Udall Center Theme: Degeneration of brain cholinergic pathways produces cognitive deficits which disrupt integration of cognitive, sensory, and motor functions critical for normal gait and balance
The central theme of the University of Michigan Udall Center is the role of cholinergic deficits in treatment-refractory aspects of Parkinson disease (PD), particularly gait and balance disorders, and cognitive decline. Through an interrelated and complementary set of neuroimaging and behavioral studies in patients with PD and unique animal model experiments, Center investigators examine the contribution of distinct cholinergic projection system deficits to abnormalities of gait, balance, and cognition in PD. A major aspect of this central theme is the role of cholinergic systems in integrating afferent sensory, attentional, and cognitive information with motor functions.
Multiple neurochemical systems degenerate in Parkinson’s Disease (PD). Progressive gait and balance difficulties, with 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. Similarly, cognitive decline is a prominent, common, and disabling feature of advancing PD, overlapping significantly with gait and balance disorders.
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, gait abnormalities, and cognitive decline 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 developed data that led to the development of a conceptual model of cognitive-motor integration (the Attentional-Motor Interface above) in which cholinergic systems’ interactions with basal ganglia and cortical circuits are critical for normal function. This model provides a systems-level framework for understanding the interactive nature of gait, balance, and cognitive dysfunctions in PD and focuses experimental attention on critical nodes of this system.
The lack of effective therapies for gait, balance, and cognitive 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 and balance depends upon 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 molecular imaging work of Udall Center investigators demonstrated that PD subjects with a history of falls and/or gait freezing have differing deficits of specific cholinergic systems. Parallel work with a unique animal model demonstrated the critical role of cholinergic systems subserving attentional functions in normal gait and balance functions. In recent preliminary work, Udall Center molecular imaging data shows that other cholinergic deficits are related to other important aspects of motor and cognitive functions. Complementary experimental animal model work is illuminating the specific cellular mechanisms by which the cholinergic systems and nodes identified as abnormal by Udall Center clinical research integrate diverse circuits to produce normal cognitive and motor functions. All of this work is a necessary prelude to developing interventions for these treatment refractory aspects of PD.
Project I: Evolution of cholinergic deficits within multisensory, cognitive, and motor integration brain regions and development of PIGD features in PwP (Project Lead: Bohnen):
Postural instability and gait difficulty (PIGD) motor features are common in Parkinson disease (PD), and a significant cause of treatment-refractory disability. Accumulating evidence implicates cholinergic systems dysfunctions as significant contributors to gait and balance impairment. During the initial funding period, we established the vesicular acetylcholine transporter (VAChT) ligand [18F]FEOBV, which uniquely assesses cholinergic terminal density in high density regions such as the striatum. Our recent cross-sectional findings suggest that PwP participants with isolated falls and those with freezing of gait (FoG) status share common cholinergic deficits in the thalamus (lateral geniculate nucleus [LGN]) and striatum (caudate) with more extensive striatal, limbic, and prefrontal VAChT reductions in PwP with FoG. Consistent with Project II preclinical data indicating a critical role for striatal cholinergic interneurons (SChI) in integration of attentional and motor functions, these data suggest that SChI deficits are a common denominator in the etiology of falls and FoG. These results emphasize the need to understand PIGD, falls, and FoG as products of cholinergic projection dysfunctions within the framework of failing Attentional-Motor Integration (AMI) combined with failures of additional multisensory and cognitive integration.
Episodic mobility disturbances (falls, FoG) are typically preceded by insidiously developing non-episodic PIGD features. We have novel preliminary data that cholinergic deficits of the medial geniculate nucleus (MGN) and the entorhinal cortex (ERC) are robustly associated with non-episodic PIGD deficits, These results imply a significant role of impaired sensorimotor integration underlying non-episodic PIGD motor features in PwP. The overarching goal of this project is to investigate the evolution of cholinergic deficits within multisensory, cognitive and motor integration brain regions and development of PIGD features in PwP. We hypothesize that this progresses from the MGN and ERC, then LGN and caudate nucleus, and then more diffuse striatal, limbic and cortical (prefrontal followed by anterior cingulum and insula) cholinergic deficits. To assess our hypotheses, we propose to perform a prospective cohort study with [18F]FEOBV brain PET at baseline and 2-year follow-up in PD subjects at risk of conversion to non-episodic and episodic (falls and FoG) PIGD motor features. Novel insights in cholinergic changes underlying incident development of PIGD may inform new therapeutic interventions to treat these debilitating motor complications. Project I is highly integrated thematically with Project II and the Catalyst Research Project, complementary to Project III, and will interact extensively with all Cores. Our work is based on a unique, deeply phenotyped cohort of PD participants developed in the prior funding cycle allowing us to recruit an enriched sample of patients likely to convert to fall and FoG status, allowing longitudinal within-subject assessments.
Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls (Project Lead: Sarter):
Approximately two thirds of patients with Parkinson’s disease (PD) experience falls; a primary cause of hospitalization and nursing home admission. These debilitating features of PD are resistant to dopamine replacement therapy, emphasizing the urgent need for basic research and therapeutic development focused on non-dopaminergic systems degenerating in PD. We previously established a rodent model of PD falls and developed novel behavioral paradigms that reflect critical elements of PD falls. Our work identified disruptions of the Attentional-Motor Interface (AMI) network as a major pathophysiologic substrate of impaired gait and balance in PD. The novel Michigan Complex Motor Control Task (MCMCT) assesses falls resulting from impaired AMI function in rats. We also demonstrated that rats with dual losses of cortical cholinergic and striatal dopamine (DL rats), reflecting PET-based findings in PD fallers, exhibit high rates of falls on the MCMCT. As in PD fallers, impairments in attention of DL rats predict fall rates. Treatment with an α4β2* nicotinic acetylcholine receptor agonist, combination treatments of AChase inhibitors and a 5-HT6 receptor antagonist (idalopirdine) reduce fall rates, indicating translational value of our system. We now propose rigorous mechanistic studies identifying critical synaptic dysfunction within key AMI nodes. We will assess the role of basal forebrain cholinergic signaling in falls of cholinergically-driven cortico-striatal information transfer, and of the role of striatal cholinergic interneurons. This work will directly complement the research of Projects I and III. The proposed research is supported by extensive preliminary evidence demonstrating: 1) the impact of optogenetic manipulations of basal forebrain cholinergic signaling on complex movement control; 2) that cues guiding complex movements are “imported’ into the striatum via cortico-striatal glutamatergic activity; 3) that DREADD-based inhibition or stimulation of striatal cholinergic interneuronal activity cause and prevent falls, respectively; 4) that these interneurons broadly code cues utilized to execute movements. The proposed research will identify mechanisms of nodal and synaptic AMI dysfunctions, identify novel intervention targets, extend a valuable preclinical model for therapy development, and substantiate falls as a useful behavioral endpoint for studying key nodes of the AMI.
