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Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Choi, Se Joon; Ma, Thong C; Ding, Yunmin; Cheung, Timothy; Joshi, Neal; Sulzer, David; Mosharov, Eugene V; Kang, Un Jung
Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.
PMID: 32687053
ISSN: 2050-084x
CID: 4533332

Comparative study of cerebrospinal fluid α-synuclein seeding aggregation assays for diagnosis of Parkinson's disease

Kang, Un Jung; Boehme, Amelia K; Fairfoul, Graham; Shahnawaz, Mohammad; Ma, Thong Chi; Hutten, Samantha J; Green, Alison; Soto, Claudio
BACKGROUND:PD diagnosis is based primarily on clinical criteria and can be inaccurate. Biological markers, such as α-synuclein aggregation, that reflect ongoing pathogenic processes may increase diagnosis accuracy and allow disease progression monitoring. Though α-synuclein aggregation assays have been published, reproducibility, standardization, and validation are key challenges for their development as clinical biomarkers. OBJECTIVE:To cross-validate two α-synuclein seeding aggregation assays developed to detect pathogenic oligomeric α-synuclein species in CSF using samples from the same PD patients and healthy controls from the BioFIND cohort. METHODS:CSF samples were tested by two independent laboratories in a blinded fashion. BioFIND features standardized biospecimen collection of clinically typical moderate PD patients and nondisease controls. α-synuclein aggregation was measured by protein misfolding cyclic amplification (Soto lab) and real-time quaking-induced conversion (Green lab). Results were analyzed by an independent statistician. RESULTS:Measuring 105 PD and 79 healthy control CSF samples, these assays showed 92% concordance. The areas under the curve from receiver operating characteristic curve analysis for the diagnosis of PD versus healthy controls were 0.93 for protein misfolding cyclic amplification, 0.89 for real-time quaking-induced conversion, and 0.95 when considering only concordant assay results. Clinical characteristics of false-positive and -negative subjects were not different from true-negative and -positive subjects, respectively. CONCLUSIONS:These α-synuclein seeding aggregation assays are reliable and reproducible for PD diagnosis. Assay parameters did not correlate with clinical parameters, including disease severity or duration. This assay is highly accurate for PD diagnosis and may impact clinical practice and clinical trials. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
PMID: 30840785
ISSN: 1531-8257
CID: 3733802

The role of neuroplasticity in dopaminergic therapy for Parkinson disease

Zhuang, Xiaoxi; Mazzoni, Pietro; Kang, Un Jung
Dopamine replacement is a mainstay of therapeutic strategies for Parkinson disease (PD). The motor response to therapy involves an immediate improvement in motor function, known as the short-duration response (SDR), followed by a long-duration response (LDR) that develops more slowly, over weeks. Here, we review evidence in patients and animal models suggesting that dopamine-dependent corticostriatal plasticity, and retention of such plasticity in the absence of dopamine, are the mechanisms underlying the LDR. Conversely, experience-dependent aberrant plasticity that develops slowly under reduced dopamine levels could contribute substantially to PD motor symptoms before initiation of dopamine replacement therapy. We place these findings in the context of the role of dopamine in basal ganglia function and corticostriatal plasticity, and provide a new framework suggesting that therapies that enhance the LDR could be more effective than those targeting the SDR. We further propose that changes in neuroplasticity constitute a form of disease modification that is distinct from prevention of degeneration, and could be responsible for some of the unexplained disease-modifying effects of certain therapies. Understanding such plasticity could provide novel therapeutic approaches that combine rehabilitation and pharmacotherapy for treatment of neurological and psychiatric disorders involving basal ganglia dysfunction.
PMID: 23588357
ISSN: 1759-4766
CID: 3501622

Seed Amplification Assay to Diagnose Early Parkinson's and Predict Dopaminergic Deficit Progression [Letter]

Concha-Marambio, Luis; Farris, Carly M; Holguin, Bret; Ma, Yihua; Seibyl, John; Russo, Marco J; Kang, Un J; Hutten, Samantha J; Merchant, Kalpana; Shahnawaz, Mohammad; Soto, Claudio
PMID: 34236720
ISSN: 1531-8257
CID: 4937472

