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	Moderate	[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, insects, 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 not-for-profit and non-commercial blog.

Both tables were made by me.

Supplementary:

This paper on diet and Parkinson's is open access from Movement Disorders.  It shows that diet may not be a significant factor relative to other environmental and genetic factors.  8 healthy dietary patterns were examined the the quintile with the highest adherence was compared to the quintile with the lowest adherence.  Higher low fat dairy intake was associated with higher Parkinson's risk. 

Chen X, Chen H, Wang P, Schwarzschild MA, Hung AY, Gao X, Ascherio A, Flores-Torres MH, Bjornevik K. Healthy Dietary Patterns and Risk of Parkinson's Disease. Mov Disord. 2026 Jun 4. doi: 10.1002/mds.70358. Epub ahead of print. PMID: 42237654.

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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

 

 Additional References:

Gut Connection;

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.

 

IDPs:

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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The Semantic Memory of Physicians - and More...

 

I have the somewhat grandiose plan to model psychiatric diagnosis based on the cognition of a physician rather than focusing on the externals.  By the externals I mean classification systems and critiques of classification systems.  At a later date – I might try to comment on how this approach compares with AI.  For now, I will try to keep it focused on human diagnosticians.  I have an interest in this is because I have made and witnessed incredible diagnoses and treatments by physicians and psychiatrists who I have been affiliated with. I don’t think there has been much of a focus on the process.  A secondary consideration is that cognitive neuroscience is a neglected subject in psychiatry and I hope to make the point that should change. I would go as far as suggesting that cognitive neuroscience should be taught to all psychiatrists more urgently than focusing on another DSM.    

Since the early 1970s, memory functions are divided along various lines clinically and functionally. The first division is long term memory and working memory (also called short term memory).  On the long-term side there is a further division to declarative and procedural memory.  Declarative memory is divided into episodic and semantic memory.  Episodic memory is the ability to recall discrete events.  Semantic memory can have a number of graded definitions.  A minimalist definition is factual knowledge independent of the source (7). A definition more informed by recent research in cognitive psychology: “General (encyclopedic) knowledge as well as schematic representations of events distilled from lifelong experiences, retrieved independently from their original spatial or temporal context” (9).  The authors in that case give examples of knowing who wrote the book “1984” and what generally happens at a birthday party.  That naturally raises the question how does all of this freestanding knowledge occur in the first place?  And also – does that imply a connection to episodic memory? In other words, does semantic memory occur when the context surrounding episodic memory is forgotten?

In the case of physicians there is a very long list of formative experiences across the course of one’s career.  The ability to recall them often assists in making diagnoses and provides an advantage over a physician who has not experienced that event.  Semantic memory is about concepts, words, and their relationship independent of a specific event or experience.  It typically consists of a collection of general facts and word meanings.  For example, it would include facts that apples can be red, green, or yellow and what a mechanic does.

Anyone familiar with cognitive screening examinations has probably asked questions focused on semantic memory.  Naming, word similarities, verbal fluency by word generation, general knowledge questions, are all examples. 

The semantic memory of a physician will contain many unique concepts and they will vary based on experience and exposure to clinical scenarios.  The general categories can be described as the following:

1:  Meaningful prior experiences – even though episodic memory stores specific events at specific intervals, semantic memory contains the specific meaning.  In the case of psychiatry an example would be seeing the effects of CMV encephalitis in a major university transplant unit and a decade later seeing similar behavior and consulting on a case in a general community hospital for similar findings.  That similarity triggers non-analytic hypothesis generation.

2:  Prototypes - the patterns noted in the above example can be averaged over a group of patients and those averages can be consolidated into prototypes.  In the above case a psychiatrist may have seen many cases of encephalitis and many cases of meningitis resulting in encephalitis and meningitis prototypes.  Similar prototypes may exist for all major neurological, medical, and psychiatric condition that they have encountered.  Note that the prototype differs from diagnostic criteria (the typical focus) because it is recall of all of the relevant and in many cases unique clinical features that were experienced.

3:  Specific patient memories (exemplars) – all physicians recall specific patients.  These memories are important for non-analytical reasoning like pattern matching.

4:  Knowledge Encapsulation – medicine like most professions is based on a system of graduated learning.  Basic science transitions rapidly into clinical medicine and then into clinical practice and lifelong learning.  At each stage prior knowledge is reorganized in a more efficient way.  In this case – general biomedical knowledge from basic science is organized under higher level concepts. 

