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.

Baseline Large-Scale Network Dynamics Associated with Disease Progression in Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a genetically determined disease with motor, cognitive, and neuropsychiatric disorders. However, the links between clinical progression and disruptions to dynamics in motor and cognitive large-scale networks are not well established. OBJECTIVE: To investigate changes in dynamic and static large-scale networks using an established tool of disease progression in Huntington's disease, the composite Unified Huntington's Disease Rating Scale (cUHDRS). METHODS: Sixty-four mutation carriers were included. Static and dynamic baseline functional connectivity as well as topological features were correlated to 2-year follow-up clinical assessments using the cUHDRS. RESULTS: Decline in cUHDRS scores was associated with higher connectivity between frontal default-mode and motor networks, whereas higher connectivity in posterior, mainly visuospatial regions was associated with a smaller decline in cUHDRS scores. CONCLUSIONS: Structural disruptions in HD were evident both in posterior parietal/occipital and frontal motor regions, with reciprocal increases in functional connectivity. However, although higher visuospatial network connectivity was tied to a smaller cUHDRS decline, increased motor and frontal default-mode connections were linked to a larger cUHDRS decreases. Therefore, divergent functional compensation mechanisms might be at play in the clinical evolution of HD.

Long-term outcomes of deep brain stimulation for treatment-resistant schizophrenia: Exploring potential targets.

BACKGROUND: Schizophrenia is a complex and disabling disorder. Around 30% of patients have treatment-resistant schizophrenia (TRS). OBJECTIVE: This study summarizes the outcomes after three years follow-up of the first series of patients with TRS treated with deep brain stimulation (DBS) and discuss surgical, clinical and imaging analysis. METHODS: Eight patients with TRS treated with DBS in the nucleus accumbens (NAcc) or the subgenual cingulate gyrus (SCG) were included. Symptoms were rated with the PANSS scale and normalized using the illness density index (IDI). A reduction in IDI-PANSS of ≥25% compared to baseline was the criterion of good response. The volume of activated tissue was calculated to perform a connectomic analysis for each patient. An estimation of the tracts and cortical areas modulated was generated. RESULTS: Five women and three men were analyzed. After 3 years' follow-up, positive symptoms improved in 50% of the SCG group and 75% of the NAcc group (p = 0.06), and general symptoms improved in 25% and 50% respectively (p = 0.06). The SCG group showed activation of the cingulate bundle and modulation of orbitofrontal and frontomesial regions; in contrast, the NAcc group showed activation of the ventral tegmental area projections pathway and modulation of regions associated with the "default mode network" (precuneus) and Brodmann areas 19 and 20. CONCLUSIONS: These results showed a trend toward improvement for positive and general symptoms in patients with TRS treated with DBS. The connectomic analysis will help us understand the interaction of this treatment with the disease to pursue future trial designs.

Cortical macro and microstructural correlates of cognitive and neuropsychiatric symptoms in Parkinson's disease.

BACKGROUND: Cognitive and neuropsychiatric disturbances in Parkinson's disease are as common and as disabling as its well-known motor symptoms. Even though several neural substrates for these symptoms have been suggested, to which extent these symptoms reflect cortical neurodegeneration in Parkinson's disease remains to be fully elucidated. METHODS: In a representative sample of 44 Parkinson's disease patients, the data about the following symptoms was recorded: cognitive performance, apathy, depression and anxiety. Surface-based vertexwise multiple regression analyses were performed to investigate the cortical macro (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of each symptom. A group of 18 healthy controls with similar sociodemographics was also included to assess the disease specificity of the neuroimaging results. RESULTS: Compared to healthy controls, Parkinson's disease patients showed significantly increased scores in all the considered non-motor scales (p < 0.01). Within the Parkinson's disease group, increased scores in these scales were associated with cortical macro- and microstructural neurodegeneration (p < 0.05 corrected). Each of the considered non-motor scales was associated with a specific pattern of cortical degeneration. When observing both neuroimaging techniques, intracortical diffusivity revealed similar but extensive patterns of cortical compromise than cortical thickness for each symptom, with the exception of anxiety. CONCLUSIONS: Cognitive and neuropsychiatric symptoms in Parkinson's disease reflect cortical degeneration. Increases in intracortical diffusivity were able to detect symptom-specific cortical microstructural damage in the absence of cortical thinning. A better understanding of this association may contribute to characterize the brain circuitry and the neurotransmitter pathways underlying these highly prevalent and debilitating symptoms in Parkinson's disease.

