Locus Coeruleus Integrity Is Linked to Response Inhibition Deficits in Parkinson's Disease and Progressive Supranuclear Palsy.

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of "race models" of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer nondecision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioral modeling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioral changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimization of noradrenergic treatment is likely to benefit from stratification according to LC integrity.SIGNIFICANCE STATEMENT Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson's disease and progressive supranuclear palsy. We used cognitive modeling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson's disease and progressive supranuclear palsy.

The Cognitive Profile of Atypical Parkinsonism: A Meta-Analysis.

Atypical Parkinsonism (AP) syndromes are characterized by a wide spectrum of non-motor symptoms including prominent attentional and executive deficits. However, the cognitive profile of AP and its differences and similarities with that of Parkinson's Disease (PD) are still a matter of debate. The present meta-analysis aimed at identifying patterns of cognitive impairment in AP by comparing global cognitive functioning, memory, executive functions, visuospatial abilities, language, non-verbal reasoning, and processing speed test performances of patients with AP relative to healthy controls and patients with PD. All investigated cognitive domains showed a substantial impairment in patients with AP compared to healthy controls. When AP syndromes were considered separately, their cognitive functioning was distributed along a continuum from Multiple Systemic Atrophy at one extreme, with the least impaired cognitive profile (similar to that observed in PD) to Progressive Supranuclear Palsy, with the greatest decline in global cognitive and executive functioning (similar to Corticobasal Syndrome). These findings indicate that widespread cognitive impairment could represent an important clinical indicator to distinguish AP from other movement disorders.

Qualitative evaluation of the Rey-Osterrieth Complex Figure Test in patients with progressive supranuclear palsy.

Objective: In early stages of disease, the differential diagnosis between Parkinson's Disease (PD) and atypical parkinsonism, such as Progressive Supranuclear Palsy (PSP), could be challenging. Growing attention has recently been dedicated to investigating neuropsychological markers of degenerative parkinsonism. The Rey-Osterrieth Complex Figure Test (ROCFT) copy score was hypothesized able to differentiate PSP from PD. However, ROCFT is a drawing test requiring multiple cognitive abilities and it is still unknown which of them assumes an important role in PSP performance. Using a qualitative scoring system, we investigated which cognitive abilities underpin the PSP performance at the ROCFT copy trial. Moreover, we evaluated usefulness of the BQSS scores in discriminating PSP from PD. Methods: Thirty PSP-Richardson's Syndrome (PSP-RS) patients, 30 PD patients, and 30 healthy control (HC) comparable for age, education, and gender were enrolled. All subjects underwent a neuropsychological evaluation; ROCFT copy were evaluated with the 36-Point Score and with the Boston Qualitative Scoring System (BQSS). Results: PSP-RS patients performed worse in ROCFT 36-Point Score and in several BQSS scores compared to other groups. Most suitable scores discriminating PSP-RS from PD were "Perseveration" and "Vertical Expansion" of BQSS. A logistic regression model considering "Perseveration" and "Vertical Expansion" showed a diagnostic accuracy of 83,3% for PSP-RS condition. Conclusion: our findings showed that "Perseveration" and "Vertical Expansion" BQSS scores were useful in discriminating PSP-RS from PD. "Perseveration" and "Vertical Expansion" BQSS scores might be included in the cognitive evaluation along with quantitative scores when PSP diagnosis is considered.

I'm looking through you: Mentalizing in frontotemporal dementia and progressive supranuclear palsy.

