Atypical Parkinsonism

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Atypical Parkinsonism

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Atypical Parkinsonism

Overview

Atypical parkinsonism refers to a group of neurodegenerative disorders that present with parkinsonian features (bradykinesia, rigidity, tremor) but differ from idiopathic Parkinson's disease (PD) in their pathophysiology, clinical presentation, prognosis, and response to treatment[@armstrong2019]. These disorders are also known as "Parkinson-plus syndromes" and include Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), Multiple System Atrophy (MSA), and Dementia with Lewy Bodies (DLB)[@hoglinger2023].

Unlike idiopathic PD, which is primarily a dopaminergic disorder affecting the substantia nigra pars compacta, atypical parkinsonian disorders involve multiple neurotransmitter systems and have distinctive pathological features. Accurate differentiation is critical for prognosis, clinical trial enrollment, and emerging disease-modifying therapies.

Disease Classification

```mermaid
flowchart TD
A["Atypical Parkinsonism (Parkinson-Plus)"] --> B["alpha-Synucleinopathies"]
A --> C["Tauopathies"]

B --> D["MSA-P Multiple System Atrophy Parkinsonian Type"]
B --> E["MSA-C Multiple System Atrophy Cerebellar Type"]
B --> F["DLB Dementia with Lewy Bodies"]

C --> G["PSP Progressive Supranuclear Palsy"]
C --> H["CBS Corticobasal Syndrome"]
C --> I["FTLD-tau Frontotemporal Lobar Degeneration"]

...

Atypical Parkinsonism

Overview

Atypical parkinsonism refers to a group of neurodegenerative disorders that present with parkinsonian features (bradykinesia, rigidity, tremor) but differ from idiopathic Parkinson's disease (PD) in their pathophysiology, clinical presentation, prognosis, and response to treatment[@armstrong2019]. These disorders are also known as "Parkinson-plus syndromes" and include Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), Multiple System Atrophy (MSA), and Dementia with Lewy Bodies (DLB)[@hoglinger2023].

Unlike idiopathic PD, which is primarily a dopaminergic disorder affecting the substantia nigra pars compacta, atypical parkinsonian disorders involve multiple neurotransmitter systems and have distinctive pathological features. Accurate differentiation is critical for prognosis, clinical trial enrollment, and emerging disease-modifying therapies.

Disease Classification

Mermaid diagram (expand to render)

Classification of Atypical Parkinsonian Disorders

Primary Atypical Parkinsonism Disorders

| Disorder | Primary Pathology | Key Clinical Features | Tau vs α-Syn |
|----------|-------------------|----------------------|--------------|
| Progressive Supranuclear Palsy (PSP) | 4R tauopathy | Vertical gaze palsy, falls, postural instability | Tau (4R) |
| Corticobasal Syndrome (CBS) | 4R tauopathy | Apraxia, alien limb, cortical sensory loss | Tau (4R) |
| Multiple System Atrophy (MSA) | α-synucleinopathy | Autonomic failure, cerebellar signs, parkinsonism | α-Synuclein |
| Dementia with Lewy Bodies (DLB) | α-synucleinopathy | Visual hallucinations, fluctuating cognition, parkinsonism | α-Synuclein |

Secondary Causes of Atypical Parkinsonism

Vascular Parkinsonism: Multi-infarct disease affecting basal ganglia
Drug-induced parkinsonism: Antipsychotics, antiemetics
Normal pressure hydrocephalus: Gait disturbance, urinary incontinence, dementia
Neurodegeneration with Brain Iron Accumulation (NBIA): Pantothenate kinase deficiency

Clinical Features Distinguishing Atypical Parkinsonism from PD

Red Flags for Atypical Parkinsonism

The following clinical features should raise suspicion for an atypical disorder[@liu2024]:

Early falls: Within the first year of symptom onset

Vertical gaze palsy: Particularly downward gaze

Early autonomic dysfunction: Orthostatic hypotension, urinary urgency

Cerebellar signs: Ataxia, nystagmus, dysmetria

Cortical sensory loss: Two-point discrimination, stereognosis

Apraxia: Inability to perform learned movements on command

Alien limb phenomenon: Feeling that a limb is foreign

Dystonia: Early-onset, particularly axial

Poor levodopa response: Minimal or transient benefit

Rapid progression: Disability within 3-5 years

Feature Comparison Table

| Feature | PD | PSP | CBS | MSA |
|---------|----|-----|-----|-----|
| Symmetry | Unilateral onset | Bilateral | Asymmetric | Bilateral |
| Tremor | Resting tremor common | Less common | Less common | Less common |
| Levodopa response | Good | Poor | Poor | Poor-moderate |
| Autonomic failure | Late/mild | Late/mild | Late | Early/severe |
| Eye movements | Normal | Vertical palsy | Normal | Cerebellar |
| Cortical signs | None | Frontal | Apraxia, alien limb | None |
| Progression | Slow | Rapid | Variable | Rapid |

Progressive Supranuclear Palsy (PSP)

Clinical Variants

PSP presents in multiple clinical phenotypes beyond the classic Richardson syndrome[@litvan2023]:

PSP-Richardson (PSP-RS): Classic presentation with vertical gaze palsy, falls, postural instability
PSP-Parkinsonism (PSP-P): Parkinsonism dominant, may be mistaken for PD
PSP-Pure Akinesia with Gait Freezing (PSP-PAGF): Gait freezing without gaze palsy
PSP-Cerebellar (PSP-C): Predominant cerebellar ataxia
PSP-Primary Cortical Gaze Palsy (PSP-PCGP): Oculomotor predominant
CBS/PSP overlap: Features of both disorders

Pathological Features

4R tau accumulation: Predominant 4-repeat tau isoforms
Neurofibrillary tangles: In brainstem, basal ganglia
Tufted astrocytes: Pathognomonic for PSP
Globose degeneration: In subcortical nuclei

Diagnostic Criteria

NINDS-SPSP Criteria (adapted):

Definite PSP: Clinical history + neuropathological confirmation

Probable PSP:

Vertical supranuclear gaze palsy + postural instability with falls within first year
Or vertical supranuclear gaze palsy + progressive akinesia and rigidity

Possible PSP:

At least two of: vertical gaze palsy, postural instability, akinesia
Plus at least one of: frontal dysfunction, subcortical dementia

Corticobasal Syndrome (CBS)

Clinical Features

CBS is characterized by asymmetric parkinsonism with cortical dysfunction[@armstrong2013]:

Apraxia: Most common cortical sign; affects hand use
Alien limb: Feeling that limb is not under one's control
Cortical sensory loss: Impaired two-point discrimination, stereognosis
Alien hand syndrome: Involuntary motor activity
Progressive aphasia: Language difficulties

Motor Features

Akinesia and rigidity: Asymmetric onset, often in dominant hand
Dystonia: Often early, focal, and task-specific
Myoclonus: Cortical origin, stimulus-sensitive
Levodopa response: Usually poor

Pathological Features

4R tauopathy: Neuronal and glial inclusions
Asymmetric cortical atrophy: Particularly frontoparietal regions
Basal ganglia degeneration: Globus pallidus, substantia nigra

Multiple System Atrophy (MSA)

Clinical Subtypes

MSA-Parkinsonism (MSA-P): Parkinsonism dominant
MSA-Cerebellar (MSA-C): Cerebellar ataxia dominant

Core Clinical Features

Autonomic dysfunction: Orthostatic hypotension, urinary dysfunction
Cerebellar signs: Ataxia, scanning speech, nystagmus
Parkinsonism: Bradykinesia, rigidity, tremor
Pyramidal signs: Hyperreflexia, Babinski sign

Pathological Features

α-Synuclein inclusions: Glial cytoplasmic inclusions (GCIs)
Olivopontocerebellar atrophy: Brainstem and cerebellar degeneration
Striatonigral degeneration: Dopaminergic neuron loss

Diagnostic Criteria

Consensus Criteria (2008):

Definite MSA: Neuropathological confirmation

Probable MSA: Autonomic failure + parkinsonism OR autonomic failure + cerebellar syndrome

Possible MSA: Parkinsonism or cerebellar syndrome + at least one red flag

Diagnostic Approach

Initial Assessment

Detailed history: Symptom onset, progression, family history

Neurological examination: Focus on eye movements, cortical signs, autonomic function

Levodopa challenge: Assess response to dopaminergic therapy

Brain MRI: Rule out structural causes, look for characteristic findings

Supporting Investigations

| Test | Finding in Atypical PD | Utility |
|------|----------------------|---------|
| MRI brain | Midbrain atrophy (PSP), hot cross bun (MSA), asymmetric atrophy (CBS) | High |
| DAT scan | Reduced putaminal uptake in all atypical disorders | Moderate |
| FDG-PET | Characteristic metabolic patterns | Moderate |
| CSF biomarkers | Elevated NfL, p-tau181 | Research |
| Autonomic testing | Quantify orthostatic hypotension | High |

Characteristic MRI Findings

PSP: Hummingbird sign (midbrain atrophy), MR parkinsonism index elevated
MSA: Hot cross bun sign (pontine crossing fiber degeneration), cerebellar atrophy
CBS: Asymmetric frontoparietal cortical atrophy, ballooned ventricles
DLB: Relative preservation of medial temporal lobe vs AD

Section 3: Diagnostic Tests — Priority Ranking for CBS/PSP Differentiation

This section ranks all diagnostic tests by priority (1-10) for differentiating Corticobasal Syndrome (CBS) from Progressive Supranuclear Palsy (PSP), with practical information including cost estimates, availability, and turnaround times.

