Parkinson Disease (PD)

A comprehensive overview of current knowledge

Thar Thar Oo

Parkinson disease statistics

A chronic neurological condition that develops slowly after decades.

More than 10 million people worldwide have PD.

The number of people with PD is projected to exceed 17 million by 2040.

PD is the second most common neurodegenerative disease, after Alzheimer’s Disease.

The incidence of PD increases with age (average age of onset is 60-65), but about 4% of people with PD are diagnosed before age 50.

Men are about 1.5 times more likely to have PD than women.

Fig 1: Global prevalence of Parkinson’s disease by age and sex

Fig 2: Prevalence of Parkinson’s disease in ASEAN countries

Symptoms of PD

Classic motor symptoms

Rest tremors

Loss of facial expression

Slow movement (bradykinesia)

Low volume or hoarse voice

Muscle stiffness (rigidity)

Small handwriting

Fig 3: Determinant of PD

Cardinal Symptoms of PD

4 cardinal features of PD are :

1. Tremor of the limb at rest
2. Slow movement (bradykinesia)
3. Muscular stiffness (rigidity)
4. Change in walking, balance and posture

Common motor symptoms of PD

• Loss of facial expression
• Low volume or hoarse voice
• Small handwriting
• Problem swelling
• Stooped posture
• Loss of arm swing
• Short, shuffled steps
• Freezing while walking
• Problem with balance

Common non-motor (pre-motor) symptoms of PD

• Loss of smell
• Depression and anxiety
• Apathy
• Excessive daytime sleepiness and fatigue
• Problem with concentration and memory
• Acting out dreams while sleeping
• Lightheadedness while standing
• Constipation
• Urinary frequency or urgency
• Oily skin and dandruff

The collection and intensity of symptoms varies from patient to patient.

Natural history of PD

The progression of PD is generally slow, taking place over years (often many years).

While diagnosis tends to occur with the onset of motor symptoms, this can be preceded by a long prodromal phase of 15 years or more.

This prodromal phase is typically characterised by a range of non-motor symptoms, including sleep disorders, depression, and constipation.

Fig 4: Natural history of PD

One of the most common symptoms is ‘REM sleep behavior disorder’, in which affected individuals can become physically, even violently, active during the REM (rapid eye movement) stage of sleep.

Additional non-motor symptoms develop following clinical diagnosis and, as the disease progresses, cause increasing disability.

Some symptoms, such as postural instability, dysphagia, and dementia, tend to occur in more advanced disease.

After several years of levodopa therapy, complications can begin to appear. These may include ‘fluctuations’, when patients alternate between periods of good symptom control (ON periods) and poor symptom control (OFF periods).The occurrence of these dopa-related response complications remains a major limitation of levodopa as a dopamine replacement therapy.

Thresholds for the appearance of Parkinson’s disease symptoms

Fig 5: The ascending pathological process within the PD brain

Regions of the brain that are particularly vulnerable to Lewy pathology and degeneration during the earliest phase of PD include :

• the olfactory bulb, a critical component of the sense of smell
• the locus coeruleus, which produces noradrenaline and regulates sleep/wake cycles
• the dorsal motor nucleus of the vagus nerve, which is involved in regulating gastrointestinal function

The early involvement of these brain regions could explain several of the non-motor symptoms of PD that occur during Stages 1 and 2 of the six stages Braak stages

During Stage 1 of PD, many individuals experience a loss of smell (hyposmia) and/or suffer from constipation. In addition, sleep may become disordered or disturbed, accompanied by crying out, punching, or kicking during rapid eye movement (REM) sleep.

Stages 3 and 4 mark the transition from prodromal stage to clinically overt PD, as the disease spreads from the brainstem up into the midbrain and forebrain.

The classic symptoms of PD – bradykinesia, tremor, and muscular rigidity – start to appear as the substantia nigra loses its capacity to produce dopamine, and intrinsic compensatory mechanisms are overwhelmed.

Diagnosis typically occurs around this point.

Gradually, initial clinical symptoms worsen while new ones start to appear. Resting tremors may begin to affect both sides of the body, rather than just one, and normal balance becomes increasingly difficult to maintain.

Hereditary nature of PD

Less than 10% of PD cases are directly inherited (due to specific gene mutations).

Directly inherited genes are Alpha-synuclein, Parkin and LRRK 2 genes.

In most inherited cases, there is a strong family history (more than one member family member) and most start at young age (<40 years)

Environmental exposures and PD

Head injury (repeated or associated with altered consciousness)

Heavy metal exposure (higher incidence of PD in welders)

Chronic amphetamine use

Solvent exposure

Long-term pesticide/herbicide exposure

How/where PD starts in the body (Pathogenesis)

Evidence suggests that PD pathology may start in the GI tract or nasal mucosa nerve endings and then spread to the brain.