Reduplicative paramnesia as an atypical form of presentation of a Heidenhain variant of Creutzfeldt-Jakob disease: A case report.

A previously healthy woman began to present recurrent episodes of reduplicative paramnesia within her home and later structured visual hallucinations. The case was initially oriented as an incipient vascular dementia. Detailed anamnesis and neuropsychological examination suggested a rapidly progressive pattern of neuropsychological deficits mostly attributable to parieto-occipital disturbances with some component of fronto-temporal involvement. Subsequently, cerebellar symptoms were added. Although the initial imaging studies were inconclusive, the MRI performed during follow-up showed a series of findings compatible with a prion disease. Based on the neuropsychological and clinical features and the imaging pattern, the diagnosis of Heidenhain Variant of Creutzfeldt-Jakob disease was established. This is the first report of a Heidenhain Variant of Creutzfeldt-Jakob disease presenting as a reduplicative paramnesia as the first manifestation of this disease.

Predicting Impulse Control Disorders in Parkinson Disease through Incentive Biomarkers.

OBJECTIVE: This study was undertaken to evaluate whether the feedback-related negativity (FRN)-a neurophysiological marker of incentive processing-can be used to predict the development of impulse control disorders (ICDs) in Parkinson disease (PD). METHODS: The longitudinal cohort consisted of consecutive nondemented PD patients with no ICD history. We recorded FRN signals while they performed a gambling task. We calculated the mean amplitude difference between losses and gains (FRNdiff) to be used as a predictor of future ICD development. We performed prospective biannual follow-up assessments for 30 months to detect incident ICDs. Finally, we evaluated how basal FRNdiff was associated with posterior development of ICDs using survival models. RESULTS: Between October 7, 2015 and December 16, 2016, we screened 120 patients. Among them, 94 patients performed the gambling and 92 completed the follow-up. Eighteen patients developed ICDs during follow-up, whereas 74 remained free of ICDs. Baseline FRNdiff was greater in patients who developed ICDs than in those who did not (-2.33µV vs -0.84µV, p = 0.001). No other significant baseline differences were found. The FRNdiff was significantly associated with ICD development in the survival models both when not adjusted (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.58-0.91, p = 0.006) and when controlling for dopamine replacement therapy, sex, and age (HR = 0.74, 95% CI = 0.55-0.97, p = 0.035). None of the impulsivity measures evaluated was related to ICD development. INTERPRETATION: Reward-processing differences measured by FRN signals precede ICD development in PD. This neurophysiological marker permits identification of patients with high risk of ICD development. ANN NEUROL 2022;92:974-984.

The role of attentional control over interference in minor hallucinations in Parkinson's disease.

BACKGROUND: Minor hallucinations in Parkinson's disease are associated with connectivity changes in attentional networks and increased risk of structured hallucinations. However, the clinical translation of these abnormalities in attention processes is not well-defined, and commonly used neuropsychological tests are not able to detect significant deficits in Parkinson's disease patients with isolated minor hallucinations. OBJECTIVES: To analyze the behavioral and electrophysiological correlates of minor hallucinations in Parkinson's disease during an attentional task assessing response inhibition and interference control. METHODS: Fifty-five non-demented Parkinson's disease patients with (PD-mH; n = 27) and without minor hallucinations (PD-NH; n = 28) were included in the analysis. An Ericksen flanker task was performed to compare the effect of presenting congruent and incongruent stimuli on accuracy, reaction times and stimulus-locked event-related potentials morphology. RESULTS: Although both groups showed equivalent performance in a standard neuropsychological assessment, in the flanker task accuracy rates were lower in the PD-mH group in incongruent trials (p = 0.005). In the event-related potentials, PD-mH patients showed increased amplitude of the N2 at Fz [t(53); p < 0.05] and decreased amplitude of the P300 at Pz [t(53); p < 0.05] for the incongruent trials. CONCLUSIONS: Parkinson's disease patients with isolated minor hallucinations were more susceptible to interference mediated by irrelevant stimuli and had less cognitive control for suppressing these interferences. The failure of these systems could precipitate the intrusion and overrepresentation of peripheral irrelevant stimuli perceived as minor hallucinations. The Ericksen flanker task could be used as a sensitive clinical marker of the attentional defects leading to hallucinations in Parkinson's disease.

