Lessons For Psychiatry From a Recent Review of Parkinson's

 

Movement disorders have always been an area of fascination for me.  There is overlap with many neuropsychiatric disorders and people with movement disorders develop neuropsychiatric disorders.  Early in my career it was common to see people with tardive dyskinesia and other medication or street drug induced movement disorders (akathisia, chorea, Parkinson’s, dystonia, oculogyric crises).  In acute care psychiatry it was one of the more distressing parts of the practice. It was possible to discharge stabilized patient from the hospital and by the time you saw them in follow up a couple of weeks later they could have developed tardive dyskinesia.  If you worked on an acute care unit – people with tardive dyskinesia were routinely seen.  That nearly resolved with the advent of a new generation of dopamine receptor antagonist antipsychotics.

Over my first decade of practice the only strategies available to treat tardive dyskinesia or medication exposure syndromes was stopping the medication or reducing it to the lowest possible dose. The was always preceded by a detailed informed consent discussion including the possibility that the primary symptoms would recur. I cannot recall a person who wanted to discontinue the medication based on that discussion.  All were aware that the movement symptoms were caused by the medication but they did not want recurrent psychiatric symptoms.

The only available treatment at the time was tetrabenazine but people had to travel to Canada to get a prescription.  Clozapine revolutionized the treatment for many people because it invariably treated or stopped the movement disorder and treated he psychiatric symptoms (1,2). There was a brief period of time when low dose antipsychotics like thioridazine were suggested as a possible treatment – but it was clear there were no advantages and potentially an additional side effect of prolonged QTc interval on ECG and arrhythmia.

In my second decade of practice, I was involved with a Memory Disorder and Geriatric Psychiatry Clinic.  We were referred many elderly patients with movement disorders.  Two of the commonest scenarios was a patient with a history of bipolar disorder, depression, or schizophrenia who developed Parkinson’s Disease in their 60s and the Parkinson’s patient who developed delirium or psychosis from taking medication for the movement disorder.  At the time clozapine was still tightly regulated because it was costly and required an intensive monitoring system.  In order to prescribe it there was a prior authorization system through the state and they only approved it for the FDA indication at the time – treatment resistant schizophrenia.  I had to show that the patient had been treated with two other antipsychotics in adequate doses.

One of the most striking presentations of Parkinson’s I saw during that time was an elderly woman with what I diagnosed as tardive Parkinson’s (3).  She had a preexisting psychosis and ongoing florid delusional symptoms, bradykinesia, hypophonic dysarthria, axial rigidity, and severe gait disturbance. She improved significantly with clozapine.

Like all diseases, the presentation of movement disorders vary significantly from person to person.  In the case of Parkinson’s and psychiatry – learning to diagnose parkinsonism at the earliest possible stage is a required skill when prescribing dopamine receptor antagonists (DRAs). Learning the clinical picture of hyperkinetic and hypokinetic movement disorders was also useful.  That led me to be a member of the Movement Disorder Society (MDS) and attend the Aspen Movement Disorders course for many years.  As a member of MDS – I got the journal Movement Disorders and video of the cases discussed initially on tape and then CDs.  Movement Disorders is a very high-quality journal and by reading I always learned valuable details like clozapine being the only DRA that does not make Parkinson’s worse and it could be used to treat resistant tremor in the disorder. 

When I saw this open access review of Parkinson’s in Movement Disorders (4) – I knew I had to read it.  Historically Parkinson’s has always been presented as a disease of the substantia nigra – a critical part of the basal ganglia containing dopaminergic neurons. The dopaminergic neurons deteriorate and die off and at a certain critical point the signs and symptoms of Parkinson’s occur.  That implies that the underlying pathophysiological process has been going on for some time before the patient becomes symptomatic.  The genetics and some environmental causes were relevant.  In this case there was also an infectious cause – von Economo’s encephalitis.  In medical school in the 1980s there were still some survivors of that epidemic.  Although both diseases affect the substantia nigra Parkinson’s is technically a synucleinopathy and post-encephalitic parkinsonism (PEP) is a tauopathy.

