The central theme of the University of Michigan Udall Center is the role of cholinergic lesions in gait and balance abnormalities in Parkinson’s Disease (PD). Through an interrelated and complementary set of neuroimaging, behavioral and pharmacological studies in patients with PD and a unique animal model, Center investigators examine the contribution of distinct cholinergic projections to abnormalities of gait and balance in PD and to develop proof-of-concept target engagement for a therapy to treat these debilitating symptoms
Multiple neurochemical systems degenerate in Parkinson’s Disease (PD). Common and profoundly disabling PD symptoms remain largely levodopa resistant. Progressive gait and balance difficulties, and associated falls, are among the most common levodopa resistant symptoms, eventually occurring in nearly all patients. The consequences of these levodopa resistant symptoms are devastating, and include bone fractures, hospitalizations, self-imposed isolation because of fear of falling, wheelchair confinement, and eventual nursing home placement.
The University of Michigan Udall Center of Excellence for Parkinson’s Disease Research conducts experimental, computational and human research to investigate the cause of cholinergic projections degeneration in the pathogenesis of gait dysfunction in PD. The central themes of the Udall Center are the role of cholinergic lesions in gait and balance abnormalities in PD and the development of novel treatment strategies targeted at cholinergic neurotransmission.
Data collected by Center investigators indicates that gait and postural control are not purely “motor” functions but require complex integration of motor, sensory, and cognitive functions. Defining the relationship between cholinergic dysfunction and gait abnormalities requires a multidisciplinary approach in which investigators view the relationship between cholinergic function, gait, and cognition through different lenses, share insights and challenge each other in ways that yield progress far beyond that achievable were each project pursued separately. The research team at the Center has developed preliminary data that lead to the development of a “3-Hit” model of gait dysfunction in PD which posits that the typical clinical progression of gait and postural abnormalities in PD is caused by the interaction of striatal dopamine loss with degeneration of cholinergic neurons in the basal forebrain (BF) and pedunculopontine (PPN) nucleus.
The lack of effective therapies for gait and balance abnormalities in advancing PD stems in large part from a limited understanding of the role of non-dopaminergic systems in the pathophysiology of these symptoms. It is increasingly clear that normal gait depends upon a complex interplay of motor, sensory and cognitive functions, indicating that the full spectrum of PD neuropathology must be considered to identify the responsible neural substrates. The PET work of Udall Center investigators demonstrated that PD patients with a history of falls have significantly reduced cholinergic function compared to non-falling patients, whereas these groups do not differ in the degree of dopaminergic denervation. This was the first in vivo study to link cholinergic deficits explicitly to gait dysfunction in PD patients, and is consistent with a considerable and growing body of work supporting a critical role for cholinergic function in locomotion. This work includes several reports indicating that enhancing cholinergic neurotransmission improves gait, while anti-cholinergic drugs may have deleterious effects.
Despite these intriguing observations, the relationship between cholinergic lesions and gait dysfunction in PD is poorly understood, and it is not clear whether or how these lesions synergize with striatal dopamine deficiency. Two cholinergic projections in the brain degenerate in PD and are implicated in the control of locomotion. The basal forebrain (BF) complex, including the nucleus basalis of Meynert, provides the principal cholinergic input to the entire cortical mantle. The pedunculopontine nucleus (PPN) provides cholinergic inputs to the thalamus, cerebellum, several brainstem nuclei, the basal ganglia, and the spinal cord. The extent to which gait dysfunction in PD is caused by independent or combined BF or PPN cholinergic lesions is not well understood.
Recent Significant Advances
Several recent advances made by Center investigators support a key role for cholinergic dysfunction in PD gait and balance abnormalities.
Project I: Modeling and treating cholinergic impairment and fall propensity in PD (Project Leader: Sarter): To mechanistically dissect PD-related gait abnormalities, Dr. Sarter has continued to study the rodent model of PD gait dysfunction developed by his group (Kucinski et. al., J. Neuroscience 2013). This model demonstrates how attentional impairment, caused by partial basal forebrain cholinergic neuron loss, causes pronounced abnormalities of gait by “unmasking” striatal dysfunction caused by dorsal striatal dopaminergic denervation. These “dual lesioned” (“DL”) rodents exhibit a high propensity for falls in situations requiring attentional supervision of complex movements and freezing-type behavior when walking through model “doorways” that is strikingly reminiscent of PD symptomatology. Further study of the cholinergic system explored a role for the pedunculopontine nucleus cholinergic neurons (PPN-C), the principal brainstem cholinergic projection system. Animals with cholinergic lesions of both the basal forebrain and PPN-C fall significantly more frequently than those with isolated basal forebrain lesions, indicating a synergistic effect of these pathways (Kucinski, et al, Behav Brain Res. 2015). The PPN-C lesion did not overtly worsen fall propensity in these mice with basal forebrain and dorsal striatal dopaminergic lesions; this may be due to a “floor” effect on motor dysfunction, a possibility that is being explored currently. An explicit prediction of these experiments is that brief phasic increases in forebrain cholinergic tone control are essential for cue detection – slips, or losses of balance in the context of falls. Dr. Sarter’s group tested this prediction by up- and down-regulating basal forebrain cholinergic neurotransmission using optogenetic methods. These experiments confirmed that generating cholinergic “transients” enhances cue detection rates, while inhibiting transients has the opposite effect (Gritton, H. J. et al. PNAS 2016). Remarkably, stimulating cholinergic transients increased the number of invalid claims for cue detection (e.g., the animals reported the existence of cues not actually present). These studies strongly support the proposed function of basal forebrain cholinergic signaling in cue detection. Additional advances in this project include the design of an improved behavioral apparatus that will allow for dialysate collection and optogenetic manipulation of cholinergic signaling during the performance of beam walking behavior to better dissect how cholinergic and dopaminergic dysfunction interact to disrupt gait. This model was also used to test novel therapeutic strategies to reduce falls. Previous work demonstrated the 5HT6 receptor antagonist idalopirdine to exhibit pro-cholinergic activity in rats and improved cognition in patients with moderate cognitive dysfunction. However, idalopirdine did not reduce falls in DL rodents, nor did it benefit sustained attention performance (Kucinski, A. et al. EJN 2016). Assessment of behavior during near-fall events indicated that idalopirdine improved the efficacy and speed of reinstating forward movements after short gait stoppages, suggesting a potential role for this drug in gait freezing.
Project II: Imaging of cholinergic systems in Parkinson’s disease (Project Leader: Bohnen): The goal of this project is to perform a prospective neuroimaging study to test the distinct contributions of cholinergic projection system degenerations (i.e., basal forebrain and pedunculopontine nucleus) to PD gait and postural dysfunction. Cholinergic projections are imaged using the novel vesicular acetylcholine transporter (VAChT) PET imaging using the novel ligand [18F]FEOBV. Outstanding progress continues to be made in recruiting subjects – a total of 70 subjects have been recruited,68 of whom have completed all assessments. Comprehensive assessments include well-established clinical, motor, and neuropsychological instruments that are consistent with NINDS CDEs. All subjects also underwent [11C]DTBZ PET and brain MRI.