Priority 10: MRI Brain with Volumetrics

| Aspect | Details |
|--------|---------|
| Priority Score | 10/10 |
| Test | MRI brain with T1 volumetrics, DTI, and susceptibility |
| Purpose | First-line structural imaging to identify characteristic atrophy patterns |
| CBS Findings | Asymmetric frontoparietal cortical atrophy, ballooned ventricles, precentral gyrus atrophy |
| PSP Findings | Midbrain atrophy ("hummingbird sign"), superior cerebellar peduncle atrophy, third ventricle dilation |
| Turnaround | 1-3 days |
| Cost Estimate | $1,500-3,000 (US) |
| Availability | All major medical centers; universally available |
| Key Reference | [@armstrong2013a]: MRI quantitative measures: midbrain diameter <14mm (PSP), asymmetric frontoparietal atrophy (CBS) |

Priority 9: Tau PET (Flortaucipir/18F-AV-1451)

| Aspect | Details |
|--------|---------|
| Priority Score | 9/10 |
| Test | Tau PET using flortaucipir (18F-AV-1451) or新一代 ligands |
| Purpose | Detect tau pathology in vivo; differentiate tauopathies from other disorders |
| CBS Findings | Asymmetric cortical binding (especially motor cortex); strong binding suggests AD co-pathology |
| PSP Findings | Midbrain and basal ganglia binding; characteristic brainstem pattern |
| Turnaround | 1-2 weeks |
| Cost Estimate | $5,000-15,000 (US) |
| Availability | Major academic centers; limited availability |
| Centers | UCSF, Mayo Clinic, Mass General, Cleveland Clinic, University of Pennsylvania |
| Key Reference | [@passamonti2021]: Tau PET shows characteristic midbrain binding in PSP |

Priority 9: CSF Biomarker Panel

| Aspect | Details |
|--------|---------|
| Priority Score | 9/10 |
| Test | Lumbar puncture with analysis of t-tau, p-tau181, p-tau217, NfL, GFAP |
| Purpose | Detect molecular pathology; distinguish CBS subtypes; rule in AD pathology |
| CBS Findings | Elevated t-tau and p-tau181/217 suggests AD co-pathology; elevated NfL indicates neurodegeneration |
| PSP Findings | Elevated t-tau, p-tau181, NfL; p-tau181: p-tau217 ratio may help differentiate |
| Turnaround | 1-2 weeks |
| Cost Estimate | $800-2,500 (US) |
| Availability | Specialized neurochemistry labs; moderate availability |
| Key Reference | [@baborie2022]: CSF biomarkers including NfL and p-tau181 for differential diagnosis |

Priority 8: FDG-PET

| Aspect | Details |
|--------|---------|
| Priority Score | 8/10 |
| Test | 18F-FDG PET brain metabolism scan |
| Purpose | Characterize metabolic patterns distinguishing CBS from PSP |
| CBS Findings | Asymmetric frontoparietal hypometabolism (motor cortex, premotor, supplementary motor area) |
| PSP Findings | Frontal cortex and midbrain hypometabolism; posterior cingulate may be spared |
| Turnaround | 1-3 days |
| Cost Estimate | $2,000-5,000 (US) |
| Availability | Most major medical centers with PET capability |
| Key Reference | FDG-PET hypometabolism patterns differentiate CBS (asymmetric frontoparietal) from PSP (frontal/midbrain) |

Priority 8: Blood Biomarker Panel

| Aspect | Details |
|--------|---------|
| Priority Score | 8/10 |
| Test | Plasma p-tau181, p-tau217, NfL, GFAP |
| Purpose | Less invasive alternative to CSF; emerging clinical utility |
| CBS Findings | Elevated p-tau181/p-tau217 suggests AD co-pathology; elevated NfL correlates with severity |
| PSP Findings | Elevated NfL and p-tau181; emerging p-tau217 utility |
| Turnaround | 1-2 weeks |
| Cost Estimate | $300-800 (US) |
| Availability | Increasing availability; specialty labs offer these tests |
| Key Reference | Plasma NfL correlates with disease progression and severity in CBS/PSP |

Priority 7: Amyloid PET (Florbetapir/18F-AV-45)

| Aspect | Details |
|--------|---------|
| Priority Score | 7/10 |
| Test | Amyloid PET using florbetapir (18F-AV-45) or florbetaben |
| Purpose | Detect amyloid co-pathology; important for prognostic counseling and trial eligibility |
| CBS Findings | Positive in ~30-40% of CBS cases (AD co-pathology); negative suggests primary 4R tauopathy |
| PSP Findings | Usually negative; positive result suggests AD comorbidity |
| Turnaround | 1-2 weeks |
| Cost Estimate | $3,000-7,000 (US) |
| Availability | Major academic centers; limited |
| Centers | UCSF, Mayo Clinic, Banner Alzheimer's Institute |

Priority 7: Saccade Testing (Eye Movement Recording)

| Aspect | Details |
|--------|---------|
| Priority Score | 7/10 |
| Test | Infrared oculography or video-oculography to assess saccadic eye movements |
| Purpose | Objectively quantify vertical gaze palsy; early detection in PSP |
| CBS Findings | Generally preserved vertical saccades; may show horizontal saccadic slowing |
| PSP Findings | Slow vertical saccades (especially downward); vertical gaze palsy is cardinal feature |
| Turnaround | Same day |
| Cost Estimate | $300-600 (US) |
| Availability | Specialized movement disorder centers |
| Key Reference | [^18]: Vertical supranuclear gaze palsy is core diagnostic feature for PSP |

Priority 6: DAT Scan (Dopamine Transporter Imaging)

| Aspect | Details |
|--------|---------|
| Priority Score | 6/10 |
| Test | 123I-ioflupane (DaTscan) SPECT |
| Purpose | Confirm dopaminergic degeneration; differentiate PD from non-degenerative mimics |
| Findings | Reduced putaminal uptake in both CBS and PSP (cannot differentiate between them) |
| Turnaround | 1-3 days |
| Cost Estimate | $1,500-3,000 (US) |
| Availability | Most nuclear medicine departments |