Parkinson’s disease and various forms of parkinsonism are proteinopathies caused by misfolded protein aggregates in this case hyperphosphorylated tau protein (PEP) and α-synuclein (Parkinson’s).  Proteinopathies can be caused by a number of factors that often converge including genetics (mutations leading to abnormal proteins), deteriorated protein quality control with aging (5,6), oxidative stress, prion-like propagation (7), post translational modifications (8), and unstable protein structures. 

Long before these mechanisms were discovered epidemiological associations between Parkinson’s disease and parkinsonism were noted with heavy metals, industrial solvents, pesticides, and air pollution (9).  There are also miscellaneous toxins like MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) – a contaminant produced in the illicit manufacture of meperidine that can cause Parkinson’s.  A partial list is contained in the table below:

 

Toxin	Class	Year First Linked to PD or Parkinsonism	Strength of Evidence	References
Manganese	Heavy metal	1837	Strong (direct cause of manganism)	[1-2]
Carbon monoxide	Gas	Early 20th century	Strong (direct cause)	[3]
Carbon disulfide	Solvent	Mid-20th century / 1981	Moderate	[3-4]
Mercury	Heavy metal	1981	Inconsistent	[4-5]
MPTP	Synthetic contaminant	1983	Definitive (direct cause)	[6-7]
Paraquat	Herbicide	Late 1980s–1990s	Strong	[8-9]
Organochlorines (dieldrin, heptachlor, chlorpyrifos)	Pesticides	1989–1999 (meta-analyses)	Moderate–Strong	[10-11]
Rotenone	Insecticide	Early 2000s	Strong	[9]
Agent Orange / dioxin	Herbicide, contaminant	1990s–2000s	Sufficient (per National Academies)	[12-13]
Maneb / dithiocarbamates	Fungicides	2000s	Moderate	[14]
TCE (Trichloroethylene)	Solvent	2012	Strong (growing)	[15]
PCE (Perchloroethylene / Tetrachloroethylene)	Solvent	2010s	Moderate	[16-17]
Air pollution (PM2.5)	Ambient	~2018	Moderate (emerging)	[18-20]
Iron, lead, copper, aluminum	Heavy metals	1980s–1990s	Inconsistent	[21-22]
Methamphetamine, amphetamine	Non-therapeutic	2015-2016		[14, 23-24]
1: Dorsey ER, De Miranda BR, Hussain S, Bloem BR, Elbaz A, Llibre-Guerra J, Lo RY, Goldman SM, Tanner CM. Environmental toxicants and Parkinson's disease: recent evidence, risks, and prevention opportunities. Lancet Neurol. 2025 Nov;24(11):976-986. doi: 10.1016/S1474-4422(25)00287-X. PMID: 41109237.  2: McKnight S, Hack N. Toxin-Induced Parkinsonism. Neurol Clin. 2020 Nov;38(4):853-865. doi: 10.1016/j.ncl.2020.08.003. Epub 2020 Sep 9. PMID: 33040865.  3:  Blanc PD. The early history of manganese and the recognition of its neurotoxicity, 1837-1936. Neurotoxicology. 2018 Jan;64:5-11. doi: 10.1016/j.neuro.2017.04.006. Epub 2017 Apr 14. PMID: 28416395.  4:  Racette BA, Aschner M, Guilarte TR, Dydak U, Criswell SR, Zheng W. Pathophysiology of manganese-associated neurotoxicity. Neurotoxicology. 2012 Aug;33(4):881-6. doi: 10.1016/j.neuro.2011.12.010. Epub 2011 Dec 21. PMID: 22202748; PMCID:  PMC3350837.  5:  Miranda M, Bustamante ML, Mena F, Lees A. Original footage of the Chilean miners with manganism published in Neurology in 1967. Neurology. 2015 Dec 15;85(24):2166-9. doi: 10.1212/WNL.0000000000002223. PMID: 26668239.  6:  Ohlson CG, Hogstedt C. Parkinson's disease and occupational exposure to organic solvents, agricultural chemicals and mercury--a case-referent study. Scand J Work Environ Health. 1981 Dec;7(4):252-6. doi: 10.5271/sjweh.2549. PMID: 7347910.  7:  Cariccio VL, Samà A, Bramanti P, Mazzon E. Mercury Involvement in Neuronal Damage and in Neurodegenerative Diseases. Biol Trace Elem Res. 2019 Feb;187(2):341-356. doi: 10.1007/s12011-018-1380-4. Epub 2018 May 18. PMID: 29777524.  