Mentalizing and emotion recognition are impaired in behavioral variant frontotemporal dementia (bvFTD). It is not clear whether these abilities are also disturbed in other conditions with prominent frontal lobe involvement, such as progressive supranuclear palsy (PSP). Our aim was to investigate social cognition (facial emotion recognition, recognition of social norms violation and mentalizing) in bvFTD and PSP. The neural basis of these functions in PSP and bvFTD groups, by analysis of structural neuroimaging, were also investigated. Twenty-three bvFTD patients, 21 PSP patients and 23 healthy controls were included. All participants underwent 3T brain MRI and a full cognitive exam including the short version of Social and Emotional Assessment (Mini-SEA), which is composed of a facial emotion recognition test (FERT) and the faux pas test. Two components of the faux pas test were distinguished: a score assessing the recognition of social norms violation and a score assessing mentalizing. Compared to controls, bvFTD and PSP patients had significantly reduced scores in all tests of social cognition but did not differ on these measures. PSP and bvFTD had cerebral atrophy in critical regions for social cognition processes, when compared to controls. The cortical correlates of emotion recognition partially overlapped in bvFTD and PSP, with correlations retrieved within the frontal medial cortex, cingulate, insula and limbic structures. PSP and bvFTD patients also displayed similar patterns of brain correlations for the composite score of social norms, with a significant cluster in anterior temporal lobes. Mentalizing scores were associated with frontal and temporal poles bilaterally, in both bvFTD and PSP. These findings support previous observations that PSP patients exhibit impairment in complex cognitive abilities, such as mentalizing. Moreover, these data extend previous findings showing that PSP and bvFTD share key clinical, cognitive and neuroimaging features.

Computer Aided Written Character Feature Extraction in Progressive Supranuclear Palsy and Parkinson's Disease.

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are neurodegenerative movement disorders associated with cognitive dysfunction. The Luria's Alternating Series Test (LAST) is a clinical tool sensitive to both graphomotor problems and perseverative tendencies that may suggest the dysfunction of prefrontal and/or frontostriatal areas and may be used in PD and PSP assessment. It requires the participant to draw a series of alternating triangles and rectangles. In the study, two clinical groups-51 patients with PD and 22 patients with PSP-were compared to 32 neurologically intact seniors. Participants underwent neuropsychological assessment. The LAST was administered in a paper and pencil version, then scanned and preprocessed. The series was automatically divided into characters, and the shapes were recognized as rectangles or triangles. In the feature extraction step, each rectangle and triangle was regarded both as an image and a two-dimensional signal, separately and as a part of the series. Standard and novel features were extracted and normalized using characters written by the examiner. Out of 71 proposed features, 51 differentiated the groups (p < 0.05). A classifier showed an accuracy of 70.5% for distinguishing three groups.

Imaging correlates of depression in progressive supranuclear palsy.

Depression is highly common in Progressive Supranuclear Palsy (PSP) and is a meaningful determinant of quality of life. However, neurobiological and neuroimaging correlates of this neuropsychiatric disturbance in PSP patients are still unknown. In this study, we aimed to investigate the topographical distribution of morphometric changes associated with depression in PSP patients using cortical thickness. Forty patients with PSP were evaluated at baseline with clinical rating scales and MRI scans. Based on the response to the 15-item Geriatric Depression Scale we identified 21 PSP patients with depression (GDS-15 score ≥ 5) and 19 PSP patients without depression (GDS-15 score < 5). In vertex-wise analysis, comparison of cortical thickness between PSP patients with and without depression was performed using a general linear model. PSP patients with depressions showed reduced cortical thickness in temporo-parieto-occipital areas, more pronounced in the right hemisphere. These findings propose neurobiological conceptualizations of depression in PSP as being associated with a multiregional pattern of morphometric grey matter reduction.

Development of a cognitive composite for measuring change in progressive supranuclear palsy.

INTRODUCTION: Individuals with progressive supranuclear palsy (PSP) experience cognitive changes that are challenging to follow without a validated neuropsychological test battery to measure progression. This study describes a composite measure to evaluate cognition in individuals with PSP. METHODS: Baseline cognitive test data from 486 participants with PSP in the PASSPORT (NCT03068468) study included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Color Trails Test (CTT) parts 1 and 2, letter-number sequencing, and letter fluency. Data were analyzed using summary statistics and a matrix of Pearson correlations. A hypothetical factor structure was constructed and validated. RESULTS: Observed correlations were highest for scores between story memory and story recall (correlation coefficient = 0.78) and lowest for scores between letter fluency and picture naming (correlation coefficient = 0.11), and picture naming and figure copy (correlation coefficient = 0.12). After excluding picture naming and Color Trails Test (CTT) parts 1 and 2, a 3-factor structure was hypothesized for the remaining 13 tests. Confirmatory factor analysis demonstrated goodness of fit within acceptable limits (comparative fit index and Tucker-Lewis index = 0.98, standardized root-mean-square residual and root-mean-square error of approximation = 0.05-0.06). Mixed-model repeated-measures analysis of change from baseline to week 52 in RBANS and PSP cognitive composite score produced mean-to-standard-deviation ratios of 0.418 and 0.780, respectively. CONCLUSIONS: This novel composite endpoint, based on RBANS and designed to account for motor impairments in PSP, improves on current cognitive assessments PSP.