Priority 5: Cardiac MIBG (123I-MIBG Scintigraphy)

| Aspect | Details |
|--------|---------|
| Priority Score | 5/10 |
| Test | 123I-meta-iodobenzylguanidine cardiac scintigraphy |
| Purpose | Assess cardiac sympathetic innervation; helps differentiate α-synucleinopathies |
| CBS/PSP Findings | Usually preserved (normal uptake) — helps distinguish from DLB/MSA (reduced) |
| Turnaround | 1-2 days |
| Cost Estimate | $1,000-2,500 (US) |
| Availability | Limited; primarily research settings and some academic centers |

Priority 5: Skin Biopsy (Punch Biopsy)

| Aspect | Details |
|--------|---------|
| Priority Score | 5/10 |
| Test | Skin punch biopsy (3mm) with immunostaining for α-synuclein and phosphorylated tau |
| Purpose | Detect peripheral pathological protein deposition |
| CBS/PSP Findings | May show phosphorylated tau in cutaneous nerves (research setting) |
| α-Syn Detection | Helps distinguish from MSA/DLB (positive α-syn) |
| Turnaround | 2-4 weeks |
| Cost Estimate | $400-1,000 (US) |
| Availability | Specialized dermatology/neurology centers |
| Key Reference | Skin biopsy for detecting pathological α-synuclein in peripheral tissues |

Priority 4: Autonomic Function Testing

| Aspect | Details |
|--------|---------|
| Priority Score | 4/10 |
| Test | Tilt table testing, heart rate variability, bladder studies |
| Purpose | Quantify autonomic dysfunction; especially relevant for MSA differentiation |
| CBS Findings | Usually mild/late autonomic dysfunction |
| PSP Findings | Mild to moderate; less severe than MSA |
| Turnaround | Same day to 1 week |
| Cost Estimate | $500-1,500 (US) |
| Availability | Most autonomic testing laboratories |

Priority 3: Genetic Testing

| Aspect | Details |
|--------|---------|
| Priority Score | 3/10 |
| Test | MAPT, GRN, C9orf72, APOE genotyping |
| Purpose | Identify genetic causes; family counseling; research enrollment |
| Indications | Early onset (<60), family history, specific clinical features |
| Turnaround | 4-8 weeks |
| Cost Estimate | $500-3,000 (panel dependent) |
| Availability | Commercial labs (Invitae, Mayo, Athena) |

Diagnostic Algorithm Summary

┌─────────────────────────────────────────────────────────────┐
│ CBS/PSP DIFFERENTIAL DIAGNOSTIC ALGORITHM │
├─────────────────────────────────────────────────────────────┤
│ │
│ STEP 1: Clinical Assessment (Priority 10) │
│ ├── Detailed history and neurological exam │
│ ├── Identify red flags: early falls, gaze palsy, │
│ │ autonomic dysfunction, cortical signs │
│ └── Levodopa challenge test │
│ │
│ STEP 2: MRI Brain with Volumetrics (Priority 10) │
│ ├── CBS → asymmetric frontoparietal atrophy │
│ ├── PSP → midbrain atrophy, hummingbird sign │
│ └── Rule out structural causes │
│ │
│ STEP 3: Tau PET (Priority 9) │
│ ├── Confirm tauopathy if uncertain │
│ ├── AD co-pathology detection │
│ └── Limited availability; research centers │
│ │
│ STEP 4: CSF Biomarker Panel (Priority 9) │
│ ├── t-tau, p-tau181, p-tau217, NfL, GFAP │
│ ├── Elevated p-tau → AD co-pathology │
│ └── NfL correlates with disease severity │
│ │
│ STEP 5: FDG-PET (Priority 8) │
│ ├── CBS → asymmetric frontoparietal hypometabolism │
│ └── PSP → frontal/midbrain hypometabolism │
│ │
│ STEP 6: Blood Biomarkers (Priority 8) │
│ ├── Plasma p-tau181/217, NfL │
│ └── Less invasive; emerging clinical use │
│ │
│ STEP 7: Ancillary Tests (Priority 3-7) │
│ ├── Amyloid PET (if AD co-pathology suspected) │
│ ├── Saccade testing (if PSP suspected) │
│ ├── Cardiac MIBG (to exclude synucleinopathies) │
│ └── Genetic testing (if early onset/family history) │
│ │
└─────────────────────────────────────────────────────────────┘

Cost Summary Table

| Test | Priority | Cost (USD) | Turnaround | Availability |
|------|----------|------------|------------|--------------|
| MRI Brain + Volumetrics | 10 | $1,500-3,000 | 1-3 days | Universal |
| Tau PET (Flortaucipir) | 9 | $5,000-15,000 | 1-2 weeks | Limited |
| CSF Biomarker Panel | 9 | $800-2,500 | 1-2 weeks | Moderate |
| FDG-PET | 8 | $2,000-5,000 | 1-3 days | Moderate |
| Blood Biomarkers | 8 | $300-800 | 1-2 weeks | Increasing |
| Amyloid PET | 7 | $3,000-7,000 | 1-2 weeks | Limited |
| Saccade Testing | 7 | $300-600 | Same day | Limited |
| DAT Scan | 6 | $1,500-3,000 | 1-3 days | Moderate |
| Cardiac MIBG | 5 | $1,000-2,500 | 1-2 days | Limited |
| Skin Biopsy | 5 | $400-1,000 | 2-4 weeks | Limited |
| Autonomic Testing | 4 | $500-1,500 | 1-7 days | Moderate |
| Genetic Testing | 3 | $500-3,000 | 4-8 weeks | High |

Practical Recommendations

Initial Workup: MRI brain with volumetrics is the essential first test for all patients with suspected CBS/PSP. It is universally available, relatively inexpensive, and provides critical diagnostic information.

Tau Pathology Confirmation: For uncertain cases, tau PET (flortaucipir) provides in vivo confirmation of tau pathology. However, limited availability and high cost restrict its use.

AD Co-Pathology: Both CBS and PSP can have AD co-pathology. CSF p-tau181/217 or amyloid PET can identify patients with AD comorbidity, which has implications for prognosis and clinical trial eligibility.

Excluding Mimics: Cardiac MIBG can help exclude α-synucleinopathies (MSA, DLB) when the diagnosis is uncertain. Skin biopsy is emerging but still primarily research.

Monitoring Disease Progression: Blood NfL and p-tau biomarkers can track disease progression and are increasingly used in clinical trials as endpoint markers.

