Parkinson’s Disease (PD)

Authors
Affiliations

Nathaniel Yomogida, B.S., SPT

Doctor of Physical Therapy

B.S. in Kinesiology

Chloë Kerstein, B.S., SPT

Doctor of Physical Therapy

B.A. in Neuroscience

Resources

Epidemiology

2nd most prevalent progressive neurodegenerative disorder after Alzheimer’s Disease2

Age

Primary risk factor: Age2.

Gender

Parkinson’s Disease is more frequent in men than women2.

Etiology

  • Most cases of PD are likely the result of a combination of environmental and genetic factors1

  • Primary PD (idiopathic)

  • Secondary PD

  • Parkinson-Plus

Genetic

  • Heritability of PD3:
    • 5-10% for the monogenic form (one gene responsible)3
      • Inc risk for developing PD with monogenic mutations3
    • Some studies report 15% of PD patients have a family hx of the disease3, compared to 3.5% of the general population4.
  • Using genome wide complex trait analysis, studies have found even higher percent estimates of 22-40% of PD cases having a genetic component → capturing both highly penetrant monogenic forms/cumulative effect of common variants5.
    • 22-40% of PD cases have genetic factors that contributed to developing their PD
  • Just because one has some genetic predisposition to PD does NOT mean they will get PD
  • There are gene-environment interactions: (with outside influences like pesticides, tobacco use, chemicals etc) which can exacerbate genetic susceptibility to developing the disease5.

A Family with an autosomal dominant Parkinson’s disease allowed the discovery of a mutation in the SNCA gene → leading to identification of alpha synuclein protein as a hallmark component of lewy bodies/neurites in PD5.

  • Pathogenesis of DJ-1/PARK7-Mediated Parkinson’s Disease6

Sub types

Primary Parkinsonism (Idiopathic)

Secondary Parkinsonism

  • Postencephalitic Parkinsonism
  • Toxic Parkinsonism
  • Drug-Induced Parkinsonism

Postencephalitic Parkinsonism7

  • Viral brain infection
  • Not seen today

Toxic Parkinsonism(O’Sullivan, Schmitz, and Fulk 2019)

Exposure to environmental toxins Pesticides Industrial chemicals (manganese, CO, cyanide, methanol) Synthetic heroin + MPTP

Drug-Induced Parkinsonism

Drug-Induced Parkinsonism7 - Drugs that result in extra-pyramidal dysfunction → Pseudo PD symptoms - Neuroleptic drugs: (chlorpromazine) (Thorazine®), haloperidol (Haldol®), thioridazine (Mellaril®), and thiothixene (Navane®) - Antidepressant drugs: amitriptyline (Triavil®), amoxapine (Asendin®), and trazodone (Desyrel®) - Antihypertensive drugs: Methyldopa (Aldomet®) and reserpine

Metabolic PD

  • PD d/t metabolic conditions
  • Rare
  • Calcium metabolism dysfunction → BG Calcification
  • Hypothyroidism
  • Hyperparathyroidism
  • Wilson’s Disease

Parkinson-Plus

Parkinson-Plus refers to a group of neurodegenerative diseases can affect the substantia nigra and produce parkinsonian symptoms along with other neurological signs7

Pathologies

  • Cortical–basal ganglionic degeneration (CBGD)
  • Progressive supranuclear palsy (PSP)
  • Multiple system atrophy (MSA) syndromes (striatonigral degeneration [SND])
  • Shy-Drager syndrome
  • Sporadic olivopontocerebellar atrophy [OPCA]
  • Motor neuron disease parkinsonism

Parkinson-like symptoms

  • Multi-infarct vascular disease
  • Dementia syndromes (Alzheimer’s disease, diffuse Lewy body disease [DLBD], and frontotemporal dementia [FTD])
  • Normal pressure hydrocephalus (NPH)
  • Creutzfeldt-Jakob disease (CJD)
  • Wilson’s disease (WD)
  • Juvenile Huntington’s disease