Interim analyses of combined PD patients and non-PD control subjects have shown evidence for bidirectional changes of VAChT in PD patients compared to non-PD control subjects. These include areas of relatively increased activity in striatal, thalamic and anterior cortical (esp. frontal) regions and decreased activity in the posterior (parieto-occipital) cortices. This is a novel observation and differs from the results obtained with the cholinesterase ligand ([11C]PMP). This is likely due to fact that [11C]PMP assesses enzyme activity. Based on this finding, we have developed a new FEOBV-specific criterion of hypocholinergic status based on posterior cortical activity. This finding also raises the question of whether the increases observed in subcortical- anterior cortical [18F]FEOBV binding are absolutely increased compared to non-PD control subjects. To address this important issue we have begun to validate a non- invasive quantification method of VAChT binding based on delayed static [18F]FEOBV by analyzing a dynamic (including arterial sampling) dataset of normal subjects (n=20). Preliminary results show that the supratentorial white matter region can be effectively used to calculate VAChT binding ratios. We are currently preparing methodological and in vivo imaging analysis manuscripts to report on these findings. If absolute increases in VAChT in a subset of PD patients are confirmed, this will allow us to study clinical (including motor) phenotypic correlates of regional hypercholinergic tone. Finally, given higher than expected age-decline of VAChT binding we are studying additional normal elderly subjects to explore this in more details.
Project III: α4β2* nAChRs, gait, and balance in Parkinson’s disease (co-Project Leaders: Albin & Dauer): This project is a target engagement investigation of the alpha4beta2 nicotinic cholinergic receptor to determine whether agonism of this target improves laboratory-based measures of gait. During the past year, we initiated the initial, dose-finding, experiment using [18F]flubatine PET imaging to determine the lowest oral dose of varenicline that produces high α4β2* nAChR occupancy. We are now in the final phase of this experiment, scanning subjects in highest dose group. Varenicline has been generally well tolerated and our studies show substantial (>70%) receptor occupancy. These studies will be completed within the next 6-8 weeks and then we will initiate the next experiment. We had a Data Safety and Monitoring Board meeting last fall and our second DSMB meeting will take place later this month.
All relevant details for generating the novel rodent model of PD gait dysfunction, including the Michigan Complex Motor Task (MCMCT), are available in Kucinski, A, et. al., Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci. 2013;33(42):16522–16539. We would be happy to help any interested investigators set up this model system in their laboratories. We would also be happy to assist interested investigators in the generation of FEOBV and its use and quantification, as well as the methods we are employing to assess alpha4beta2 cholinergic receptor occupancy with flubatine. DNA sample from all patients recruited for this study are also being deposited with the NINDS Biorepository and will be freely available for use by PD researchers.
Select Recent Publications
Gritton HJ, Howe WM, Mallory CS, Hetrick VL, Berke JD, Sarter M. Cortical cholinergic signaling controls the detection of cues. Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E1089-97. PMID: 26787867; PMCID: PMC4776505
Kett LR, Stiller B, Bernath MM, Tasset I, Blesa J, Jackson-Lewis V, Chan RB, Zhou B, Di Paolo G, Przedborski S, Cuervo AM, Dauer WT. α-Synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal Parkinsonism protein Atp13a2. J Neurosci. 2015 Apr 8;35(14):5724-42. PMID: 25855184; Central PMCID: PMC4388928.
Kucinski A, Sarter M. Modeling Parkinson’s disease falls associated with brainstem cholinergic systems decline. Behav Neurosci. 2015 Apr;129(2):96-104. PMID: 25798629; PMCID: PMC4392884.
Kucinski, A., Paolone, G., Bradshaw, M., Albin, R. L. & Sarter, M. Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci 33, 16522-16539 (2013).
Kucinski, A., de Jong, I. E. & Sarter, M. Reducing falls in Parkinson’s disease: interactions between donepezil and the 5-HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. Eur J Neurosci (2016).
Moon SW, Dinov ID, Hobel S, Zamanyan A, Choi YC, Shi R, Thompson PM, Toga AW, Alzheimer’s Disease Neuroimaging Initiative. Structural Brain Changes in Early-Onset Alzheimer’s Disease Subjects Using the LONI Pipeline Environment. J Neuroimaging. 2015 Sep-Oct;25(5):728-37. PMID: 25940587; PMCID: PMC4537660.
Müller ML, Bohnen NI, Kotagal V, Scott PJ, Koeppe RA, Frey KA, Albin RL. Clinical markers for identifying cholinergic deficits in Parkinson’s disease. Mov Disord. 2015 Feb;30(2):269-73. PMID: 25393613; PMCID: PMC4318774.
Petrou M, Davatzikos C, Hsieh M, Foerster BR, Albin RL, Kotagal V, Müller ML, Koeppe RA, Herman WH, Frey KA, Bohnen NI. Diabetes, Gray Matter Loss, and Cognition in the Setting of Parkinson Disease. Acad Radiol. 2016 May;23(5):577-81. PMID: 26874576; NIHMSID: 778098.
Sarter M, Lustig C, Berry AS, Gritton H, Howe WM, Parikh V. What do phasic cholinergic signals do?. Neurobiol Learn Mem. 2016 Apr;130:135-41. PMID: 26911787; PMCID: PMC4818703.
Shah N, Frey KA, L T M Müller M, Petrou M, Kotagal V, Koeppe RA, Scott PJ, Albin RL, Bohnen NI. Striatal and Cortical β-Amyloidopathy and Cognition in Parkinson’s Disease. Mov Disord. 2016 Jan;31(1):111-7. PMID: 26380951; PMCID: PMC4724301.
To mechanistically dissect PD-related gait abnormalities, Dr. Sarter developed a novel rodent model of PD gait dysfunction demonstrating how attentional impairment, caused by partial basal forebrain cholinergic neuron loss, causes pronounced abnormalities of gait by “unmasking” striatal dysfunction caused by dorsal striatal dopaminergic denervation. These rodents exhibit a high propensity for falls in situations requiring attentional supervision of complex movements and freezing-type behavior when walking through model “doorways” that is strikingly reminiscent of PD symptomatology. In the past year, this work has been extended to explore the potential contribution of PPN degeneration to gait dysfunction (Kucinski, et al, Behav Neurosci. 2015). These studies demonstrated that PPN cholinergic lesions did not worsen the motor phenotype, when combined together with either striatal dopaminergic lesions or striatal dopaminergic lesions plus basal forebrain lesions (“triple lesioned” animals). This important result indicates that the dominant cholinergic effects for gait emanate from basal forebrain corticopetal projections and associated attentional functions, at least in this rodent model. Further studies in this model also demonstrate that isolated, large dopaminergic lesions are themselves able to impair gait. In contrast to the lack of effects of smaller, dorsal striatal dopamine (DA) losses and sham lesions, this work showed that larger striatal lesions increased falls and slips and caused slowing while traversing dynamic surfaces. Falls in rats with large DA lesions were associated specifically with spontaneous or slip-triggered stoppages of forward movement. Collectively, these data suggests that low motivation or vigor for movement in general, and for initiating corrective movements in particular, are major sources for falls in rats with large DA losses. Additional advances in this project include the design of an improved behavioral apparatus that will allow for dialysate collection and optogenetic manipulation of cholinergic signaling during the performance of beam walking behavior to better dissect how cholinergic and dopaminergic dysfunction interact to disrupt gait.
Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program. Gwinn K, David KK, Swanson-Fischer C, Albin R, Hillaire-Clarke CS, Sieber BA, Lungu C, Bowman FD, Alcalay RN, Babcock D, Dawson TM, Dewey RB Jr, Foroud T, German D, Huang X, Petyuk V, Potashkin JA, Saunders-Pullman R, Sutherland M, Walt DR, West AB, Zhang J, Chen-Plotkin A, Scherzer CR, Vaillancourt DE, Rosenthal LS. Biomark Med. 2017 May;11(6):451-473. doi: 10.2217/bmm-2016-0370. Epub 2017 Jun 23. PMID: 28644039. PMCID:PMC5619098
Mentally stimulating activities associate with better cognitive performance in Parkinson disease. Bohnen JLB, Müller MLTM, Haugen J, Bohnen NI. J Neural Transm (Vienna). 2017 Oct;124(10):1205-1212. doi: 10.1007/s00702-017-1761-4. Epub 2017 Jul 19. PMID:28726034. PMCID:PMC5693756
Many genes involved in Tourette syndrome pathogenesis. Albin RL. Mov Disord. 2017 Jul;32(7):993. doi: 10.1002/mds.27070. Epub 2017 Jun 8. No abstract available. PMID: 28594134. PMCID:PMC5528167
The missing, the short, and the long: Levodopa responses and dopamine actions. Albin RL, Leventhal DK. Ann Neurol. 2017 Jul;82(1):4-19. doi: 10.1002/ana.24961. Epub 2017 Jun 5. No abstract available. PMID:28543679. PMCID: PMC5526730
Association between autonomic dysfunction and fatigue in Parkinson disease. Chou KL, Gilman S, Bohnen NI. J Neurol Sci. 2017 Jun 15;377:190-192. doi: 10.1016/j.jns.2017.04.023. Epub 2017 Apr 17. PMID: 28477694 PMCID:PMC5536106
Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta-Gamma Coupling during Cue Detection. Howe WM, Gritton HJ, Lusk NA, Roberts EA, Hetrick VL, Berke JD, Sarter M. J Neurosci. 2017 Mar 22;37(12):3215-3230. doi: 10.1523/JNEUROSCI.2737-16.2017. Epub 2017 Feb 17. PMID:28213446.PMCID:PMC5373115
Motor Speech Apraxia in a 70-Year-Old Man with Left Dorsolateral Frontal Arachnoid Cyst: A [18F]FDG PET-CT Study. Bohnen NI, Haugen J, Kluin K, Kotagal V. Case Rep Neurol Med. 2016;2016:8941035. doi: 10.1155/2016/8941035. Epub 2016 Nov 24. PMID: 28003922
Thalamic cholinergic innervation makes a specific bottom-up contribution to signal detection: Evidence from Parkinson's disease patients with defined cholinergic losses. Kim K, Müller ML, Bohnen NI, Sarter M, Lustig C. Neuroimage. 2017 Apr 1;149:295-304. doi: 10.1016/j.neuroimage.2017.02.006. Epub 2017 Feb 5. PMID:28167350 PMCID:PMC5386784
Unresponsive Choline Transporter as a Trait Neuromarker and a Causal Mediator of Bottom-Up Attentional Biases. Koshy Cherian A, Kucinski A, Pitchers K, Yegla B, Parikh V, Kim Y, Valuskova P, Gurnani S, Lindsley CW, Blakely RD, Sarter M. J Neurosci. 2017 Mar 15;37(11):2947-2959. doi: 10.1523/JNEUROSCI.3499-16.2017. Epub 2017 Feb 13. PMID:28193693 PMCID:PMC5354335
What would Dr. James Parkinson think today? II. Neuroimaging in Parkinson’s Disease. Albin Roger L. Mov Disord 2017 Feb;32(2):179-180
Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease. Ridder A, Müller ML, Kotagal V, Frey KA, Albin RL, Bohnen NI. Parkinsonism Relat Disord. 2017 Jan;34:15-19. doi: 10.1016/j.parkreldis.2016.10.006. Epub 2016 Oct 7. PMCID: 5222688
Cerebral Amyloid Burden and Hoehn and Yahr Stage 3 Scoring in Parkinson Disease. Kotagal V, Bohnen NI, Müller ML, Frey KA, Albin RL. J Parkinsons Dis. 2017;7(1):143-147. doi: 10.3233/JPD-160985. PMID:28106566 PMCID: PMC54701152016
T2-Imaging Changes in the Nigrosome-1 Relate to Clinical Measures of Parkinson's Disease. Fu KA, Nathan R, Dinov ID, Li J, Toga AW. Front Neurol. 2016 Oct 20;7:174. eCollection 2016.PMID:27812347 PMCID:PMC5071353
Endolysosomal dysfunction in Parkinson's disease: Recent developments and future challenges. Kett LR, Dauer WT. Mov Disord. 2016 Oct;31(10):1433-1443. doi: 10.1002/mds.26797. PMID:27619535 PMCID:PMC5061051
COMPASS: A computational model to predict changes in MMSE scores 24-months after initial assessment of Alzheimer's disease. Zhu F, Panwar B, Dodge HH, Li H, Hampstead BM, Albin RL, Paulson HL, Guan Y. Sci Rep. 2016 Oct 5;6:34567. doi: 10.1038/srep34567. PMID: 27703197 PMCID:PMC5050516
Orthostatic hypotension predicts motor decline in early Parkinson disease. Kotagal V, Lineback C, Bohnen NI, Albin RL; CALM-PD Parkinson Study Group Investigators..Parkinsonism Relat Disord. 2016 Nov;32:127-129. doi: 10.1016/j.parkreldis.2016.09.011. Epub 2016 Sep 9. PMID:27639815 PMCID:PMC5114666
2-Year Natural Decline of Cardiac Sympathetic Innervation in Idiopathic Parkinson Disease Studied with 11C-Hydroxyephedrine PET. Wong KK, Raffel DM, Bohnen NI, Altinok G, Gilman S, Frey KA. J Nucl Med. 2017 Feb;58(2):326-331. doi: 10.2967/jnumed.116.176891. Epub 2016 Aug 18. PMID:27539837 PMCID:PMC5288743
Predictive Big Data Analytics: A Study of Parkinson's Disease Using Large, Complex, Heterogeneous, Incongruent, Multi-Source and Incomplete Observations. Dinov ID, Heavner B, Tang M, Glusman G, Chard K, Darcy M, Madduri R, Pa J, Spino C, Kesselman C, Foster I, Deutsch EW, Price ND, Van Horn JD, Ames J, Clark K, Hood L, Hampstead BM, Dauer W, Toga AW. PLoS One. 2016 Aug 5;11(8):e0157077. doi: 10.1371/journal.pone.0157077. eCollection 2016. PMID:27494614 PMCID:PMC4975403
