Two pathways through the basal ganglia:

1. Direct pathway (facilitates movement): Cortex → Striatum → GPi/SNr (inhibition) → Thalamus released → Movement facilitated

   • Dopamine from SNpc acts on D1 receptors → stimulates the direct pathway → promotes movement

2. Indirect pathway (suppresses movement): Cortex → Striatum → GPe → STN → GPi/SNr (excitation) → Thalamus inhibited → Movement suppressed

   • Dopamine from SNpc acts on D2 receptors → inhibits the indirect pathway → reduces suppression of movement (net effect: promotes movement)

In iPD: Loss of dopaminergic neurons in SNpc → reduced dopamine → direct pathway underactive, indirect pathway overactive → net result is excessive inhibition of thalamus → bradykinesia, rigidity

In Parkinson-plus syndromes, neurodegeneration extends beyond the nigrostriatal system:

α-Synuclein is a presynaptic protein normally involved in synaptic vesicle recycling and neurotransmitter release. When it misfolds and aggregates:

• In iPD and DLB: forms intraneuronal Lewy bodies and Lewy neurites

  • iPD: Lewy bodies predominantly in brainstem (SNpc) → cortex (later)
  • DLB: Lewy bodies in cortex early → explains early dementia
  • The difference between iPD-dementia and DLB is essentially a matter of timing (the "1-year rule" — see classification)

• In MSA: α-synuclein forms glial cytoplasmic inclusions (GCIs) in oligodendrocytes (not neurons)

  • This is unique — MSA is the only major synucleinopathy where the inclusions are glial rather than neuronal
  • Oligodendrocyte dysfunction → demyelination and axonal degeneration → explains the widespread, multi-system nature of the disease
  • Glial inclusion and myelin degeneration in various sites, e.g. BG, pontine nuclei, cerebellum ^[3]

Tau is a microtubule-associated protein that normally stabilises axonal microtubules (the "railway tracks" of intracellular transport). When hyperphosphorylated, tau dissociates from microtubules and aggregates into neurofibrillary tangles (NFTs).

• In PSP: predominantly 4-repeat (4R) tau accumulates in neurons and glia (astrocytic tufts) in midbrain, basal ganglia, and frontal cortex
• In CBD: also 4R tau but in an asymmetric frontoparietal distribution → asymmetric frontoparietal atrophy associated with tau NFT inclusions ^[3]
  • CBD shows ballooned (achromatic) neurons and astrocytic plaques on histology (distinct from the tufted astrocytes of PSP)

High yield: PSP = tufted astrocytes; CBD = astrocytic plaques; MSA = glial cytoplasmic inclusions; DLB/iPD = Lewy bodies

• Etiology: Sporadic; no established strong genetic or environmental risk factors
• Pathology: GCIs (α-synuclein in oligodendrocytes) → neuronal loss and gliosis in:
  • Striatonigral system → MSA-P (parkinsonian features)
  • Olivopontocerebellar system → MSA-C (cerebellar features)
  • IML column and Onuf's nucleus → autonomic failure
• Pathophysiology:
  • Striatal neuron loss → postsynaptic denervation → poor levodopa response
  • Cerebellar/pontine loss → ataxia, dysarthria, nystagmus
  • Autonomic neuron loss → orthostatic hypotension, urogenital dysfunction

• Etiology: Sporadic (rare familial cases with MAPT mutations); strong association with MAPT H1/H1 haplotype
• Pathology: 4R tauopathy → NFTs, tufted astrocytes, and coiled bodies in:
  • Midbrain tegmentum (vertical gaze centres)
  • Subthalamic nucleus
  • Globus pallidus
  • Frontal cortex
  • Cerebellar dentate nucleus
• Pathophysiology:
  • Midbrain degeneration → vertical gaze palsy (especially downward) → difficulty reading, eating, walking downstairs
  • STN degeneration → loss of postural reflexes → early falls (typically backwards)
  • Frontal cortex → executive dysfunction, apathy, pseudobulbar affect
  • Axial rigidity > appendicular rigidity (neck hyperextended) ^[2] — the opposite of iPD where patients are flexed

