¶ Cognitive and Neuropsychiatric Profiles Distinguishing Atypical Parkinsonian Syndromes
Distinguishing between corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and Parkinson's disease (PD) is a major clinical challenge. While motor features often overlap, the 2025 study by Hu MT et al. in Brain demonstrates that cognitive and neuropsychiatric profiles provide valuable discriminative information that can be used alongside neuroimaging and biomarker data.
This page synthesizes the key findings from this landmark study and related 2025 research on the neuropsychological signatures of atypical parkinsonian syndromes.
- Large cohort of patients with CBS (n=~120), PSP (n=~150), MSA (n=~100), and matched PD (n=~120) and healthy controls
- Comprehensive neuropsychological battery assessing global cognition, executive function, memory, visuospatial ability, and language
- Neuropsychiatric assessment including depression, anxiety, apathy, impulsivity, and psychosis
- Correlation with plasma neurofilament light chain (NfL) as a neurodegeneration marker
¶ Main Cognitive Findings
CBS shows the most severe overall cognitive impairment among the atypical parkinsonian syndromes, with the lowest average scores on global cognitive measures. The pattern is distinct from PSP:
| Domain |
CBS Pattern |
PSP Pattern |
MSA Pattern |
Clinical Utility |
| Global Cognition |
Most impaired (lowest MMSE/MoCA) |
Moderate impairment |
Mild impairment |
CBS < PSP < MSA |
| Visuospatial |
Most prominent deficit — hallmark of CBS |
Less prominent, varies by subtype |
Relatively spared |
Key discriminator: CBS >> PSP |
| Executive Function |
Moderate impairment |
More prominent than CBS |
Mild-moderate impairment |
PSP > CBS > MSA |
| Memory |
Amnestic pattern (AD co-pathology possible) |
Less severe than CBS |
Mild, encoding deficit |
CBS with AD co-pathology shows worst memory |
| Language |
Variable (AOS in speech-onset CBS) |
Less prominent |
Mild anomia |
Speech-onset CBS differential |
The visuospatial deficit in CBS is particularly prominent and includes:
- Impaired face recognition (prosopagnosia)
- Object agnosia
- Visuoperceptual impairments on standard tests (VOSP, Rey-Osterrieth copy)
- This reflects the asymmetric parietal-occipital cortical involvement characteristic of CBS
¶ Neuropsychiatric Findings — Better Discriminators Than Cognitive Domains
Critically, the Hu et al. study found that neuropsychiatric features better discriminated between syndromes than cognitive tests alone:
flowchart LR
subgraph CBS_Neuropsychiatric
A1"Depression: 40-60%"
A2"Anxiety: 30-50%"
A3"Apathy: 70%"
A4"Irritability: 40-55%"
A5"Emotional Lability: 15-30%"
end
subgraph PSP_Neuropsychiatric
B1"Apathy: 80-90% (most prominent)"
B2"Depression: 30-40%"
B3"Impulsivity: less common"
B4"Disinhibition: rare"
end
subgraph MSA_Neuropsychiatric
C1"Anxiety: prominent (50-60%)"
C2"Apathy: 50-60%"
C3"RBD: 70-80% (most specific)"
C4"Depression: 40-50%"
end
A3 -.->|"shared"| B1
A4 -.->|"distinct"| C1
style A1 fill:#bbf
style A2 fill:#bbf
style A3 fill:#bbf
style A4 fill:#bbf
style A5 fill:#bbf
style B1 fill:#f93
style B2 fill:#f93
style C1 fill:#9f9
style C3 fill:#9f9
Compared to PSP, CBS patients show:
- Higher rates of depression and anxiety — up to 60% for depression vs. ~35% in PSP
- More irritability and emotional lability — reflecting cortical involvement
- Less prominent apathy than PSP (though still 70%)
- Higher frequency of psychotic symptoms (15-25%) vs. PSP (~10%)
A key finding from the Hu et al. study: Motor function predicted cognition in PSP, CBS, and PD but NOT in MSA. This suggests that in MSA, cognitive dysfunction is at least partially independent of motor degeneration — possibly due to cerebellar or brainstem pathology affecting cognitive circuits directly.