Pathophysiology

Molecular mechanisms contributing to PD5

Molecular mechanisms contributing to PD5
Note

“Physical manifestation of lewy bodies in the brain, whereas Dementia is the cognitive manifestation of lewy bodies in the brain” -Adria Thompson

Primary disturbances in the dopamine systems of basal ganglia (BG)7

The pathophysiology of PD is characterized by 2 phases7

  1. Degeneration of dopaminergic neurons in the SNpc7
  2. Addition of Lewy Bodies7
Table 1: Proposed pathogenic mechanisms of Parkinson’s Disease
Proposed pathogenesis Genetic evidence Biomarkers Therapeutic implications
↑ SNCA expression ↑ in α-syn protein results in increased aggregation in cell death and dysfunction ↑ SNCA gene dose results in PD α-syn and phospho-syn blood and CSF measures ↓ in SNCA transcription or translation
↑ α-syn aggregation Formation of oligomers and fibrils is toxic to cells Coding mutations in SNCA gene lead to α-syn aggregation rt-QUIC assays of CSF, skin and olfactory mucosal biopsies Anti-aggregation therapies
Mitochondrial dysfunction Reduced complex 1 activity
abnormal calcium homeostasis
increased reactive oxygen species
reduced mitochondrial ATP production 		Multiple PD gene mutations lead to changes in mitochondrial function
e.g. PRKN, PINK1 and LRRK2 		Magnetic resonance spectroscopy analysis of Pi/ATP ratios;
Measurement of ATP and mitochondrial function in skin biopsies 		Enhancing mitochondrial biogenesis and function
Altered endosomal-lysosomal trafficking Activation of LRRK2 and VPS35 lead to phosphorylation of RAB proteins leading to ↓ lysosomal function; and altered response to membrane damage Rare pathogenic variants in LRRK2 (e.g. G2019S) and VPS35 lead to ↑ RAB phosphorylation Serum Rab protein phosphorylation Reducing LRRK2 protein levels and/or kinase activity via ASO therapy or kinase inhibitors
Lysosomal dysfunction Impaired α-synuclein degradation leading to increased cellular α-synuclein GBA1 mutations are associated with PD;
rare variants in other genes may be relevant 		GCase protein and enzyme activity measurements;
GSLs in blood and CSF 		Modulators of β-glucocerebrosidase activity
Immune activation & neuroinflammation Multiple factors (α-syn aggregates, mitochondrial antigens, and gut endotoxins) trigger immune responses, driving neuroinflammation and neuronal toxicity HLA variants are associated with PD;
LRRK2, PRKN and PINK1 are involved in inflammatory pathways 		C-Reactive protein
interleukins
PET imaging of activated microglia 		Immunomodulatory or anti-inflammatory therapies
Cell to cell spread Toxic α-syn can spread to neighboring and distant cells via extracellular vesicles (potentially) N/a α-syn aggregations via rt-QUIC assays of CSF, skin, and olfactory mucosal biopsies Monoclonal antibodies or other therapies:
↓ release of toxic proteins
Inhibition of extracellular transit
↓ reuptake by recipient cells
Source: Morris et al. 20245

Degeneration of Dopaminergic neurons

  • Loss of the melanin-containing neurons produces characteristic results in Depigmentation in the substantia nigra with a characteristic pallor7.
  • Numerous other brain regions of people with PD show structural and functional changes resulting in impaired modulation of other neurotransmitters (acetylcholine, serotonin, noradrenaline, glutamate, and GABA)7.

α-Synuclein & Lewy bodies

In normal systems, α-synuclein is an amino acid protein found in brain abundantly in the synaptic terminals of neurons to help facilitate vesicle transport/neurotransmitter release5.

When dysfunction occurs, α-synuclein can aggregate into clumps known as lewy bodies5.