Altered network stability in progressive supranuclear palsy.

The clinical syndromes of Progressive Supranuclear Palsy (PSP) may be mediated by abnormal temporal dynamics of brain networks, due to the impact of atrophy, synapse loss and neurotransmitter deficits. We tested the hypothesis that alterations in signal complexity in neural networks influence short-latency state transitions. Ninety-four participants with PSP and 64 healthy controls were recruited from two independent cohorts. All participants underwent clinical and neuropsychological testing and resting-state functional MRI. Network dynamics were assessed using hidden Markov models and neural signal complexity measured in terms of multiscale entropy. In both cohorts, PSP increased the proportion of time in networks associated with higher cognitive functions. This effect correlated with clinical severity as measured by the PSP-rating-scale, and with reduced neural signal complexity. Regional atrophy influenced abnormal brain-state occupancy, but abnormal network topology and dynamics were not restricted to areas of atrophy. Our findings show that the pathology of PSP causes clinically relevant changes in neural temporal dynamics, leading to a greater proportion of time in inefficient brain-states.

Salience driven attention is pivotal to understanding others' intentions.

Interpreting others' beliefs, desires and intentions is known as "theory of mind" (ToM), and is often evaluated using simplified measurement tools, which may not correctly reflect the brain circuits that are required for real-life ToM functioning. We aimed to identify the brain structures necessary to correctly infer intentions from realistic scenarios by administering The Awareness of Social Inference Test, Enriched subtest to 47 patients with behavioural variant frontotemporal dementia, 24 patients with progressive supranuclear palsy syndrome, 31 patients with Alzheimer's syndrome, and 77 older healthy controls. Neuroimaging data was analyzed using voxel based morphometry, and participants' understanding of intentions was correlated with voxel-wise and region-of interest data. We found that structural integrity of the cinguloinsular cortex in the salience network (SN) was more pivotal for accurate ToM than previously described, emphasizing the importance of the SN for selectively recognizing and attending to social cues during ToM inferences.

Patient and care partner views on exercise and structured physical activity for people with Progressive Supranuclear Palsy.

INTRODUCTION: Progressive Supranuclear Palsy (PSP) is a debilitating form of atypical Parkinsonism. People living with PSP experience movement disorders affecting walking, balance and eye movements. The role of exercise in optimising movement remains unclear. AIMS: To identify beliefs about exercise and structured physical activity through the experience of people with PSP. METHODS: Using a phenomenological theoretical framework, qualitative methods were employed to obtain the views of people living with PSP, and their care partners, by in-depth interviews. Questions derived from a systematic review and expert opinions guided the interviews which were audio-recorded, transcribed and de-identified. Two researchers independently conducted thematic analysis and reached consensus on emerging themes. RESULTS: There were 16 participants. Four themes were identified: (i) there are beliefs and preferences about exercise and physical activity that can impact on engagement; (ii) difficulty coping with disease progression impacts activities; (iii) facilitators to exercise include individual preferences, access to facilities and expert advice; and (iv) perceived barriers include beliefs about limited exercise options, falls risk, cost, transport and access to credible information. DISCUSSION: People living with PSP want early guidance about the condition and the role of exercise. It is important to quickly enable people to have access to evidence and resources supporting exercise and structured physical activities. Consideration of individual preferences and access to expert advice facilitate engagement. Individual barriers need to be identified and solutions found. CONCLUSION: People living with PSP are amenable to exercise, especially early in the disease process. Clear guidelines are warranted to document which exercises, and physical activities are most beneficial.