Project III: Cingulo-Opercular Task Control Network Cholinergic Dysfunction in PD (Project Lead: Albin):
Cognitive deficits are a morbid dopamine replacement therapy-refractory feature of Parkinson disease (PD). The pathophysiology of PD-related cognitive deficits is complex, likely involving interacting and variable impairments of several brain systems, particularly in early to moderate disease. Incidence and natural history of PD cognitive deficits is heterogeneous. Understanding the pathophysiologies of PD cognitive impairments is essential for development of personalized therapies. PD heterogeneity is a major obstacle to effective clinical research. Identifying PD subgroups will enhance discovery of useful interventions through subgroup specific or stratified clinical trials, identify biomarkers, improve prognosis assessment in clinical care, and assist etiopathogenic research. Some of the “highest priority recommendations” of the NINDS PD 2014 Research Report call for research to understand the pathophysiology of cognitive impairments and for PD subgroup identification. The U-M Udall Center established a deeply phenotyped PD cohort imaged with the vesicular acetylcholine transporter PET ligand [18F]FEOBV, revealing heterogeneous cholinergic deficits. Cholinergic terminal deficits in Cingulo-Opercular Task Control network (COTC) nodes – Anterior Cingulate and Insular Cortices (AC-I) – correlate with both domain specific and global cognitive deficits. An important component of the Attentional-Motor Interface, the COTC subserves tonic attention, coordinating network activities across different cognitive domains. Preliminary analysis suggests that early COTC node (AC-I) cholinergic deficits are a subgroup defining-feature in PD, predicting more rapid cognitive decline. The central hypothesis of Project III is that early COTC node (AC-I) cholinergic denervation contributes significantly to cognitive impairment in early to moderate PD and identifies a D subgroup with accelerated cognitive decline In addition to our established Udall subject cohort, we have access to a separate cohort of incident PD subjects through collaboration with the University of Groningen, deeply phenotyped and imaged with [18F]FEOBV PET, for rigorous experimental replication and validation of our primary hypothesis. We will correlate early COTC node (AC-I) cholinergic denervation with domain-specific and general measures of cognitive function. In a prospective analyses, we will determine if early COTC node (AC-I) cholinergic denervation predicts more rapid cognitive decline. In an integrated analysis with Project I, we will determine if COTC node (AC-I) cholinergic denervation is associated with Freezing of Gait (FoG). In exploratory analyses, we will assess if more accessible MRI or other measures correlate with COTC node (AC-I) cholinergic denervation, identifying potential, accessible biomarkers of COTC node (AC-I) cholinergic denervation. Project III will identify an important substrate of PD cognitive impairment and identify a PD subgroup with a more aggressive natural history – a “malignant hypocholinergic disease phenotype.” These results will identify potential targets for therapeutic interventions and biomarker development.
Catalyst Research Project: Retrosplenial Cholinergic and Attentional-Motor Integration Dysfunction (Project Lead: Ahmed):
Many patients with Parkinson’s disease (PD) suffer from spatial disorientation – inability to link external landmark cues to internal estimates of self-orientation. These deficits are not improved by dopamine replacement therapy (DRT). The same spatial disorientation features are found in patients with specific lesions, due to a stroke or hemorrhage, of the retrosplenial cortex (RSC), a brain region critical for encoding the combination of allocentric and egocentric navigational information. Attentional and emotional processing impairments in PD patients are accompanied by altered BOLD responses in the retrosplenial cortex. The retrosplenial cortex is densely interconnected with the secondary motor cortex, hippocampus, visual cortex, cingulate cortex and anterior thalamus (containing head orientation cells), and is therefore part of the Attentional-Motor Interface (AMI) and ideally positioned to help transform attentional and spatial information into planned actions. Furthermore, multiple basal forebrain structures send cholinergic projections to the RSC. There are pronounced increases in acetylcholine (ACh) release in the retrosplenial cortex during attentive spatial navigation. Cholinergic deficits, such as those seen in PD, are likely to severely impair the spatial orientation functions of the retrosplenial cortex. Little is known about 1) how cholinergic inputs influence the synapses, cells and circuits of the retrosplenial circuits, and 2) the impact of cholinergic dysfunction on retrosplenial-dependent spatial orientation and navigation. Our central hypothesis is that dysfunctional cholinergic systems projecting to the retrosplenial cortex will manifest in altered navigational encoding by retrosplenial circuits and spatially disoriented behaviors. We will decipher the mechanisms of cholinergic control of retrosplenial cells and synapses, with preliminary data suggesting both cell-type- and synapse-specific cholinergic controls. We will investigate how the loss of cholinergic inputs impairs retrosplenial encoding of space and how it impacts orientation-guided movement. These investigations will elucidate the contributions of the retrosplenial orientation coding circuit to the Attentional-Motor Interface, and lay the groundwork for understanding how altered perception of spatial orientation in Parkinson’s disease can directly impact motor control.
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- Complex movement control in a rat model of Parkinsonian falls: bidirectional control by striatal cholinergic interneurons. Sarter M, Avila C, Kucinski A. J Neurosci. 2020 Jun 18:JN-RM-0220-20. doi: 10.1523/JNEUROSCI.0220-20.2020. Epub ahead of print. PMID: 32554512. PMCID: PMC7392507.