Comparison of genomic data via statistical distribution. Amiri S, Dinov ID. J Theor Biol. 2016 Oct 21;407:318-27. doi: 10.1016/j.jtbi.2016.07.032. Epub 2016 Jul 25. PMID: 27460589 PMCID:PMC5361063
Cholinergic genetics of visual attention: Human and mouse choline transporter capacity variants influence distractibility. Sarter M, Lustig C, Blakely RD, Koshy Cherian A. J Physiol Paris. 2016 Sep;110(1-2):10-18. doi: 10.1016/j.jphysparis.2016.07.001. Epub 2016 Jul 9. Review. PMID:27404793 PMCID: PMC5164965
Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET. Scott PJ, Shao X, Desmond TJ, Hockley BG, Sherman P, Quesada CA, Frey KA, Koeppe RA, Kilbourn MR, Bohnen NI. ACS Med Chem Lett. 2016 Jun 1;7(8):746-50. doi: 10.1021/acsmedchemlett.5b00435. eCollection 2016 Aug 11. PMID: 27563397 PMCID:PMC4983726
Is PIGD a legitimate motor subtype in Parkinson disease? Kotagal V.Ann Clin Transl Neurol. 2016 May 11;3(6):473-7. doi: 10.1002/acn3.312. eCollection 2016 Jun. PMID:27547776 PMCID:PMC4892002
Diabetes, Gray Matter Loss, and Cognition in the Setting of Parkinson Disease. Petrou M, Davatzikos C, Hsieh M, Foerster BR, Albin RL, Kotagal V, Müller ML, Koeppe RA, Herman WH, Frey KA, Bohnen NI. Acad Radiol. 2016 May;23(5):577-81. doi: 10.1016/j.acra.2015.07.014. PMID: 26874576; PMCID: PMC4859345.
What do phasic cholinergic signals do? Sarter M, Lustig C, Berry AS, Gritton H, Howe WM, Parikh V. Neurobiol Learn Mem. 2016 Apr;130:135-41. doi:10.1016/j.nlm.2016.02.008. Review.PMID: 26911787; PMCID: PMC4818703.
Prevalence of impaired odor identification in Parkinson disease with imaging evidence of nigrostriatal denervation. Haugen J, Müller ML, Kotagal V, Albin RL, Koeppe RA, Scott PJ, Frey KA, Bohnen NI. J Neural Transm (Vienna). 2016 Apr;123(4):421-4. doi: 10.1007/s00702-016-1524-7. PMID: 26911386; PMCID: PMC4805466.
Interactive effects of age and multi-gene profile on motor learning and sensorimotor adaptation. Noohi F, Boyden NB, Kwak Y, Humfleet J, Müller ML, Bohnen NI, Seidler RD. Neuropsychologia. 2016 Apr;84:222-34. doi: 10.1016/j.neuropsychologia.2016.02.021. Epub 2016 Feb 27.PMID:26926580 PMCID: PMC4849282
Methodological challenges and analytic opportunities for modeling and interpreting Big Healthcare Data. Dinov ID. Gigascience. 2016 Feb 25;5:12. doi: 10.1186/s13742-016-0117-6. eCollection 2016. Review.PMID:26918190 :PMCID:PMC4766610
Cortical cholinergic signaling controls the detection of cues. Gritton HJ, Howe WM, Mallory CS, Hetrick VL, Berke JD, Sarter M.Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E1089-97. doi: 10.1073/pnas.1516134113.PMID: 26787867;PMCID: PMC4776505.
Parkinson's disease-related fatigue: A case definition and recommendations for clinical research. Kluger BM, Herlofson K, Chou KL, Lou JS, Goetz CG, Lang AE, Weintraub D, Friedman J. Mov Disord. 2016 May;31(5):625-31. doi: 10.1002/mds.26511. Epub 2016 Feb 16. Review. PMID: 26879133 PMCID:PMC4863238
Fatigue in Parkinson's disease: report from a mutidisciplinary symposium. Friedman JH, Beck JC, Chou KL, Clark G, Fagundes CP, Goetz CG, Herlofson K, Kluger B, Krupp LB, Lang AE, Lou JS, Marsh L, Newbould A, Weintraub D. NPJ Parkinsons Dis. 2016;2. pii: 15025. Epub 2016 Jan 14. PMID:27239558 PMCID:PMC4883681
Mini-review: Retarding aging in murine genetic models of neurodegeneration. Albin RL, Miller RA. Neurobiol Dis. 2016 Jan;85:73-80. doi:10.1016/j.nbd.2015.10.014. Review.PMID: 26477301 PMCID:PMC4688232.
Striatal and cortical β-amyloidopathy and cognition in Parkinson's disease. Shah N, Frey KA, Müller ML, Petrou M, Kotagal V, Koeppe RA, Scott PJ, Albin RL, Bohnen NI.Mov Disord. 2016 Jan;31(1):111-7. doi: 10.1002/mds.26369.PMID:26380951;PMCID: PMC4724301.2015
Neuroimaging and clinical predictors of fatigue in Parkinson disease. Chou KL, Kotagal V, Bohnen NI. Parkinsonism Relat Disord. 2016 Feb;23:45-9. Epub 2015 Dec 2. PMID:26683744 PMCID:PMC4724499
Big biomedical data as the key resource for discovery science.Toga AW, Foster I, Kesselman C, Madduri R, Chard K, Deutsch EW, Price ND, Glusman G, Heavner BD, Dinov ID, Ames J, Van Horn J, Kramer R, Hood L. J Am Med Inform Assoc. 2015 Nov;22(6):1126-31. Epub 2015 Jul 21.PMID:26198305 PMCID:PMC5009918
Post-Mortem evaluation of amyloid-dopamine terminal positron emission tomography dementia classifications. Albin RL, Fisher-Hubbard A, Shanmugasundaram K, Koeppe RA, Burke JF, Camelo-Piragua S, Lieberman AP, Giordani B, Frey KA.Ann Neurol. 2015 Nov;78(5):824-30. doi: 10.1002/ana.24481. PMID: 26183692; PMCID: PMC4836870.
Non-exercise physical activity attenuates motor symptoms in Parkinson disease independent from nigrostriatal degeneration. Snider J, Müller ML, Kotagal V, Koeppe RA, Scott PJ, Frey KA, Albin RL, Bohnen NI. Parkinsonism Relat Disord. 2015 Oct;21(10):1227-31. doi: 10.1016/j.parkreldis.2015.08.027. PMID:26330028; PMCID: PMC4587298.