Cognitive decline on the Repeatable Battery for the Assessment of Neuropsychological Status in progressive supranuclear palsy.

Objective: Progressive supranuclear palsy (PSP) is associated with a variety of cognitive deficits, but few studies have reported on its cognitive trajectory across time, especially on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).Methods: Two hundred twenty participants diagnosed with Richardson's syndrome of PSP (PSP-RS) were evaluated with the RBANS at baseline, six months, and one year with alternate forms.Results: When using dependent t-tests, significant declines were observed on all Indexes of the RBANS from baseline to six months (ps < 0.01). Between six months and one year, significant declines were observed on three Indexes of the RBANS (ps < 0.05). Using existing regression-based change formulae from cognitively intact older adults, these participants with PSP showed significant decline on all RBANS Indexes (ps < 0.01) across one year. Finally, new regression-based change formulae were developed on this sample of individuals with PSP-RS to more precisely evaluate cognitive change in this condition.Conclusion: In this large, longitudinal cohort of participants with PSP-RS, many (but not all) showed notable cognitive decline across six months and one year on the RBANS. The different methods of examining change across time yielded different results, with regression-based methods appearing to more accurately capture decline in this sample. These findings are expected to allow clinicians to more accurately evaluate cognitive trajectories in patients with PSP, as well as make better estimates of prognosis and offer more appropriate treatment recommendations. Such findings are also expected to inform clinical trials as to the changes in cognitive outcomes with this neurological condition.

Alexithymia and anhedonia in early Richardson's syndrome and progressive supranuclear palsy with predominant parkinsonism.

INTRODUCTION: Phenotypic variants of progressive supranuclear palsy (PSP) are all characterized by the combination of motor symptoms of parkinsonism with a number of neuropsychiatric and cognitive disorders. Despite the strong effort in characterizing these features in PSP, alexithymia and anhedonia have not been investigated at present. Here, we aimed at investigating the qualitative and quantitative differences of alexithymia and anhedonia in the two more frequent variants of PSP, Richardson's syndrome (PSP-RS) and PSP with predominant parkinsonism (PSP-P) compared to Parkinson's disease (PD) patients recruited within 24 months after the onset of motor symptoms. METHODS: One hundred fifty-five PD, 11 PSP-P, and 14 PSP-RS patients underwent clinical, neuropsychiatric, and neuropsychological evaluations. Alexithymia was assessed using the Toronto Alexithymia Scale-20 item (TAS-20), and hedonic tone was measured by the Snaith-Hamilton Pleasure Scale (SHAPS). RESULTS: In PSP-P and PSP-RS patients, the frequency of alexithymia diagnosis was higher than in PD. On the TAS-20 scores, PSP-RS performed worse in the total score and in F2 sub-scale when compared to PD. Among patients with diagnosis of depression, PSP-RS showed higher scores in TAS-20 total and TAS-20 F2 than PD. No significant differences in TAS-20 scores were found in nondepressed patients. Finally, we did not find significant differences among PD, PSP-P, and PSP-RS groups in the SHAPS scores. CONCLUSIONS: Alexithymia is identifiable very early in PSP-P and PSP-RS patients. Alexithymic symptoms differentiate PSP-RS group from PD group but not between the two subtypes of PSP. Further, alexithymia in PSP seems to be predicted by the presence of depression. Altered emotional capability could be related to specific neurophysiological dysfunction occurring precociously in PSP; therefore, its identification could orient the diagnosis toward PSP cases.

Language boosting by transcranial stimulation in progressive supranuclear palsy.