Constipation and/or loss of smell may predate the diagnosis of PD by 10 years or more.

The brain-gut-axis is the bidirectional communication regulated by neural, hormonal and immunological factors.

Abnormal gut microbiome can alter the communication with the brain.

The pathogenesis of PD is related to environmental and genetic factors, and exposure to toxins and gene mutations leading to α-synuclein aggregation, oxidative stress, ferroptosis, mitochondrial dysfunction, neuroinflammation, and gut dysbiosis.

Distribution of α-synuclein pathology in Parkinson’s disease

The Lewy pathology and aggregated α-synuclein proteins associated with PD are not only confined to the central nervous system (CNS) but they can also be found in the peripheral nervous system at various sites around the body, such as the skin, gastrointestinal tract, and salivary glands.

The cause of these α-synuclein deposits as well it affects to damage or loss of function in these areas is still unclear.

The relatively recent discovery of peripheral α-synuclein pathology could have profound consequences for the development of a useful biomarker of PD – one that could be measured during the pre-clinical or prodromal stages of the disease.

Peripheral α-synuclein is easier to sample (in a skin or gut biopsy) than brain tissue.

If viable, such a biomarker would not only be able to detect PD early, but it could also be used to distinguish the disease from similar forms of parkinsonism, such as multiple system atrophy.

Fig 6: Multi-organ α-synuclein deposits in PD

Diagnosis of PD

There is no specific blood or imaging test available to diagnose PD.

A detailed medical history, a neurological examination and response to dopamine-based medications is more than 95% accurate in most cases.

Blood tests and brain imaging (CT or MRI) may be used to rule out other conditions that are mimicking PD.

Structural Imaging

Structural MRI is usually normal in patients with PD.

It can be useful in detecting causes of secondary parkinsonism, such as infarcts, iron deposition, normal pressure hydrocephalus, or space-occupying lesions such as neoplasms.

Radiotracer Imaging

Radionuclide tracers can assess presynaptic and postsynaptic striatal dopaminergic functions using PET or SPECT) imaging.

α-synuclein based tests

Syntap

• Look for α-synuclein in CSF
• 87% sensitivity and 97% specificity

Syn One

• Sensitivity 95% and specificity of 99%
• Cannoy distinguish between PD, Lewy body dementia (LBD), and multiple system atrophy (MSA)

Conditions sometimes confused with PD

• Medication induced parkinsonism
• Vascular parkinsonism
• Normal pressure hydrocephalus
• Essential tremor
• Parkinson plus syndromes (atypical parkinsonian syndromes)
  • Lewy body dementia (LBD)- early and prominent cognitive changes and hallucinations
  • Multiple system atrophy (MSA)- early wide based gait, early and severe problem with changes in blood pressure, and severe urinary problems
  • Progressive supranuclear palsy (PSP)- early loss of balance and falls, problem with moving eyes (upward and downward gaze palsy)
  • Corticobasal syndrome (CBS)- prominent and early dysfunction of one limb, altered sensation and alien limb

Red flags of the possibility of an alternative diagnosis other than idiopathic PD

• Rapid progression requiring use of wheelchair within 5 years of diagnosis (often seen in MSA and PSP)
• No motor progression for 5 years (suggesting essential tremor)
• Early bulbar dysfunction (dysphonia, dysarthria, or dysphagia, suggesting MSA)
• Inspiratory respiratory dysfunction (stridor, suggesting MSA)
• Severe autonomic failure within 5 years of diagnosis (orthostatic hypotension or urinary incontinence, suggesting MSA or Lewy bodies dementia [LBD])
• Recurrent falls (>1 per year) within 3 years of diagnosis (suggesting PSP)
• Disproportionate anterocollis within 10 years of diagnosis (suggesting MSA)
• Absence of nonmotor symptoms (suggesting either dystonic or essential tremor)
• Unexplained pyramidal signs (seen in PSP and MSA)
• Bilateral symmetric disease from onset (seen in PSP and MSA)

Fig 7: Motor symptoms can define three stages of Parkinson’s disease

(a)The early stage

During the early phase of PD, symptoms are mild-to-moderate and can be treated effectively with levodopa therapy. Over time, such treatment can become more complicated as the levodopa is required at higher doses and at shorter intervals.

During early PD, patients may experience one or more motor symptoms. Some patients live with mild symptoms for many years whereas others develop moderate/advanced PD more quickly. The precise length of the ‘early/mild’ stage is hard to determine.