  • Detrimental to neurons- they are space occupying lesions that could alter cellular function
  • Braak + colleagues used alpha syn staining to detect Lewy bodies post mortem
  • Found PD can start in gut or olfactory system then spread to cortical/subcortical brain regions

Pathophysiology of α-Synuclein in Parkinson’s Disease5

Pathophysiology of α-Synuclein in Parkinson’s Disease5
Note

While presence of Lewy bodies is a hallmark of Parkinson’s disease, they are not universally found in all patients with the condition. This highlights the heterogeneity of PD and the complexity of its underlying pathophysiology5.

Some PD cases start in brainstem or limbic system or other areas Hypothesis of spreading alpha syn has been validated in multiple studies: Injection of alpha syn fibrils into brain leading to aggregation found in post mortem PD (performed in mice, primates) Found A-Syn can spread from periphery to CNS or from brain to other organs

Changes are seen in the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (nbM) that release acetylcholine (ACh) Degeneration & Alpha Synuclein deposition (early in PD) at Locus coeruleus that releases noradrenaline

Gut-Brain Axis

The relationship between the gut brain axis and pathogenesis of Parkinson’s Disease was suggested in Braak’s hypothesis1

  • This hypothesis builds upon that idea that in PD, α-synclein aggregates in other areas in the body, not just the substantia nigra (the hallmark site)
  • Braak’s Hypothesis places emphasis on the gastrointestinal tract1.
Animal studies

Researchers have found a bidirectional spread of α-syn from the duodenum to the brainstem and the stomach after injecting α-syn in rats1

The fact that 20% of patients experience constipation prior to motor symptoms could be evidence that the gut-brain axis plays a role in the mechanism of Parkinson’s Disease8.

Mitochondrial pathomechanisms

Mitochondria, the powerhouse of the cell, play a key role in cellular energy production/cell signalling5. Mitochondrial dysfunction is proposed to be an early event in pathogenesis of PD5. Alterations of mitochondrial structure/dynamics linked to increased production of reactive oxidative species (ROS), abnormal intracellular calcium levels, and reduced ATP production5.

The results of the following studies supported this pathological mechanism:

  • Inhibition of mitochondrial complex 1 induces PD like symptoms in animal models5
  • Mitochondrial dysfunction can result in production of ROS → leading to oxidative stress/neuronal damage5
  • Mitochondrial DNA mutations have been implicated in risk of developing PD5
  • Alpha Syn aggregation can impair mitochondrial function5
  • Decreased mitochondrial complex 1 activity has been reported in PD5.

Lysosomes

  • PD ⇒ could involve a decline in clearance capacity of autophagy-lysosomal systems or ubiquitin-proteasome systems5.
  • Lysosomes are involved in autophagy- they clean out abnormal/accumulated proteins5.
  • α-syn degradation is lysosomal dependent5.
  • If lysosomes are impaired, this would affect A-syn turnover, causing an aggregation of &alpha-syn into lewy bodies5.
  • Mutations in lysosomal pathway genes have been shown to result in increased a syn accumulation which could lead/progress PD5.
Caution

This lysosome pathophysiology is not fully straightforward and the mechanisms are not fully understood5.

Auto-immune & Inflammatory Mechanisms

In post-mortem studies, microglial activation/ elevated inflammatory cytokines found in post-mortem brains of those with PD5.

  • Found in blood low grade elevation of inflammatory cytokines → linked to rapid disease progression5.
  • Immune activation has different roles that could give benefit → particularly in early stages of neurodegeneration with promoting clearance of abnormal protein aggregates5.
  • Later on, dysfunction of immune mediated clearance mechanisms could cause more a-syn aggregate accumulation although if this is protective to balance shifts is yet to be explored5.
    • Is immune activation is a primary determinant of disease progression or a secondary phenomenon? This is a debate5.
      • Lots of evidence to support that it is actually a Primary determinant5.
      • Monogenic causes of PD are linked to the immune system (LRRK2 gene)5.
      • Use of immunosuppressants/corticosteroids are associated with reduced PD risk5.
      • Changes in gut microbiome can cause the pro inflammatory species found in PD5.
        • Gut inflammation can cause 3 potential mechanisms or a combo:5.
        • → gut leakage of inflammatory mediators to blood/BBB (thru blood brain barrier),5.
        • →A syn aggregation promoted in enteric neurons travels via vagus nerve to brain5.
        • → A syn T cell response in gut w trafficking of these T cells to sites of alpha syn pathology in brain5.