A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson's Disease.

Background: Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence. Objective: We studied the effects of safinamide on apathy in PD. Methods: Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented PD on stable dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of change, and safety and tolerability measures. Results: In total, 30 participants (active treatment = 15; placebo = 15; 80% showing clinically significant apathetic symptoms according to the AS) were enrolled, and included in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance [p = 0.059] mediated by a more marked decrease in AS score with safinamide (-7.5 ± 6.9) than with placebo (-2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant positive change in the AS score between 12-week and 24-week [p = 0.001] only in the active group. No significant or trend changes were found for any of the secondary outcome variables. Adverse events were few and only mild in both treatment groups. Conclusions: Safinamide was safe and well-tolerated, but failed to provide evidence of improved apathy. The positive trend observed in the post-hoc analyses deserves to be studied in depth in larger studies. Trial Registration: EudraCT 2017-003254-17.

Dissociable contribution of plasma NfL and p-tau181 to cognitive impairment in Parkinson's disease.

BACKGROUND: Cognitive dysfunction is a disabling complication in Parkinson's disease (PD). Accuracy of diagnosis of mild cognitive impairment in PD (PD-MCI) depends on the tests performed, which limits results generalization. Blood-based biomarkers could provide additional objective information for PD-MCI diagnosis and progression. Blood neurofilament light chain (NfL), a marker of neuronal injury, has shown good performance for PD disease stratification and progression. While NfL is not disease-specific, phosphorylated-tau at threonine-181 (p-tau181) in blood is a highly specific marker of concomitant brain amyloid-ß and tau pathology. METHODS: We investigated the potential of plasma NfL and p-tau181 levels as markers of cognitive impairment in a prospective cohort of 109 PD patients with and without PD-MCI (age 68.1 ± 7 years, education 12.2± 5 years), and 40 comparable healthy controls. After a follow-up of 4 years, we evaluated their predictive value for progression to dementia. RESULTS: Although NfL and p-tau181 levels were significantly increased in PD compared with healthy controls, only NfL levels were significantly higher in PD-MCI compared with PD with normal cognition (PD-NC) at baseline. After a follow-up of 4 years, only NfL predicted progression to dementia (HR 1.23, 95% CI 1.02-1.53; p = 0.038). Significant correlations between fluid biomarkers and neuropsychological examination were only found with NfL levels. CONCLUSIONS: Plasma NfL levels objectively differentiates PD-MCI from PD-NC patients, and may serve as a plasma biomarker for predicting progression to dementia in PD. Plasma levels of p-tau181 does not seem to help in differentiating PD-MCI or to predict future cognitive deterioration.

Plasma TDP-43 Reflects Cortical Neurodegeneration and Correlates with Neuropsychiatric Symptoms in Huntington's Disease.

PURPOSE: Huntington's disease (HD) is a monogenic neurodegenerative disease with no effective treatment currently available. The pathological hallmark of HD is the aggregation of mutant huntingtin in the medium spiny neurons of the striatum, leading to severe subcortical atrophy. Cortical degeneration also occurs in HD from its very early stages, although its biological origin is poorly understood. Among the possible pathological mechanisms that could promote cortical damage in HD, the in vivo study of TDP-43 pathology remains to be explored, which was the main objective of this work. METHODS: We investigated the clinical and structural brain correlates of plasma TDP-43 levels in a sample of 36 HD patients. Neuroimaging alterations were assessed both at the macrostructural (cortical thickness) and microstructural (intracortical diffusivity) levels. Importantly, we controlled for mutant huntingtin and tau biomarkers in order to assess the independent role of TDP-43 in HD neurodegeneration. RESULTS: Plasma TDP-43 levels in HD specifically correlated with the presence and severity of apathy (p = 0.003). The TDP-43 levels also reflected cortical thinning and microstructural degeneration, especially in frontal and anterior-temporal regions (p < 0.05 corrected). These TDP-43-related brain alterations correlated, in turn, with the severity of cognitive, motor and behavioral symptoms. CONCLUSION: Our results suggest that the presence of TDP-43 pathology in HD has an independent contribution to the severity of neuropsychiatric symptoms and frontotemporal degeneration. These findings point out the importance of TDP-43 as an additional pathological process to be taken into consideration in this devastating disorder.