• Etiology: Sporadic; 4R tauopathy
• Pathology: Asymmetric frontoparietal atrophy with ballooned neurons, astrocytic plaques, tau NFTs ^[3]
• Pathophysiology:
  • Cortical degeneration (parietal) → limb apraxia (inability to perform learned skilled movements despite intact motor/sensory function), cortical sensory loss (astereognosis, agraphaesthesia), alien limb phenomenon
  • Asymmetric basal ganglia degeneration → markedly asymmetric rigid-akinetic parkinsonism
  • Frontal cortex → behavioural changes, dementia (usually late)

• Etiology: Sporadic (genetic risk factors: GBA mutations, APOE ε4, SNCA)
• Pathology: Widespread cortical and subcortical Lewy bodies; copathology with Alzheimer's disease (amyloid plaques, NFTs) present in ≥ 50% of cases ^[5]
• Pathophysiology:
  • Cortical Lewy bodies → early cognitive impairment (attention, executive function, visuospatial — relatively preserved memory initially, unlike AD)
  • Fluctuating acetylcholine levels → cognitive fluctuations (varying alertness/attention)
  • Temporal/occipital cortex involvement → recurrent well-formed visual hallucinations
  • Brainstem involvement → parkinsonism (usually milder and more symmetric than iPD)
  • Pontine/brainstem → REM sleep behaviour disorder

Three recognised prodromal presentations:

1. Mild cognitive impairment (MCI-LB): mild cognitive decline with Lewy body features but preserved function
2. RBD-onset: isolated REM sleep behaviour disorder years before cognitive/motor symptoms (> 80% of isolated RBD eventually converts to a synucleinopathy)
3. Psychiatric-onset DLB: late-onset depression, psychosis, visual hallucinations, systematized delusions including Capgras syndrome, apathy, anxiety ^[5]

Drug-induced parkinsonism, e.g. neuroleptics, dopamine-depleting/anti-dopaminergic drugs, lithium, antihistamines ^[3]

I learned that drug-induced parkinsonism from metoclopramide, antipsychotics, or antihistamines is particularly important to identify as it is reversible. ^[8]

Why it mimics PD: These drugs block D2 dopamine receptors in the striatum (antipsychotics, metoclopramide) or deplete dopamine stores (reserpine, tetrabenazine), creating an iatrogenic dopamine-deficient state identical in mechanism to iPD.

How to differentiate:

• Temporal relationship: Parkinsonism develops within weeks–months of starting the offending drug
• Bilateral and symmetric from onset (iPD is asymmetric)
• Tardive dyskinesia may coexist (stereotypical orofacial movements — chewing, tongue protrusion) ^[6]
• Resolves upon withdrawal of offending agent (may take weeks–months)
• No response to levodopa (because the receptors are blocked, not the presynaptic neuron lost)

Type C adverse drug reaction → long term use. Tardive dyskinesia → parkinson's-like symptoms. E.g. long term use of Chlorpromazine → you develop stereotypical repetitive movements (chewing, facial tics, uncontrollable) ^[6]

Signs to r/o other d/dx: Tardive dyskinesia for drug-induced parkinsonism ^[3]

Toxic: MPTP, manganese, CO poisoning, rotenone ^[3]

Post-encephalitic, e.g. encephalitis lethargica (not present anymore) ^[3]

Historical importance (epidemic of encephalitis lethargica in 1917–1928); modern relevance includes parkinsonism following viral encephalitis (e.g. Japanese encephalitis — relevant in HK/Asia), autoimmune encephalitis, or HIV.

Parkinsonism can result from any structural lesion affecting basal ganglia circuits:

• Tumours: parasagittal meningioma compressing motor cortex/basal ganglia
• Head trauma: chronic traumatic encephalopathy ("punch-drunk" syndrome / pugilist encephalopathy) — repetitive head trauma → tau accumulation
• Normal pressure hydrocephalus (see pseudoparkinsonism below)

Wilson's disease: Can mimic Parkinson's, extrapyramidal deposition of the copper ^[7]

Why it matters: Wilson's disease is a treatable cause of parkinsonism. It should be excluded in any patient < 40 years presenting with parkinsonism or other movement disorders.