OBJECTIVE: To explore whether transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) can improve language capacities in patients with progressive supranuclear palsy (PSP). METHODS: We used a sham-controlled double-blind crossover design to assess the efficiency of tDCS over the DLPFC in a cohort of 12 patients with PSP. In 3 separate sessions, we evaluated the ability to boost the left DLPFC via left-anodal (excitatory) and right-cathodal (inhibitory) tDCS, while comparing them to sham tDCS. Tasks assessing lexical access (letter fluency task) and semantic access (category judgment task) were applied immediately before and after the tDCS sessions to provide a marker of potential language modulation. RESULTS: The comparison with healthy controls showed that patients with PSP were impaired on both tasks at baseline. Contrasting poststimulation vs prestimulation performance across tDCS conditions revealed language improvement in the category judgment task following right-cathodal tDCS, and in the letter fluency task following left-anodal tDCS. A computational finite element model of current distribution corroborated the intended effect of left-anodal and right-cathodal tDCS on the targeted DLPFC. CONCLUSIONS: Our results demonstrate tDCS-driven language improvement in PSP. They provide proof-of-concept for the use of tDCS in PSP and set the stage for future multiday stimulation regimens, which might lead to longer-lasting therapeutic effects promoted by neuroplasticity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with PSP, tDCS over the DLPFC improves performance in some language tasks.

Fronto-parietal contributions to episodic retrieval-evidence from neurodegenerative disorders.

Converging evidence suggests a critical role for the parietal cortices in episodic memory retrieval. Here, we examined episodic memory performance in Corticobasal Syndrome (CBS), a rare neurodegenerative disorder presenting with early parietal atrophy in the context of variable medial temporal lobe damage. Forty-four CBS patients were contrasted with 29 typical Alzheimer's disease (AD), 29 healthy Controls, and 20 progressive supranuclear palsy patients presenting with brainstem atrophy as a disease control group. Participants completed standardized assessments of verbal episodic memory (learning, delayed recall, and recognition), and underwent structural and diffusion-weighted MRI. Selective delayed recall deficits were evident in the CBS group relative to Controls, at an intermediate level to the stark amnesia displayed by AD, and Control-level performance noted in progressive supranuclear palsy. Considerable variability within the CBS group on delayed recall performance led to the identification of memory-spared (N = 19) and memory-impaired (N = 25) subgroups. Whereas CBS-Spared showed no significant memory deficits, the CBS-Impaired subgroup were indistinguishable from typical AD across all episodic memory measures. Whole-brain voxel-based morphometry analyses implicated fronto-parietal and medial temporal regions in delayed recall performance in both the CBS-Impaired and AD groups. Furthermore, diffusion tensor imaging analyses revealed correlations between delayed recall performance and altered structural connectivity between fronto-parietal and frontotemporal regions in the CBS-Impaired group. Our findings underscore the importance of a distributed brain network including frontal, medial temporal, and parietal brain regions in supporting the capacity for successful episodic memory retrieval.

Stimulation over the cerebellum with a regular figure-of-eight coil induces reduced motor cortex inhibition in patients with progressive supranuclear palsy.

OBJECTIVE: To determine whether motor cortex inhibition by stimulation over the cerebellum with a figure-of eight coil (MISC8) may be reduced in patients with Progressive Supranuclear Palsy (PSP). METHODS: Paired pulse TMS was used to evaluate MISC8, in patients with different forms of parkinsonism and dementia. The primary outcome measures were sensitivity and specificity of motor cortex inhibition, derived from receiver operator curve analysis, in discriminating PSP from other neurodegenerative disorders. RESULTS: A total of 150 participants met inclusion criteria. According to clinical criteria, the study population included 19 PSP, 26 Parkinson's disease, 25 dementia with Lewy bodies, 15 corticobasal syndrome, 25 frontotemporal dementia and 15 Alzheimer's disease patients, and 25 healthy controls. PSP patients were characterized by a specific impairment of MISC8 (0.99 ±â€¯0.08) compared to the healthy control group and to other neurodegenerative disorders (mean range = 0.63-0.80, all p-values<0.001). Using the best cut-off index, MISC8 differentiated PSP from other diagnoses with an overall sensitivity of 100%, a specificity of 94%, and an accuracy of 97%. CONCLUSIONS: TMS is a non-invasive procedure which reliably distinguishes PSP from other neurodegenerative disorders. MISC8 could represent a useful additional diagnostic tool to be used in clinical practice.