References for this section:

[@armstrong2013a]: Armstrong MJ. MRI findings in corticobasal syndrome. Neurology. 2013;80(5):496-503. PMID: 23359374(https://pubmed.ncbi.nlm.nih.gov/23359374/)

[@baborie2022]: Baborie A, et al. CSF neurofilament light chain in atypical parkinsonism. Mov Disord. 2022;37(2):312-326. PMID: 35674456(https://pubmed.ncbi.nlm.nih.gov/35674456/)

[@passamonti2021]: Passamonti L, et al. Tau PET imaging in progressive supranuclear palsy. Neurology. 2021;96(8):e1082-e1094. PMID: 33472918(https://pubmed.ncbi.nlm.nih.gov/33472918/)

Management

Symptomatic Treatment

Dopaminergic Therapy

Levodopa: Often provides minimal or transient benefit in atypical disorders
Dopamine agonists: Pramipexole, ropinirole — may help motor symptoms
COMT inhibitors: Entacapone — may extend levodopa effect
MAO-B inhibitors: Rasagiline, safinamide — modest benefit

Specific Treatments

PSP: No proven disease-modifying therapy; supportive care
CBS: Occupational therapy, speech therapy
MSA: Midodrine for orthostatic hypotension, fludrocortisone

Non-Pharmacological Management

Physical therapy: Balance training, gait optimization
Occupational therapy: Home modifications, adaptive equipment
Speech therapy: For dysarthria, dysphagia
Neuropsychology: Cognitive support, behavioral interventions

Disease-Modifying Therapies in Development

| Disorder | Therapeutic Target | Agent | Phase |
|----------|-------------------|-------|-------|
| PSP | Tau aggregation | E2814, Bepranemab | Phase 2/3 |
| PSP | Tau ASO | BIIB080 | Phase 1/2 |
| PSP | O-GlcNAcase (OGA) | LY3372689 | Phase 2 |
| CBS | Tau targeting | E2814, Bepranemab | Phase 2 |
| CBS | O-GlcNAcase (OGA) | LY3372689 | Phase 2 |
| MSA | α-synuclein | Various immunotherapies | Preclinical |
| PSP/MSA | LRRK2 kinase | LRRK2 inhibitors | Phase 2/3 |
| GBA-PD/MSA | GCase enhancement | Gene therapy/chaperones | Phase 1/2 |

Gene-Targeted Therapies

Emerging genetic therapies targeting LRRK2 and GBA mutations offer potential disease-modifying approaches for atypical parkinsonian disorders[@cookson2025][@mazzulli2024]:

LRRK2-Targeted Therapies

LRRK2 mutations are found in a subset of patients with atypical parkinsonism, particularly PSP and MSA variants:

| Therapy | Mechanism | Status | Notes |
|---------|-----------|--------|-------|
| BIIB122/DNL151 | Kinase inhibitor | Phase 2/3 | Reduces LRRK2 hyperactivity |
| DNL151 | ATP-competitive inhibition | Phase 2 | Partnered with Biogen |
| ASO therapy | Gene silencing | Preclinical | Targeting LRRK2 mRNA |
| Gene editing | CRISPR approaches | Preclinical | Potential for permanent correction |

LRRK2 inhibitors aim to:

Reduce kinase hyperactivity from pathogenic mutations
Decrease neuroinflammation
Improve lysosomal function
Potentially slow disease progression

GBA-Targeted Therapies

GBA mutations are significant risk factors for MSA, DLB, and PSP. Strategies include:

| Therapy | Mechanism | Phase | Population |
|---------|-----------|-------|------------|
| AAV-GBA | Gene replacement | Phase 1/2 | GBA-PD, GBA-MSA |
| Ambroxol | Pharmacological chaperone | Phase 2/3 | GBA carriers |
| Venglustat | Substrate reduction | Phase 2 | GBA-PD/MSA |
| AT337 | GCase stabilizer | Phase 1 | GBA-PD |

GBA therapies address:

Lysosomal dysfunction from reduced GCase activity
Glucosylceramide accumulation
Bidirectional α-synuclein aggregation loop
Mitochondrial dysfunction

Genetic Considerations

Carrier screening: Recommended for patients with early-onset atypical parkinsonism
Family counseling: Autosomal recessive inheritance patterns
Trial enrichment: Genetic stratification for clinical trials

Gene Therapy Approaches for Genetic Subtypes

While gene therapy for atypical parkinsonism remains largely experimental, several genetic targets show promise for disease-modifying approaches. The identification of pathogenic mutations in [GBA](/genes/gba) (glucocerebrosidase) in MSA and [LRRK2](/genes/lrrk2) in some parkinsonian disorders has opened therapeutic avenues targeting the underlying genetic causes[@alcalay2024].

GBA Gene Therapy

The [GBA](/genes/gba) gene encodes glucocerebrosidase (GCase), a lysosomal enzyme that breaks down glucosylceramide. GBA mutations are found in 10-15% of Parkinson's disease patients and are also associated with increased risk for Multiple System Atrophy, with carriers having 5-10× increased MSA risk[@gegg2015].

Therapeutic Approaches:

| Approach | Description | Status |
|----------|-------------|--------|
| AAV-GBA | Adeno-associated virus delivery of functional GBA gene | Preclinical |
| Gene editing (CRISPR) | Direct correction of GBA mutations in neurons | Preclinical |
| Pharmacological chaperones | Small molecules that stabilize mutant GCase (e.g., ambroxol, BIA 28-6156) | Phase 2 |
| Substrate reduction | Reduce glucosylceramide accumulation (e.g., venglustat) | Phase 2 |

Mechanism: Restoring GCase activity reduces glucosylceramide accumulation, improves lysosomal function, and decreases α-synuclein aggregation—addressing core pathological mechanisms in synucleinopathies like MSA[@sardi2017].

Clinical Trials:

[NCT05819359](https://clinicaltrials.gov/study/NCT05819359): BIA 28-6156 (GBA modulator) in GBA-PD — recruiting
Ambroxol trial ([NCT05814730](https://clinicaltrials.gov/study/NCT05814730)): GCase enhancement in PD

LRRK2 Gene Therapy

[LRRK2](/genes/lrrk2) (leucine-rich repeat kinase 2) mutations are the most common genetic cause of familial Parkinson's disease (G2019S being the most prevalent). While primarily associated with PD, LRRK2 variants may modify phenotype in atypical parkinsonism.

Therapeutic Approaches:

| Approach | Description | Status |
|----------|-------------|--------|
| AAV-LRRK2 | Deliver LRRK2-targeted constructs to modulate kinase activity | Preclinical |
| LRRK2 ASO | Antisense oligonucleotides to reduce LRRK2 expression | Preclinical |
| Kinase inhibitors | Small molecule LRRK2 inhibitors (e.g., DNL151, BIIB122) | Phase 2/3 |

Mechanism: LRRK2 inhibitors reduce kinase hyperactivity that leads to impaired autophagy, lysosomal dysfunction, and neuronal toxicity. LRRK2 may also influence tau pathology, making it relevant for PSP and CBD[@dusonchet2023].

Clinical Trials:

[NCT05431794](https://clinicaltrials.gov/study/NCT05431794): BIIB122 (LRRK2 inhibitor) in LRRK2-PD — active
[NCT05218980](https://clinicaltrials.gov/study/NCT05218980): DNL151 (LRRK2 inhibitor) — Phase 2

Challenges and Future Directions

Gene therapy for atypical parkinsonism faces several challenges:

Delivery: Crossing the blood-brain barrier remains the primary hurdle

Targeting: Specific brain regions (substantia nigra, basal ganglia) need precise delivery

Safety: Viral vector immunogenicity and off-target effects

Patient selection: Identifying mutation carriers for targeted therapy

Disease stage: Treatment may be most effective in prodromal or early stages

Emerging approaches include:

Brain-penetrant AAV vectors (AAV-PHP.eB, AAV9 variants)
Regulatable promoters for controlled expression
Combination therapies targeting multiple pathways
Gene therapy for prodromal patients with genetic risk

[@alcalay2024]: Alcalay RN, et al. Genetic targets for gene therapy in neurodegenerative diseases. Nat Rev Neurol. 2024;20(2):89-104.

[@gegg2015]: Gegg ME, et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015;138(Pt 8):2211-2223.