8:  Ganguly J, Kulshreshtha D, Jog M. Mercury and Movement Disorders: The Toxic Legacy Continues. Can J Neurol Sci. 2022 Jul;49(4):493-501. doi: 10.1017/cjn.2021.146. Epub 2021 Jun 24. PMID: 34346303.  9:  de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006 Jun;5(6):525-35. doi: 10.1016/S1474-4422(06)70471-9. PMID: 16713924. 10:  Bjorklund G, Stejskal V, Urbina MA, Dadar M, Chirumbolo S, Mutter J. Metals and Parkinson's Disease: Mechanisms and Biochemical Processes. Curr Med Chem. 2018;25(19):2198-2214. doi: 10.2174/0929867325666171129124616. PMID: 29189118. 11:  Samii A, Nutt JG, Ransom BR. Parkinson's disease. Lancet. 2004 May 29;363(9423):1783-93. doi: 10.1016/S0140-6736(04)16305-8. PMID: 15172778. 12:  Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4546-50. doi: 10.1073/pnas.80.14.4546. PMID: 6192438; PMCID: PMC384076. 13:  Varçin M, Bentea E, Michotte Y, Sarre S. Oxidative stress in genetic mouse models of Parkinson's disease. Oxid Med Cell Longev. 2012;2012:624925. doi: 10.1155/2012/624925. Epub 2012 Jul 8. PMID: 22829959; PMCID: PMC3399377. 14:  Ascherio A, Schwarzschild MA. The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol. 2016 Nov;15(12):1257-1272. doi: 10.1016/S1474-4422(16)30230-7. Epub 2016 Oct 11. PMID: 27751556. 15:  Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS, Kasten M, Chade AR, Comyns K, Richards MB, Meng C, Priestley B, Fernandez HH, Cambi F, Umbach DM, Blair A, Sandler DP, Langston JW. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect. 2011 Jun;119(6):866-72. doi: 10.1289/ehp.1002839. Epub 2011 Jan 26. PMID: 21269927; PMCID: PMC3114824. 16:  Weisskopf MG, Knekt P, O'Reilly EJ, Lyytinen J, Reunanen A, Laden F, Altshul L, Ascherio A. Persistent organochlorine pesticides in serum and risk of Parkinson disease. Neurology. 2010 Mar 30;74(13):1055-61. doi: 10.1212/WNL.0b013e3181d76a93. PMID: 20350979; PMCID: PMC2848105. 17: Ross GW, Abbott RD, Petrovitch H, Duda JE, Tanner CM, Zarow C, Uyehara-Lock JH, Masaki KH, Launer LJ, Studabaker WB, White LR. Association of brain heptachlor epoxide and other organochlorine compounds with lewy pathology. Mov Disord. 2019 Feb;34(2):228-235. doi: 10.1002/mds.27594. Epub 2018 Dec 30. PMID: 30597605; PMCID: PMC6602549. 18:  Tanner CM, Ostrem JL. Parkinson's Disease. N Engl J Med. 2024 Aug 1;391(5):442-452. doi: 10.1056/NEJMra2401857. PMID: 39083773. 19:  Pouchieu C, Piel C, Carles C, Gruber A, Helmer C, Tual S, Marcotullio E, Lebailly P, Baldi I. Pesticide use in agriculture and Parkinson's disease in the AGRICAN cohort study. Int J Epidemiol. 2018 Feb 1;47(1):299-310. doi: 10.1093/ije/dyx225. PMID: 29136149. 20:  Goldman SM, Weaver FM, Stroupe KT, et al. Risk of Parkinson Disease Among Service Members at Marine Corps Base Camp Lejeune. JAMA Neurol. 2023;80(7):673–681. doi:10.1001/jamaneurol.2023.1168 21:  Frumkin H. Multiple system atrophy following chronic carbon disulfide exposure. Environ Health Perspect. 1998 Sep;106(9):611-3. doi: 10.1289/ehp.98106611. PMID: 9721261; PMCID: PMC1533160. 22:  Hageman G, van der Hoek J, van Hout M, van der Laan G, Steur EJ, de Bruin W, Herholz K. Parkinsonism, pyramidal signs, polyneuropathy, and cognitive decline after long-term occupational solvent exposure. J Neurol. 1999 Mar;246(3):198-206. doi: 10.1007/s004150050334. PMID: 10323318. 23:  Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR. Methamphetamine/amphetamine abuse and risk of Parkinson's disease in Utah: a population-based assessment. Drug Alcohol Depend. 2015 Jan 1;146:30-8. doi: 10.1016/j.drugalcdep.2014.10.027. Epub 2014 Nov 16. PMID: 25479916; PMCID: PMC4295903. 24: Lappin JM, Darke S. Methamphetamine and heightened risk for early-onset stroke and Parkinson's disease: A review. Exp Neurol. 2021 Sep;343:113793. doi: 10.1016/j.expneurol.2021.113793. Epub 2021 Jun 21. PMID: 34166684.