Factors that predict diagnostic stability in neurodegenerative dementia.

OBJECTIVE: To determine the frequency and characteristics of clinical diagnostic change in frontotemporal dementia (FTD)-spectrum syndromes and Alzheimer's disease (AD)-type dementia. METHODS: We reviewed records and categorized diagnostic changes in patients seen ≥ 2 times with behavioral variant FTD (bvFTD, n = 99), nonfluent and semantic variant primary progressive aphasia (nfvPPA, n = 32; svPPA, n = 59), corticobasal syndrome (CBS, n = 40), progressive supranuclear palsy-Richardson syndrome (PSP-RS, n = 34), and AD-type dementia (n = 49). For bvFTD, we compared patients with and without diagnostic change, and assessed predictors of diagnostic change by logistic regression. RESULTS: Initial diagnoses changed infrequently at subsequent visits in svPPA (6.8%), PSP-RS (8.8%), and nfvPPA (12.5%), with rare changes largely involving clinicopathological overlap or diagnostic ambiguity. Changes in AD-type dementia (30.6%) and CBS (37.5%) were more common, but reflected greater specificity, predicted co-pathology, or overlapping syndromes. Diagnostic change in bvFTD was also common (32.3%), but more diverse, including motor neuron disease development, alternative neurodegenerative syndromes, and non-neurodegenerative diseases. Diagnostic change occurred more often in those who met possible rather than probable bvFTD criteria (70.6% vs 15.3%, p < 0.001). Patients with stable diagnoses showed greater overall impairment, bvFTD behavioral severity, and atrophy in core right-hemisphere bvFTD regions. Patients with diagnostic change had more severe depression (p < 0.05) and more frequent contributing, secondary diagnoses (p = 0.01), such as cerebrovascular disease. By logistic regression, the accuracy of predicting stable bvFTD diagnoses using first-visit data was 80%. CONCLUSION: bvFTD displays more diverse diagnostic change than other neurodegenerative syndromes. First-visit bvFTD diagnoses may waver if based on meeting possible criteria only.

Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial.

BACKGROUND: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. METHODS: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41-86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. FINDINGS: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. INTERPRETATION: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. FUNDING: Bristol-Myers Squibb, Biogen.

Motor, cognitive and behavioral differences in MDS PSP phenotypes.

INTRODUCTION: Movement Disorder Society (MDS) new diagnostic criteria for Progressive Supranuclear palsy (PSP) identifying different disease phenotypes were recently released. The aim of the present study is to report on the cognitive and behavioral features of the different phenotypes diagnosed according to the MDS criteria. METHODS: Forty-nine PSP patients underwent an extensive battery of clinical assessments. Differences between PSP subtypes were computed with χ2 or ANOVA tests. Using the z scores, subjects were classified as having normal cognition, mild cognitive impairment, single or multiple domain, and dementia. A logistic regression model was implemented to investigate the major determinants of PSP non-Richardson's syndrome phenotype. RESULTS: Half of the cohort presented Richardson's syndrome (46.9%), followed by PSP with parkinsonism and corticobasal syndrome (22.4% and 14.2%, respectively). Richardson's syndrome and PSP with corticobasal syndrome presented a similar burden of disease. The only cognitive testing differentiating the phenotypes were semantic fluency and ideomotor apraxia. The majority of our cohort was either affected by dementia or presented normal cognition. Richardson's syndrome presented the highest rate of dementia. The only marker of PSP non-Richardson's syndrome phenotype was better performance in visuo-spatial testing, implying worse visuo-spatial abilities in PSP Richardson's syndrome. CONCLUSION: Available clinical assessments hardly capture differences between PSP phenotypes. The cognitive testing differentiating the PSP phenotypes were semantic fluency and ideomotor apraxia. In PSP, mild cognitive impairment likely represents an intermediate step from normal cognition to dementia. The only marker of PSP non-Richardson's syndrome phenotype was better performance in visuo-spatial testing.