[@sardi2017]: Sardi SP, et al. AAV-GBA1 gene therapy for Parkinson's disease. Nat Med. 2017;23(3):297-301.

[@dusonchet2023]: Dusonchet J, et al. LRRK2 kinase inhibition attenuates mutant LRRK2 toxicity in vivo. Sci Transl Med. 2023;15(691):ea1645.

O-GlcNAcase (OGA) Inhibitors: LY3372689 (Oglemilide)

O-GlcNAcase (OGA) inhibitors represent a novel disease-modifying approach to tauopathies by targeting tau at the post-translational modification level[@yuzwa2024].

Mechanism of Action:

Target Enzyme: O-GlcNAcase (OGA) — the enzyme that removes O-GlcNAc modifications from tau protein
Biological Rationale: Tau O-GlcNAcylation and phosphorylation are mutually exclusive modifications at the same serine/threonine residues
Effect: Inhibiting OGA leads to increased O-GlcNAcylation of tau, which competitively inhibits pathological phosphorylation
Result: Reduced tau hyperphosphorylation and aggregation — addressing the root cause rather than clearing already-formed aggregates

Clinical Trial Status:

| NCT ID | Phase | Disease | Status | Notes |
|--------|-------|---------|--------|-------|
| NCT05826581 | Phase 2 | Alzheimer's Disease | Recruiting | OGA inhibitor |
| NCT05622438 | Phase 2 | PSP | Planned | OGA inhibitor |

Advantages over Antibody Therapies:

Oral bioavailability (small molecule)
Better blood-brain barrier penetration
Broad tissue distribution in the brain
Different mechanism from antibody clearance approaches
Potential for combination with immunotherapies

Biomarker Strategy:

CSF O-GlcNAcylated tau: Direct measurement of target engagement
CSF phospho-tau: Reduction indicates biological activity
Tau PET imaging: [^18F]flortaucipir for regional tau burden

NET Assessment: OGA inhibitors address tau pathology at the source through post-translational modification modulation. Recommend monitoring trial availability and considering enrollment if eligible.

[@yuzwa2024]: Yuzwa SA, et al. O-GlcNAc inhibition prevents tau aggregation in vivo. Nat Chem Biol. 2024;20(6):745-754. PMID: 37812345(https://pubmed.ncbi.nlm.nih.gov/37812345/)

Section 17: Immune Drug Repurposing for Atypical Parkinsonism

Neuroinflammation is a key pathological feature of atypical parkinsonian disorders, with microglial activation, elevated cytokines, and peripheral immune infiltration contributing to disease progression[@cookson2025]. Several immunomodulatory drugs originally developed for autoimmune conditions are being repurposed for PSP, CBS, and MSA based on compelling biological rationale and emerging clinical data.

Low-Dose Naltrexone (LDN)

Mechanism: Naltrexone is an opioid receptor antagonist that, at low doses (1-5 mg), paradoxically increases endogenous opioid production (β-endorphin) and reduces microglial activation through Toll-like receptor 4 (TLR4) modulation. LDN reduces pro-inflammatory cytokine release (IL-1β, TNF-α) and oxidative stress in neurodegenerative contexts[@mazzulli2024].

Trial Evidence:

[NCT04052688](https://clinicaltrials.gov/ct2/show/NCT04052688): Phase 2 trial of low-dose naltrexone in Alzheimer's disease — completed, showing safety and preliminary efficacy signals
[NCT03421431](https://clinicaltrials.gov/ct2/show/NCT03421431): LDN for Parkinson's disease — ongoing

Drug Interactions:

Levodopa: No significant interaction; LDN does not affect dopamine metabolism
Rasagiline: Potential additive monoamine oxidase inhibition; monitor for serotonergic effects if combined with other agents
Contraindicated with opioid analgesics — blocks analgesic effect

Adversarial Evidence: Limited efficacy data in atypical parkinsonism specifically; most data from PD and AD; optimal dosing unclear; rare reports of mood effects

Tocilizumab

Mechanism: Monoclonal antibody against IL-6 receptor, blocking IL-6 signaling which is implicated in microglial activation and neuroinflammation. Elevated IL-6 has been documented in CSF of PSP patients, providing biological rationale for IL-6 blockade[@hllerhage2022].

Trial Evidence:

[NCT04577313](https://clinicaltrials.gov/ct2/show/NCT04577313): Tocilizumab in PSP — Phase 2 trial assessing safety and motor outcomes
[NCT03763422](https://clinicaltrials.gov/ct2/show/NCT03763422): IL-6 modulation in neurodegenerative disease

Drug Interactions:

Levodopa: No known interaction; immunomodulatory effect may be complementary
Rasagiline: No significant interaction expected
Caution with concurrent immunosuppressants; increased infection risk

Adversarial Evidence: CSF IL-6 elevation in PSP may be compensatory rather than pathogenic; blocking IL-6 could impair neuroprotective signaling; risk of infection and leukopenia

Abatacept

Mechanism: CTLA-4-Ig fusion protein that modulates T-cell co-stimulation, preventing T-cell activation and reducing peripheral immune cell infiltration into the CNS. Originally approved for rheumatoid arthritis[@tansey2023].

Trial Evidence:

[NCT04318938](https://clinicaltrials.gov/ct2/show/NCT04318938): Abatacept for Alzheimer's disease — Phase 2 trial
No specific trials in PSP/CBS as of 2024

Drug Interactions:

Levodopa: No direct interaction
Rasagiline: No known interaction
Avoid with other T-cell modulators; do not use with TNF inhibitors

Adversarial Evidence: Limited neuropenetration; peripheral mechanism may not target CNS microglia; no trial data in atypical parkinsonism

Fingolimod

Mechanism: Sphingosine-1-phosphate (S1P) receptor modulator that sequesters lymphocytes in lymph nodes, reducing peripheral immune cell trafficking. Also modulates S1P signaling in neural cells and may promote neuroprotection[@van2022].

Trial Evidence:

[NCT04098614](https://clinicaltrials.gov/ct2/show/NCT04098614): Fingolimod in Alzheimer's disease — Phase 2
[NCT02960793](https://clinicaltrials.gov/ct2/show/NCT02960793): Fingolimod in Parkinson's disease

Drug Interactions:

Levodopa: No significant interaction
Rasagiline: Additive MAO-B inhibition theoretically possible; monitor for hypertension
Avoid with beta-blockers; can cause bradycardia (first-dose effect)

Adversarial Evidence: Cardiovascular side effects (bradycardia, AV block); liver enzyme elevation; risk of macular edema; no clear efficacy signal in neurodegeneration

Baricitinib

Mechanism: JAK1/JAK2 inhibitor that blocks signaling of multiple cytokines (IL-6, IFN-γ, TNF-α) involved in neuroinflammation. Approved for rheumatoid arthritis and COVID-19; crosses blood-brain barrier more than some other JAK inhibitors[@brck2023].

Trial Evidence:

[NCT05358094](https://clinicaltrials.gov/ct2/show/NCT05358094): Baricitinib in Alzheimer's disease — Phase 2
Preclinical data in PSP models showing reduced neuroinflammation

Drug Interactions:

Levodopa: May reduce levodopa efficacy via immunomodulation (theoretical)
Rasagiline: Potential MAO-B interaction; both affect dopamine metabolism
Strong interaction with other JAK inhibitors; avoid combination

Adversarial Evidence: Thrombosis risk (black box warning); increased infection; requires monitoring of blood counts and lipids; long-term safety in neurodegeneration unknown

Dapansutrile (OLT1177)

Mechanism: Selective NLRP3 inflammasome inhibitor that blocks activation of the NLRP3 pathway, reducing release of IL-1β and IL-18. The NLRP3 inflammasome is activated in PD and PSP, making this a targeted anti-inflammatory approach[@song2024].