A Functional Connectivity Study to Investigate the Role of the Right Anterior Insula in Modulating Emotional Dysfunction in Borderline Personality Disorder.

OBJECTIVE: Previous imaging studies in patients with borderline personality disorder (BPD) have detected functional brain dysfunctions. Mindfulness training may improve the symptoms of BPD, although the neural mechanisms involved remain poorly understood. This study had several key aims: a) to investigate the role of right anterior insula (rAI) functional connectivity in modulating baseline emotional status in BPD, b) to compare differences in connectivity changes after mindfulness training versus interpersonal effectiveness intervention, and c) to explore the correlation between longitudinal changes in imaging data and clinical indicators. METHODS: Thirty-eight patients with BPD underwent resting-state functional magnetic resonance imaging. Participants completed self-report clinical scales and participated in a dialectical-behavioral therapy (mindfulness versus interpersonal effectiveness modules). Changes in clinical and imaging variables were evaluated longitudinally after completion of the first 10-week sessions of psychotherapeutic intervention. RESULTS: At baseline, the rAI was strongly connected with the other salience network nodes and anticorrelated with most core nodes of the default mode network (p < .05, corrected). The functional connectivity of the rAI correlated with emotional dysregulation and deficits in mindfulness capacities (p < .05, corrected). After completion of psychotherapeutic intervention, both groups (mindfulness and interpersonal effectiveness) showed divergent posttherapy functional connectivity changes, which were in turn associated with the clinical response. CONCLUSIONS: The functional connectivity of the rAI seems to play an important role in emotion dysregulation and deficits in mindfulness capacities in individuals with BPD. Psychotherapy seems to modulate this functional connectivity, leading to beneficial changes in clinical variables.

Tipping the scales: how clinical assessment shapes the neural correlates of Parkinson's disease mild cognitive impairment.

Mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with consistent structural and functional brain changes. Whether different approaches for diagnosing PD-MCI are equivalent in their neural correlates is presently unknown. We aimed to profile the neuroimaging changes associated with the two endorsed methods of diagnosing PD-MCI. We recruited 53 consecutive non-demented PD patients and classified them as PD-MCI according to comprehensive neuropsychological examination as operationalized by the Movement Disorders Task Force. Voxel-based morphometry, cortical thickness, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. 18 patients (32%) were classified as PD-MCI with Level-II criteria, 19 (33%) with the Parkinson's disease Cognitive Rating Scale (PD-CRS) and 32 (60%) with the Montreal Cognitive Assessment (MoCA) scale. Though regions of atrophy differed across classifications, reduced gray matter in the precuneus was found using both Level-II and PD-CRS classifications in PD-MCI patients. Patients diagnosed with the PD-CRS also showed extensive changes in cortical thickness, concurring with the MoCA in regions of the cingulate cortex, and again with Level-II regarding cortical thinning in the precuneus. Functional connectivity analysis found higher coherence within salience network regions of interest, and decreased anticorrelations between salience/central executive and default-mode networks in the PD-CRS classification for PD-MCI patients. Graph theoretical metrics showed a widespread decrease in node degree for the three classifications in PD-MCI, whereas betweenness centrality was increased in select nodes of the default mode network (DMN). Clinical and neuroimaging commonalities between the endorsed methods of cognitive assessment suggest a corresponding set of neural correlates in PD-MCI: loss of structural integrity in DMN structures, mainly the precuneus, and a loss of weighted connections in the salience network that might be counterbalanced by increased centrality in the DMN. Furthermore, the similarity of the results between exhaustive Level-II and screening Level-I tools might have practical implications in the search for neuroimaging biomarkers of cognitive impairment in Parkinson's disease.