Insulin Insensitivity

Insulin resistance + impaired glucose metabolism are associated with the development and progression of PD9. Insulin resistances promotes PD through increased α-syn expression, mitochondrial dysfunction, and elevated ROS production9.

In 2023, Ruiz-Pozo et al.10, performd a systematic review investigating the relationship between insulin resistance and Parkinson’s Disease. Insulin resistance was associated with α-syn aggregation, dopaminergic neuronal loss, autophagy, and neuroinflammation10.

Based on this information, this can be helpful in both risk assessment and treatment.

Blood tests determining insulin sensitivity/metabolic health can be useful in determining risk of developing PD10.

For patients who already have PD, metabolic health and specifically insulin sensitivity should be considered when developing a plan of care. Enhancing insulin signaling pathways can have neuroprotective effects/improve motor and cognitive fxns in PD patients11,12.

Interventions to enhance insulin sensitivity include:

  • Balanced diet
  • Exercise
  • Antidiabetic agents
  • Insulin therapies

Exercise - increases glucose uptake in muscles thu insulin independence paths/improves mitochondrial fxn

Diet -

Antidiabetic agents like exenatide, which improve insulin sensitivity, have shown promise in clinical trials for PD, leading to significant improvements in motor and non-motor symptoms

Basal Ganglia Loop Dysfunction

Direct Loop

  • Consists of signals transmitted from the cortex to putamen to globus pallidus, to ventrolateral (VL) nucleus of the thalamus, and back to cortex (supplementary motor area [SMA]).
  • This VL-SMA connection is excitatory and facilitates discharge of cells in the SMA7.
  • The BG thus serves to activate the cortex via a positive-feedback loop and assists in the initiation of voluntary movement7
  • Inhibition of the thalamus by the BG is thought to underlie the hypokinesia seen in PD7

Indirect Loop

  • STn, Gpi, and SNpr → Superior colliculus and midbrain tegmentum7.
  • Serves to decrease thalamocortical activation7.
  • BG projection to the superior colliculus assists in regulation of saccadic eye movements7.
  • The BG projection to the reticular formation assists in the regulation of trunk and limb musculature (via extrapyramidal pathways), sleep and wakefulness, and arousal. Other circuits in the BG are involved with memory and cognitive functions7.

Clinical Presentation

Onset

  • It is currently believed that PD begins many years before motor symptoms become clinically relevant, but the non-motor symptoms may appear around onset1

Symptoms

Symptons can be divided into “motor” and “non-motor” symptoms.

Hallmark Motor Symptoms

Non-Motor Symptoms

  • Depression1
  • Hyposmia (reduced sense of smell)1
  • Cognitive impairment1
  • Sleep disorders1
  • Constipation1

Gait Symptoms

Diagnosis

Parkinson’s Disease (PD) is defined by the Movement Disorder Society Clinical Criteria: as Bradykinesia with rest tremor, Rigidity, or both13.

Note

These features must be clearly demonstratable, and cannot be due to confounding factors13.

Diagnostic criteria from MDS-PD can place patients into 2 categories:

  1. Diagnosis of clinically established PD
  2. Diagnosis of clinically probable PD

Clinically established PD

  1. Absence of absolute exclusion criteria
  2. ≥2 supportive criteria
  3. No red flags

Clinically probable PD

  1. Absence of absolute exclusion criteria
  2. Presence of red flags counterbalanced by supportive criteria
    See more
    • 1 red flag is present there must also be at ≥1 supportive criterion13.
    • If there are 2 red flags then ≥2 supportive criteria are needed13.
    • >2 red flags then clinically probable PD cannot be diagnosed13.