How it mimics PD: Copper deposits in the basal ganglia (especially putamen and caudate) → neuronal damage → parkinsonism, dystonia, tremor, dysarthria

How to differentiate:

• Young age of onset (typically 5–35 years, average 13 years) ^[9]
• Neurological features rarely isolated parkinsonism — usually mixed with dystonia, ataxia, tremor, choreoathetosis, cognitive impairment, psychiatric symptoms ^[9]
• Kayser-Fleischer rings (corneal copper deposits) present in 98% with neurological disease ^[9]
• Liver disease (hepatitis, cirrhosis) often coexists or precedes neurological onset
• Coombs-negative haemolytic anaemia — unique clue ^[9]
• Investigations: low serum ceruloplasmin, high 24h urinary copper, KF rings on slit lamp

Genetic test does not have to be positive to reach a diagnosis → with compatible clinical and history still can diagnose, since hereditary pathway of Wilson's is very heterogeneous → not just ATP7B ^[7]

Huntington's disease: autosomal dominant condition caused by CAG trinucleotide repeats on chromosome 4p16.3, leading to atrophy of the caudate and putamen. The triad of chorea, psychiatric manifestations including depression and psychosis, and progressive dementia. ^[8]

• Classic HD: chorea (hyperkinetic) rather than parkinsonism (hypokinetic)
• Westphal variant / juvenile-onset HD: can present with akinetic-rigid syndrome (bradykinesia, rigidity) mimicking parkinsonism — the "akinetic form of Huntington's chorea" ^[3]
• Family history of autosomal dominant transmission with anticipation (earlier onset in successive generations, especially paternal transmission)
• Caudate atrophy on imaging → "box car" ventricles

Hallervorden-Spatz syndrome: neurodegeneration with brain iron accumulation ^[3]

• Rare; presents in childhood/early adulthood with dystonia, parkinsonism, cognitive decline
• "Eye of the tiger" sign on T2 MRI (bilateral pallidal hyperintensity within hypointensity)
• PANK2 gene mutation (pantothenate kinase 2)

Cerebral arteriosclerotic disease: stepwise deterioration, LL > UL involvement, more symmetrical, with poor response to levodopa ^[3]

Why it looks like PD: Multiple lacunar infarcts in the basal ganglia or white matter disrupt the same circuits that degenerate in iPD.

How to differentiate:

• "Lower body parkinsonism": gait disorder disproportionate to upper limb involvement (shuffling magnetic gait, postural instability)
• Stepwise rather than insidiously progressive course
• Vascular risk factors (hypertension, diabetes, smoking, AF)
• Poor response to levodopa
• Imaging shows multiple lacunar infarcts or extensive white matter disease

Normal pressure hydrocephalus: classical triad of frontal dementia, apraxic gait and urinary incontinence. ALL ventricles enlarged disproportionate to sulcal effacement. ^[10]

Why it mimics PD: The gait in NPH is a wide-based, magnetic, shuffling "apraxic" gait that superficially resembles parkinsonian gait. Cognitive slowing and frontal features overlap.

How to differentiate (the triad: "Wet, Wacky, Wobbly"):

• Urinary incontinence (wet) — not typically early in iPD
• Dementia (wacky) — frontal subcortical type
• Gait apraxia (wobbly) — wide-based, magnetic (feet "glued to floor"), NOT festinating
• Imaging: all ventricles enlarged disproportionate to sulcal effacement + periventricular lucency ^[10]
• Treatable: Large-volume LP (30–50 mL) → temporary gait improvement → predicts shunt response
• No tremor or rigidity (differentiates from true parkinsonism)

• Radiopharmaceutical: ¹²³I-FP-CIT (DaTSCAN) for SPECT; ¹⁸F-DOPA for PET
• What it measures: Presynaptic dopamine transporter density in the striatum (reflects the integrity of nigrostriatal dopaminergic terminals)
• Principle: In any parkinsonian syndrome with nigrostriatal degeneration, DAT uptake is reduced in the striatum (comma-shaped normal → dot-shaped abnormal)

Dopaminergic SPECT/PET: ↓dopamine activity in basal ganglia → Does not differentiate between different forms of Parkinsonism (only from non-Parkinsonism, e.g. ET) ^[3]

Dopamine transporter imaging is most helpful in distinguishing DLB from Alzheimer disease. ^[5]

Measures regional cerebral glucose metabolism (a proxy for neuronal activity).