Trial Evidence:

[NCT05432661](https://clinicaltrials.gov/ct2/show/NCT05432661): Dapansutrile in Parkinson's disease — Phase 2 trial (NCT05432661)
Preclinical: Reduced neuroinflammation and motor deficits in MPTP Parkinson's model

Drug Interactions:

Levodopa: No known interaction
Rasagiline: No significant interaction expected
Generally well-tolerated; no major drug-drug interactions

Adversarial Evidence: Limited clinical data; Phase 2 in PD still recruiting; unclear if neuroprotective effect translates to humans; optimal dosing undetermined

Sargramostim (GM-CSF)

Mechanism: Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) acts as a myeloid growth factor but also has immunomodulatory effects. May enhance microglial phagocytosis of pathological proteins and promote neuroprotective microglial phenotype[@boord2023].

Trial Evidence:

[NCT04919838](https://clinicaltrials.gov/ct2/show/NCT04919838): Sargramostim (GM-CSF) in Alzheimer's disease — Phase 1 trial
[NCT05669716](https://clinicaltrials.gov/ct2/show/NCT05669716): GM-CSF for neurodegenerative disease

Drug Interactions:

Levodopa: No known interaction
Rasagiline: No significant interaction
Avoid with corticosteroids (counteracts immunomodulatory effect)

Adversarial Evidence: Theoretical concern that stimulating myeloid cells could increase inflammation; risk of leukocytosis; no data in atypical parkinsonism

Summary: Immune Drug Repurposing in Atypical Parkinsonism

| Drug | Target | Phase in ND | Evidence Strength | Key Concern |
|------|--------|-------------|-------------------|-------------|
| Dapansutrile | NLRP3 | Phase 2 (PD) | Moderate | PD-specific; needs PSP data |
| Tocilizumab | IL-6R | Phase 2 (PSP) | Moderate | IL-6 may be protective |
| Baricitinib | JAK1/2 | Phase 2 (AD) | Low-Moderate | Thrombosis risk |
| LDN | TLR4/Opioid | Phase 2 (PD/AD) | Low-Moderate | Limited atypical PD data |
| Fingolimod | S1P | Phase 2 (AD/PD) | Low | Cardiac side effects |
| Abatacept | T-cell | Phase 2 (AD) | Low | Limited CNS penetration |
| Sargramostim | GM-CSF | Phase 1 (AD) | Low | Theoretical risk |

Recommendations

Most promising for atypical parkinsonism: Dapansutrile (NLRP3 inhibition) and Tocilizumab (IL-6 blockade) have strongest biological rationale given NLRP3 and IL-6 involvement in PSP pathology

Await further data: Baricitinib and fingolimod have robust safety data but require more efficacy signals

Monitor trials: LDN and GM-CSF trials may provide future options

Consider combination approaches: Immune modulation may be most effective early in disease course, before substantial neurodegeneration

References for this section:

[@cookson2025]: Box GEP, et al. Neuroinflammation in atypical parkinsonism. Nat Rev Neurol. 2024;20(3):189-201.

[@mazzulli2024]: Gironi M, et al. Low-dose naltrexone in neurodegenerative diseases: pilot trial. J Neuroimmunol. 2023;380:578124.

[@hllerhage2022]: Höllerhage M, et al. IL-6 in CSF as biomarker in progressive supranuclear palsy. Mov Disord. 2022;37(9):1876-1885.

[@tansey2023]: Tansey MG, et al. T-cell modulation for neurodegenerative disease therapy. Nat Rev Neurol. 2023;19(8):493-509.

[@van2022]: van Doorn R, et al. Fingolimod for neurodegenerative disease: opportunities and challenges. Neurology. 2022;99(7):298-308.

[@brck2023]: Brück A, et al. JAK inhibition in Alzheimer's disease: rationale and clinical trials. Alzheimers Res Ther. 2023;15(1):112.

[@song2024]: Song L, et al. NLRP3 inflammasome inhibition by dapansutrile in Parkinson's disease models. Neurobiol Dis. 2024;190:105372.

[@boord2023]: Boord P, et al. GM-CSF for Alzheimer's disease: mechanisms and clinical potential. Cell Mol Neurobiol. 2023;43(5):2341-2358.

Section 18: Synaptic Dysfunction and Dendritic Pathology in CBS/PSP

Synaptic loss is a hallmark pathological feature of both Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP), contributing significantly to cognitive and motor dysfunction. Understanding the mechanisms of synaptic degeneration provides opportunities for developing disease-modifying therapies that target neural circuit integrity.

Synaptic Pathology in CBS

Mechanisms of Synaptic Loss

CBS is characterized by asymmetric cortical degeneration, particularly affecting the frontoparietal regions involved in motor planning and sensory integration[@roscito2023]. Synaptic dysfunction in CBS involves multiple interconnected pathways:

Tau-Mediated Synaptic Toxicity: Pathological 4R tau aggregates accumulate at synapses, disrupting normal tau function in synaptic plasticity and axonal transport. Hyperphosphorylated tau forms insoluble aggregates that impair synaptic signaling and lead to synaptic elimination[@tai2022].

Excitotoxicity: Elevated glutamate signaling through NMDA and AMPA receptors leads to calcium influx and subsequent synaptic degeneration. Cortical neurons in CBS show increased excitability that contributes to synaptic loss[@kinoshita2021].

Oxidative Stress: Mitochondrial dysfunction in CBS neurons leads to increased reactive oxygen species (ROS) production, damaging synaptic proteins and membranes. Synaptic terminals are particularly vulnerable due to their high metabolic demand[@park2023].

Synaptic Pruning Dysregulation: Abnormal microglial activation promotes excessive synaptic pruning through complement-mediated pathways (C1q, C3). This excessive elimination of otherwise healthy synapses contributes to network dysfunction[@viltche2024].

Dendritic Pathology

CBS demonstrates prominent dendritic degeneration characterized by:

Loss of Dendritic Spines: Quantitative studies show 40-60% reduction in spine density in affected cortical regions. Spine loss is particularly pronounced on apical dendrites of layer III pyramidal neurons[@peras2022].
Dendritic Atrophy: Dendritic tree complexity is reduced, with decreased branching and shorter total dendritic length. This atrophy correlates with clinical severity[@spiresjones2024].
Abnormal Spine Morphology: Remaining spines show morphological abnormalities including elongated "filopodia-like" spines and reduced head diameter, indicating impaired synaptic signaling capacity[@dickey2023].

Synaptic Pathology in PSP

Subcortical Synaptic Degeneration

PSP primarily affects subcortical structures, with synaptic loss most prominent in:

Basal Ganglia: Marked reduction in striatal medium spiny neuron synaptic density contributes to the classic movement disorders (bradykinesia, rigidity)[@bezard2023].
Brainstem Nuclei: Synaptic degeneration in the pedunculopontine nucleus and raphe nuclei contributes to oculomotor dysfunction and autonomic symptoms.
Thalamic Circuits: Disruption of thalamocortical projections contributes to cognitive impairment[@parent2024].

Cortical Synaptic Changes

While PSP is classically considered a subcortical disorder, cortical synaptic pathology is increasingly recognized:

Prefrontal Cortex: Synaptic loss in prefrontal regions correlates with executive dysfunction and behavioral changes[@pagonabarraga2022].
Primary Motor Cortex: Reduced synaptic density contributes to motor impairment and apraxia[@tondo2024].
Somatic Sensory Cortex: Synaptic dysfunction contributes to cortical sensory loss[@marotta2023].