Alzheimer's Disease Neuroimaging Initiative. Structural brain changes in early-onset Alzheimer's Disease subjects using the LONI Pipeline environment. Moon SW, Dinov ID, Hobel S, Zamanyan A, Choi YC, Shi R, Thompson PM, Toga AW; J Neuroimaging. 2015 Sep-Oct;25(5):728-37. doi: 10.1111/jon.12252. PMID:25940587; PMCID: 4537660.
Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators. Lancet Neurol. 2015 Aug;14(8):795-803. Epub 2015 Jun 23. Erratum in: Lancet Neurol. 2015 Oct; 14(10):979. PMID: 26116315 PMCID:PMC4574625
Educational attainment and motor burden in Parkinson disease. Kotagal V, Bohnen NI, Müller ML, Koeppe RA, Frey KA, Langa KM, Albin RL.Mov Disord. 2015 Jul;30(8):1143-7. doi: 10.1002/mds.26272. PMID: 26096339; PMCID: PMC4504749.
Sharing big biomedical data. Toga AW, Dinov ID. J Big Data. 2015;2. pii: 7. Epub 2015 Jun 27. PMID:26929900 PMCID: PMC4768816
Probability Distributome: A Web Computational Infrastructure for Exploring the Properties, Interrelations, and Applications of Probability Distributions.Dinov ID, Siegrist K, Pearl DK, Kalinin A, Christou N. Comput Stat. 2016 Jun;31(2):559-577. Epub 2015 Jun 26. PMID:27158191
Amyloid deposition in Parkinson's disease and cognitive impairment: A systematic review. Petrou M, Dwamena BA, Foerster BR, MacEachern MP, Bohnen NI, Müller ML, Albin RL, Frey KA. Movement Disorders. Mov Disord. 2015 Jun;30(7):928-35. doi: 10.1002/mds.26191.
Altered cerebellar connectivity in Parkinson's patients ON and OFF L-DOPA medication. Festini SB, Bernard JA, Kwak Y, Peltier S, Bohnen NI, Müller ML, Dayalu P, Seidler RD. Front Hum Neurosci. 2015 Apr 21;9:214. doi: 10.3389/fnhum.2015.00214. eCollection 2015. PMID:25954184 PMCID:PMC4405615
α-Synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal Parkinsonism protein Atp13a2. Kett LR, Stiller B, Bernath MM, Tasset I, Blesa J, Jackson-Lewis V, Chan RB, Zhou B, Di Paolo G, Przedborski S, Cuervo AM, Dauer WT.J Neurosci. 2015 Apr 8;35(14):5724-42. doi: 10.1523/JNEUROSCI.0632-14.2015. PMID: 25855184; PMCID:PMC4388928.
Modeling falls in Parkinson’s disease: Slow gait, freezing episodes, and falls in rats with extensive striatal dopamine loss. Kucinski A, Albin RL, Lustig C, Sarter M. Behav Brain Res. 2015 Apr 1;282:155-64. doi:10.1016/j.bbr.2015.01.012.PMID: 25595423; PMCID:PMC4323874.
Modeling Parkinson’s disease falls associated with brainstem cholinergic systems decline. Kucinski A, Sarter M.Behav Neurosci. 2015 Apr;129(2):96-104. doi: 10.1037/bne0000048.PMID: 25798629; PMCID: PMC4392884.
Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators., Kieburtz K, Tilley BC, Elm JJ, Babcock D, Hauser R, Ross GW, Augustine AH, Augustine EU, Aminoff MJ, Bodis-Wollner IG, Boyd J, Cambi F, Chou K, Christine CW, Cines M, Dahodwala N, Derwent L, Dewey RB Jr, Hawthorne K, Houghton DJ, Kamp C, Leehey M, Lew MF, Liang GS, Luo ST, Mari Z, Morgan JC, Parashos S, Pérez A, Petrovitch H, Rajan S, Reichwein S, Roth JT, Schneider JS, Shannon KM, Simon DK, Simuni T, Singer C, Sudarsky L, Tanner CM, Umeh CC, Williams K, Wills AM. JAMA. 2015 Feb 10;313(6):584-93.PMID:25668262 PMCID:PMC4349346
Clinical markers for identifying cholinergic deficits in Parkinson's disease. Müller ML, Bohnen NI, Kotagal V, Scott PJ, Koeppe RA, Frey KA, Albin RL. Mov Disord. 2015 Feb;30(2):269-73. doi: 10.1002/mds.26061. PMID: 25393613; PMCID: PMC4318774.
Interpreting chemical neurotransmission in vivo: techniques, time scales, and theories. Sarter M, Kim Y. ACS Chem Neurosci. 2015 Jan 21;6(1):8-10. doi:10.1021/cn500319m. Review.PMID: 25514622; PMCID:PMC4304491.
Alzheimer's Disease Neuroimaging Initiative (ADNI). Gene interactions and structural brain change in early-onset Alzheimer's disease subjects using the pipeline environment. Moon SW, Dinov ID, Zamanyan A, Shi R, Genco A, Hobel S, Thompson PM, Toga AW; Psychiatry Investig. 2015 Jan;12(1):125-35. doi:10.4306/pi.2015.12.1.125.PMID: 25670955; PMCID:PMC4310910.
Validation of an ambulatory capacity measure in Parkinson disease: a construct derived from the Unified Parkinson's Disease Rating Scale. Parashos SA, Elm J, Boyd JT, Chou KL, Dai L, Mari Z, Morgan JC, Sudarsky L, Wielinski CL. J Parkinsons Dis. 2015;5(1):67-73. doi: 10.3233/JPD-140405.PMID:25311202 PMCID:PMC4478048
SOCR data dashboard: an integrated big data archive mashing medicare, labor, census and econometric information. Husain SS, Kalinin A, Truong A, Dinov ID. J Big Data. 2015;2. pii: 13.PMID:26236573 PMCID: PMC4520712
Structural Neuroimaging Genetics Interactions in Alzheimer's Disease. Moon SW, Dinov ID, Kim J, Zamanyan A, Hobel S, Thompson PM, Toga AW. J Alzheimers Dis. 2015;48(4):1051-63. doi: 10.3233/JAD-150335.PMID: 26444770; PMCID: PMC4730943.2014
Cholinergic capacity mediates prefrontal engagement during challenges to attention: evidence from imaging genetics. Berry AS, Blakely RD, Sarter M, Lustig C. Neuroimage. 2015 Mar;108:386-95. doi: 10.1016/j.neuroimage.2014.12.036. Epub 2014 Dec 20. PMID:25536497 PMCID:PMC4469545
Modeling test and treatment strategies for presymptomatic Alzheimer Disease. Burke JF, Langa KM, Hayward RA, Albin RL.PLoS One. 2014 Dec 4;9(12):e114339.PMID: 25474698; PMCID: PMC4256252.