This has diagnostic implications: in MSA, cognitive impairment can progress even when motor symptoms are relatively stable.
Plasma neurofilament light chain (NfL) correlated with cognitive deficits across syndromes:
- Higher NfL = worse cognitive scores across all groups
- In PSP, NfL was the strongest predictor of executive dysfunction
- In CBS, NfL correlated with visuospatial impairment severity
- NfL may serve as a surrogate biomarker for cognitive deterioration rate
Jellinger KA's 2025 reviews provide additional context:
- PSP: Apathy dominates (80-90%), often with vertical supranuclear gaze palsy-associated cognitive slowing. Frontal executive dysfunction is prominent, particularly in PSP-RS (Richardson syndrome).
- CBS: Visuospatial dysfunction is the primary cognitive deficit, but cortical signs (apraxia, alien limb, cortical sensory loss) also contribute to functional impairment. Depression and anxiety are more frequent than in PSP.
- MSA: Cognitive deficits are milder overall, but anxiety (especially in MSA-P) and RBD (most specific for MSA) are prominent. Memory encoding deficits are common.
- PD: Mild cognitive impairment (MCI) occurs in ~30% of patients, usually dysexecutive or visuospatial, but less severe than atypical parkinsonian syndromes.
Based on combined cognitive-neuropsychiatric profiles:
flowchart TD
Start"Atypical Parkinsonism<br/>Suspected" --> Q1{"Visuospatial<br/>Deficit?"}
Q1 -->|YES| Q2{"Apraxia/Alien Limb<br/>Present?"}
Q1 -->|NO| Q3{"Vertical Saccade<br/>Impairment?"}
Q2 -->|YES| CBS"Corticobasal Syndrome<br/>Likely"
Q2 -->|NO| Q4{"Frontal Apathy<br/>Prominent?"}
Q3 -->|YES| PSP"Progressive Supranuclear<br/>Palsy Likely"
Q3 -->|NO| Q5{"RBD+<br/>Dysarthria?"}
Q5 -->|YES| MSA"Multiple System<br/>Atrophy Likely"
Q5 -->|NO| Unclear"Further Workup:<br/>MRI, FDG-PET,<br/>NfL, Genetic Testing"
Q4 -->|YES| PSP2"PSP Variant<br/>Likely"
Q4 -->|NO| MSA2"MSA Variant<br/>Likely"
style CBS fill:#bbf,stroke:#333
style PSP fill:#f93,stroke:#333
style MSA fill:#9f9,stroke:#333
Recommended neuropsychological instruments for differentiating atypical parkinsonian syndromes:
| Test |
CBS |
PSP |
MSA |
Notes |
| MoCA |
Lowest scores |
Moderate |
Mild |
Screen for MCI |
| VOSP (Visuospatial) |
Most impaired |
Mild |
Spared |
Best CBS discriminator |
| Trail Making Test B |
Moderate |
Most impaired |
Moderate |
Executive, PSP |
| Stroop Test |
Moderate |
Impaired |
Mild |
Frontal inhibition |
| FAB |
Moderate |
Impaired |
Mild |
Frontal assessment |
| ACE-III |
Variable |
Mild |
Mild |
Language evaluation |
| NPI |
Depression, anxiety prominent |
Apathy dominant |
Anxiety, RBD |
Neuropsychiatric |
| AES |
Moderate apathy |
Severe apathy |
Moderate |
Apathy evaluation |
| BDI-II |
Higher depression |
Moderate |
Higher |
Depression severity |
Understanding cognitive-neuropsychiatric profiles guides treatment:
- CBS with depression: SSRIs (avoid high-dose anticholinergics), cognitive behavioral therapy, consider methylphenidate for apathy
- CBS with visuospatial impairment: Occupational therapy adaptations for safety, environmental modifications
- PSP with apathy: Aggressive stimulant therapy (methylphenidate, modafinil), caregiver training for engagement
- MSA with anxiety: SSRIs, clonazepam for RBD-related anxiety, sleep hygiene