Supportive Criteria

If a patient has the “supportive criteria” (need 1 for probable and at least 2 for clinical PD):

  • Dramatic beneficial response to dopaminergic therapy (improvement in motor sx)13.
  • Levodopa induced dyskinesia13.
  • Rest tremor of limb (usually 1 limb)13.
  • Loss of olfaction (loss of smell)13.
  • Cardiac sympathetic denervation (loss of postganglionic sympathetic nerve fibers, hallmark of PD)13.
  • Autonomic dysfunction can lead to OH/Arrhythmias13.
  • No exclusion criteria13.
  • No red flags13.

Absolute exclusion criteria

  1. Cerebellar abnormalities: The presence of cerebellar signs such as ataxia, which are not consistent with PD13.
  2. Downward vertical supranuclear gaze palsy: This includes significant slowing of vertical saccades, which is more indicative of progressive supranuclear palsy (PSP)13.
  3. Parkinsonian features restricted to the lower limbs for more than three years: This presentation is atypical for PD13.
  4. Treatment with a dopamine receptor blocker or dopamine-depleting agent: If parkinsonism persists despite discontinuation of the offending drug, it suggests drug-induced parkinsonism rather than PD13.
  5. Absence of response to high-dose levodopa: If there is no significant improvement in motor symptoms with adequate doses of levodopa, it suggests an alternative diagnosis13.
  6. Cortical sensory loss, ideomotor apraxia, or progressive aphasia: These features are more consistent with corticobasal degeneration (CBD)13.
  7. Normal functional neuroimaging of the presynaptic dopaminergic system: This includes normal findings on DaTSCAN or similar imaging, which would be inconsistent with PD13.
  8. Documentation of an alternative condition known to cause parkinsonism: This includes conditions such as multiple system atrophy (MSA), PSP, or CBD, confirmed by clinical or imaging findings13.

Red flags

“Red flags” as defined by the clinical criteria refer to signs or symptoms that, if observed, If you see these, need to differentiate from atypical PD like MSA, PSP, CBD

  1. Rapid progression of gait impairment requiring wheelchair use within 5 years of onset13.
  2. Absence of progression of motor symptoms or signs over 5 years unless stability is related to treatment13.
  3. Early bulbar dysfunction, such as severe dysphonia or dysarthria within the first 5 years13.
  4. Inspiratory respiratory dysfunction13.
  5. Severe autonomic failure within the first 5 years, including orthostatic hypotension or severe urinary retention/incontinence13.
  6. Recurrent (>1/year) falls within 3 years of onset13.
  7. Disproportionate anterocollis or contractures of hand or feet within the first 10 years13.
  8. Absence of any response to high-dose levodopa despite at least moderate severity of disease13.
  9. Unexplained pyramidal tract signs13.
  10. Bilateral symmetric parkinsonism from the onset13.

Subgroups

The subgroups of PD are not pathophysiologically different, but are used to describe which symptoms the patient presented with first:

  • Tremulous (Tremor predominant)
  • Akinetic Rigidity or Postural Instability and Gait Disturbances

Assessment

Hoehn and Yahr Scale can be used to assess symptom severity14.

  • Higher H&Y scores have been linked with a more rapid cognitive decline in PD patients14.
  • In general, patients with higher H&Y scores report poorer quality of life14.

Sleep

  • Parkinson Disease Sleep Scale

Considerations

Psychosocial

  • The severity of idiopathic PD (IPD) has been associated with patients’ degree of depression14.
    • as studies have revealed a direct correlation with Hoehn-Yahr scores/stages, as well as elevated scores on depression rating scales including the Geriatric Depression Scale (GDS) and the Montgomery Asberg Depression Rating Scale (MADRS)

Symptom Treatment

Depression

  • Community-based exercise improved depression15

Cognition

  • Community-based exercise improved cognition15

Sleep

  • Community-based exercise improved the Parkinson Disease Sleep Scale15

Interventions

No current treatments can stop or reverse the neurodegenerative process2.

Community-Based Exercise

  • High level of evidence and recommendation by APTA’s CPG15
  • studies that improved nonmotor symptoms all included interventions for breathing and relaxation, with frequency and duration ranging from 1 to 2 hours per week for 8 to 25 weeks.