Validity and Efficacy of Screening Algorithms for Assessing Deep Brain Stimulation Candidacy in Parkinson Disease. Coleman RR, Kotagal V, Patil PG, Chou KL. Mov Disord Clin Pract. 2014 Dec 1;1(4):342-347. PMID:25505791 PMCID:PMC4258408
Abnormal MoCA and normal range MMSE scores in Parkinson disease without dementia: cognitive and neurochemical correlates. Chou KL, Lenhart A, Koeppe RA, Bohnen NI.Parkinsonism Relat Disord. 2014 Oct;20(10):1076-80. doi: 10.1016/j.parkreldis.2014.07.008. Epub 2014 Jul 19. PMID:25085750 PMCID:PMC4180768
Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function. Sarter M, Albin RL, Kucinski A, Lustig C.Exp Neurol. 2014 Jul;257:120-9.PMID: 24805070; PMCID: PMC4348073.
Deterministic functions of cortical acetylcholine. Sarter M, Lustig C, Howe WM, Gritton H, Berry AS.Eur J Neurosci. 2014 Jun;39(11):1912-20. PMID: 24593677; PMCID: PMC4371531.
Project I: Modeling and Treating Cholinergic Impairment and Fall Propensity in PD
Project I develops a novel rodent model of PD gait dysfunction demonstrating how attentional impairment, caused by partial BF cholinergic neuron loss, causes pronounced abnormalities of gait by “unmasking” striatal dysfunction caused by dorsal striatal dopaminergic denervation. These rodents exhibit a high propensity for falls in situations requiring attentional supervision of complex movements and freezing-type behavior when walking through model “doorways” that is strikingly reminiscent of PD symptomatology. Using these established methods and supported by extensive additional preliminary data, Project I defines the motoric impact of loss of PPN cholinergic neurons, alone and in combination with cortical cholinergic and striatal dopaminergic loss. Project investigators employ this model to explore mechanisms of cholinergic dysfunction directly relevant to therapeutic development. Using cutting-edge technology to record cholinergic neurotransmission at millisecond resolution in awake behaving rodents we investigate the circuit mechanisms that enable cholinergic neurons to compensate for striatal dysfunction prior to their degeneration; identification of these mechanisms is critical to develop novel therapeutic approaches to mimic these effects. Our preliminary data show that administering a combination of L-DOPA and the α4β2* nAChR agonist ABT-089 appears to reduce falls and freezing, supporting the value of this model for identifying the mechanisms underlying functional improvement. The α4β2* agonist varenicline (VCN) will also be tested, and comparisons with the effects VCN administration to PD patients will advance therapeutic validation of this model.
All relevant details for generating the novel rodent model of PD gait dysfunction, including the Michigan Complex Motor Task (MCMCT), are available in Kucinski, et.al. J Neurosci. 2013;33(42):16522–16539; we would be happy to help any interested investigators set up this model system in their laboratories. We would also be happy to assist interested investigators in the generation of FEOBV and its use and quantification, as well as the methods we are employing to assess alpha4beta2 cholinergic receptor occupancy with flubatine. DNA sample from all patients recruited for this study are also being deposited with the NINDS Biorepository and will be freely available for use by PD researchers.
Project II: Imaging of Cholinergic Systems in Parkinson’s Disease
Project II images PD patients with varying degrees of gait and balance difficulty using a novel PET ligand ([18F]FEOBV) for the vesicular acetylcholine transporter (VAChT). This new ligand reveals selective visualization of presynaptic cholinergic terminals with previously unattainable resolution. The superior resolution enables investigators to delineate cholinergic pathways arising from the PPN that have been implicated in gait abnormalities in PD, including to the cerebellar vermis. The high resolution topology of cholinergic lesions identified in Project II enables prospectively evaluation and exploration of the unique roles of BF and PPN loss in PD-related gait abnormalities. The findings of Project II aid interpretation of the detailed analyses of gait and cognition that will be pursued in Project III and the Clinical Resource Core.
Our preliminary data show evidence that cholinergic changes are not uniform in the brain in persons with PD. More specifically, our data show evidence of reduced activity in more posterior brain regions whereas anterior regions show evidence of preserved to increased activity. Reduced activity is associated with balance and gait difficulties. In contrast, novel observations suggest that preserved to increased cholinergic activity is more frequent in persons with PD who have more prominent tremor symptoms in the absence of balance and gait difficulties.
Project III: α4β2* nAChRs, Gait, and Balance in Parkinson’s Disease
Project III translates insights from animal model research in Project I and clinical research in Project II in an effort to identify a target for treatment of gait and balance disorders in PD. Brain alpha 4-beta 2 nicotinic cholinergic neurotransmitter receptors (α4β2* nAChRs) are a key mediator of attentional functions. Cholinergic deficits in some PD patients are likely to result in deficient activation of these receptors. We are evaluating a commercially available drug, varenicline, that acts through α4β2* nAChRs to determine if it has positive effects of gait and balance in PD. In a “personalized medicine” approach, only PD subjects demonstrated to have significant cholinergic degeneration (in Project II) will be studied. Novel PET methods are used to examine therapeutically relevant pharmacological features of α4β2* nAChRs in these hypocholinergic subjects. We test the hypothesis that activating α4β2* nAChRs in PD improves laboratory measures of gait, postural control, and attentional function. Related information comes from the comparison of α4β2* nAChR agonism in patients and the rodent model developed in Project I. Our goal is develop evidence that would support using varenicline, or a drug with similar action, in clinical trials for gait and balance disorders in PD.
Udall Center Pilot Grant Program
The central themes of the Udall Center are the role of cholinergic signaling in gait and balance abnormalities in Parkinson’s Disease — or PD — and the development of novel treatment strategies targeted at cholinergic neurotransmission. The overarching hypothesis is that the loss of striatal dopamine in PD imposes increased demands for compensation on other brain systems, including systems involved in attentional function and the control of gait and posture, and that the subsequent loss of these systems contributes significantly to the gait abnormalities that characterize later stages of the disease.
The Udall Pilot Grant Program aims to advance or expand upon these scientific themes.
A call for proposals is typically announced in January/February each year. Faculty from all schools and colleges at U-M are eligible to apply.
We seek applications in the following research areas (but is not limited to): biomechanical characterization of gait, especially in relation to PD; the functional relationship between cholinergic and dopaminergic neurotransmission in behavior, including manipulation or detection of these systems during defined behaviors; development of novel compounds or technologies to modulate cholinergic neurotransmission; interface between attention and motor function; analysis of other behaviorally relevant examples where a lesion in dopaminergic neurotransmission places additional compensatory demands on a different neural circuit; relevant human neuropathological studies.
Applications are especially encouraged from junior faculty or to support the activities of postdoctoral fellows considering work in relevant areas. Preference will be given to applicants not currently engaged directly in PD research, in accordance with the center’s goal of increasing and enhancing the PD research effort at U-M.
This grant mechanism will support one $50,000 grant annually. The support can be used for the direct support of salary and/or supplies (no indirect support is allowed). No tuition support is available. Equipment in excess of $5.000 needs special justification, and is in general not encouraged.
Once the call for proposals is announced, applications should be submitted through the Medical School Office of Research’s Competition Space portal.