- Apathy rating scores and β-amyloidopathy in patients with Parkinson disease at risk for cognitive decline. Zhou Z, Müller MLTM, Kanel P, Chua J, Kotagal V, Kaufer DI, Albin RL, Frey KA, Bohnen NI. Neurology. 2020 Jan 28;94(4):e376-e383. doi: 10.1212/WNL.0000000000008683. Epub 2019 Nov 15. PMID: 3173256 PMCID: PMC7079689
- Increased striatal dopamine in carriers of GBA mutations: compensation or epiphenomenon? Bohnen NI, Albin RL. Lancet Neurol. 2020 Jan;19(1):27-29. doi: 10.1016/S1474-4422(19)30355-2. Epub 2019 Oct 31. No abstract available. PMID: 31678033. PMCID: PMC6924570
- Freezing of gait: understanding the complexity of an enigmatic phenomenon. Weiss D, Schoellmann A, Fox MD, Bohnen NI, Factor SA, Nieuwboer A, Hallett M, Lewis SJG. Brain. 2020 Jan 1;143(1):14-30. doi: 10.1093/brain/awz314. PMID: 31647540 PMCID: PMC6938035
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- Model-based and model free techniques for Amyotrophic Lateral Sclerosis diagnostic prediction and patient clustering. Tang M, Gao C, Goutman SA, Kalinin A, Mukherjee B, Guan Y, Dinov ID. Neuroinformatics. 2019 Jul;17(3):407-421. doi: 10.1007/s12021-018-9406-9. PMID: 30460455; PMCID: PMC6527505.
- Machine learning techniques for personalized breast cancer risk prediction: comparison with the BCRAT and BOADICEA models. Ming C, Viassolo V, Probst-Hensch N, Chappuis PO, Dinov ID, Katapodi MC Breast Cancer Res. 2019;21(1):75. Published 2019 Jun 20. doi:10.1186/s13058-019-1158-4. PMID: 31221197. PMCID: PMC6585114850517
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- Serotonin, beta-amyloid, and cognition in Parkinson disease. Kotagal V, Spino C, Bohnen NI, Koeppe R, Albin RL. Ann Neurol. 2018 May;83(5):994-1002. PubMed PMID: 29665066; PubMed Central PMCID: PMC6021203; DOI: 10.1002/ana.25236.
- Imaging markers of progression in Parkinson's disease.Strafella AP, Bohnen NI, Pavese N, Vaillancourt DE, van Eimeren T, Politis M, Tessitore A, Ghadery C, Lewis S; IPMDS‐Neuroimaging Study Group. Mov Disord Clin Pract. 2018 Oct 9;5(6):586-596. doi: 10.1002/mdc3.12673. eCollection 2018 Nov-Dec. Review. PMID: 30637278 PubMed Central PMCID: PMC6277366
- Regional vesicular acetylcholine transporter distribution in human brain: A [18F]Fluoroethoxy benzovesamicol Positron Emission Tomography Study. Albin RL, Müller MLT, Bohnen NI, Dauer WT, Sarter M, Frey KA, Koeppe RA. J Comp Neurol.2018 Dec 1;526(17):2884-2897. doi: 10.1002/cne.24541. Epub 2018 Oct 19.
- Finding useful biomarkers for Parkinson's disease.Chen-Plotkin AS, Albin R, Alcalay R, Babcock D, Bajaj V, Bowman D, Buko A,Cedarbaum J, Chelsky D, Cookson MR, Dawson TM, Dewey R, Foroud T, Frasier M,German D, Gwinn K, Huang X, Kopil C, Kremer T, Lasch S, Marek K, Marto JA,Merchant K, Mollenhauer B, Naito A, Potashkin J, Reimer A, Rosenthal LS,Saunders-Pullman R, Scherzer CR, Sherer T, Singleton A, Sutherland M, Thiele I,van der Brug M, Van Keuren-Jensen K, Vaillancourt D, Walt D, West A, Zhang J. Sci Transl Med. 2018 Aug15;10(454). pii: eaam6003. doi: 10.1126/scitranslmed.aam6003. Review. PubMedPMID: 30111645; PubMed Central PMCID: PMC6097233.
- 3D shape modeling for cell nuclear morphological analysis and classification. Kalinin AA, Allyn-Feuer A, Ade A, Fon GF, Meixner W, Dilworth D, Husain SS, de Wet JR, Higgins GA, Zheng G, Creekmore A, Wiley JW, Verdone JE, Veltri RW, Pienta KJ, Coffey DS, Athey BD, Dinov ID. Sci Rep. 2018; 8: 13658. Published online 2018 Sep 12. doi: 10.1038/s41598-018-31924-2 Correction in: Sci Rep. 2018; 8: 16142. PMCID: PMC6135819
- Controlled feature selection and compressive big data analytics: Applications to biomedical and health studies. Marino, S, Xu, J, Zhao, Y, Zhou, N, Zhou, Yi, Dinov, ID. PLoS One. 2018; 13(8): e0202674. Published online 2018 Aug 30. doi: 10.1371/journal.pone.0202674 PMCID: PMC6116997
- ‘Hot’ vs. ‘cold’ behavioural-cognitive styles: motivational-dopaminergic vs. cognitive-cholinergic processing of a Pavlovian cocaine cue in sign- and goal-tracking rats. Pitchers KK, Kane LF, Kim Y, Robinson TE, Sarter M. Eur J Neurosci. 2017 Dec; 46(11): 2768–2781. Published online 2017 Nov 6. doi: 10.1111/ejn.13741. PMCID: PMC6088792
- Targeting the pedunculopontine nucleus in Parkinson's disease: Time to go back to the drawing board. Albin RL, Surmeier DJ, Tubert C, Sarter M, Müller MLTM, Bohnen NI, Dauer WT. Mov Disord. 2018 Nov 6. doi: 10.1002/mds.27540. [Epub ahead of print] No abstract available. PMID: 30398673
- Regional subcortical shape analysis in premanifest Huntington's disease. Tang X, Ross CA, Johnson H, Paulsen JS, Younes L, Albin RL, Ratnanather JT, Miller MI. Hum Brain Mapp. 2018 Oct 30. doi: 10.1002/hbm.24456. [Epub ahead of print.] PMID: 30376191
- Molecular imaging of the cholinergic system in Parkinson's disease. Bohnen NI, Kanel P, Müller MLTM. Int Rev Neurobiol. 2018;141:211-250. doi: 10.1016/bs.irn.2018.07.027. Epub 2018 Sep 20. PMID: 30314597 PMCID: PMC6218162
- Randomization-based statistical inference: A resampling and simulation infrastructure. Dinov ID, Palanimalai S, Khare A, Christou N. Teach Stat. 2018 Summer;40(2):64-73. doi: 10.1111/test.12156. Epub 2018 Apr 11. PMID: 30270947. PMCID: PMC6155997