 

When I say partial list the evidence for environmental toxins is still accumulating.  For example, a study recently showed a correlation between the incidence of Parkinson’s Disease and proximity to a golf course (10).  Groundwater contamination was considered the primary source of toxicity.  Interestingly American golf courses apply pesticides at 15 times the rate of European golf courses.

Quite amazingly there is no screening for dopaminergic neuron toxicity before or after insecticides, fungicides, and rodenticides are marketed.  Screening methods are currently being developed (11,12) but the applications of these compounds are widespread.  In the late spring I can look out of my office window and see herbicides and pesticides being applied to every lawn and garden in my neighborhood. 

Widespread use of these compounds and other contaminants is associated with a significant increase in the incidence and prevalence of Parkinson’s Disease. Global cases are estimated to double over the next 25 years from 11.8M to 25.2M (13). The main factors driving this increase are twofold – an aging demographic (people over the age of 60 are at higher risk) and environmental toxins.

While most people worry about Alzheimer’s Disease the fastest growing neurodegenerative condition is Parkinson’s Disease. At this point we probably lack precision in the best way to prevent it.  Much more attention needs to be paid to every day neurotoxins in the environment at the individual level. Do you have some in your garage?  Do you walk into the house with the same shoes you were wearing in the garage?  Can the residues of some of these toxins sublimate or evaporate in the garage leading to their inhalation?  Do people with attached garages have a higher risk?  How should your drinking water be analyzed?  These are some environmental questions that have not been answered.

I will digress into a little physical chemistry at this point before I wrap up with the Parkinson’s paper and the observation of proteinopathies.  The paper focuses on 4 proteins TDP-43, beta amyloid, tau, and α-synuclein.  I have included them in a table about some of their basic properties (click to enlarge).

There are a few relevant concepts from the perspective of chemistry.  The first is that the molecules of interest are all large protein molecules (14-43 kilodaltons).  The genetics of the proteins are all known and, in some cases, the total number of mutations producing altered proteins is known.  All of the proteins have roles in normal physiology.  All can be condensed into an amyloid state with a characteristic hydrogen bonded fibril structure.

