Parkinsons and Parkinsonian Syndromes

Question 1

Parkinsonism syndromes?

Answer 1

Parkinsonian syndromes comprehend several neurodegenerative pathologies, typical of elderly people. As we can see from this very important summary on the right, Parkinsonian syndrome include : Parkinson’s disease, atypical Parkinsonism and secondary Parkinsonism.

Question 2

Parkinson’s disease epidemiology? Risk factors ?

Answer 2

PD is the second most common neurodegenerative disease after AD. Incidence rapidly increases with age, especially after 65. Median age of onset is 60 and average duration from diagnosis to death is 15 years.

Risk factors include age after 60, family history, male gender, Caucasian ethnicity, history of melanoma, exposition to herbicides and pesticides, exposure to heavy metals, repeated head trauma.

Question 3

Pathology of PD?

Answer 3

Parkinson’s disease is primarily characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the midbrain. This degeneration leads to a visible change in the affected brain structures.

Macroscopic changes include :
• The substantia nigra (SN) of the midbrain is visibly paler in PD patients compared to healthy individuals.
• This is due to the loss of dopaminergic pigmented neurons, particularly in the pars compacta (SNc).

Microscopic changes include :
• Loss of dopaminergic neurons (60-70%): The ventrolateral portion of the substantia nigra pars compacta is affected first, leading to early motor symptoms.
• Lewy bodies : round, eosinophilic inclusion in the cytoplasm of neurons, central dense core with fibrillation peripheral halo, composed of alpha synuclein.

Question 4

Role of alpha synuclein in PD?

Answer 4

The protein α-synuclein plays a fundamental role in PD, but its exact physiological function is not fully understood. Evidence suggests that in healthy neurons, α-synuclein is involved in the regulation of neurotransmitter release at synapses. However, in Parkinson’s disease, this protein undergoes abnormal misfolding and aggregation, leading to toxic oligomer and fibril formation. These aggregates accumulate within neurons, forming Lewy bodies, which are considered a pathological hallmark of PD.

Question 5

Genetics of PD?

Answer 5

While most cases of PD are sporadic, about 10-15% are genetic. Several monogenic forms of PD are due to genes involved in proteostasis and oxidative stress. The most important genes include SNCA, Parkin, PINK1, LRRK2 and Glucocerebrosidase-1.

Question 6

Pathophysiology of PD?

Answer 6

The motor symptoms of Parkinson’s disease arise from dysfunction in the basal ganglia circuits, which are responsible for regulating movement. Two key pathways control motor activity:
1. The Direct Pathway (DP): This pathway stimulates movement by exciting the motor cortex.
2. The Indirect Pathway (IP): This pathway inhibits movement, preventing unnecessary or excessive motor activity.

Dopamine, produced by neurons in the substantia nigra pars compacta, plays a critical role in maintaining the balance between these pathways. It excites the direct pathway while simultaneously inhibiting the indirect pathway, ultimately promoting movement.

In Parkinson’s disease, the loss of dopaminergic neurons disrupts this balance:
• The direct pathway becomes underactive, leading to reduced cortical stimulation and bradykinesia.
• The indirect pathway becomes overactive, resulting in excessive inhibition of movement and contributing to rigidity and tremor.

As the disease progresses, the lack of dopamine leads to overactivity of the globus pallidus internus (GPi), which increases inhibition of the thalamus, further reducing movement. This dysfunction explains why levodopa (L-DOPA), a dopamine precursor, can temporarily alleviate motor symptoms by restoring dopamine levels in the basal ganglia circuits.

Question 7

Clinical presentation of PD?

Answer 7

The four main motor features are bradykinesia, rigidity, resting tremor and postural instability (the first 3 are the most important as the last arrived late.)

• bradykinesia : 80 to 90% of patients. Slowness in movements and progressive decrepit in amplitude or speed.
• Rigidity : >90%, increase in muscle tone, It presents itself with the “Cogwheel” phenomenon or lead pipe.
• Resting tremor : 70% of patients, Pill rolling tremor characterized by 5-6 here mono lateral or asymmetrical tremor.
• postural instability : it is indicative of advanced-stage of the disease and it’s a frequent cause of falls.

Other manifestations include hypomimia, hypophonia.

Question 8

PD staging and progression?