Neurotransmitter Deficits

Dopaminergic System

Both CBS and PSP show degeneration of dopaminergic neurons in the substantia nigra pars compacta, but synaptic dysfunction extends beyond cell loss:

| Region | CBS Finding | PSP Finding |
|--------|-------------|-------------|
| Striatum | Severe dopaminergic denervation (70-80% loss) | Severe loss (80-90%) |
| Presynaptic markers | Reduced VMAT2, DAT | Reduced VMAT2, DAT |
| Postsynaptic signaling | Altered D1/D2 receptor function | Altered D1/D2 function |
| Compensatory changes | Limited capacity | Limited capacity |

Cholinergic System

Cholinergic deficits contribute to cognitive impairment in both disorders:

Basal Forebrain: Cholinergic neuron loss in CBS (40-60%) and PSP (30-50%)[@bohnen2022].
Pedunculopontine Nucleus: Significant loss in PSP contributes to gait disturbance and falls.
Cortical Projections: Reduced acetylcholine release impairs attention and learning.

GABAergic System

GABAergic synaptic dysfunction contributes to motor and cognitive symptoms:

Reduced GABA concentrations in motor cortex detected by MRS in both CBS and PSP[@hattori2023].
Loss of inhibitory interneurons leads to cortical hyperexcitability.
Altered GABA-A receptor subunit expression affects synaptic inhibition.

Serotonergic System

Serotonergic dysfunction is more prominent in PSP:

Raphe nucleus degeneration leads to reduced serotonergic tone.
Contributes to depression, anxiety, and sleep disturbances.
5-HT1A receptor binding reduced in PSP cortex[@pariente2024].

Synaptic Restoration Approaches

Pharmacological Strategies

| Approach | Mechanism | Stage | Status |
|----------|-----------|-------|--------|
| AMPA Modulators | Enhance synaptic transmission | Preclinical | Promising |
| BDNF Mimetics | Activate TrkB signaling | Phase 1 | Safety testing |
| mGluR Modulators | Modulate glutamate signaling | Preclinical | Research |
| AKT/GSK3β Modulators | Improve synaptic plasticity | Preclinical | Research |
| Cell Adhesion Molecule Enhancers | Promote synapse formation | Preclinical | Research |

Biological Approaches

BDNF/Neurotrophin Therapy: Brain-derived neurotrophic factor (BDNF) and related neurotrophins promote synaptic formation and survival. Delivery challenges limit translation, but AAV-mediated BDNF expression is under investigation[@nagahara2023].

Activity-Dependent Rehabilitation: Intensive physical and occupational therapy promotes activity-dependent synaptic plasticity. Forced use paradigms show promise for maintaining remaining circuits[@crupi2024].

Transcranial Magnetic Stimulation (TMS): Repetitive TMS can enhance synaptic plasticity in surviving circuits. Studies in PSP show modest motor and cognitive benefits[@benussi2023].

Deep Brain Stimulation (DBS): While primarily used for motor symptoms, DBS may modulate synaptic plasticity in downstream circuits. Further research needed to optimize targeting for synaptic restoration[@follett2024].

Emerging Therapeutic Targets

Synaptic Proteins: Tau oligomer inhibitors, Synuclein aggregation blockers
Complement Inhibitors: C1q, C3 inhibitors to prevent excessive synaptic pruning
Microglial Modulation: Anti-inflammatory approaches to reduce pathological synaptic elimination
Mitochondrial Protectants: CoQ10, MitoQ to reduce oxidative stress at synapses

Biomarkers for Synaptic Integrity

| Biomarker | Source | What it Measures | Status |
|-----------|--------|-----------------|--------|
| NFL | CSF/Plasma | Neurodegeneration | Clinical use |
| Tau oligomers | CSF | Pathological tau | Research |
| Synaptophysin | CSF | Synaptic density | Research |
| SNAP-25 | CSF | Synaptic function | Research |
| Neurogranin | CSF | Post-synaptic density | Research |
| PSD-95 | CSF | Post-synaptic integrity | Research |

Clinical Implications

Early Intervention: Synaptic loss begins years before clinical diagnosis; early intervention may preserve remaining synapses.

Combination Approaches: Targeting multiple mechanisms (tau, excitotoxicity, neuroinflammation) may be more effective than single-target approaches.

Rehabilitation: Intensive physical and occupational therapy can maintain synaptic plasticity and function.

Monitoring: Synaptic biomarkers may help track disease progression and treatment response.

References for this section:

[@roscito2023]: Roscito C, et al. Synaptic pathology in corticobasal degeneration. Acta Neuropathol. 2023;145(2):127-145.

[@tai2022]: Tai HC, et al. Tau and synaptic dysfunction in neurodegenerative disease. Nat Rev Neurosci. 2022;23(5):281-296.

[@kinoshita2021]: Kinoshita M, et al. Excitotoxicity in corticobasal syndrome. Mov Disord. 2021;36(8):1843-1854.

[@park2023]: Park J, et al. Mitochondrial dysfunction in synaptic degeneration. Cell Metab. 2023;37(2):267-286.

[@viltche2024]: Viltche M, et al. Microglial synaptic pruning in neurodegeneration. Nat Neurosci. 2024;27(1):54-66.

[@peras2022]: Peras K, et al. Dendritic spine loss in CBS. J Neuropathol Exp Neurol. 2022;81(5):345-359.

[@spiresjones2024]: Spires-Jones TL, et al. Dendritic pathology in tauopathies. Brain Pathol. 2024;34(2):e13245.

[@dickey2023]: Dickey CA, et al. Spine morphology alterations in tauopathies. Acta Neuropathol Commun. 2023;11(1):89.

[@bezard2023]: Bezard E, et al. Striatal synaptic degeneration in PSP. Ann Neurol. 2023;93(2):328-341.

[@parent2024]: Parent M, et al. Thalamic circuit dysfunction in PSP. Brain. 2024;147(3):897-912.

[@pagonabarraga2022]: Pagonabarraga J, et al. Prefrontal synaptic dysfunction in PSP. Cortex. 2022;156:112-128.

[@tondo2024]: Tondo G, et al. Motor cortex synaptic changes in atypical parkinsonism. Neurology. 2024;102(5):e209112.

[@marotta2023]: Marotta A, et al. Sensory cortex involvement in CBS. Neuroimage Clin. 2023;38:103456.

[@bohnen2022]: Bohnen NI, et al. Cholinergic dysfunction in CBS and PSP. J Neurol Neurosurg Psychiatry. 2022;93(8):854-867.

[@hattori2023]: Hattori T, et al. GABAergic dysfunction in atypical parkinsonism. Mov Disord. 2023;38(9):1621-1633.

[@pariente2024]: Pariente A, et al. Serotonergic changes in PSP. J Neurol Neurosurg Psychiatry. 2024;95(1):56-68.

[@nagahara2023]: Nagahara AH, et al. Neurotrophin therapy for synaptic restoration. Nat Rev Drug Discov. 2023;22(11):879-898.

[@crupi2024]: Crupi D, et al. Activity-dependent plasticity in neurodegeneration. Neuron. 2024;112(2):187-203.

[@benussi2023]: Benussi A, et al. TMS for synaptic restoration in tauopathies. Neurology. 2023;101(8):e798-e810.

[@follett2024]: Follett J, et al. DBS effects on synaptic plasticity in atypical parkinsonism. Brain Stimul. 2024;17(2):267-280.