Motor Control

  • Facilitate Bigger amplitude

Rehabilitation

Resources

  • DPT 835 recommended readings
    • O’Sullivan – CH 18
    • Blumenfeld – CH 16; page 251-254
    • Shumway-Cook – CH 11, 15
    • Neuroanatomy: Blumenfield 2022
  • Continuum:
    • Parkinson Disease(Zesiewicz 2019)
  • Textbook
  • Localization in clinical neurology
  • CPG:
  • Physical Therapist Management of Parkinson Disease: A Clinical Practice Guideline From the American Physical Therapy Association (Osborne et al. 2022)

References

1.
Montalbán-Rodríguez A, Abalo R, López-Gómez L. From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson’s Disease. International Journal of Molecular Sciences. 2024;25(2):1294. doi:10.3390/ijms25021294
2.
Muleiro Alvarez M, Cano-Herrera G, Osorio Martínez MF, et al. A Comprehensive Approach to Parkinson’s Disease: Addressing Its Molecular, Clinical, and Therapeutic Aspects. International Journal of Molecular Sciences. 2024;25(13):7183. doi:10.3390/ijms25137183
3.
Deng H, Wang P, Jankovic J. The genetics of Parkinson disease. Ageing Research Reviews. 2018;42:72-85. doi:10.1016/j.arr.2017.12.007
4.
Elbaz A, Grigoletto F, Baldereschi M, et al. Familial aggregation of Parkinson’s disease: A population-based case-control study in Europe. Neurology. 1999;52(9):1876-1876. doi:10.1212/WNL.52.9.1876
5.
Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson’s disease. The Lancet. 2024;403(10423):293-304. doi:10.1016/S0140-6736(23)01478-2
6.
Skou LD, Johansen SK, Okarmus J, Meyer M. Pathogenesis of DJ-1/PARK7-Mediated Parkinson’s Disease. Cells. 2024;13(4):296. doi:10.3390/cells13040296
7.
O’Sullivan SB, Schmitz TJ, Fulk GD, eds. Physical Rehabilitation. 7th ed. F.A. Davis Company; 2019.
8.
Breen DP, Halliday GM, Lang AE. Gut–brain axis and the spread of \(A\)-synuclein pathology: Vagal highway or dead end? Movement Disorders. 2019;34(3):307-316. doi:10.1002/mds.27556
9.
Hong CT, Chen KY, Wang W, et al. Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of \(\alpha\)-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling. Cells. 2020;9(3):740. doi:10.3390/cells9030740
10.
Ruiz-Pozo VA, Tamayo-Trujillo R, Cadena-Ullauri S, et al. The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson’s Disease Pathogenesis. Nutrients. 2023;15(16):3585. doi:10.3390/nu15163585
11.
Sharma T, Kaur D, Grewal AK, Singh TG. Therapies modulating insulin resistance in Parkinson’s disease: A cross talk. Neuroscience Letters. 2021;749:135754. doi:10.1016/j.neulet.2021.135754
12.
Wang SY, Wu SL, Chen TC, Chuang CS. Antidiabetic Agents for Treatment of Parkinson’s Disease: A Meta-Analysis. International Journal of Environmental Research and Public Health. 2020;17(13):4805. doi:10.3390/ijerph17134805
13.
Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease: MDS-PD Clinical Diagnostic Criteria. Movement Disorders. 2015;30(12):1591-1601. doi:10.1002/mds.26424
14.
Modestino EJ, Reinhofer A, Blum K, Amenechi C, O’Toole P. Hoehn and Yahr staging of Parkinson’s disease in relation to neuropsychological measures. Frontiers in Bioscience (Landmark Edition). 2018;23(7):1370-1379. doi:10.2741/4649
15.
Osborne JA, Botkin R, Colon-Semenza C, et al. Physical Therapist Management of Parkinson Disease: A Clinical Practice Guideline From the American Physical Therapy Association. Physical Therapy. 2022;102(4):pzab302. doi:10.1093/ptj/pzab302

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