Answer 8

The progression of PD is monitored using two main clinical scales: the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr Staging system. These scales help clinicians assess disease severity, track functional decline, and evaluate treatment response over time.

UPDRS : it is divided in four parts which are non motor aspects of daily living, motor aspects of daily living, motor examination and motor complications. Severity grade is from 0 to 4 which is severe.

Hoehn and Yahr is a simpler 5 stage classification based on disability and functional impairment. Stage 1 is given when we have unilateral symptoms only, no disability. Stage 5 is full end stage PD, patient is wheelchair bound or bedridden.

Question 9

Diagnostic criteria for PD?

Answer 9

For a diagnosis patient must meet all of the following criteria :
1. Presence of parkinsonism, defined as bradykinesia plus at least one of the following:
• Rigidity.
• Resting tremor.
2. No absolute exclusion criteria (i.e., features that rule out PD). (Cerebellar signs suggestive of MSA, supranuclear gaze palsy suggestive of progressive supranuclear palsy).
3. At least two supportive criteria (characteristics that strongly indicate PD).
4. No red flags (features that suggest an alternative diagnosis.) (rapid deterioration of gait, no progression of motor symptoms over 5 years, early bulbar dysfunction)

Question 10

Diagnostic assessment for PD?

Answer 10

1. Levodopa challenge test : it assesses the patient’s response to dopamine replacement therapy.
   • The test involves administering a high dose of levodopa (e.g., carbidopa-levodopa 25/250 mg) or subcutaneous apomorphine (1.5 to 4.5 mg).
   • Motor symptoms are assessed before and after the drug administration using the MDS-UPDRS Part III motor score.
   • A positive response is defined as a 15-30% improvement in motor symptoms, which strongly supports a diagnosis of PD.
2. DaT-Scan (Dopamine Transporter Imaging) : 123I-Ioflupane SPECT is used to visualize presynaptic dopamine transporters in the basal ganglia. In PD patients, there is reduced dopamine transporter binding, reflecting loss of dopaminergic neurons in the substantia nigra.
3. Metaiodobenzylguanidine (MIBG) Scintigraphy
   • Assesses cardiac sympathetic denervation, which occurs in PD but not in atypical parkinsonism.
   • Not commonly performed, but can be a supportive diagnostic test.
4. Conventional MRI is generally normal in PD and does not show direct pathological signs. However it is crucial to rule out atypical Parkinsonism.
5. Advanced MRI techniques like 7 Tesla MRI and nigrosome 1 detection.

Question 11

Evolution of clinical progression of PD?

Answer 11

1. Motor symptoms are preceded by non-motor symptoms, resulting in the so-called prodromal Parkinson’s disease. Motor symptoms comprehend constipation, depression, anxiety, hyposmia and REM sleep behaviour disorders.
2. Early-stage which starts with the onset of the classical motor symptoms (bradykinesia, rigidity and tremor); these symptoms usually allow a proper diagnosis of PD.
3. Then we have the mid-stage, where also fluctuations (due to dopaminergic treatment) and dyskinesia
   may be present.
4. Lastly, in the late-stage, there is also postural instability and dementia (Parkinson’s disease dementia, PDD). Psychiatric symptoms and falls may be present.

Question 12

Extra motor features of PD?

Answer 12

While Parkinson’s disease is primarily known for its motor symptoms (bradykinesia, tremor, rigidity, and postural instability), it also includes a wide range of extra-motor features that can significantly impact quality of life. These non-motor symptoms affect cognition, autonomic function, sleep, mood, and sensory processing. Some appear before motor symptoms, while others develop as the disease progresses.

One of the most significant features is cognitive decline, which can progress from mild cognitive decline to Parkinson disease dementia. PDD is seen in 30-40% of PD patients during disease progression.

Autonomic dysfunction : include bladder dysfunction, GI issues, excessive sweating, erectile dysfunction.

Sleep disorders : REM sleep behavior disorder, insomnia, fragmented sleep, excessive daytime sleepiness.

Mood and psychiatric symptoms : depression, anxiety disorders, apathy, hallucinations, psychosis.

Sensory symptoms : hyposmia (reduced sense of smell), pain syndromes.

Question 13

Pharmacological treatment of PD?

Answer 13

The cornerstone of PD treatment is dopaminergic therapy, primarily levodopa. However, medication choice depends on disease stage, patient age, and symptom severity.