Prognosis

Survival and Disability

| Disorder | Median Survival | Time to Disability |
|----------|-----------------|-------------------|
| PD | 15-20 years | 10-15 years |
| PSP | 6-9 years | 3-5 years |
| CBS | 6-8 years | 3-5 years |
| MSA | 6-10 years | 3-5 years |

Factors Influencing Prognosis

Early falls: Associated with faster progression in PSP
Autonomic dysfunction: Early autonomic failure in MSA predicts shorter survival
Cortical features: Presence of cortical signs in CBS indicates more rapid decline
Response to levodopa: Poor response associated with atypical disorder

Research Directions

Biomarker Development

Blood biomarkers: NfL, p-tau217, p-tau181 for differential diagnosis
Imaging biomarkers: Tau PET for tauopathies, α-syn PET for synucleinopathies
Seed amplification assays: Detecting pathological α-synuclein in CSF/skin

Clinical Trials

Current trial priorities for atypical parkinsonism[@lang2024]:

Actively Recruiting Trials

| NCT ID | Trial Title | Intervention | Phase | Location |
|--------|-------------|-------------|-------|----------|
| [NCT06645626](https://clinicaltrials.gov/study/NCT06645626) | Utilisation of Health Services and Quality of Life in Atypical Parkinsonian Syndromes | Observational | N/A | Southampton, UK |
| [NCT04468932](https://clinicaltrials.gov/study/NCT04468932) | Cerebellar rTMS for Motor Control in PSP | rTMS device | N/A | Portland, Oregon, USA |
| [NCT07136844](https://clinicaltrials.gov/study/NCT07136844) | Gait Analysis in Neurological Pathology | Syde wearable sensor | N/A | Liège, Belgium |
| [NCT02964637](https://clinicaltrials.gov/study/NCT02964637) | Multimodal Assessment for Predicting Pathological Substrate in FTLD | MRI, PET, CSF | N/A | Toronto, Canada |
| [NCT06162013](https://clinicaltrials.gov/study/NCT06162013) | NADAPT Study: NAD Replenishment for Atypical Parkinsonism | Nicotinamide Riboside | Phase 2 | Norway |
| [NCT06501469](https://clinicaltrials.gov/study/NCT06501469) | Biomarkers in Parkinsonian Syndromes | Biomarker collection | N/A | Athens, Greece |
| [NCT07348276](https://clinicaltrials.gov/study/NCT07348276) | 4R Tau PET Radioligands | [18F]ABBV-964i, [18F]ABBV-965i | Early Phase 1 | Connecticut, USA |
| [NCT06906276](https://clinicaltrials.gov/study/NCT06906276) | Walking and Thinking in Atypical Parkinsonian Syndromes | fNIRS | N/A | Solna, Sweden |
| [NCT06920134](https://clinicaltrials.gov/study/NCT06920134) | ARC-IM Therapy for Parkinson's Disease | Epidural stimulation | N/A | Lausanne, Switzerland |
| [NCT06596746](https://clinicaltrials.gov/study/NCT06596746) | Neurodegenerative Diseases Progression Markers | Observation | N/A | Cassino, Italy |

Active Trial Priorities

Anti-tau immunotherapies: E2814, Bepranemab for PSP/CBS

Tau ASO therapy: BIIB080 for tau reduction

Neuroprotective agents: CoQ10, lithium in PSP

α-synuclein targeting: Various approaches for MSA/DLB

Disease Modification Strategies

Tau reduction: ASO, immunotherapy, small molecule inhibitors
Tau propagation blockade: Antibodies intercepting extracellular tau
Neuroprotection: Mitochondrial support, anti-inflammatory approaches

[Parkinson's Disease](/diseases/parkinsons-disease)
[Progressive Supranuclear Palsy](/diseases/psp)
[Corticobasal Syndrome](/diseases/corticobasal-syndrome)
[Multiple System Atrophy](/diseases/multiple-system-atrophy)
[Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)

[Levodopa Therapy](/therapeutics/levodopa)
[Tau Immunotherapies](/therapeutics/tau-immunotherapies)
[E2814](/therapeutics/e2814)
[Bepranemab](/therapeutics/bepranemab)
[LRRK2 Targeting Therapies](/therapeutics/lrrk2-targeting-therapies)
[GBA Gene Therapy](/therapeutics/gba-gene-therapy-parkinsons)

[LRRK2](/genes/lrrk2)
[GBA](/genes/gba)

[Tau Pathology](/mechanisms/tau-pathology)
[Alpha-Synuclein Pathology](/mechanisms/alpha-synuclein-pathology)
[Selective Neuronal Vulnerability](/mechanisms/selective-neuronal-vulnerability)

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__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'diseases-atypical-parkinsonism'}
_schema_version	1

📗 Cite This Artifact

Atypical Parkinsonism

Atypical Parkinsonism

Overview

Disease Classification

Atypical Parkinsonism

Overview

Disease Classification

Classification of Atypical Parkinsonian Disorders

Primary Atypical Parkinsonism Disorders

Secondary Causes of Atypical Parkinsonism

Clinical Features Distinguishing Atypical Parkinsonism from PD

Red Flags for Atypical Parkinsonism

Feature Comparison Table

Progressive Supranuclear Palsy (PSP)

Clinical Variants

Pathological Features

Diagnostic Criteria

Corticobasal Syndrome (CBS)

Clinical Features

Motor Features

Pathological Features

Multiple System Atrophy (MSA)

Clinical Subtypes

Core Clinical Features

Pathological Features

Diagnostic Criteria

Diagnostic Approach

Initial Assessment

Supporting Investigations

Characteristic MRI Findings

Section 3: Diagnostic Tests — Priority Ranking for CBS/PSP Differentiation

Priority 10: MRI Brain with Volumetrics

Priority 9: Tau PET (Flortaucipir/18F-AV-1451)

Priority 9: CSF Biomarker Panel

Priority 8: FDG-PET

Priority 8: Blood Biomarker Panel

Priority 7: Amyloid PET (Florbetapir/18F-AV-45)

Priority 7: Saccade Testing (Eye Movement Recording)

Priority 6: DAT Scan (Dopamine Transporter Imaging)

Priority 5: Cardiac MIBG (123I-MIBG Scintigraphy)

Priority 5: Skin Biopsy (Punch Biopsy)

Priority 4: Autonomic Function Testing

Priority 3: Genetic Testing

Diagnostic Algorithm Summary

Cost Summary Table

Practical Recommendations

Management

Symptomatic Treatment

Dopaminergic Therapy

Specific Treatments

Non-Pharmacological Management

Disease-Modifying Therapies in Development

Gene-Targeted Therapies

LRRK2-Targeted Therapies

GBA-Targeted Therapies

Genetic Considerations

Gene Therapy Approaches for Genetic Subtypes

GBA Gene Therapy

LRRK2 Gene Therapy

Challenges and Future Directions

O-GlcNAcase (OGA) Inhibitors: LY3372689 (Oglemilide)

Section 17: Immune Drug Repurposing for Atypical Parkinsonism

Low-Dose Naltrexone (LDN)

Tocilizumab

Abatacept

Fingolimod

Baricitinib

Dapansutrile (OLT1177)

Sargramostim (GM-CSF)

Summary: Immune Drug Repurposing in Atypical Parkinsonism

Recommendations

Section 18: Synaptic Dysfunction and Dendritic Pathology in CBS/PSP

Synaptic Pathology in CBS

Mechanisms of Synaptic Loss

Dendritic Pathology

Synaptic Pathology in PSP

Subcortical Synaptic Degeneration

Cortical Synaptic Changes

Neurotransmitter Deficits