The cingulate island sign (preserved metabolism of the posterior cingulate gyrus) is relatively specific for DLB vs AD (where posterior cingulate is affected early).

Cerebral Perfusion Study — Clinical indications: evaluation of cerebrovascular disease, aid diagnosis of dementia. Demonstrates perfusion to specific brain areas. Different types of dementia typically present with different patterns of perfusion changes. ^[13]

Perfusion patterns largely mirror FDG-PET patterns (reduced perfusion correlates with reduced metabolism):

• AD: Bilateral posterior temporal + parietal hypoperfusion ^[13]
• FTD: Bilateral frontal + temporal hypoperfusion ^[13]
• DLB: Occipital hypoperfusion

• What it measures: Postganglionic sympathetic cardiac innervation
• Principle: ¹²³I-MIBG is a norepinephrine analogue taken up by cardiac sympathetic nerve terminals
• In Lewy body diseases (iPD, DLB): Cardiac sympathetic denervation occurs (Lewy body deposition in cardiac sympathetic ganglia) → reduced MIBG uptake (low heart-to-mediastinum ratio)
• In MSA: Cardiac sympathetic innervation is relatively preserved (the autonomic failure in MSA is predominantly preganglionic) → normal or mildly reduced MIBG uptake

Abnormal (low uptake) iodine-123 MIBG myocardial scintigraphy is an indicative biomarker for DLB ^[5]

• Purpose: Confirm REM sleep behaviour disorder (RBD)
• Finding: REM sleep without atonia — EMG shows sustained or excessive phasic muscle activity during REM sleep ^[5]
• Clinical significance: RBD is a core feature of DLB and a prodromal feature of all synucleinopathies (> 80% of isolated RBD converts to a synucleinopathy within 10–15 years)
• Polysomnographic confirmation of REM sleep without atonia is an indicative biomarker for DLB ^[5]

• In DLB: Posterior slow-wave EEG activity with frequencies slower than 8 Hz ^[5]
• This reflects cortical dysfunction in posterior regions (temporal-parietal-occipital), consistent with Lewy body deposition

• A 2020 systematic review revealed that slowing of the posterior dominant EEG rhythm was observed in approximately 90% of patients with DLB and approximately 10% of patients with Alzheimer disease ^[5]

• Supportive biomarker for DLB (high sensitivity)

• In MSA: Shows denervation of the external urethral and anal sphincters (motor unit potentials are large, polyphasic, with prolonged duration)
• Why: Degeneration of Onuf's nucleus (sacral motor neurons innervating external sphincters) is relatively specific to MSA among parkinsonian disorders
• Caveat: Abnormal sphincter EMG can also occur in cauda equina/conus lesions; clinical context is essential

This is a relatively new and increasingly important test:

The α-synuclein-based seed amplification assay performed in CSF can detect α-synuclein across the spectrum of Lewy body-related disorders, which includes DLB, PD, isolated RBD, and primary autonomic failure with sensitivity from 59% to 95% and specificity from 83% to 98%. ^[5]

• Principle: Misfolded α-synuclein in CSF acts as a "seed" that can recruit normal α-synuclein to misfold and aggregate in vitro. The assay amplifies this process and detects it fluorometrically.
• Clinical use: Supports diagnosis of synucleinopathies (iPD, DLB, MSA) vs non-synucleinopathies (PSP, CBD, AD)

• Studies have demonstrated high specificity and sensitivity when Lewy body pathology affects the neocortex (97% to 100%) and limbic regions (96%), and the sensitivity was lower in amygdala-predominant LBD (43% to 50%) and brainstem-predominant LBD (17% to 50%) ^[5]