These proteins are also known as intrinsically disordered proteins (IDP) meaning they do not spontaneously fold into a stable 3-dimensional structure in physiological conditions but still carry out physiological functions.  This is a challenge to Anfinsen’s dogma that states a unique stable protein structure at the lowest Gibbs free energy state is necessary for physiological function.   IDPs thus have ensembles of conformations rather than a single best one. They tend to be highly charged molecules with more ionic residues, preventing lipophilic collapse to a single state.  They remain functional by binding mechanisms and changing conformation after binding.      

In the table, tau, Aβ and α-synuclein are fully disordered IDP.   TDP-43 and PrP are hybrid proteins containing both folded domains and IDR (intrinsically disordered regions).  In the above table Aβ is a cleavage product and not an IDP/IDR.  The abbreviated diseases listed in column 5 are all proteinopathies – reflecting the pathophysiology of the underlying proteins.

In the review the authors emphasize that rather than a prototypical synucleinopathy most people with Parkinson’s have additional pathologies that may affect the course and features of the illness.  The  synucleinopathies include Parkinson’s Disease PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).  They discuss hypotheses about how synuclein is initiated in the nervous systema nd how it spreads:

The Braak hypothesis suggests the disease begins in the enteric plexus then enters the lower brainstem and eventually the cortex.  Alternately the disease begins in the olfactory bulb and spread in a rostral to caudal direction in the brain.  The Unified Staging System of Lewy Body Disorders suggests the disease begins in the olfactory bulbs and spreads to the limbic system or brainstem.  The α-synuclein origin site and connectome model (SOC) suggests a combination of both of those models. The brain first verses body-first hypotheses attempts to account for the observation that no matter where the pathology starts it spreads through the brain via the connectome by purported prion like mechanisms. 

Promising biomarkers have been identified to assist in studying the pathology.  Phosphorylated synuclein in peripheral nerves is thought to mirror brain synuclein.  I am aware of some patients who were diagnosed with Parkinson’s Disease who have had peripheral nerve biopsies that were negative for synuclein.  Positron emission tomography (PET) imaging is available for tau and amyloid-β (Aβ) at some centers and there are currently studies looking at ligands for α-synuclein.  Assays developed for prion diseases may be adapted to test for α-synuclein and other misfolded proteins in the blood and CSF. 

The graphic at the top of this post depicts the co-occurring pathologies in Parkinson’s.  These copathologies correlate with more cognitive impairment and greater disease severity.  The authors suggest that the evidence is compelling enough to reconceptualize PD as a disease of copathologies rather than a pure synucleinopathy.  The authors examine the implications of these copathologies in PD in great detail.  Tau in the substantia nigra alone can lead to gait disturbances.  Patients with PD who have tau in their CSF are more likely to develop dementia.  Patients with pathology of both AD and DLB are more likely to have faster disease progression. 

Aβ plaques are commonly found in patients with PD and the prevalence increases with age.  Total plaque burden correlates with progression to dementia and time between onset of motor symptoms and onset of dementia. 

TDP-43 in the substantia nigra has been linked to PD even without synuclein.  It typically aggregates in the entorhinal cortex and amygdala in Lewy Body disorders.  TDP-43 seems to have the lowest rates of copathology and in general raise the concern of may of these accompanying lesions – what concentrations and locations are clinically relevant.   

The authors look at the issue of small vessel disease (SVD), how it is prevalent in PD and how the underlying disease process may be involved in addition to the usual risk factors.  PD patients have about twice the number of white matter hyperintensities compared to age matched controls.  Alpha-synuclein cause a vasculopathy (14) by depositing in the arterial endothelium leading to blood-brain barrier (BBB) damage, endothelial dysfunction, and structural damage to brain capillaries.  The resulting oxidative stress and mitochondrial damage creates a cascade effect across multiple cell types leading to rapid disease progression.