An example in one of the references is a person with an infection who is experiencing progressive physiological problems.  At the medical student/basic science level the analysis might proceed from the basic science level and pathophysiology first.  At the clinician level the relevant pathophysiology is organized as sepsis and that provides a more immediate pathway for intervention.  The encapsulation encompasses and efficiently organizes the lower-level information.  At the same time experts must retain a significant amount of that earlier information.  

5:  Illness Scripts – are mental representations of diseases containing three different dimensions.  The first is enabling conditions like risk factors, demographics, predisposition, and context.  The second is fault or underlying pathophysiology.  The third is consequences including signs, symptoms, lab findings, and course or natural history.  Experts have a significant collection of these features.   

One of the questions in this area is what kind of illness script do physicians have?  Should they all be from their particular specialty or should these scripts encompass the totality of their training?  Some authors suggest that the pathophysiological mechanisms from basic science needs to be retained for true expertise – so my conclusion is that the illness scripts from the entirety of a physicians training probably remain relevant.

This is important in psychiatry because the general pathophysiology important in today’s environment was probably not taught is any detail in medical school and most conditions that are not secondary to medical conditions or the effects of drugs do not easily lend themselves to physiological explanations.  I would suggest that medical stability, generalized seizures and seizure variants, increased intracranial pressure, meningitis, encephalitis, cerebral localization, cerebellar dysfunction, peripheral neuropathies, coma, confusion/stupor/delirium, intoxication, and cranial nerve deficits are some of the illness scripts that every psychiatrist must have.

6:  Semantic Qualifiers - every physician has a lexicon of semantic qualifiers acquired in both medical school and post graduate training. They include anatomic descriptions (areas, more specific locations), pathological descriptions, disease course descriptions, and many others. Framing clinical scenarios with these qualifiers is often all that is needed to acquire associations to the disease of interest.

7:   Base rates and Context – experts by way of their clinical practice have an intuitive grasp of the base rates of various clinical conditions and how they typically present in their practice.  These rates of presentations and findings are integrated with the other features of semantic memory (disease scripts, patterns, etc) for more analysis and hypothesis generation.

These features of semantic memory are of course models of brain function for the most part determined by experimental models in cognitive psychology. Examples include testing for specific functions and seeing how those modelled functions vary among trainees and experts at various stages of development. 

Apart from the descriptive approaches used in many studies on physicians at various levels of training are there any more general models that could apply?  Cognitive neuroscience and cognitive psychology offer a more complete model of memory and knowledge structures as well as the underlying biology.  The lead figure for this post is a case in point and has the potential to consolidate many of the descriptions under a more comprehensive model based on experimental validation.

At levels B and C in the diagram we see a perceptual episode being processed from the left to the right in the diagram.  The activated or instantiated schema is a template for extracting relevant features and repressing irrelevant features.  In the diagram circles represent general concepts and squares are action scripts. Gist in the case of the model is a representation of a single episode where much of the detailed information is removed.  The overall sequence at level B depicts how a schema serves to form semantic type memory (gists) and at the same time can be altered or accommodated by new information.

Level A in the diagram illustrates what is known about the localization of these processes largely from human fMRI and preclinical studies.  Memory schemas are stored in various sites including the retrosplenial cortex (RSPL), middle and superior temporal gyrus (MTG/STG), anterior temporal lobe (ATL), and temporoparietal junction (TPJ).  These sites are bound per the diagram to the ventromedial prefrontal cortex (vmPFC).    Solid lines are context sensitive associative pathways biased by the vmPFC. Broken lines in the diagram represent context irrelevant associations that are not activated or inhibited.

How might all of this model work for psychiatry?  In general physicians are seeing a lot of patients in their training and practice.  In the course of that work - schemas are developed for diagnoses, signs, symptoms, and situations.  Here is a comparison of two scenarios that all psychiatrists are trained to recognize acute encephalitis and bipolar disorder, manic with psychotic features. 

	Encephalitis	Bipolar disorder, manic with psychosis
Schema	Acute illness, acute altered mental status, fever, seizures, focal neurological deficits, CSF/MRI abnormalities	Acute illness, euphoria/irritability/anger, hyperactivity, functional impairment, psychosis, temporal pattern, exclusion features
Subschema	Predisposing factors, pathophysiology patterns, temporal pattern	Euphoric expansive Irritable dysphoric Spontaneous v. precipitated
Gist	Acute confusion + fever + temporal lobe MRI changes = treat as HSV until proven otherwise" "Young woman + new psychosis + movement disorder = think anti-NMDAR, look for teratoma" "Summer encephalitis + flaccid paralysis = arboviral, likely West Nile" “Immunocompromised man with acute agitation = think CMV encephalitis	Episodic psychosis +/- mood changes (diagnosis gist) Mood stabilizer + antipsychotic (treatment gist) Severe postpartum psychosis = think bipolar disorder, manic with psychotic features Catatonia – think bipolar disorder, manic/depressed/mixed with psychotic features.