- Hypothesis: Caco-2 cell rotational 3D mechanogenomic turing patterns have clinical implications to colon crypts. Zheng G, Kalinin AA, Dinov ID, Meixner W, Zhu S, Wiley JW. J Cell Mol Med. 2018 Dec;22(12):6380-6385. doi: 10.1111/jcmm.13853. Epub 2018 Sep 25. PMID: 30255651 PMCID: PMC6237597
- The human brainome: network analysis identifies HSPA2 as a novel Alzheimer's disease target. Petyuk VA, Chang R, Ramirez-Restrepo M, Beckmann ND, Henrion MYR, Piehowski PD, Zhu K, Wang S, Clarke J, Huentelman MJ, Xie F, Andreev V, Engel A, Guettoche T, Navarro L, De Jager P, Schneider JA, Morris CM, McKeith IG, Perry RH, Lovestone S, Woltjer RL, Beach TG, Sue LI, Serrano GE, Lieberman AP, Albin RL, Ferrer I, Mash DC, Hulette CM, Ervin JF, Reiman EM, Hardy JA, Bennett DA, Schadt E, Smith RD, Myers AJ. Brain. 2018 Aug 20. doi: 10.1093/brain/awy215. PMID: 30137212 PMCID: PMC6136080
- Big data analytical approaches to the NACC dataset: Aiding preclinical trial enrichment. Lin M, Gong P, Yang T, Ye J, Albin RL, Dodge HH. Alzheimer Dis Assoc Disord. 2018 Jan-Mar;32(1):18-27. doi: 10.1097/WAD.0000000000000228. PMID: 29227306 PMCID: PMC5854492
- Model-based and model-free machine learning techniques for diagnostic prediction and classification of clinical outcomes in Parkinson's disease. Gao C, Sun H, Wang T, Tang M, Bohnen NI, Müller MLTM, Herman T, Giladi N, Kalinin A, Spino C, Dauer W, Hausdorff JM, Dinov ID. Sci Rep. 2018 May 8;8(1):7129. doi: 10.1038/s41598-018-24783-4. PMID: 29740058
- An updated diagnostic approach to subtype definition of vascular parkinsonism - Recommendations from an expert working group. Rektor I, Bohnen NI, Korczyn AD, Gryb V, Kumar H, Kramberger MG, de Leeuw FE, Pirtošek Z, Rektorová I, Schlesinger I, Slawek J, Valkovič P, Veselý B. Parkinsonism & related disorders. 2018 April;49:9-16. PubMed PMID: 29310988; PubMed Central PMCID: PMC5857227.
- Cardiovascular risk factor burden in veterans and non-veterans with Parkinson Disease. Kotagal V, Albin RL, Müller MLTM, Bohnen NI. J Parkinsons Dis. 2018;8(1):153-160. doi: 10.3233/JPD-171271. PMID: 29480230 PubMed Central PMCID: PMC5872149.
- The hot 'n' cold of cue-induced drug relapse. Pitchers KK, Sarter M, Robinson TE. Learn Mem. 2018 Aug 16;25(9):474-480. doi: 10.1101/lm.046995.117. Print 2018 Sep. PMID: 30115769 PMCID: PMC6097766
- Addiction vulnerability trait impacts complex movement control: Evidence from sign-trackers. Kucinski A, Lustig C, Sarter M. Behav Brain Res. 2018 Sep 17;350:139-148. doi: 10.1016/j.bbr.2018.04.045. Epub 2018 Apr 26. PMID: 29705686
- Vascular and dopaminergic contributors to mild parkinsonian signs in older adults.Rosso AL, Bohnen NI, Launer LJ, Aizenstein HJ, Yaffe K, Rosano C. Neurology. 2018 January 16;90(3):e223-e229. PubMed PMID: 29247072; PubMed Central PMCID: PMC5772161.
- Tourette syndrome: a disorder of the social decision-making network.Albin RL. Brain: a journal of neurology. 2018 February 1;141(2):332-347. PubMed PMID: 29053770; PubMed Central PMCID: PMC5837580.
- The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models. Behavioral neuroscience.Sarter M, Phillips KB. 2018 February;132(1):1-12. PubMed PMID: 29355335; PubMed Central PMCID: PMC5881169.
- Reader response: Odor identification as a biomarker of preclinical AD in older adults at risk.Bohnen NI, Muller M. 2018 February 13;90(7):343. PubMed PMID: 29440547.
- A motif within the armadillo repeat of Parkinson's-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway.Antoniou N, Vlachakis D, Memou A, Leandrou E, Valkimadi PE, Melachroinou K, Re DB, Przedborski S, Dauer WT, Stefanis L, Rideout HJ. Scientific reports. 2018 February 22;8(1):3455. PubMed PMID: 29472595; PubMed Central PMCID: PMC5823876.
- Recent advances in cholinergic imaging and cognitive decline-Revisiting the cholinergic hypothesis of dementia. Current geriatrics reports.Bohnen NI, Grothe MJ, Ray NJ, Müller MLTM, Teipel SJ. 2018 March;7(1):1-11. PubMed PMID: 29503795; PubMed Central PMCID: PMC5831510.
- Subtype definition of vascular parkinsonism.Rektor I, Bohnen NI, Korczyn AD. Parkinsonism & related disorders. 2018 March 9. PubMed PMID: 29544882. PMCID: PMC6019183
- Hypercholinergic activity in LRRK2 Parkinson's disease. Bohnen NI, Albin RL. The Lancet. Neurology. 2018 April;17(4):290-291. PubMed PMID: 29456160; PubMed Central PMCID: PMC5858987
- Peripheral neuropathy is associated with more frequent falls in Parkinson's disease. Parkinsonism & related disorders. Beaulieu ML, Müller MLTM, Bohnen NI. 2018 April 3. PubMed PMID: 29625874.
- Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes.Bohnen NI, Teipel SJ. Neurology. 2018 April 4. PubMed PMID: 29618621.
- A computerized microelectrode recording to magnetic resonance imaging mapping system for subthalamic nucleus Deep Brain Stimulation Surgery. Dodani SS, Lu CW, Aldridge JW, Chou KL, Patil PG. Oper Neurosurg (Hagerstown). 2018 Jun 1;14(6):661-667. doi: 10.1093/ons/opx169. PMID: 28961898; PMCID: PMC6888019.