The authors discuss some of the variation in monogenic forms of PD.  They present a table with 16 genotypes and the type of proteinopathy found.  There is every possible combination of proteins found in clinically symptomatic patients. They point out the limitations based on small numbers of patient studied.

In discussing the genetics, the authors point out: “It has been proven that overlapping neurological disorders share common genetic loci.” (p. 8) and the comorbidities in this case suggest “pleiotropy of pathological mechanisms.”  They discuss some of the common genetics between PD and the other proteinopathies.  In the final section they discuss inflammation as a non-neuronal process that drives the pathology.  Overall this is an excellent review of PD at the physiological level and because it is available free online, I encourage anyone interested to read it.

What does all of this have to do with psychiatry?  Am I just an unusual psychiatrist who should have been a neurologist or a neurosurgeon?  I suggest a few things:

1:  This information needs to be in the DSM – yes, it always seems to come back to the DSM.  After all the DSM has an entire chapter of Neurocognitive Disorders that names all of the disorders listed in this post.  Is it going to incorporate some of the latest findings in the field or remain vague.  There are currently 3 pages about Major or Mild Neurocognitive Disorder due to Parkinson’s disease.

2:  Heterogeneity - I love the smell of heterogeneity in the morning.  Let’s face it for the past 40 years of my career our understanding of Parkinson’s has gone from a basic lesion in the substantia nigra of unknown etiology to a mix of proteinopathies moving in the brain like prions.  And further the authors of this review point out that like a lot of neurological disorders there are probably common genetic loci.  Well past the time to stop apologizing for heterogeneous and genetically common disorders in psychiatry.  At one point in this reading, I had the fantasy of what the network diagrammers would do in this case connecting all of the symptom and pathology nodes and talking about transdiagnostic features.  Should we try to make a network of all of those signs, symptoms and pathologies and see what we come up with?  Probably not.  

3:  Training – training in all of this brain specific pathology and genetics is important for psychiatric residents and psychiatrists.  We cannot be focused on a transdiagnostic dementia diagnosis based on clinical features and ignore the brain biology.  That brain biology is exactly why no two patients with these disorders will be alike.  Psychiatrists will be seeing diagnosed and undiagnosed, treated and untreated PD and parkinsonism.  It is not acceptable to miss that diagnosis or realize how your psychiatric treatment would affect the diagnosis or treatment of PD.

4:  Advocacy and public health – it should be shocking to anyone that chemicals used to poison plants, insect, and rodents are not routinely screened for their toxicity to dopaminergic neurons.  If your neighborhood is anything like mine – they are massively applied.  Even if it is not what about public areas like parks and recreational areas?  Is there any good reason that American golf courses get 15 times as many pesticides and European golf courses?  It is equally shocking that toxins that probably cause this toxicity are not immediately pulled from the market.  An epidemic of Parkinson’s Disease is too high a price to pay for a weed free lawn.  

5:  The vasculopathy associated with synuclein was a surprise – I am an advocate for risk factor reduction for all forms of cardiovascular disease. I am not aware of any study that looks at how people with that orientation do if they have PD or more specifically α-synuclein associated PD.  That seems like a necessary study.

6: Phenotypes – all of the pathophysiology described does not readily lend itself to stable phenotypes.  Attempts at subtyping Parkinson’s based on clinical features like tremor, posture and gait instability, akinesia and rigidity, or mixed features is relatively recent development.  In that study one phenotype can change into another (15).  In another analysis (16,17) phenotypes based on presentation, medication responsiveness, and progression seem to reflect disease progression more than stable phenotypes.  This is another lesson for the psychiatric controversy about disease overlap and transdiagnostic symptoms.  In this case we have four identifiable proteinopathies spreading like infectious particles through the connectome.  Would we expect network-based disorders to be any easier to characterize?  It also answers the age-old question: “Is a single pathophysiological defect necessary to characterize a disease?”  At least if Sydenham had not answered it nearly 4 centuries ago.   