 

I came up with the following graphic (click to enlarge) based on the descriptive categories and the cognitive neuroscience model of Gilboa and Marlatte (12).  From left to right – the  “heterogenous construct supported by clinical utility” characterization is probably the most charitable one from philosophers.  Others like “this disorder does not exist” or “this disorder is not real” are two additional examples.  The central semantic memory category includes investigations and models of diagnostic reasoning conducted largely on medical students and physicians.  The cognitive neuroscience model contains schema and I have attempted to show how the concepts and actions map from the semantic memory to the schema model.  In both the semantic memory and cognitive neuroscience model, although the focus is memory the conceptualizations are really knowledge structures emphasizing a dynamic role for the schema in incorporating features of reality – in this case patient encounters. The cognitive neuroscience and semantic memory models also map on to brain anatomy – with a more comprehensive map for the cognitive neuroscience model as illustrated in the figure at the top.

What have I learned about this so far:

1:  The pattern matching of yesterday is more complicated today – I taught a course in diagnosis and diagnostic reasoning for 15 years into the early part of this century.  Pattern matching and pattern completion was a big part of that course.  The patterns were fairly simple and involved visual diagnoses (diabetic retinopathy, rashes) comparing physicians at various levels of training.  The most dynamic aspect was the implication that experts were better at matching incomplete patterns than novices.  Today’s conceptualizations of knowledge structures and schemas contain concepts, actions, and dynamically alter what is retained in memory and what is not. 

2:  There are clear implications for psychiatric diagnosis -   the DSM classification and all of the criteria do not capture the reality of medical and psychiatric diagnoses.  There is a qualifier in the manual that it is not a substitute for experience but that is never defined.  That reason becomes a lot clearer looking these cognitive models.  Classification systems attempt to operationalize the diagnostic reasoning of a physician by averaging a verbal description of those events.  I don’t think that is possible and I will cite a couple of examples.

Example 1:  A psychotherapist refers a 27-year-old woman to a psychiatrist because of concerns that she has histrionic personality disorder.  She has not been able to make progress in therapy.  The psychiatrist seeing the patient knows within minutes that she is manic.

Example 2:  An intern is presenting the history of a 68-year-old man to his psychiatric attending.  The patient is extremely depressed to the point that he believes that he is cursed based on a trivial event that occurred in his childhood. Within the first 5 minutes the attending realizes that the patient is delusional and communicates that to the intern. The intern acknowledges that this is true and wonders how he failed to make that diagnosis.

Both cases highlight that knowledge of a classification system is not enough.  The psychotherapist and the intern both know the DSM and use it regularly. They have both had didactics in classification of mental disorders.  The only difference is that the psychiatrist in both cases has experienced cases of the disorder and had knowledge structures and schema to make the diagnosis.  Written descriptions of schema and knowledge structures are an incomplete approach to diagnostic reasoning. 

3: Classifications artificially separate actions from concepts – any reading of the DSM gives the impression that “this is the universe of psychiatric disorders – in order to function as a psychiatrist, pick one and then come up with a treatment plan.”  This is problematic at two levels.  First, if the cognitive neuroscience model of memories and knowledge structures is correct – a classification system is operating at a sublevel that averages features.  It is blind to the overall gist that despite this averaging no two people are alike.  Second, it removes action features that are necessary to function as a physician.  That would include top level schemas like “This patient is medically unstable and requires medical or surgical care first” or “This is a life-threatening problem that requires a safe and closely monitored environment." Some will argue that is not the goal of classification.  I would argue that many consider classification to be a diagnosis and in order for it to function that way – it needs to include action items in addition to a general rule out of causative intoxication states and medical problems. The DSM as it exists is classification without diagnosis.

