Predicting Disability in Progressive Supranuclear Palsy Using Bedside Frontal-Lobe Signs.

BACKGROUND: Frontal lobe signs in progressive supranuclear palsy (PSP) are prevalent and occur early in the disease. Although they are recognized in clinical practice, studies are needed to systematically investigate them for an in-depth understanding of the neurological substrate and their potential prognostic implications in the disease. OBJECTIVES: To study the predictive role of frontal lobe signs in PSP, as well as to describe their neuropsychological and anatomical correlations. METHODS: Nine recognized signs of frontal lobe dysfunction were assessed in 61 patients with PSP. Those signs able to predict PSP Rating Scale (PSPRS) score at baseline were selected, a survival analysis was performed and associations with neuropsychological tests and cortical thickness parameters in brain MRI were studied. RESULTS: Grasping, anosognosia and orobuccal apraxia predicted the PSPRS score independently of age, gender, clinical subtype and disease duration. The occurrence of groping in the first 4 years could be a predictor of survival. Grasping and anosognosia were associated with frontal cognitive dysfunction, whereas orobuccal apraxia and groping were related to a more widespread cognitive impairment, involving temporal-parietal areas. Presence of groping showed an extensive cortical atrophy, with predominant prefrontal, temporal and superior parietal cortical thinning. CONCLUSIONS: Grasping, groping, anosognosia and orobuccal apraxia are easily evaluable bedside clinical signs that reflect distinct stages of disease progression. Grasping, anosognosia and orobuccal apraxia predict disease disability in patients with PSP, and early onset groping could be a survival predictor.

Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies.

Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible and reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin of tauopathies patients, we aimed to exploit the ultrasensitive seeding activity assay (SAA) to assess tau seeding activity in skin of patients with tauopathies. In this multicentric, case-control study, patients with tauopathies and synucleinopathies were consecutively recruited and sex-matched to healthy controls (HC). Subjects underwent a double 3 mm skin biopsy in cervical area and ankle. Skin tau-SAA, using TauK18 and TauK19 as reaction substrates for 4R and 3R isoforms, seeding score, clinical scales, biochemical and morphological characterization of SAA end-products were evaluated. We analyzed 58 subjects: 24 tauopathies (18 progressive supranuclear palsy, PSP, and 6 corticobasal degeneration, CBD), 20 synucleinopathies (14 Parkinson's disease, PD, and 6 multiple system atrophy, MSA), and 14 HC. PSP and CBD showed higher tau seeding activity at both anatomical sites. A greater sensitivity of 4R-SAA than 3R-SAA was observed. 4R tau-SAA identified tauopathies with 71% sensitivity and 93% specificity. Accuracy was higher for PSP than CBD: PSP vs HC / PD (AUC 0.825), while CBD vs HC / PD (AUC 0.797), and PSP vs MSA (AU 0.778). SAA end-products showed differences in biochemical and morphological characterization according to the anatomical site. Skin tau-SAA identifies tauopathies with good accuracy and can be used to implement the in-vivo clinical diagnosis of patients with neurodegenerative diseases. Further characterization of peripheral tau seed in skin may elucidate the structure of tau deposits in brain.

Association Between Orthostatic Hypotension and Dementia in Patients With Parkinson Disease and Multiple System Atrophy.

BACKGROUND AND OBJECTIVES: Orthostatic hypotension (OH) increases dementia risk in patients with Parkinson disease (PD), although the underlying mechanisms and whether a similar association between OH and cognitive impairment exists in other synucleinopathies remain unknown. The aim is to evaluate the association between OH and dementia risk in patients with PD, and cognitive impairment risk in patients with multiple system atrophy (MSA), and to explore relevant clinical and neuropathologic factors to understand underlying pathogenic mechanisms. METHODS: This is a retrospective cohort study. Medical records throughout the entire disease course of consecutive patients with neuropathology-confirmed PD and MSA from the Queen Square Brain Bank were systematically reviewed. Time of onset and severity of OH-related symptoms were documented, and their association with other clinical and neuropathologic variables was evaluated. Dementia risk for patients with PD and cognitive impairment risk for patients with MSA were estimated using multivariable hazard regression. RESULTS: One hundred thirty-two patients with PD and 137 with MSA were included. Patients with MSA developed OH more frequently, earlier in the disease course and with more severe symptoms. Cumulative dementia prevalence was higher in patients with PD. Multivariable adjusted regression models showed that early OH, but not its symptom severity, increased dementia risk in patients with PD by 14% per year (hazard ratio [HR] = 0.86; 95% CI, 0.80-0.93) and cognitive impairment risk in patients with MSA by 41% per year (HR = 0.59; 95% CI, 0.42-0.83). Early OH was not associated with increased α-synuclein, ß-amyloid, tau, Alzheimer, or cerebrovascular pathologies. No significant associations were found between severity of OH symptoms and other clinical or neuropathologic variables. DISCUSSION: Early OH, but not its symptom severity, increases the risk of cognitive impairment in patients with PD and MSA. OH is not associated with more extensive Lewy, ß-amyloid, tau, Alzheimer, or cerebrovascular pathologies. It is likely that OH contributes to cognitive impairment in patients with PD and MSA by hypoxia-induced nonspecific neurodegeneration. Further research should evaluate whether improving brain perfusion by treating OH may modify the risk of dementia in these conditions.

Genotype-Phenotype Correlation in Progressive Supranuclear Palsy Syndromes: Clinical and Radiological Similarities and Specificities.

The progressive supranuclear palsy (PSP) syndrome encompasses different entities. PSP disease of sporadic origin is the most frequent presentation, but different genetic mutations can lead either to monogenic variants of PSP disease, or to other conditions with a different pathophysiology that eventually may result in PSP phenotype. PSP syndrome of monogenic origin is poorly understood due to the low prevalence and variable expressivity of some mutations. Through this review, we describe how early age of onset, family history of early dementia, parkinsonism, dystonia, or motor neuron disease among other clinical features, as well as some neuroimaging signatures, may be the important clues to suspect PSP syndrome of monogenic origin. In addition, a diagnostic algorithm is proposed that may be useful to guide the genetic diagnosis once there is clinical suspicion of a monogenic PSP syndrome.