Levodopa —> it is the most effective drug for motor symptoms, it is a precursor of dopamine that crosses the BBB and is converted into dopamine in the CNS. Typically combined with carbidopa or benserazide to prevent peripheral metabolism of dopamine and reduce side effects.
Use may be delayed in younger patients as prolonged use can lead to motor fluctuations and dyskinesias.

Alternative medications before levodopa :
1. Dopamine agonists (pramipexole) directly stimulate dopamine receptors, less effective than levodopa but have fewer motor complications.
2. MAO-B inhibitors (selegiline) prevent dopamine breakdown.
3. COMT inhibitors (entacapone) block dopamine degradation.
4. Amantadine which increases dopamine released, reduces dyskinesias.
5. anticholinergics to reduce tremor but have significant cognitive side effects.

Question 14

What is deep brain stimulation? When is it considered?

Answer 14

Electrodes are implanted in deep brain structures, usually the subthalamic nucleus (STN) or globus pallidus internus (GPi).
• Electrical stimulation modulates abnormal PD-related neuronal activity, reducing involuntary movements and rigidity.
• DBS does NOT stop disease progression; it only improves motor symptoms.

It is taken into consideration when medications become ineffective or cause severe side effects. A good candiate is one with good response to dopaminergic therapy, severe levodopa induced motor complications, reasonable cognitive function and without psychiatric symptoms.

It is not a cure but an end stage treatment.

Question 15

What are atypical parkinsonisms?

Answer 15

Atypical parkinsonism refers to neurodegenerative disorders that present with parkinsonian features (bradykinesia, rigidity, tremor, and postural instability) but differ from idiopathic Parkinson’s disease (PD) in two key ways:
1. Faster Progression: Atypical parkinsonian syndromes progress more rapidly than PD.
2. Poor or No Response to Levodopa: Unlike PD, where levodopa improves motor symptoms, atypical parkinsonisms show minimal or no benefit from dopamine replacement therapy.

These syndromes are classified based on the type of pathological protein accumulation, so either alpha synucleinopathies or tauopathies.

They include multiple system atrophy, dementia with Lewis bodies, corticobasal syndrome and progressive supranuclear palsy.
The first 2 are alpha synucleinopathies the last 2 are tauopathies.

Question 16

What is progressive supranuclear palsy?

Answer 16

Epidemiology : rare disorder with a prevalence of 5 for 100k individuals, M:F ratio 2:1, average onset 65 yrs. Median survival is 7-8 years.

Key differences from PD :
• Faster progression than PD.
• Minimal or no response to Levodopa.
• Early and frequent falls (within the first year of symptom onset), especially falling backward.
• Supranuclear gaze palsy, particularly affecting vertical eye movements (difficulty looking up and later down).

Core symptoms : Parkinsonism with poor levodopa response, bradykinesia and rigidity but tremor are less common, axial rigidity and postural instability, supranuclear gaze palsy, severely reduced blinking, pyramidal signs 30%, cognitive impairment.

Key Imaging Feature : “Hummingbird Sign” (Sagittal T1 MRI)
• Atrophy of the midbrain makes it appear slimmer than usual, resembling a hummingbird.
• The pons and middle cerebellar peduncles remain preserved, helping differentiate PSP from other parkinsonian syndromes.

Other MRI Features :
• “Mickey Mouse Sign” on axial MRI (midbrain atrophy with preserved cerebellar peduncles).
• Can show vascular signs in some cases (used for differential diagnosis with vascular parkinsonism).

Question 17

What is corticobasal syndrome?

Answer 17

Corticobasal Syndrome is a rare neurodegenerative disorder classified as a tauopathy.

Key pathological features :
• Cortical (parietal lobe) degeneration → Causes cognitive impairment, apraxia, and sensory deficits.
• Basal ganglia involvement → Leads to parkinsonian motor symptoms, including rigidity and dystonia.
• Strongly asymmetric presentation → One side of the body is dramatically more affected.
• Poor response to Levodopa, unlike idiopathic Parkinson’s disease.

Additional clinical features include : due to parietal lobe damage include apraxia, cortical sensory loss, cortical myoclonus, alien limb phenomenon. Due to basal ganglia dysfunction the patient may have focal rigidity with systolic posturing, tremors, bradykinesia.