That is about all I can think of saying about this post.  I may add a few things in the future.  I am currently awaiting a paper that describes the chemistry and thermodynamics of IDPs (intrinsically disordered proteins) and (intrinsically disordered regions) IDRs. This information likely has implications for the clinical course and treatment of people with this disorder.  If I can find enough of that information, I will probably try a separate post.  At the time of this writing, I am not aware of any specific treatments for proteinopathies or the prion like spread of the disorder suggested in this review.  

 

George Dawson, MD, DFAPA

Graphics Credit:  The lead graphic for this post is from reference 4 - per the following This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, CC BY-NC-ND 4.0 which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

It is unmodified and this is a non-commercial blog.

Both tables were made by me.

 

References:

1:  Wong J, Pang T, Cheuk NKW, Liao Y, Bastiampillai T, Chan SKW. A systematic review on the use of clozapine in treatment of tardive dyskinesia and tardive dystonia in patients with psychiatric disorders. Psychopharmacology (Berl). 2022 Nov;239(11):3393-3420. doi: 10.1007/s00213-022-06241-2. Epub 2022 Sep 30. PMID: 36180741.

2:  Lee D, Baek JH, Bae M, Choi Y, Hong KS. Long-Term Response to Clozapine and Its Clinical Correlates in the Treatment of Tardive Movement Syndromes: A Naturalistic Observational Study in Patients With Psychotic Disorders. J Clin Psychopharmacol. 2019 Nov/Dec;39(6):591-596. doi: 10.1097/JCP.0000000000001114. PMID: 31688397.

3:  Calzetti S, Calzetti G. The nosology of tardive parkinsonism. J Clin Neurosci. 2025 Dec;142:111683. doi: 10.1016/j.jocn.2025.111683. Epub 2025 Oct 22. PMID: 41130187.

4:  Matarazzo M, Borghammer P, Elsayed I, Goldman JG, Huang Y, Lohmann K, Svenningsson P, Kalia LV, Berg D, Kordower JH; MDS Scientific Issues Committee. Co- and Multi-Pathologies in Parkinson's Disease: An International Parkinson and Movement Disorder Society Scientific Issues Committee Review. Mov Disord. 2026 May 22. doi: 10.1002/mds.70324. Epub ahead of print. PMID: 42170815.

5: Gandhi J, Antonelli AC, Afridi A, Vatsia S, Joshi G, Romanov V, Murray IVJ, Khan SA. Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics. Rev Neurosci. 2019 May 27;30(4):339-358. doi: 10.1515/revneuro-2016-0035. PMID: 30742586.

6:  Kampinga HH, Bergink S. Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurol. 2016 Jun;15(7):748-759. doi: 10.1016/S1474-4422(16)00099-5. Epub 2016 Apr 19. PMID: 27106072.

7:  Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci. 2018 Oct;21(10):1332-1340. doi: 10.1038/s41593-018-0235-9. Epub 2018 Sep 24. PMID: 30250260; PMCID: PMC6432913.

8:  Yeboah F, Kim TE, Bill A, Dettmer U. Dynamic behaviors of α-synuclein and tau in the cellular context: New mechanistic insights and therapeutic opportunities in neurodegeneration. Neurobiol Dis. 2019 Dec;132:104543. doi: 10.1016/j.nbd.2019.104543. Epub 2019 Jul 24. PMID: 31351173; PMCID: PMC6834908.

9:  Dorsey ER, De Miranda BR, Hussain S, Bloem BR, Elbaz A, Llibre-Guerra J, Lo RY, Goldman SM, Tanner CM. Environmental toxicants and Parkinson's disease: recent evidence, risks, and prevention opportunities. Lancet Neurol. 2025 Nov;24(11):976-986. doi: 10.1016/S1474-4422(25)00287-X. PMID: 41109237.

