. In the present study, we tested the hypothesis that proton ((1) H) and phosphorus ((31) P) magnetic resonance spectroscopy (MRS) measures of brain metabolites are able to differentiate between individuals with early PD and healthy volunteers (HVs).

Methods: During this cross-sectional study including 20 subjects with early PD and 15 age-matched HV, ventricular lactate (anaerobic glycolysis); and regional levels of N-acetylaspartate (neuronal integrity); choline (membrane turnover); creatine (energy metabolism); ATP and other phosphate-containing compounds (oxidative phosphorylation) were determined using brain (1) H and (31) P MRS.

Results: No metabolic abnormalities were detectable in early-stage PD patients. Metabolite concentrations were not related to age, disease duration, or Unified Parkinson's Disease Rating Scale motor scores.

Discussion: In early PD, neither (1) H nor (31) P MRS were able to detect metabolic abnormalities, a finding that is in contrast to published data in more advanced PD cohorts. MRS under dynamic conditions might uncover latent energy deficits in early PD, thus warranting future study.
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http://dx.doi.org/10.1111/jon.12074DOI Listing
September 2015

Neuroimaging markers of motor and nonmotor features of Parkinson's disease: an 18f fluorodeoxyglucose positron emission computed tomography study.

Dement Geriatr Cogn Disord 2013 22;35(3-4):183-96. Epub 2013 Feb 22.

Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10021, USA. chh2019 @ med.cornell.edu

Aim: We sought to identify markers of motor and nonmotor function in Parkinson's disease (PD) using advanced neuroimaging techniques in subjects with PD.

Methods: We enrolled 26 nondemented PD subjects and 12 control subjects. All subjects underwent [(18)F]fluorodeoxyglucose positron emission computed tomography (FDG-PET) and magnetic resonance imaging, and a complete neuropsychological battery.

Results: FDG-PET of subjects with PD revealed significant metabolic elevations in the bilateral posterior lentiform nucleus, posterior cingulate, and parahippocampus, and metabolic reductions in the bilateral temporoparietal association cortex and occipital lobe versus controls. PD subjects had significant reductions in executive/attention function, memory/verbal learning, and speed of thinking, and significantly increased depression, anxiety and apathy scores compared with controls. Motor dysfunction correlated with increased metabolism in the posterior lentiform nucleus, pons, and cerebellum, and decreased metabolism in the temporoparietal lobe. Cognitive dysfunction correlated with increased posterior cingulate metabolism and decreased temporoparietal lobe metabolism. Depressive symptoms correlated with increased amygdala metabolism; anxiety scores correlated with decreased caudate metabolism, and apathy scores correlated with increased metabolism in the anterior cingulate and orbitofrontal lobe and decreased metabolism in the temporoparietal association cortex.

Conclusions: Our findings showed that motor, cognitive, and emotional dysfunction in PD are associated with distinct patterns of cerebral metabolic changes.
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http://dx.doi.org/10.1159/000345987DOI Listing
October 2013

Biomarkers in Parkinson's disease: an update.

Curr Opin Neurol 2012 Aug;25(4):460-5

Department of Neurology and Neuroscience, Weil Cornell Medical College and Hospital for Special Surgery, New York, New York 10021, USA.

Purpose Of Review: This review article is focused upon the most recent biomarker studies of Parkinson's disease. It provides an update on promising areas of biomarker research in a rapidly expanding field, and discusses future directions that might lead to successful development of Parkinson's disease biomarkers.

Recent Findings: Studies of molecular-genetic and biochemical biomarkers of Parkinson's disease have not only targeted hypothesis-driven measures of specific substrates involved in processes such as protein misprocessing, but also have made use of sophisticated analyses such as transcriptomic, proteomic, and metabolomic approaches. Whereas none of these are yet established as Parkinson's disease biomarkers, brain imaging using the 123I-ioflupane ligand with single-photon emission computed tomography was recently approved in the United States to aid in Parkinson's disease diagnosis, and research on other imaging modalities is ongoing. Neurophysiological tests are also being adapted for biomarker research, and we review recent promising data.

Summary: The search for effective biomarkers for diagnosis and surveillance of Parkinson's disease continues. A battery of biomarkers comprising different modalities might be required to address clinical needs in this complex disorder. Critically, collaborative efforts including centralized tissue repository and clinical research infrastructure that are being organized will advance this field further.
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http://dx.doi.org/10.1097/WCO.0b013e3283550c0dDOI Listing
August 2012