Atypical parkinsonian syndromes are distinguished from Parkinson's disease (PD) by additional neurological signs and characteristic underlying neuropathology. However, they can be diagnostically challenging, rapidly progressive and are often diagnosed late in disease course. Their different demographic features and prognoses are well studied, but the accompanying cognitive and psychiatric features may also facilitate diagnosis. Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may cause cognitive and behavioural manifestations that overlap with frontotemporal dementia, including non-fluent aphasia, apathy and impulsivity. Clinical diagnostic criteria have limited sensitivity, with pathologically confirmed PSP often having presented an initial clinical syndrome other than PSP-Richardson's syndrome. Here, we integrate cross-sectional multicentre baseline data from the PROSPECT-M-UK and Oxford Discovery cohorts. This allowed us to compare cognitive and psychiatric features across a total of 1138 people with PSP, CBS, multiple-system atrophy (MSA) and idiopathic PD. Data from the different cohorts were harmonized and compared using multiple linear regression. There were five key results: (i) different syndromes showed distinctive cognitive profiles, using readily applicable 'bedside' screening tools. Frontal executive dysfunction was most evident in PSP, visuospatial deficits in CBS, with milder deficits in memory and executive function in MSA, as compared with PD; (ii) the most prevalent neuropsychiatric features were depression and anxiety in CBS, apathy in PSP, with sleep disturbances common in PD. As expected, apathy correlated positively with impulsivity across all disorders. Neuropsychiatric features were generally better at discriminating between atypical parkinsonian syndromes than were the cognitive domains; (iii) both cognitive function and motor severity declined with disease duration, and motor function predicted cognition in PSP, CBS and PD but not in MSA, suggesting that in MSA cognitive and motor dysfunction are decoupled; (iv) plasma neurofilament light chain (NFL) levels, measured in a subset of patients, correlated with cognitive deficits in PSP, but not motor deficits; (v) cognitive deficits contributed to the impairment in activities of daily living after controlling for motor severity, with every two points on the Montreal Cognitive Assessment worsening the Schwab and England score by one point. In anticipation of future neuroprotective therapies, we present a classifier to improve diagnostic accuracy for atypical parkinsonian syndromes in vivo. Longitudinal cohort studies with resources for neuropathological gold standard diagnosis remain important to validate better diagnostic tools for people with PSP, CBD, MSA and atypical parkinsonism.

The history from a relative or caregiver is an important tool for differentiating neurodegenerative disease. We characterized patterns of caregiver questionnaire responses, at diagnosis and follow-up, on the Cambridge Behavioural Inventory (CBI). Data-driven multivariate analysis (n = 4952 questionnaires) was undertaken for participants (n = 2481) with Alzheimer's disease (typical/amnestic n = 543, language n = 50, and posterior cortical n = 50 presentations), Parkinson's disease (n = 740), dementia with Lewy bodies (n = 55), multiple system atrophy (n = 55), progressive supranuclear palsy (n = 422), corticobasal syndrome (n = 176), behavioral variant frontotemporal dementia (n = 218), semantic (n = 125) and non-fluent variant progressive aphasia (n = 88), and motor neuron disease (n = 12). Item-level support vector machine learning gave high diagnostic accuracy between diseases (area under the curve mean 0.83), despite transdiagnostic changes in memory, behavior, and everyday function. There was progression in CBI subscores over time, which varied by diagnosis. Our results highlight the differential diagnostic information for a wide range of neurodegenerative diseases contained in a simple, structured collateral history. We analyzed 4952 questionnaires from caregivers of 2481 participants with neurodegenerative disease. Behavioral and neuropsychiatric manifestations of neurodegenerative disease had overlapping diagnostic boundaries. Simple questionnaire response patterns were sufficient for accurate diagnosis of each disease. We reinforce the value of a collateral history to support a diagnosis of dementia. The Cambridge Behavioural Inventory is sensitive to change over time and suitable as an outcome measure in clinical trials.