The α-synuclein skin biopsy test identifies phosphorylated α-synuclein in cutaneous nerve fibres with a sensitivity greater than 92% for synucleinopathies. ^[5]

• Procedure: Punch biopsies from three sites (posterior cervical, posterior thigh, posterior distal leg)
• Rationale: α-synuclein deposits in autonomic nerve fibres in the skin, making this a less invasive alternative to CSF-based assays

• Useful for differentiating DLB from AD (both can present with dementia)
• AD pattern: Low Aβ42, elevated phospho-tau and total tau
• DLB pattern: Aβ42 may be low (copathology in ~50%), but phospho-tau is typically normal or only mildly elevated

Despite the poor overall response, a structured levodopa trial is recommended in all Parkinson-plus syndromes because:

• A small subset of patients (especially early MSA-P and some DLB) may have a partial, transient benefit
• Confirming poor levodopa response supports the diagnosis of Parkinson-plus over iPD

• Generally less effective than in iPD and more likely to cause side effects (hallucinations, confusion, impulse control disorders)
• May be tried cautiously in MSA-P or PSP-P if levodopa has partial benefit and motor fluctuations develop
• Contraindicated in DLB (risk of worsening psychosis and hallucinations)

• Mechanism: NMDA receptor antagonist → anti-dyskinetic properties ^[3]
• In Parkinson-plus syndromes: occasionally tried for rigidity/akinesia in PSP or MSA but evidence is limited
• May help with fatigue in some patients
• Caution: Can cause confusion, hallucinations, livedo reticularis, ankle oedema; avoid in cognitively impaired patients

• Indication: Focal dystonia (e.g. blepharospasm in PSP, limb dystonia in CBD, anterocollis in MSA)
• Mechanism: Blocks presynaptic acetylcholine release at the neuromuscular junction → localised muscle relaxation
• Particularly useful for:
  • PSP: Apraxia of eyelid opening, blepharospasm (injection into pretarsal orbicularis oculi)
  • CBD: Fixed dystonic posturing of the affected limb
  • MSA: Anterocollis (but use with caution — may worsen dysphagia if injected into neck flexors near swallowing muscles)

This is often the most functionally limiting symptom. Management follows a stepwise approach:

• Increase dietary fibre + adequate fluid
• Osmotic laxatives (macrogol/PEG), stimulant laxatives (senna, bisacodyl)
• Prokinetics (prucalopride — 5-HT4 agonist) if refractory

This is a medical emergency — vocal cord abductor paralysis can cause sudden death during sleep.

Treatment of DLB — Cognition and neuropsychiatric S/S: Cholinesterase inhibitor often 1st line due to C/I to antipsychotics ^[12]

PD drug-induced psychosis: Levodopa is least likely. Mx: ↓amantadine / selegiline → ↓DA agonist → ↓levodopa → start atypical antipsychotics (clozapine) / ECT ^[2]

This stepwise approach from iPD-related psychosis is adapted for Parkinson-plus syndromes:

Step 1: Identify and treat precipitants (infection, dehydration, metabolic derangement, constipation)

Step 2: Review and reduce/stop offending medications in order:

• Stop anticholinergics first (highest risk of confusion)
• Reduce/stop amantadine
• Reduce/stop dopamine agonists
• Reduce levodopa (if being used)

Step 3: If psychosis persists despite medication reduction:

Depression: recommend desipramine and citalopram ^[3]

REM sleep behaviour disorder: clonazepam, melatonin ^[3][12]

• Involuntary laughing/crying (common in PSP, MSA)
• Dextromethorphan/quinidine combination (Nuedexta): approved for pseudobulbar affect
• SSRIs or TCAs may also help

Falls management is arguably the most important intervention in PSP — aspiration pneumonia and fall-related injuries (hip fractures, subdural haematomas) are leading causes of death.

Mx: supportive ^[3]

Treatment: symptomatic (no disease-modifying Tx available) ^[12]