4:  Cognitive neuroscience models highlight the fact that the separation between diagnosis and treatment is artificial.  All physicians are taught to do exhaustive evaluations of medical problems.  That is the initial step in a career.  It is also critical to learn when that exhaustive process needs to be immediately interrupted to focus on a more acute problem. I can still recall seeing a 7-year-old boy who have been hit by a car while playing in the street. He was alert but had significant abdominal pain.  The car bumper struck him just below his left rib cage.  It took me less than 5 minutes to determine that he had an acute abdomen and call the trauma surgeons. That non-linear process happens frequently in acute care psychiatry and in outpatient psychiatry with patients in crisis who need verbal interventions to assist in the diagnostic and treatment process.  

5:  Psychotherapy – there are recent perspectives on how cognitive psychology applies to the psychotherapeutic process at both the psychological and biological levels using these models.  Basically, maladaptive schemas are confronted and modified during the therapy.  There is some empirical evidence that this may happen particularly in the area of positive and negative self-schemas.  Much of this literature draws on existing cognitive behavioral therapy.  That leads to a question of what is the difference between a therapy focused on a cognition or an isolated memory compared with a schema focused therapy?

At the highest level of analysis memory focused therapies generally involve isolated autobiographical memories and schema focused therapies are about knowledge structures abstracted across multiple events that involve emotion, cognition, and behavior.  In theory the schema focused therapies may be useful in cases where the memory focused therapy is not effective, but a competing consideration is that schemas can be entrenched and difficult to change.  The memory focused therapy could be considered a bottom-up type of approach and the schema focused a top-down approach. 

6:  Criticisms – Criticizing the DSM as a diagnostic system is a cottage industry in the US and the UK.  As we approach a new version of the DSM expect most media sites to start months and even years of criticism. Practically everybody does it rarely discussing their motivations, understanding, and the limitations of their proposed system if they have one.  If diagnostic reasoning is a complex process consistent with the cognitive neuroscience models and requires direct experience, criticism of the manual rings hollow.  It is equivalent to reading about things that might exist and proclaiming you are an expert.  Psychiatrists with criticisms are also limited if they have insufficient experience in the areas they are criticizing.  Psychiatrists with the broadest experience will produce the best criticism. If you are criticizing a list of diagnostic criteria in a classification system in isolation – that is exactly what you are doing.  It is trivial compared with an actual diagnosis by a trained and experienced psychiatrist.        

This brief focus on the cognitive neuroscience of diagnosis should highlight that psychiatric education and practice is seriously lagging in this knowledge base.  If we are taking the “diagnosis” in DSM seriously it has to be modified to include this important brain science.  All of the current competing models face the same criticism.  A diagnosis by a physician is much more than typed criteria attempting to capture a dynamic process.  Secondly, psychiatry needs modern approaches to the mind. Approaches that correlate with neurobiology and have a clear empirical basis. Much of the DSM claims a sketchy atheoretical basis that should no longer be acceptable when powerful explanatory theories may exist.  Philosophy is no substitute.  Finally, we must find a way to implement these across all of our training programs and practitioners.  We should be devoting as many resources to integrating cognitive neuroscience into psychiatry as we do modifying the DSM.

And that should be the first step.  What does a DSM looked like with cognitive neuroscience baked in?  The answer goes a lot farther than “dimensions”.      

   

George Dawson, MD, DFAPA

 

 

References:

 

1:  Norman G, Young M, Brooks L. Non-analytical models of clinical reasoning: the role of experience. Med Educ. 2007 Dec;41(12):1140-5. doi: 10.1111/j.1365-2923.2007.02914.x. Epub 2007 Nov 13. PMID: 18004990.

2:  Brush JE Jr, Sherbino J, Norman GR. Diagnostic reasoning in cardiovascular medicine. BMJ. 2022 Jan 5;376:e064389. doi: 10.1136/bmj-2021-064389. PMID: 34987062.

3:  Custers EJ. Thirty years of illness scripts: Theoretical origins and practical applications. Med Teach. 2015 May;37(5):457-62. doi: 10.3109/0142159X.2014.956052. Epub 2014 Sep 2. PMID: 25180878.

4:  Koufidis C, Manninen K, Nieminen J, Wohlin M, Silén C. Unravelling the polyphony in clinical reasoning research in medical education. J Eval Clin Pract. 2021 Apr;27(2):438-450. doi: 10.1111/jep.13432. Epub 2020 Jun 22. PMID: 32573080.

 5:  Binder JR, Desai RH, Graves WW, Conant LL. Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies. Cereb Cortex. 2009 Dec;19(12):2767-96. doi: 10.1093/cercor/bhp055. Epub 2009 Mar 27. PMID: 19329570; PMCID: PMC2774390.