One page proposals should be written in the format of an R01 specific aims page, budget and budget justification, biosketch in NIH format, and Other Support/Supplemental Documentation forms.
All documents are submitted as a single pdf. Biosketch, budget and budget justification, and Other Support templates are provided in the Competition Space. The start date is expected to be June 1, but is somewhat flexible.Pilot Project 1: Synthesis and Evaluation of PET Radiotracers for the Presynaptic High-affinity Choline Transporter
Project 1 is funded as a Udall Pilot Grant and directed by Dr. Peter Scott. Dr. Scott is Assistant Professor of Radiology, Director of PET Radiochemistry, and Interdepartmental Program Faculty in Medicinal Chemistry in the Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School.
Positron emission tomography (PET) imaging is an important medical imaging technique that allows us to better understand the complex mechanisms underlying diseases. Dr. Scott’s one year project will develop new methods for using PET imaging to understand the biology of Parkinson’s disease, and potentially support the development of possible new treatments for the disease.
Dr. Scott's group is involved in all aspects of Radiopharmaceutical Sciences including i) developing new methods for radiolabeling bioactive molecules, ii) design and synthesis of new radiotracers for PET imaging of CNS disorders such as Alzheimer's disease, and iii) cGMP radiopharmaceutical manufacture. The goals of his lab are to use PET radiotracers to improve our understanding of disease mechanisms and, ultimately, employ them as companion diagnostics to support therapeutic development.
Dr.Scott has published 39 papers, almost 70 abstracts and 20 book chapters, edited 4 books (including 2 volumes of Radiochemical Syntheses) and is listed as an inventor on multiple patents. His laboratory is funded by the U.S. Department of Energy, the National Institute of Biomedical Imaging and Bioengineering, and the Alzheimer's Association.
Areas of Interest
Pilot Project 2: Optogenetic Interrogation of the Role of Dopamine in Motor Control
- Adaptation of state-of-the-art organic chemistry techniques (including SPOS) for radiochemical applications.
- Microwave mediated radiochemistry.
- Development of multi-modality biomarkers for PET-MRI.
Project 2 is funded as a Udall Pilot Grant and directed by Dr. Daniel Leventhal. Dr. Leventhal is Assistant Professor of Neurology, University of Michigan Medical School, and co-director of the clinical Movement Disorders DBS program at the VAAAHS.
The goal of this study is to improve the treatment of Parkinson’s disease by understanding its systems-level pathophysiology. This study will help to determine, at a behavioral level, how striatal dopamine influences motor function. The expected outcome of this research is to clarify the specific roles of nigrostriatal dopamine in fine motor control. Our results will have a positive impact by moving beyond the simple observation that dopamine replacement improves parkinsonism to understanding the mechanisms by which it works. This will have important implications for adjusting treatment strategies with current therapies. More importantly, elucidating the motor functions of dopamine will allow further work to determine the underlying neuronal mechanisms by which these functions are implemented. Our long-term strategy will be to integrate the techniques developed here with in vivo recordings to address these important questions.
Dr. Leventhal’s areas of interest are understanding changes in brain networks that underly Parkinson Disease dystonia, and other movement disorders. Investigations into mechanisms of action of deep brain stimulation and other therapies for movement disorders.Pilot Project 3: Role of Neuroserpin in Dopaminergic and Cholinergic Neurons Degeneration in Parkinson Disease
PI: Daniel Lawrence, PhD – Department of Internal Medicine, Division of Cardiology
Project 3 is funded as a 2017 Udall Pilot Project Grant and directed by Dr. Daniel Lawrence. Dr. Lawrence is the Frederick G L Huetwell Professor of Basic Research in Cardiovascular Medicine, and Professor of Cardiovascular Medicine. Dr. Lawrence is a recognized leader in the field of protease and protease inhibitor biochemistry and in animal models of disease.
The goal of this pilot study is to determine if LC noradrenergic neuronal ablation accelerates the degeneration of dopaminergic and/or cholinergic neurons in an α-Syn virus-based mouse model of PD. We will use a novel multineuronal targeted model of PD to examine if ablation of noradrenergic neurons in the LC by DSP-4 treatment when combined with overexpression of α-Syn in the SN will accelerate the loss of dopaminergic and cholinergic neurons in the SN and PPN, respectively, compared to overexpression of α-Syn alone.
Another goal is to evaluate if LC expressed Nsp participates in the protection of dopaminergic and/or cholinergic neurons in the α-Syn virus-based PD model. We hypothesize that similar to LC ablation, Nsp deficiency in the α-Syn PD model will accelerate the loss of dopaminergic and cholinergic neurons, but that LC ablation in Nsp-/- mice will not further enhance degeneration with α-Syn overexpression; whereas, transgenic mice overexpressing Nsp under the control of the Thy-1.2 promoter, which drives neuron-specific expression, will be protective against accelerated degeneration following LC ablation and α-Syn overexpression.
Join a Study
Now is the time to join our research team. Research participation is a generous gift – a gift that can be shared with future generations as we pave the way to new discoveries in treatment and prevention. Research participation contributes to the discovery of new ways to diagnose, treat and support people with Parkinson’s disease.
See enrolling studies below:
Principal Investigator: Nicolaas Bohnen, MD, PhD, University of Michigan
Balance and gait problems cause severe impairments for people with Parkinson’s disease and significantly affect their quality of life. Several changes occur in the brains of Parkinson’s disease patients. The hallmark change is a loss of a neurotransmitter (“chemical messenger” between brain cells) called dopamine. To alleviate Parkinson’s disease symptoms doctors prescribe dopamine replacement therapy, for example Sinemet (levodopa). Although effective for some of the symptoms, it typically does not sufficiently alleviate balance and gait problems. This study focuses on other changes in the brain that occur in Parkinson’s disease that may contribute to balance and gait problems. In particular we will be looking at another neurotransmitter called acetylcholine. In some Parkinson’s disease patients we see a loss of acetylcholine in the brain. In previous studies we have shown that this loss of acetylcholine is related to impaired balance and gait function in Parkinson’s disease. In this study we will take a closer look at this finding.
- Age 50 and above (Male/Female).
- PD diagnosis (with or without mild cognitive impairment; MCI) will follow the UK Parkinson’s Disease Society Brain Bank Research Center (UKPDSBRC) clinical diagnostic criteria for PD (47), consistent with the typical nigrostriatal denervation pattern on VMAT2. Absence of significant dementia confirmed by neuropsychological testing. Modified Hoehn and Yahr stages 1-4 (48, 49).
- PSP diagnosis will follow the NINDS-PSP clinical diagnostic criteria (50, 51).
- All PD subjects will be required to have nigrostriatal dopaminergic denervation as demonstrated by [11C]DTBZ PET imaging (52, 53). Subjects with Parkinsonism and absence of this PD-typical pattern will be re-categorized .