Structure and Dynamics of Large-Scale Cognitive Networks in Huntington's Disease.

BACKGROUND: Huntington's disease is a neurodegenerative disorder characterized by clinical alterations in the motor, behavioral, and cognitive domains. However, the structure and disruptions to large-scale brain cognitive networks have not yet been established. OBJECTIVE: We aimed to profile changes in large-scale cognitive networks in premanifest and symptomatic patients with Huntington's disease. METHODS: We prospectively recruited premanifest and symptomatic Huntington's disease mutation carriers as well as healthy controls. Clinical and sociodemographic data were obtained from all participants, and resting-state functional connectivity data, using both time-averaged and dynamic functional connectivity, was acquired from whole-brain and cognitively oriented brain parcellations. RESULTS: A total of 64 gene mutation carriers and 23 healthy controls were included; 21 patients with Huntington's disease were classified as premanifest and 43 as symptomatic Huntington's disease. Compared with healthy controls, patients with Huntington's disease showed decreased network connectivity within the posterior hubs of the default-mode network and the medial prefrontal cortex, changes that correlated with cognitive (t = 2.25, P = 0.01) and disease burden scores (t = -2.42, P = 0.009). The salience network showed decreased functional connectivity between insular and supramarginal cortices and also correlated with cognitive (t = 2.11, P = 0.02) and disease burden scores (t = -2.35, P = 0.01). Dynamic analyses showed that network variability was decreased for default-central executive networks, a feature already present in premanifest mutation carriers (dynamic factor 8, P = 0.02). CONCLUSIONS: Huntington's disease shows an early and widespread disruption of large-scale cognitive networks. Importantly, these changes are related to cognitive and disease burden scores, and novel dynamic functional analyses uncovered subtler network changes even in the premanifest stages.

Interaction between sex and neurofilament light chain on brain structure and clinical severity in Huntington's disease.

Female Huntington's disease (HD) patients have consistently shown a faster clinical worsening than male, but the underlying mechanisms responsible for this observation remain unknown. Here, we describe how sex modifies the impact of neurodegeneration on brain atrophy and clinical severity in HD. Cerebrospinal fluid neurofilament light chain (NfL) levels were used as a biological measure of neurodegeneration, and brain atrophy was assessed by structural magnetic resonance imaging. We found that larger NfL values in women reflect higher brain atrophy and clinical severity than in men (p < 0.05 for an interaction model). This differential vulnerability could have important implications in clinical trials.

The impact of dopaminergic treatment over cognitive networks in Parkinson's disease: Stemming the tide?

Dopamine-replacing therapies are an effective treatment for the motor aspects of Parkinson's disease. However, its precise effect over the cognitive resting-state networks is not clear; whether dopaminergic treatment normalizes their functional connectivity-as in other networks- and the links with cognitive decline are presently unknown. We recruited 35 nondemented PD patients and 16 age-matched controls. Clinical and neuropsychological assessments were performed at baseline, and conversion to dementia was assessed in a 10 year follow-up. Structural and functional brain imaging were acquired in both the ON and practical OFF conditions. We assessed functional connectivity in both medication states compared to healthy controls, connectivity differences within participants related to the ON/OFF condition, and baseline connectivity of PD participants that converted to dementia compared to those who did not convert. PD participants showed and increased frontoparietal connectivity compared to controls: a pattern of higher connectivity between salience (SN) and default-mode (DMN) networks both in the ON and OFF states. Within PD patients, this higher SN-DMN connectivity characterized the participants in the ON state, while within-DMN connectivity prevailed in the OFF state. Interestingly, participants who converted to dementia also showed higher SN-DMN connectivity in their baseline ON scans compared to nonconverters. To conclude, PD patients showed higher frontoparietal connectivity in cognitive networks compared to healthy controls, irrespective of medication status, but dopaminergic treatment specifically promoted SN-DM hyperconnectivity.