6:  Duff MC, Covington NV, Hilverman C, Cohen NJ. Semantic Memory and the Hippocampus: Revisiting, Reaffirming, and Extending the Reach of Their Critical Relationship. Front Hum Neurosci. 2020 Jan 24;13:471. doi: 10.3389/fnhum.2019.00471. PMID: 32038203; PMCID: PMC6993580.

7:  Insaustu R, Amaral DG. Hippocampal Formation. In: Mai JK, Paxinos G (eds) The Human Nervous System, 3^rd ed.  Elsevier, London, 2012: p. 933.

8:  Mazoué A, Gaultier A, Rocher L, Deruet AL, Vercelletto M, Boutoleau-Bretonnière C. Does a rabbit have feathers or fur? Development of a 42-item semantic memory test (SMT-42). J Clin Exp Neuropsychol. 2022 Sep;44(7):514-531. doi: 10.1080/13803395.2022.2133088. PMID: 36269845.

9:  Renoult L, Irish M, Moscovitch M, Rugg MD. From Knowing to Remembering: The Semantic-Episodic Distinction. Trends Cogn Sci. 2019 Dec;23(12):1041-1057. doi: 10.1016/j.tics.2019.09.008. Epub 2019 Oct 28. PMID: 31672430.

10:  Brown TI, Rissman J, Chow TE, Uncapher MR, Wagner AD. Differential Medial Temporal Lobe and Parietal Cortical Contributions to Real-world Autobiographical Episodic and Autobiographical Semantic Memory. Sci Rep. 2018 Apr 18;8(1):6190. doi: 10.1038/s41598-018-24549-y. PMID: 29670138; PMCID: PMC5906442.

11:  Teghil A, Bonavita A, Procida F, Giove F, Boccia M. Temporal Organization of Episodic and Experience-near Semantic Autobiographical Memories: Neural Correlates and Context-dependent Connectivity. J Cogn Neurosci. 2022 Nov 1;34(12):2256-2274. doi: 10.1162/jocn_a_01906. PMID: 36007071.

12:  Gilboa A, Marlatte H. Neurobiology of Schemas and Schema-Mediated Memory. Trends Cogn Sci. 2017 Aug;21(8):618-631. doi: 10.1016/j.tics.2017.04.013. Epub 2017 May 24. PMID: 28551107.

13:  Reyna VF, Edelson S, Hayes B, Garavito D. Supporting Health and Medical Decision Making: Findings and Insights from Fuzzy-Trace Theory. Med Decis Making. 2022 Aug;42(6):741-754. doi: 10.1177/0272989X221105473. Epub 2022 Jun 23. PMID: 35735225; PMCID: PMC9283268.

14:  Wilhelms EA, Fraenkel L, Reyna VF. Effects of Probabilities, Adverse Outcomes, and Status Quo on Perceived Riskiness of Medications: Testing Explanatory Hypotheses Concerning Gist, Worry, and Numeracy. Appl Cogn Psychol. 2018 Nov-Dec;32(6):714-726. doi: 10.1002/acp.3448. Epub 2018 Sep 1. PMID: 30686857; PMCID: PMC6345391.

15:  Hawke LD, Provencher MD, Parikh SV. Schema therapy for bipolar disorder: a conceptual model and future directions. J Affect Disord. 2013 May 15;148(1):118-22. doi: 10.1016/j.jad.2012.10.034. Epub 2012 Dec 4. PMID: 23218898.

16:  Lane RD, Ryan L, Nadel L, Greenberg L. Memory reconsolidation, emotional arousal, and the process of change in psychotherapy: New insights from brain science. Behav Brain Sci. 2015;38:e1. doi: 10.1017/S0140525X14000041. Epub 2014 May 15. PMID: 24827452.

Graphics Credit:

1:  The lead graphic as noted is from Cell Press and reference #12.  It is reproduced here with permission from Elsevier and this is their acknowledgement:

Reprinted from Trends in Cognitive Sciences, August 21(8), Gilboa A, Marlatte H. Neurobiology of Schemas and Schema-Mediated Memory, p. 618., Copyright 2017, with permission from Elsevier.  License 6278000229455, May 29, 2026 

2:  Second graphic was made by me using Microsoft Visio.

Supplementary 1:  Nobel Laureate and Psychiatrist Eric Kandel noted the importance of cognitive neuroscience years ago and this was a quote from his book:  The Age of Insight.