Medication may not be required, but patients who do receive treatment usually respond well to appropriate therapy. If dopaminergic treatment is initiated at this early stage, patients experience a period during which their symptoms are effectively controlled. The duration of this ‘honeymoon’ period can last from several months to several years, depending on the total dose and duration of levodopa treatment and personal factors, such as age at PD onset, gender, and body weight.

(b) The mid stage

The mid stage of PD is characterised by the appearance of disabling symptoms and a progressive impairment in the ability to carry out activities of daily living. Patients start to display a decreased response to first-line therapy.

From mid-stage disease onwards, the focus of treatment generally shifts towards achieving an optimal balance between reduction of motor symptoms and minimizing dyskinesia and other complications. Many patients experience a ‘non-troublesome’ amount of dyskinesia at this point, which does not necessarily require treatment, while other elements of motor function are adequately maintained

The middle of the disease course is also characterised by the onset of motor fluctuations brought about by ‘wearing off’ or ‘OFF’ states. From this point onwards, it becomes increasingly difficult for a patient to maintain a stable level of mobility similar to that observed during early PD.

Unfortunately, it is difficult to predict which patients will develop motor complications and fluctuations, although evidence suggests that younger age at PD onset, and greater exposure to levodopa, might make such complications more likely.

(c) The late stage

In the advanced stages of PD, the patient experiences continuing symptom progression, worsening of function, and fluctuations in the response to therapy. Patients require a high level of care and assistance with most daily activities, particularly those involving mobility and coordination. They may also start to experience impaired cognitive function, which is often associated with delusions and hallucinations. Postural instability worsens, leading to a greater risk of falls and associated fractures.

As symptoms increase and become more severe, the drugs required to manage them become increasingly complex. Optimal control of symptoms can be difficult without inducing severe complications, and eventually many patients fail to respond to therapy, or become unable to tolerate their medication. Consequently, patients experience periods of time with uncontrolled motor symptoms, such as gait disorders, dysphagia (difficulty swallowing), and dysarthria (difficulty speaking).

Pharmacological treatment for PD

Fig 8: Sites of action of principal drugs used in Parkinson disease treatment on dopamine metabolic pathway. Abbreviations: 3-OMD= 3-O-methyldopa, DOPAC= 3,4 dihydroxyphenylacetic acid, 3-MT= 3-Methoxytyramine

Medications commonly used in treatment for motor symptoms of PD

Table 1: Medications commonly used in treatment for motor symptoms of PD

Wearing off, ON-OFF and dyskinesia in PD

Levodopa is the major symptomatic therapy for PD and provides benefit to virtually all patients.

During the ‘honeymoon’ period, the effects of levodopa tend to be long-lasting and side effects are tolerable.

Wearing off

Beyond this ‘honeymoon’ period, patients may struggle to maintain good symptom control as the duration of response to levodopa therapy becomes progressively shorter. This problem is known as ‘wearing-off’.

‘Wearing-off’ is a predictable recurrence of PD symptoms that precedes a scheduled dose of levodopa and usually improves with medication.

By contrast, the less predictable fluctuations – sometimes called ‘yo yoing’ – are associated with more advanced stages of PD.

ON/OFF

ON time – period of relatively good motor symptom control, when medication seems to be working well1

OFF time – period of relatively poor motor symptom control1

Dyskinesia

Dyskinesia refers to a broad clinical spectrum of different types of involuntary movements ranging from chorea affecting limbs and trunk, slow dystonic movements, fixed dystonic postures, or (more rarely) myoclonus or ballism.

Troublesome dyskinesias have been defined as those that are painful, impair balance, or are excessive to the point of causing impairment in coordination or general function.

Drug-induced dyskinesias in Parkinson’s disease

ON-period dyskinesias (‘interdose’)

• Phasic (choreic) limb movements
• Dystonic cranio–cervical movements
• More pronounced on side initially affected by PD

Biphasic dyskinesias

• At onset or wearing-off (or both) of clinical benefits of a dose of levodopa
• Mix of phasic and dystonic movements (‘mobile dystonia’)

OFF-period dystonia

• Most often distal limb (feet)
• Painful

Fig 9: Change in levodopa response over time – ‘wearing-off’

As the extent of neurodegeneration in the substantia nigra becomes greater, its capacity to produce dopamine diminishes to the point where patients require larger doses of levodopa to maintain normal function.

Motor complications, such dyskinesia and motor fluctuations, can greatly worsen the quality of life during mid to late PD.

One of the key priorities for the management of PD during this time is to optimize the administration of dopaminergic medication, minimizing time spent in ‘OFF’ states (e.g., akinesia) or experiencing dyskinesias.

Since a patient may lack the ability to store dopamine during more advanced PD, the maintenance of dopamine levels requires multiple doses of dopaminergic medication each day, typically orally, which results in an oscillating, pulsatile form of therapy.