- Complete hazard ranking to analyze right-censored data: An ALS survival study.Huang Z, Zhang H, Boss J, Goutman SA, Mukherjee B, Dinov ID, Guan Y. PLoS computational biology. 2017 December;13(12):e1005887. PubMed PMID: 29253881; PubMed Central PMCID: PMC5749893.
- Dopaminergic polymorphisms associated with medication responsiveness of gait in Parkinson's disease.Miller NS, Chou KL, Bohnen NI, Müller MLTM, Seidler RD. Parkinsonism Relat Disord. 2017 Dec 12. pii: S1353-8020(17)30836-2. doi: 10.1016/j.parkreldis.2017.12.010. [Epub ahead of print] PMID:29249680 PMCID: PMC5826846
- Color discrimination errors associate with axial motor impairments in Parkinson's disease. Bohnen NI, Haugen J, Ridder A, Kotagal V, Albin RL, Frey KA, Müller MLTM. Mov Disord Clin Pract. 2017 Nov-Dec;4(6):864-869. doi: 10.1002/mdc3.12527. Epub 2017 Sep 8. PMID:29226177 PMCID: PMC5716634
- Hemicholinium-3 sensitive choline transport in human T lymphocytes: Evidence for use as a proxy for brain choline transporter (CHT) capacity.Koshy Cherian A, Parikh V, Wu Q, Mao-Draayer Y, Wang Q, Blakely RD, Sarter M. Neurochemistry international. 2017 September;108:410-416. PubMed PMID: 28577989; PubMed Central PMCID: PMC5524217.
- Polyglutamine inclusion body toxicity. Albin RL. Mov Disord. 2017 Dec;32(12):1686. doi: 10.1002/mds.27226. Epub 2017 Nov 9. PMID: 29119663 PMCID: PMC5744902
- 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. Movement disorders: official journal of the Movement Disorder Society. 2017 July;32(7):993. PubMed PMID: 28594134; PubMed Central PMCID: PMC5528167.
- Normal striatal vesicular acetylcholine transporter expression in Tourette Syndrome.Albin RL, Minderovic C, Koeppe RA. 2017 July;4(4). PubMed PMID: 28791334; PubMed Central PMCID: PMC5547197.
- Molecular imaging and updated diagnostic criteria in Lewy body dementias.Bohnen NI, Müller MLTM, Frey KA. Curr Neurol Neurosci Rep. 2017 Aug 14;17(10):73. doi: 10.1007/s11910-017-0789-z. Review. PMID: 28808912 PMCID: PMC5873980
- Mitigating the burden of neurological disease.Albin RL. Annals of neurology. 2017 August;82(2):315. PubMed PMID: 28752897; PubMed Central PMCID: PMC5870892.
- Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium.McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VMY, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O'Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K. Neurology. 2017 Jul 4;89(1):88-100. doi: 10.1212/WNL.0000000000004058. Epub 2017 Jun 7. Review. PMID: 28592453 PMCID: PMC5496518
- 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
- Have we been overestimating fall rates in Parkinson's disease? Beaulieu ML, Müller MLTM, Bohnen NI. Mov Disord. 2017 May;32(5):803. doi: 10.1002/mds.26994. Epub 2017 Apr 21. No abstract available. PMID: 28429881
- SOCRAT platform design: A web architecture for interactive visual analytics applications.Proceedings of the 2nd Workshop on Human-In-the-Loop Data Analytics. Kalinin AA, Palanimalai S, Dinov ID. (2nd :2017 : Chicago, Ill.). 2017 April; 2017. PubMed PMID: 29630069; PubMed Central PMCID: PMC5884130.
- 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
- Factors associated with falling in early, treated Parkinson's disease: The NET-PD LS1 cohort.Chou KL, Elm JJ, Wielinski CL, Simon DK, Aminoff MJ, Christine CW, Liang GS, Hauser RA, Sudarsky L, Umeh CC, Voss T, Juncos J, Fang JY, Boyd JT, Bodis-Wollner I, Mari Z, Morgan JC, Wills AM, Lee SL, Parashos SA; NINDS NET-PD Investigators. J Neurol Sci. 2017 Jun 15;377:137-143. doi: 10.1016/j.jns.2017.04.011. Epub 2017 Apr 11. PMID: 28477684 PMCID: PMC5518305
- 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
- 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
- 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
- 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
- Molecular imaging to track Parkinson's disease and atypical parkinsonisms: New imaging frontiers.Strafella AP, Bohnen NI, Perlmutter JS, Eidelberg D, Pavese N, Van Eimeren T, Piccini P, Politis M, Thobois S, Ceravolo R, Higuchi M, Kaasinen V, Masellis M, Peralta MC, Obeso I, Pineda-Pardo JÁ, Cilia R, Ballanger B, Niethammer M, Stoessl JA; IPMDS-Neuroimaging Study Group. Mov Disord. 2017 Feb;32(2):181-192. doi: 10.1002/mds.26907. Epub 2017 Feb 2. Review. PMID: 28150432
- What would Dr. James Parkinson think today? Neuroimaging in Parkinson’s Disease. Albin RL. Mov Disord 2017 Feb;32(2):179-180 PMID: 28218459
- 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
- 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.Kucinski A, de Jong IE, Sarter M. Eur J Neurosci. 2017 Jan;45(2):217-231. doi: 10.1111/ejn.13354. Epub 2016 Aug 18. PMID: 27469080
- Influence of intracranial air on electrode position and clinical outcomes flowing deep brain stimulation for Parkinson's disease. Bentley JN, Guan Z, Cummings KS, Chou KL, Patil PG. Stereotact Funct Neurosurg. 2017;95(1):6-12. doi: 10.1159/000452843. Epub 2017 Jan 14. PMID: 28088795
- 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:28106566PMCID: PMC5470115
- Translational MRI volumetry with NeuroQuant: Effects of version and normative data on relationships with memory performance in healthy older adults and patients with Mild Cognitive Impairment. Stelmokas J, Yassay L, Giordani B, Dodge HH, Dinov ID, Bhaumik A, Sathian K, Hampstead BM. Journal of Alzheimer’s disease: JAD. 2017;60(4):1499-1510. PubMed PMID: 29060939; PubMed Central PMCID: PMC5858697.