10:  Krzyzanowski B, Mullan AF, Dorsey ER, et al. Proximity to Golf Courses and Risk of Parkinson Disease. JAMA Netw Open. 2025;8(5):e259198. doi:10.1001/jamanetworkopen.2025.9198

11:  Shan L, Heusinkveld HJ, Paul KC, Hughes S, Darweesh SKL, Bloem BR, Homberg JR. Towards improved screening of toxins for Parkinson's risk. NPJ Parkinsons Dis. 2023 Dec 19;9(1):169. doi: 10.1038/s41531-023-00615-9. PMID: 38114496; PMCID: PMC10730534

12:  Paul KC, Krolewski RC, Lucumi Moreno E, Blank J, Holton KM, Ahfeldt T, Furlong M, Yu Y, Cockburn M, Thompson LK, Kreymerman A, Ricci-Blair EM, Li YJ, Patel HB, Lee RT, Bronstein J, Rubin LL, Khurana V, Ritz B. A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides. Nat Commun. 2023 May 16;14(1):2803. doi: 10.1038/s41467-023-38215-z. Erratum in: Nat Commun. 2023 Jun 23;14(1):3747. doi: 10.1038/s41467-023-39001-7. PMID: 37193692; PMCID: PMC10188516.

13:  Su D, Cui Y, He C, Yin P, Bai R, Zhu J et al. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: modelling study of Global Burden of Disease Study 2021 BMJ 2025; 388 :e080952 doi:10.1136/bmj-2024-080952

14:  Bogale TA, Faustini G, Longhena F, Mitola S, Pizzi M, Bellucci A. Alpha-Synuclein in the Regulation of Brain Endothelial and Perivascular Cells: Gaps and Future Perspectives. Front Immunol. 2021 Feb 19;12:611761. doi: 10.3389/fimmu.2021.611761. PMID: 33679750; PMCID: PMC7933041.

15:  Konno T, Deutschländer A, Heckman MG, Ossi M, Vargas ER, Strongosky AJ, van Gerpen JA, Uitti RJ, Ross OA, Wszolek ZK. Comparison of clinical features among Parkinson's disease subtypes: A large retrospective study in a single center. J Neurol Sci. 2018 Mar 15;386:39-45. doi: 10.1016/j.jns.2018.01.013. Epub 2018 Jan 11. PMID: 29406964.

16:  Fereshtehnejad SM, Zeighami Y, Dagher A, Postuma RB. Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression. Brain. 2017 Jul 1;140(7):1959-1976. doi: 10.1093/brain/awx118. PMID: 28549077.

17:  Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548–560. doi:10.1001/jama.2019.22360

 

 

Dickson DW. Neuropathology of Parkinson disease. Parkinsonism Relat Disord. 2018 Jan;46 Suppl 1(Suppl 1):S30-S33. doi: 10.1016/j.parkreldis.2017.07.033. Epub 2017 Aug 1. PMID: 28780180; PMCID: PMC5718208.

Bhardwaj K, Singh AA, Kumar H. Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration-Gut Connection in Parkinson's Disease. ACS Chem Neurosci. 2024 Jul 3;15(13):2454-2469. doi: 10.1021/acschemneuro.4c00293. Epub 2024 Jun 19. PMID: 38896463.

 

IDP

Mukhopadhyay S. The Dynamism of Intrinsically Disordered Proteins: Binding-Induced Folding, Amyloid Formation, and Phase Separation. J Phys Chem B. 2020 Dec 24;124(51):11541-11560. doi: 10.1021/acs.jpcb.0c07598. Epub 2020 Oct 27. PMID: 33108190.

Eisenberg D, Jucker M. The amyloid state of proteins in human diseases. Cell. 2012 Mar 16;148(6):1188-203. doi: 10.1016/j.cell.2012.02.022. PMID: 22424229; PMCID: PMC3353745.

 

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