Language impairments, hallmarks of speech/language variant progressive supranuclear palsy, also occur in Richardson's syndrome (PSP-RS). Impaired communication may interfere with daily activities. Therefore, assessment of language functions is crucial. It is uncertain whether the Aachen Aphasia Test (AAT) is practicable in PSP-RS, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's dementia (AD) and language deficits differ in these disorders. 28 PSP-RS, 24 AD, and 24 bvFTD patients were investigated using the AAT and the CERAD-Plus battery. 16-25% of all patients failed in AAT subtests for various reasons. The AAT syndrome algorithm diagnosed amnestic aphasia in 5 (23%) PSP-RS, 7 (36%) bvFTD and 6 (30%) AD patients, Broca aphasia in 1 PSP-RS and 1 bvFTD patient, Wernicke aphasia in 1 bvFTD and 3 (15%) AD patients. However, aphasic symptoms resembled non-fluent primary progressive aphasia in 14 PSP-RS patients. In up to 46% of PSP-RS patients, 61% of bvFTD and 64% of AD patients significant impairments were found in the AAT subtests spontaneous speech, written language, naming, language repetition, language comprehension and the Token subtest. The CERAD-Plus subtest semantic fluency revealed significant impairment in 81% of PSP-RS, 61% of bvFTD, 44% of AD patients, the phonemic fluency subtest in 31, 40 and 31%, respectively. In contrast to bvFTD and AD, severity of language impairment did not correlate with cognitive decline in PSP-RS. In summary, the patterns of aphasia differ between the diagnoses. Local frontal language networks might be impaired in PSP-RS, whereas in AD and bvFTD, more widespread neuropathology might underly language impairment.

Although commonly known as movement disorders, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may present with changes in speech and language alongside or even before motor symptoms. The differential diagnosis of these two disorders can be challenging, especially in the early stages. Here we review their impact on speech and language. We discuss the neurobiological and clinical-phenomenological overlap of PSP and CBS with each other, and with other disorders including non-fluent agrammatic primary progressive aphasia and primary progressive apraxia of speech. Because language impairment is often an early and persistent problem in CBS and PSP, there is a need for improved methods for language screening in primary and secondary care, and more detailed language assessments in tertiary healthcare settings. Improved language assessment may aid differential diagnosis as well as inform clinical management decisions.

Frontotemporal lobar degeneration (FTLD) is a neuropathological construct with multiple clinical presentations, including the behavioural variant of frontotemporal dementia (bvFTD), primary progressive aphasia-both non-fluent variant (nfvPPA) and semantic variant (svPPA)-progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), characterised by the deposition of abnormal tau protein in the brain. A major challenge for treating FTLD is early diagnosis and accurate discrimination among different syndromes. The main goal here was to investigate the cortical architecture of FTLD syndromes using cortical diffusion tensor imaging (DTI) analysis and to test its power to discriminate between different clinical presentations. A total of 271 individuals were included in the study: 87 healthy subjects (HS), 31 semantic variant primary progressive aphasia (svPPA), 37 behavioural variant (bvFTD), 30 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), 47 PSP Richardson's syndrome (PSP-RS) and 39 CBS cases. 3T MRI T1-weighted images and DTI scans were analysed to extract three cortical DTI derived measures (AngleR, PerpPD and ParlPD) and mean diffusivity (MD), as well as standard volumetric measurements. Whole brain and regional data were extracted. Linear discriminant analysis was used to assess the group discrimination capability of volumetric and DTI measures to differentiate the FTLD syndromes. In addition, in order to further investigate differential diagnosis in CBS and PSP-RS, a subgroup of subjects with autopsy confirmation in the training cohort was used to select features which were then tested in the test cohort. Three different challenges were explored: a binary classification (controls vs all patients), a multiclass classification (HS vs bvFTD vs svPPA vs nfvPPA vs CBS vs PSP-RS) and an additional binary classification to differentiate CBS and PSP-RS using features selected in an autopsy confirmed subcohort. Linear discriminant analysis revealed that PerpPD was the best feature to distinguish between controls and all patients (ACC 86%). PerpPD regional values were able to classify correctly the different FTLD syndromes with an accuracy of 85.6%. The PerpPD and volumetric values selected to differentiate CBS and PSP-RS patients showed a classification accuracy of 85.2%. (I) PerpPD achieved the highest classification power for differentiating healthy controls and FTLD syndromes and FTLD syndromes among themselves. (II) PerpPD regional values could provide an additional marker to differentiate FTD, PSP-RS and CBS.