MRI and imaging findings :

  • Asymmetric cortical atrophy, particularly in the parietal and frontal lobes.
• Basal ganglia atrophy, often affecting the contralateral hemisphere to the affected limb.
• Functional imaging (FDG-PET scan) shows hypometabolism in the affected cortical regions.

Question 18

What is multiple system atrophy?

Answer 18

Multiple System Atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder, it is classified as an α-synucleinopathy.

Epidemiology : 4 per 100k, mean onset 55 yrs, M:F 1:1, MSA-P more common that MSA-C.

Key features of MSA :
• Earlier onset than Parkinson’s disease (average age ~55 years).
• Faster progression than PD (mean survival: 6-10 years).
• Poor response to Levodopa.
• Combination of parkinsonian, cerebellar, and autonomic symptoms.

Subtypes : Although MSA is biologically one disease, it presents in different clinical subtypes based on the predominant area of degeneration:
1. MSA-P (Parkinsonian subtype) – Striatonigral degeneration
• Most difficult to diagnose due to its similarity to Parkinson’s disease.
• Patients present with parkinsonian features (bradykinesia, rigidity, postural instability) but do not respond well to Levodopa.
• Associated with putaminal atrophy (putaminal rim MRI).
2. MSA-C (Cerebellar subtype) – Olivopontocerebellar atrophy
• Characterized by severe ataxia, limb incoordination, dysarthria, and nystagmus.
• Postural instability due to cerebellar involvement.
• Prominent cerebellar and pontine atrophy on MRI (hot cross bun sign).
3. MSA-A (Autonomic subtype or Shy-Drager Syndrome)
• Severe autonomic dysfunction from disease onset (orthostatic hypotension, urinary incontinence, erectile dysfunction).
• Associated with degeneration of brainstem and medullary autonomic nuclei.

While one subtype may dominate early, patients often develop symptoms of all three forms as the disease progresses.

Question 19

What is secondary Parkinsonism?

Answer 19

Unlike idiopathic Parkinson’s disease, which is caused by dopaminergic neuron degeneration, secondary parkinsonism results from external factors that impair the extrapyramidal pathways. These factors mimic PD symptoms but often have distinct features that help differentiate them.

Key features : no progressive neurodegeneration, poor or no response to levodopa, can be reversible if the underlying case is treated.

1. Drug-Induced Parkinsonism (DIP)
   • Caused by dopamine-blocking drugs, particularly antipsychotics (neuroleptics) and antiemetics.
   • Common culprits : Typical antipsychotics like Haloperidol, Chlorpromazine, Atypical antipsychotics like Risperidone, Dopamine-depleting agents like Reserpine, Tetrabenazine, Antiemetics like Metoclopramid.
   • Key Differentiating Features: symmetrical symptoms (affects both sides equally, unlike PD which starts asymmetrically), younger patients (often seen in those taking antipsychotics), resolves after discontinuation of the offending drugs
2. Vascular Parkinsonism (VP) :
   • Due to multiple small strokes affecting the basal ganglia.
   • Risk factors: Hypertension, diabetes, smoking, atherosclerosis.
   • Key Differentiating Features : sudden or stepwise onset (rather than gradual progression), lower body parkinsonism (gait and postural instability are more prominent than tremor), cognitive decline follows a stepwise pattern, like vascular dementia, MRI shows white matter lesions or infarcts in the basal ganglia.
3. Infectious Causes :
   • Post-encephalitic parkinsonism.
   • HIV-associated parkinsonism (due to basal ganglia involvement in advanced HIV/AIDS).
   • Neurosyphilis (late-stage syphilis affecting the brain).
4. Toxic Parkinsonism
   • Heavy metal exposure: Manganese, Mercury, Lead.
   • Pesticide exposure: Rotenone, Paraquat.
   • Carbon monoxide poisoning.
   • MPTP toxicity (a neurotoxin that selectively destroys dopaminergic neurons, leading to irreversible PD-like symptoms).
5. Traumatic Parkinsonism :
   • Chronic traumatic encephalopathy (CTE) due to repeated head trauma (e.g., in boxers, football players).
   • Symptoms include parkinsonism, cognitive decline, depression, and behavioral changes.
6. Brain tumors affecting basal ganglia or midbrain.
7. Metabolic disorders like Wilson’s disease (abnormal copper metabolism) or hypothyroidism.