Correction to: α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; Del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
PMID: 34028589
ISSN: 1432-0533
CID: 4908432

α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; Del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.
PMID: 33991233
ISSN: 1432-0533
CID: 4889422

Correction to: A-synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
A correction to this paper has been published: https:
PSYCH:2021-49944-001
ISSN: 1432-0533
CID: 4900962

A-synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether alpha-synuclein (alpha-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured alpha-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, alpha-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between alpha-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the alpha-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring alpha-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
PSYCH:2021-47020-001
ISSN: 1432-0533
CID: 4883332

A rapid α-synuclein seed assay of Parkinson's disease CSF panel shows high diagnostic accuracy

Orrù, Christina D; Ma, Thong C; Hughson, Andrew G; Groveman, Bradley R; Srivastava, Ankit; Galasko, Douglas; Angers, Rachel; Downey, Patrick; Crawford, Karen; Hutten, Samantha J; Kang, Un Jung; Caughey, Byron
BACKGROUND:Assays that specifically measure α-synuclein seeding activity in biological fluids could revolutionize the diagnosis of Parkinson's disease. Recent improvements in α-synuclein real-time quaking-induced conversion assays of cerebrospinal fluid have dramatically reduced reaction times from 5-13 days down to 1-2 days. OBJECTIVE:To test our improved assay against a panel of cerebrospinal fluid specimens from patients with Parkinson's disease and healthy controls from the MJ Fox Foundation/NINDS BioFIND collection. METHODS:Specimens collected from healthy controls and patients with clinically typical moderate-to-advanced Parkinson's disease were tested without prior knowledge of disease status. Correlative analyses between assay parameters and clinical measures were performed by an independent investigator. RESULTS:BioFIND samples gave positive signals in 105/108 (97%) Parkinson's disease cases versus 11/85 (13%) healthy controls. Receiver operating characteristic analyses of diagnosis of cases versus healthy controls gave areas under the curve of 95%. Beyond binary positive/negative determinations, only weak correlations were observed between various assay response parameters and Parkinson's disease clinical measures or other cerebrospinal fluid analytes. Of note, REM sleep behavioral disorder questionnaire scores correlated with the reaction times needed to reach 50% maximum fluorescence. Maximum fluorescence was inversely correlated with Unified Parkinson's Disease Rating Scale motor scores, which was driven by the patients without REM sleep behavioral disorder. CONCLUSIONS:Our improved α-synuclein seed amplification assay dramatically reduces the time needed to diagnose Parkinson's disease while maintaining the high-performance standards associated with previous α-synuclein seed assays, supporting the clinical utility of this assay for Parkinson's disease diagnosis.
PMID: 33373501
ISSN: 2328-9503
CID: 4765002

COVID-19 Vaccination for Persons with Parkinson's Disease: Light at the End of the Tunnel?

Bloem, Bastiaan R; Trenkwalder, Claudia; Sanchez-Ferro, Alvaro; Kalia, Lorraine V; Alcalay, Roy; Chiang, Han-Lin; Kang, Un Jung; Goetz, Christopher; Brundin, Patrik; Papa, Stella M
Several COVID-19 vaccines have recently been approved for emergency use according to governmental immunization programs. The arrival of these vaccines has created hope for people with Parkinson's disease (PD), as this can help to mitigate their risk of becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can lead to serious, life-threatening disease, at least among those with more advanced PD. However, both persons with PD and physicians looking after these individuals have expressed concerns about the vaccine's efficacy and safety in the specific context of PD and its symptomatic treatment. Here, we discuss our perspective on these concerns, based on our interpretation of the literature plus the unfolding experience with widespread vaccination in the population at large. Because the benefits and risks of COVID-19 vaccines do not appear to be different than in the general population, we recommend COVID-19 vaccination with approved vaccines to persons with PD, unless there is a specific contraindication. Some caution seems warranted in very frail and terminally ill elderly persons with PD living in long-term care facilities.
PMID: 33523021
ISSN: 1877-718x
CID: 4791062