This pattern of administration increases the likelihood of peak-dose dyskinesias, which occur when levodopa levels are high, and ‘OFF’ states, which occur when levodopa levels are low. ‘OFF’ states can be particularly severe during the night and early morning.

Fig 10: Relationship between levodopa administration and motor fluctuations

Table 2: Management of nonmotor symptoms of PD

Procedural treatment for PD

Deep brain stimulation (DBS)

When to consider :

• PD at least 4 years (should not use as “the last resort”)
• Tremor not responsive to medications
• Good response to medications but fluctuating effect during the day
• Troublesome dyskinesia

Advantages

• Nearly 30 years’ experience since 1997
• Both side can be treated
• Titrated to a patient’s symptoms, reversible if resolved
• Reduction in medication intake is possible

Complications

Surgery related

• ICH -1% to 5%
• Neurological deficits-0.6% to 1.6%
• Risk increases with the number of passes

Device (hardware) related

• Infection
• Device malfunction (electrode or wire break etc.)
• Skin erosion
• Lead migration

Stimulation related

• STN: dysarthria, paresthesias, muscle contractions, diplopia, dyskinesia
• GPi: dysarthria, paresthesias, muscle contractions, blurred vision, light flashes
• VIM: dysarthria, paresthesias, dystonia, postural instability/ataxia, limb weakness
• Cognitive deficits: verbal fluency, executive dysfunction
• Mood effects: depression, suicide, anxiety, apathy, hypomania
• Apraxia of eyelid opening

Unilateral Thalamic FUS for treatment of refractory tremor

• High focused ultrasound energy used to create a brain lesion
• Minimally invasive- no anesthesia, incision-less, no hospital stay
• Currently only for unilateral hand tremor
• Complications after 1 year
  • Gait imbalance 27%
  • Sensory deficit 14% / Motor weakness 14%
  • Dysarthria, gait disturbances , ageusia, visual disturbance, face weakness all resolve one year after the Rx.

Prognosis of PD

Despite the severe disability that it causes in many people, PD is not considered to be a fatal condition.

A younger onset of PD is typically associated with a longer disease course, compared with those who develop the disease later in life.

While the rate of progression can vary greatly between individuals during the earlier stages of PD, the late stage tends to be characterised by a more fixed and rapid progression as the disease spreads into the cortical regions of the brain.

PD symptoms do increase the risk of potentially fatal comorbidities.

The main causes of disability are falls, choking, autonomic disturbance, neuropsychiatric symptoms, and dementia.

Dementia was more prevalent at 20 years than at 15 years (83% versus 48%, respectively.

None of these symptoms respond well to dopaminergic therapy

A higher level of comorbidity during the earlier stages of PD (0–4 years from diagnosis/recruitment) increased the likelihood of early death.

The presence of MCI in patients with PD predicts the subsequent development of dementia. Patients with PD have an almost six-fold increased risk of developing dementia, as compared with healthy controls.

Cognitive impairment reduces overall quality of life and may ultimately require an affected individual to be placed in a nursing home.

Patients with a non-tremor-dominant motor phenotype were >4 times more likely to develop dementia than tremor-dominant patients.

Summary

PD is a chronic and slowly progressive neurological disease that spans decades.

Most cases are not directly inherited by likely due to a combination of genetic and environmental risk factors.

Loss of dopamine causes classic motor symptoms, but other brain centers and brain chemical can explain the non-motor symptoms.

Treatment currently is symptomatic but many current clinical trials underway looking at both symptomatic and disease modifying therapies.

References

1. Elan D. Louis, et al. (2019) Movement Disorders, Continuum, Vol.25, No.4, doi: 10.1212/01.CON.0000578744.52598.37
2. GBD 2016 Parkinson’s Disease Collaborators “Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016” Lancet Neurol 2018;17:939-953
3. Höglinger GU, Adler CH, Berg D, et al (2024) “A biological classification of Parkinson’s disease: the SynNeurGe research diagnostic criteria” Lancet Neurol;23:191-204
4. Judith Bek, Aline I. Arakaki, et al. (2022) “More Than Movement: Exploring Motor Simulation, Creativity, and Function in Co-developed Dance for Parkinson’s” Frontiers in Psychology 13:731264,
5. Kathleen L. Poston , et al. (2022) Movement Disorders, Continuum, Vol.28, No.5, doi: 10.1212/ 01.CON.0000892536.68111.39

Author Information

Thar Thar Oo
MBBS, MD, MPH, FAAN
Senior Consultant Neurologist
Chief Clinical Neurology, Asia Royal Hospital, Yangon.