- Cognitive function in 1736 participants in NINDS Exploratory Trials in PD long-term study-1.Wills AA, Elm JJ, Ye R, Chou KL, Parashos SA, Hauser RA, Bodis-Wollner I, Hinson VK, Christine CW, Schneider JS; NINDS NET-PD Investigators. Parkinsonism Relat Disord. 2016 Dec;33:127-133. doi: 10.1016/j.parkreldis.2016.10.005. Epub 2016 Oct 8. PMID: 27743701 PMCID: PMC6091572
- 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
- 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
- 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
- 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
- Reverse translation in Parkinson disease.Albin RL, Frey KA. J Nucl Med. 2016 Oct;57(10):1497-1498. Epub 2016 May 5. No abstract available. PMID:27151982 PMCID:PMC5367440
- 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.
- Volume and value of big healthcare data.Dinov ID. J Med Stat Inform. 2016;4. pii: 3.PMID: 26998309;PMCID: PMC4795481.
- 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
- Predicting first fall in newly diagnosed Parkinson’s disease: Insights from a fall-naïve cohort. Beaulieu ML, Müller MLTM, Bohnen NI. Mov Disord. 2016 Dec; 31(12): 1829–1836. Published online 2016 Sep 13. doi: 10.1002/mds.26742 PMCID: PMC5880273
- 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. PMID: 27547776; PMCID: PMC4892002.
- Out of one mutation, many Huntington's disease effects. Albin RL. Lancet Neurol. 2015 Nov;14(11):1071-2. doi: 10.1016/S1474-4422(15)00247-1. PMID: 26466773.
- 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.
- Behavioral-cognitive targets for cholinergic enhancement.Sarter M. Current opinion in behavioral sciences. 2015 August;4:22-26. PubMed PMID: 28607947; PubMed Central PMCID: PMC5466806
- 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 PMCID: PMC4856044
- 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. PMID: 25879534 PMCID: PMC4478091
- 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.
- Neuroimaging of freezing of gait. Fasano A, Herman T, Tessitore A, Strafella AP, Bohnen NI. J Parkinsons Dis. 2015;5(2):241-54. doi: 10.3233/JPD-150536. Review. PMID: 25757831 PMCID:PMC4923721
- 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.
- 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; Alzheimer's Disease Neuroimaging Initiative (ADNI). 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.
- 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
- Potential trade-offs in treatment of premanifest Huntington's disease. Albin RL, Burke JF. Mov Disord. 2015 Sep;30(10):1319-23. doi: 10.1002/mds.26318. Epub 2015 Jul 14. PMID: 26173644; PMCID: PMC4873710.
- 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; Alzheimer's Disease Neuroimaging Initiative. J Neuroimaging. 2015 Sep-Oct;25(5):728-37. doi: 10.1111/jon.12252. Epub 2015 May 4. PMID: 25940587; PMCID: PMC4537660.
- 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.
- Deterministic functions of cortical acetylcholine. Sarter M, Lustig C, Howe WM, Gritton H, Berry AS. Eur J Neurosci. 2014 Jun;39(11):1912-20. doi: 10.1111/ejn.12515. Epub 2014 Mar 4. Review. PMID: 24593677 PMCID: PMC4371531
- 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. doi: 10.1016/j.expneurol.2014.04.032. Epub 2014 May 5. Review. PMID: 24805070 PMCID: PMC4348073
- 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
- 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
Project I: Evolution of cholinergic deficits within multisensory, cognitive, and motor integration brain regions and development of PIGD features in people with Parkinson’s disease
[18F]FEOBV PET delineates specific cortical regions and deep brain structures, including striatum and thalamic subnuclei. PD subjects with falls vs those with falls and gait freezing exhibit distinct abnormal patterns, highlighted by reduced striatal [18F]FEOBV as a shared dysfunctional node. Dr. Bohnen and his team will prospectively test the hypothesis that the cholinergic AMI network dysfunctions they describe are core features of PD gait and balance dysfunction, and that distinct patterns of cholinergic pathology predict specific features of PD gait dysfunction. The serial assessments proposed will allow unique within-subject analysis for the temporal dissection of distinct and converging elements of mobility control deficits of gait-balance motor features in PD. Unlike the prior grant cycle where longitudinal assessment was limited, esp. for PwP converting from non-fallers/freezers to fallers/freezers, the current cycle will allow clinically meaningful follow-up assessments of up to 5-6 years of PwP who completed baseline [18F]FEOBV PET. Hypotheses to test: 1) whether incident fallers exhibit [18F]FEOBV defects in the caudate, visual thalamus, and prefrontal cortex (compared to non-converters), and 2) whether the subsequent emergence of gait freezing involves additional and more widespread cholinergic vulnerability of the striatum, limbic archicortex, including the cingulo-opercular and insular cortices. The existence of the unique PD subject cohort developed in the currently funded cycle, together with newly recruited subjects, will allow study of an enriched sample of those converting to falls and/or to gait freezing. The focus on visual thalamus, based on the repeated association of falls with cholinergic dysfunction (found with both [11C]PMP and [18F]FEOBV), is another important and novel element. Many thalamic nuclei are primarily interconnected with association cortices with these thalamic nuclei are increasingly viewed as partners and/or modulators of cortical functions. Emerging evidence supports critical roles of visual thalamus in mediating visual attention. LGN function is modulated by attention, indicating a key role for this relay structure in bottom-up attention. Dr. Bohnen has new data implicating cholinergic denervation of additional regions driving non-episodic PIGD deficits preceding falls and FoG. This data indicates that cholinergic deficits within the MGN and entorhinal cortex (EC) are robustly associated with non-episodic PIGD, independent of nigrostriatal dopaminergic deficits. MGN is involved in processing multi-sensory (auditory, vestibular and proprioceptive) inputs, implying a significant role of impaired sensorimotor integration underlying early PIGD features in PwP. EC is associated with visuospatial maps, suggesting deficient attention-visuomotor integration. Complementary work will be performed in the Catalyst Research Project. The analysis of cholinergic system changes of the evolution of balance and gait disturbances will be complemented by exploratory mechanistic multisensory and attentional-motor integration studies. These studies will identify the key patterns of cholinergic systems dysfunction underlying treatment-refractory gait and balance disorders in PwP.
Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls
This project builds on Dr. Sarter’s published and preliminary work dissecting the mechanisms of the detection relevant cues, transfer of this information to striatum, and its integration with ongoing motor processing. Having established a role for BF cholinergic projections in the DL (dual lesion) rodent model of PD falling, he will use optogenetic techniques to test the hypothesis that the enhanced fall propensity caused by BF lesions is caused specifically by the loss of fast cholinergic signaling (i.e., “transients”) known to mediate attention. Additional experiments will define how BF-mediated cortical attentional information is integrated with motor selection processes. Frontostriatal circuitry (glutamatergic corticostriatal projections) is essential for action planning, particularly when habit-guided action is disrupted and task shifts are needed. Such adjustment depends critically on corticostriatal information transfer to guide adaptive movement selection and sequencing. Deficient cortical cholinergic activity impairs attentional shifts toward alternative actions, uncoupling striatal action selection from goals, causing ill-timed or absent responses. Guided by this framework, intrinsic to the AMI model, Dr. Sarter’s team acquired compelling preliminary data detecting the signals encoding attentional information transferred to the striatum (via corticostriatal terminals), where it is hypothesized to be integrated with vigor and kinematic signals supplied by nigrostriatal dopaminergic terminals. Utilizing a novel behavioral paradigm, they demonstrate that a cue instructing the animal to turn evokes a time-locked increase of striatal glutamate (that will be shown to originate from corticostriatal afferents), and a similarly timed burst of acetylcholine – hypothesized from ChIs. Dr. Sarter’s team will specifically test the hypothesis that this integrative function is essential for complex motor control, including PD gait dysfunction. Preliminary findings strongly support a role for ChIs in integrating the attentional and motor signals during gait; chemogenetic activation of these neurons reduces fall propensity in DL rats (often preceded by freezing-like motor behaviors in the animals), whereas their inhibition in intact animals mimics DL-type falls. These data support key aspects of the AMI model by implicating cholinergic neurotransmission at two successive nodes along the cortico-striatal pathway critical to support the attentional-motor interface – in cortex for signal detection, and in striatum for signal integration. These studies will identify key substrates of attentional-motor integration in the AMI.
Project III: Cingulo-Opercular Task Control Network Cholinergic Dysfunction in PD
PIs: Roger L Albin, MD
Our preliminary results indicate a global effect of key AMI node AC-I cholinergic denervation on cognitive functions. These cortical regions are key nodes of the COTC network and participate in higher level aspects of attentional function. We will confirm that AC-I denervation is associated with widespread cognitive deficits. Our established PD cohort, extensively characterized with dopaminergic and cholinergic PET, and with motor and cognitive assays, uniquely positions us to define the distinctive natural history of a PD subgroup based on a pathologic marker. Continued follow-up of this valuable cohort will assess if AC-I cholinergic denervation predicts significantly greater global cognitive decline. Quantification of cholinergic changes in the COTC subcortical and cortical (AC-I) network in this cohort will also allow the assessment that progressive cognitive changes coincide with more severe motor changes (aggressive or ‘malignant’ PD subtype). PET studies are costly and [18F]FEOBV is only operational in a handful of centers. A convenient, reliable predictor of AC-I cholinergic denervation is required to employ this phenotype as subgroup marker or stratifying method. We will capitalize on the thorough phenotyping of our cohort and apply more convenient MRI methods, complementing Project I analyses, to explore an accessible biomarker. Through collaboration with investigators at the University of Groningen (Netherlands), we have access to a similarly characterized and prospectively followed cohort of incident PD subjects who also undergo [18F]FEOBV PET. These subjects are part of the Dutch Parkinson and Cognition Study (DUPARC). This collaboration will enable us to rigorously test our hypotheses regarding the impacts and prognostic potential of AC-I cholinergic denervation and identification of a useful predictor in an independent replication cohort. Our Groningen colleagues agreed to share all phenotypic, MRI, and [18F]FEOBV imaging data to address, in parallel, the hypotheses driving Project III. These studies will identify a key substrate of cognitive impairments and predictor of more rapid cognitive decline in PwP.
Catalyst Research Project: Retrosplenial Cholinergic and Attentional-Motor Integration Dysfunction
PI: Omar Ahmed, PhD
Many PwP experience DRT-refractory spatial disorientation with inability to integrate external landmark cues with internal estimates of orientation. The retrosplenial cortex (RSC) is critical for this function with fMRI studies indicating abnormal attentional information processing in PwP. RSC, an integral AMI component, is densely interconnected with other AMI nodes, the cingulate cortex and anterior thalamus (locus of head position neurons), and receives dense BF cholinergic afferents. These cholinergic inputs are critical for attentive spatial navigation. In work funded by a U-M Udall Center Pilot Project, Dr. Ahmed uncovered a unique pattern of local inhibition in the RSC. In this Catalyst Research Project, Dr. Ahmed will evaluate the hypotheses that thalamic input mediated spatial information is modulated by BF cholinergic afferents and that cholinergic receptor mediated responses in RSC neurons are critical for maintaining attentive navigation. RSC inter-hemispheric communication is necessary to maintain attentive navigation. Dr. Ahmed specifically hypotheses that cholinergic signaling is necessary for normal inter-hemispheric RSC function. Dr. Ahmed will evaluate these hypotheses in both normal animals and in the dual lesion (DL) model of combined striatal dopaminergic denervation and cortical cholinergic denervation developed by Dr. Sarter. This study will identify mechanisms of information transfer within a key AMI node. These experiments provide a cellular level examination of cholinergic functions within an AMI node, complementing the systems and circuit level approaches of the other projects. The focus on attentive spatial navigation also complements Project I studies assessing the roles of deficient sensorimotor and visuomotor integration in PwP.
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:
FOR PARKINSON’S DISEASE
NLY-01-PD-1 (PI: Chou)
Objective: To evaluate the efficacy, safety, and tolerability of NLY01 in early-stage PD. The study will last 36 weeks with 10 visits.
- 30-80 years old
- Parkinson’s Disease, Hoehn and Yahr stage <2.5
- MoCA >26
- Diagnosis of secondary or atypical Parkinsonism
- Onset of any Parkinsonian motor sign or symptom >5 years before screening
- Previous surgical procedure for PD
- Past treatment with dopaminergic agonists or antagonists or monoamine oxidase-B inhibitors for more than 28 days
- Active major depression, BDI-II score of >19
- HX of thyroid malignancy or pancreatitis
- Current dx of T1D or T2D
- Intolerance to DaTscan
ENLITE-PD (PI: Wyant)
Randomized, Phase II, parallel-group, placebo-controlled, dose-selection clinical trial of Light therapy in patients with Parkinson’s disease.