Contact: Christine Minderovic, BS email@example.com, 734-998- 8420
Other Parkinson’s Disease Clinical Research Studies
SURE-PD3: A Randomized, Double-blind, Placebo-controlled Trial of Urate Elevating Inosine Treatment to Slow Clinical Decline in Early Parkinson’s Disease
Principal Investigator: Kelvin Chou, MD, University of Michigan
To objective of the study is to find out whether a treatment (inosine) that raises urate levels can slow the rate of worsening in PD. There is evidence that increased urate levels can predict both a lower risk of developing PD and a slower rate of its worsening over time.
- Diagnosed with idiopathic PD within the last three years
- Currently not on ANY anti-parkinson therapy (including amantadine and trihexyphenidyl) other than a monoamine oxidase-B inhibitor
- History of gout, urolithiasis, myocardial infarction, stroke, symptomatic congestive heart failure, or severe COPD
Contact: Angela Stovall firstname.lastname@example.org
Principal Investigator: Vikas Kotagal, MD and Roger Albin, MD, University of Michigan
The purpose of this study is to determine if changes in brain serotonin affects the accumulation of amyloid in the brain. The investigators will use brain imaging methods to measure the amount of serotonin and amyloid in the brain of individuals with Parkinson’s Disease (PD) and otherwise healthy older people. PD participants will undergo repeat brain imaging to assess amyloid accumulation two years after their first brain imaging session. All participants will undergo examinations to assess their motor function, and asked questions to assess their mood and thinking.
Males and females ages 45 years and older and are eligible to participate in the study. Healthy older individuals (ages 60-80) without neurologic problems are eligible to participate.
Contact: Ashley Szpara, BA email@example.com, 734-232- 2415
Cardiovascular Risk Factors in PD
Principal Investigator: Vikas Kotagal, MD
This is a study to explore the role of common cardiovascular risk factors on the development of clinical impairment in PD. This prospective observational study will involve clinical and MRI assessments at baseline and at 2 year follow-up in a cohort of 50 Veterans with PD recruited from VA Movement Disorders clinic.
- Diagnosed with idiopathic Parkinson’s disease as defined by the UK Brain Bank criteria
- Hoehn and Yahr stage 3 or less
- Age ≥50
- No contraindications for undergoing an MRI
Contact: Ashley Szpara, BA firstname.lastname@example.org, 734-232- 2415
For Parkinson’s Disease Dementia/ Dementia With Lewy Bodies
A Phase 2, double-blind, randomized, placebo-controlled crossover study evaluating the effect of RVT-101 on gait and balance in subjects with Alzheimer’s Disease, Dementia with Lewy Bodies, or Parkinson’s Disease Dementia
Principal Investigator: Nicolaas Bohnen, MD, PhD, University of Michigan
A Phase 2, double-blind, randomized, placebo-controlled crossover study evaluating the effect of RVT-101 on gait and balance in subjects with Alzheimer’s Disease, Dementia with Lewy Bodies, or Parkinson’s Disease Dementia. The objective of this study is to assess the effect of RVT-101 versus placebo on gait speed, a quantitative measure of functional mobility, evaluated under normal and dual-task walking conditions on an electronic walkway system after 2 weeks of treatment.
Principal Investigator: Nicolaas Bohnen, MD, PhD, University of Michigan
- Age 50-89 with PDD or DLB
- Must be taking cholinesterase inhibitor
- History and/or evidence of any other disorder that could be interpreted as a cause of dementia.
- History of significant psychiatric illness
Contact: Christine Minderovic, BS email@example.com, 734-998- 8420
For Huntington’s Disease
Principal Investigator: Praveen Dayalu, MD, University of Michigan
To evaluate safety and tolerability of study drug VX15/2503 vs placebo and its effect on SEMA4D with 18 monthly infusions.
- Dx of HD with documentation of ≥36 CAG repeat
- Early manifest motor symptoms (TFC ≥ 11). Subject must have been given a clinical diagnosis of HD.
Contact: Elizabeth Sullivan (firstname.lastname@example.org)
Principal Investigators: Noelle Carlozzi, PhD; Praveen Dayalu, MD, University of Michigan
An open-ended, prospective observational multi-center multi-national cohort study with a goal of enrolling approximately one-third of the HD affected population in each study region (North America, Latin America, Europe, Asia, Australia and New Zealand). Participants will be asked to participate in as many annual study visits as possible. Study procedures include annual cognitive, behavioral and motor assessments and annual biospecimen collection (blood and DNA).
We are looking for 2 categories of participants:
- Individuals who carry the HD gene expansion mutation (with or without clinical features)
- Individuals who do not carry the HD gene expansion mutation (family and community controls)
Contact: Elizabeth Sullivan (email@example.com)
For Multiple System Atrophy
Principal Investigator: Praveen Dayalu, MD, University of Michigan
Multiple system atrophy (MSA) is a disorder of the nervous system of unclear cause. In MSA there is degeneration (progressive loss) of nerve cells in several brain and spinal cord regions. The result is a variety of symptoms, from physical (parkinsonism, ataxia, incoordination, falls, slowness) to autonomic (fainting, bladder incontinence, sexual dysfunction) to sleep problems (dream enactment, sleep apnea).
This research aims to help us better understand the patterns and timing of nerve degeneration relatively early in the disease, and how this affects symptoms and progression. For instance:
- Does MSA affect certain nerves that stimulate heart pumping? If so, does the severity of loss of heart nerves affect disease progression and survival?
- It is thought that MSA does not affect memory and thinking much, unlike other diseases (such as Parkinson’s). Is this accurate? Is there loss of nerves that transmit acetylcholine (a neurochemical important in mental functioning)?
- What can we learn about mood and sleep in MSA, through visualizing the serotonin system in the brain? How does this relate to symptoms that subjects report in these often underappreciated areas?
To answer these and other questions, investigators will take images of specific nerves in the brain and heart using Positron Emission Tomography (PET) scans. Such imaging gives us information that cannot be obtained from MRIs and CT scans. We will measure the levels of several nerve cell types: serotonin, acetylcholine, and norepinephrine. Subjects will also have many standardized assessments including quality-of-life and symptom assessments, neurological examination, autonomic assessments, neuropsychological assessments, coordination tests, and even assessments of vision and sense of smell. By pooling these results from many MSA patients, and comparing with other diseases (such as Parkinson’s disease) we hope to gain a better understanding of what is happening early in MSA. Such knowledge could be very valuable in future efforts to develop better therapies in this rare disease.
- Participants aged 30-80 years old with a diagnosis of Possible or Probable MSA of the parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C)
- Participants who are less than 4 years from the time of documented MSA diagnosis
- Participants who are willing and able to give informed consent
- “Normal” cognition as assessed by Mini Mental State Examination
For Progressive Supranuclear Palsy
Principal Investigators: Nicolaas Bohnen, MD, PhD, Roger Albin, MD, William Dauer, MD
To determine the role of cholinergic deficits in gait and balance dysfunction in Parkinsonism
- Non-demented PSP subjects age 50 and above (M/F).
- Use of drugs with cholinomimetic or anti-cholinergic effects.
Contact: Christine Minderovic, BS firstname.lastname@example.org, 734-998- 8420