Progressive Supranuclear Palsy and Corticobasal Degeneration

Definition. Both are Parkinson-plus (atypical parkinsonian) syndromes and are 4-repeat tauopathies. Both are frequently misdiagnosed as Parkinson’s disease, and both show a poor or absent response to levodopa, which is the single most useful clinical discriminator.

PSP — clinical features. Early postural instability with repeated backward falls within the first year, vertical supranuclear gaze palsy (inability to look voluntarily downward, impaired saccades, eyelid-opening apraxia), axial rigidity greater than limb rigidity, retrocollis, and a startled or astonished facies. Tremor is infrequent.

PSP — course and investigations. Personality change, subcortical dementia and swallowing difficulty develop as the disease progresses. MRI shows midbrain atrophy — the normally concave upper midbrain becomes convex (hummingbird sign). Ocular electrophysiology demonstrates impaired saccades.

CBD — clinical features. A strikingly asymmetrical akinetic-rigid syndrome with limb dystonia, myoclonus, cortical sensory loss, ideomotor apraxia and the alien (foreign) hand phenomenon. MRI shows asymmetrical fronto-parietal atrophy contralateral to the affected limb.

Differentiation from other causes of parkinsonism in old age. Lewy body dementia — dementia within a year of parkinsonism, hallucinations, neuroleptic sensitivity. Multiple system atrophy — early severe dysautonomia with cerebellar or pyramidal signs. Vascular parkinsonism — lower-body predominance, multilacunar state, pseudobulbar palsy, stepwise worsening. NPH — magnetic gait with ventriculomegaly.

Management is symptomatic; no disease-modifying therapy exists. Trial levodopa (response usually poor or transient); amantadine may help. Botulinum toxin for limb dystonia, blepharospasm and sialorrhoea. Priorities are falls prevention, physiotherapy, weighted walkers, prism glasses, speech and swallow therapy, PEG feeding for aspiration, and early advance care planning. Avoid antipsychotics. Median survival is about 6–8 years; death is usually from aspiration pneumonia.

Tau-directed therapy has reached phase 3 in PSP (2024–2026). Two agents have advanced to phase 3 — NIO752, an intrathecal antisense oligonucleotide against the tau gene MAPT, and LM11A-31, a p75 neurotrophin-receptor modulator. The NIH-funded PSP Platform Trial (UCSF, from 2025) is testing LM11A-31, the anti-tau vaccine AADvac1 and AZP2006 concurrently, and tau-PET (18F-PI-2620) plus fluid biomarkers are being validated for early diagnosis. No disease-modifying drug is yet approved — management remains supportive.