Objective: Primary aim to determine if bright-white light therapy improves sleep in Parkinson’s disease.
- Dx iPD with H&Y 2-4
- Score of 2+ on the Sleep Problems question of the MDS-UPDRS (2 = Sleep problems usually cause some difficulties getting a full night of sleep)
- Willingness to wear actigraphy and complete daily sleep logs.
- Inadequately treated OSA
- Symptomatic RLS
- MMSE < 25
- Moderate depression
- Current untreated hallucinations or psychosis
- Antidepressants, hypno-sedative drugs unless stable for 60 days prior to screening
- Significant eye trauma or disease
- Use of a photosensitizing drug (amiodarone, tetracycline, St. John’s wort, etc) within 30 days of screening
Coordinator: Becky Tilley email@example.com
PPMI 2.0 (PI: Chou)
Objective: to continue to obtain information from people with and without Parkinson disease so that researchers may better understand how PD progresses, in order to inform better treatments. Study procedures include DaTscan, MRI, Lumbar puncture and skin biopsy.
- 30+ years old
- PD diagnosed w/in 2 years
- Not expected to require PD medication within at least 6 months from Baseline
- Must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia); OR either asymmetric resting tremor or asymmetric bradykinesia
- Hoehn and Yahr stage I or II
- Confirmation that participant is eligible based on Screening DaTscan imaging
- Treatment naive
- Currently taking levodopa, dopamine agonists, MAO-B inhibitors, amantadine or another PD medication.
- Has taken levodopa, dopamine agonists, MAO-B inhibitors or amantadine within 60 days of Baseline visit.
- Received any of the following drugs: dopamine receptor blockers, metoclopramide and reserpine within 6 months of Screening visit.
- A clinical diagnosis of dementia
- Previously obtained MRI scan with evidence of clinically significant neurological disorder
- Current treatment with anticoagulants that might preclude safe completion of the lumbar puncture.
Coordinator: Angela Stovall firstname.lastname@example.org
Vigor and the LDR in Parkinson Disease (PI: Albin)
Objective: To explore how levodopa treatment in PD produces the Long Duration Response (LDR).
- PD diagnosis
- Previously untreated
- H&Y I or II
- Age >45 and <81
- Presence of other neurologic disease or findings on examination
- Cognitive impairment: MoCA score of <24
- Depression: GDS score of >5
- Use of dopamine agonists or stimulants
- Evidence of a stroke or mass lesion on prior structural brain imaging (MRI or CT)
- Evidence of any confounding medical or psychiatric problem that would preclude task participation
- Demographic Data
- Clinical Rating Scales: UPDRS, PD-CRS, GDS, Lille Apathy Scale, etc.
- Simple Tests of Motor Function, Motivational Function
WATCH-PD (PI: Wyant)
Objective: Observational study to compare objective sensor-based measures with subjective clinical examination to characterize symptom progression in early, untreated PD.
- PD diagnosis < 2 years, Participants will undergo DaT scan as part of inclusion
- Treatment naïve and not expected to start treatment for at least 6 mo
- H&Y I or II
- Atypical parkinsonism or early PD-related FOG or falls
- MoCA < 26
Coordinator: Angela Stovall email@example.com
Modulation of GABA-A Receptors and Axial Impairment in Parkinson disease (PI: Bohnen)
Objective: To assess the effect of GABA-A receptor modulating drug (flumazenil) on axial motor impairments in Parkinson Disease.
- Parkinson’s disease, Hoen and Yahr stages 2-4
- Age 50 years or older.
- Absence of dementia
- Subjects on benzodiazepine, GABAB-ergic medications (baclofen, tizanidine), neuroleptic, anticholinergic (trihexiphenidyl, benztropine), or cholinesterase inhibitor drugs.
- Evidence of a mass lesion on structural brain imaging (MRI).
- Participants in whom MRI is contraindicated
- History of seizures
- History of suicide attempt
- Claustrophobia, severe anxiety
- Other criteria specific to flumazenil arm
Coordinator: Cyrus Sarosh firstname.lastname@example.org
Citalopram in PD (PI: Kotagal)
Objective: To evaluate the ability of citalopram to alter progression of visuospatial cognitive decline and amyloid-beta plaque deposition in Parkinson disease. A subject will be enrolled for 28 months and will have study visits approximately every 3 months.
- 65 years of age and older
- Diagnosis of Parkinson’s Disease, Hoehn and Yahr stage 2-3
- No current dementia
- Not currently on an SSRI, SNRI, or TCA
- Active Depression (GDS of 10/30 or greater)
- Prolonged QTc interval on EKG
- Contraindications for Brain MRI or PET imaging
FOR PARKINSON’S DISEASE DEMENTIA/DEMENTIA WITH LEWY BODIES
Lewy Body Dementia Biomarkers (PI: Frey)
Objective: To identify protein accumulations in the brain in patients with PD-related dementia using brain imaging (PET and MRI). The study is also part of the Parkinson’s Disease Biomarker Program (PDBP) and will involve annual MDS-UPDRS exams, cognitive testing, and the collection of biofluid samples that will become part of a national data repository. Participation lasts up to 5 years.
- Age 55 years and older.
- Dementia (DSM- defined cognitive impairment that impairs working, social interactions or ADLs)
- MMSE > 16
- PDD: dementia with established PD diagnosis using UKPDSBRC criteria
- Probable DLB: dementia with two of: cognitive fluctuations, visual hallucinations, parkinsonism, abnormal DATscan, RBD
- Possible DLB: dementia with any one of the above features
- Significant neurological or psychiatric conditions, other than PDD or DLB.
- Contraindication to MRI
- Neuroleptics other than quetiapine
Coordinator: Ashley Pogue email@example.com
FOR HUNTINGTON’S DISEASE
KINECT-HD (PI: Dayalu)
Objective: To evaluate the effectiveness, safety and tolerability of valbenazine to reduce chorea associated with HD. The study will last for approximately 18 weeks with 9 study visits
- 18–75 years old
- Genetic confirmed diagnosis of HD and early manifest
- Total Functional Capacity (TFC) score ≥5
- Clinically manifest dysphagia
- Cardiac issues
- Significant depression
- Use of antipsychotics or dopamine receptor blockers, CYP3A4 inducers, Dopamine agonists and precursors, MAOI’s, VMAT2 Inhibitors
Coordinator: Angela Stovall firstname.lastname@example.org