Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome.

Jabbari E ，Holland N ，Chelban V ，Jones PS ，Lamb R ，Rawlinson C ，Guo T ，Costantini AA ，Tan MMX ，Heslegrave AJ ，Roncaroli F ，Klein JC ，Ansorge O ，Allinson KSJ ，Jaunmuktane Z ，Holton JL ，Revesz T ，Warner TT ，Lees AJ ，Zetterberg H ，Russell LL ，Bocchetta M ，Rohrer JD ，Williams NM ，Grosset DG ，Burn DJ ，Pavese N ，Gerhard A ，Kobylecki C ，Leigh PN ，Church A ，Hu MTM ，Woodside J ，Houlden H ，Rowe JB ，Morris HR ... -  《-》

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.

The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression.

Street D ，Jabbari E ，Costantini A ，Jones PS ，Holland N ，Rittman T ，Jensen MT ，Chelban V ，Goh YY ，Guo T ，Heslegrave AJ ，Roncaroli F ，Klein JC ，Ansorge O ，Allinson KSJ ，Jaunmuktane Z ，Revesz T ，Warner TT ，Lees AJ ，Zetterberg H ，Russell LL ，Bocchetta M ，Rohrer JD ，Burn DJ ，Pavese N ，Gerhard A ，Kobylecki C ，Leigh PN ，Church A ，Hu MTM ，Houlden H ，Morris H ，Rowe JB ... -  《-》

A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes.

Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia. A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), β-amyloid 1-42 (Aβ42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and β (soluble amyloid precursor protein (sAPP)α, sAPPβ) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used. CSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls. A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies.

Magdalinou NK ，Paterson RW ，Schott JM ，Fox NC ，Mummery C ，Blennow K ，Bhatia K ，Morris HR ，Giunti P ，Warner TT ，de Silva R ，Lees AJ ，Zetterberg H ... -  《-》

PSP as distinguished from CBD, MSA-P and PD by clinical and imaging differences at an early stage.

Kurata T ，Kametaka S ，Ohta Y ，Morimoto N ，Deguchi S ，Deguchi K ，Ikeda Y ，Takao Y ，Ohta T ，Manabe Y ，Sato S ，Abe K ... -  《-》

Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders.

Hall S ，Öhrfelt A ，Constantinescu R ，Andreasson U ，Surova Y ，Bostrom F ，Nilsson C ，Håkan W ，Decraemer H ，Någga K ，Minthon L ，Londos E ，Vanmechelen E ，Holmberg B ，Zetterberg H ，Blennow K ，Hansson O ... -  《-》