Quantitative evaluation of oculomotor disturbances in progressive supranuclear palsy.

OBJECTIVES: To explore and quantify systematically the ocular abnormal movements present in progressive supranuclear palsy (PSP) from the early stages, to assess the ability of this standardized examination in the differential diagnosis of PSP from Parkinson's disease (PD), and to compare in more detail oculomotor disturbances between PSP variants. METHODS: Sixty-five consecutive PSP patients with <5 years of disease duration diagnosed according to MDS-PSP criteria, 25 PD patients and 25 controls comparable in age, education and disease duration were explored using a bedside battery of tests for the quantitative evaluation of oculomotor dysfunction in clinical practice. Other accepted scales were used for measurement of motor (PSPRS), cognitive (FAB) and behavioral (FBI) impairment. RESULTS: Measurement of oculomotor dysfunction significantly differentiated PSP from PD and controls (p < 0.001) and showed high accuracy in the differential diagnosis of early-to-mid stage PSP from PD. PSP-Parkinsonism and PSP-Progressive Gait Freezing phenotypes showed more preserved ocular motor function compared to PSP-Richardson Syndrome, although no differences were found between PSP subtypes in the number of square wave jerks, optokinetic nystagmus defects, degree of apraxia of eyelid opening, or presence of the "Round the Houses" sign. CONCLUSIONS: Using a bedside clinical instrument for quantifying oculomotor disturbances in PSP shows promising potential at differentiating PSP from PD, and it seems able to provide a qualitative and quantitative description of ocular motor function in parkinsonian disorders.

Cognitive and behavioral profile of progressive supranuclear palsy and its phenotypes.

BACKGROUND: Although several progressive supranuclear palsy (PSP) phenotypes have recently been described, studies identifying cognitive and neuropsychiatric differences between them are lacking. METHODS: An extensive battery of cognitive and behavioural assessments was administered to 63 PSP patients, 25 PD patients with similar sociodemographic characteristics, and 25 healthy controls. We analysed differences in phenomenology, frequency and severity of cognitive and neuropsychiatric symptoms between PSP, PD and HC, and between PSP subtypes. RESULTS: Regarding phenotypes, 64.6% met criteria for Richardson's syndrome (PSP-RS), 10.7% PSP with predominant Parkinsonism (PSP-P), 10.7% with PSP progressive gait freezing (PSP-PGF), and 10.7% PSP with predominant speech/language disorder (PSP-SL). Impairment was more severe in the PSP group than in the PD and HC groups regarding motor scores, cognitive testing and neuropsychiatric scales. Cognitive testing did not clearly differentiate between PSP phenotypes, but PSP-RS and PSP-SL appeared to have more cognitive impairment than PSP-PGF and PSP-P, mainly due to an increased impairment in frontal executive domains. Regarding neuropsychiatric disturbances, no specific behavior was more common in any of the PSP subtypes. CONCLUSION: Motor deficits delineate the phenotypes included in currently accepted MDS-PSP criteria. Cognition and behavioural disturbances are common in PSP and allow us to distinguish this disorder from other neurological diseases, but they do not differentiate between PSP phenotypes.

Subclinical affective and cognitive fluctuations in Parkinson's disease: a randomized double-blind double-dummy study of Oral vs. Intrajejunal Levodopa.

BACKGROUND: Chronic levodopa treatment in Parkinson's disease (PD) may promote undesirable motor and non-motor fluctuations. Compared to chronic oral levodopa treatment, continuous infusion of levodopa/carbidopa intestinal gel (LCIG) in advanced PD reduces motor fluctuations. However, differences in their effect on acute non-motor changes were not formally demonstrated. OBJECTIVE: We performed a randomized, double-blind, double-dummy, crossover study to compare acute non-motor changes between intermittent oral immediate-release carbidopa/levodopa (LC-IR) and LCIG. METHODS: After > 12-h OFF, thirteen PD patients chronically treated with LCIG and without history of non-motor swings, were allocated to receive first, LCIG infusion plus three oral doses of placebo, or placebo infusion plus three oral doses of LC-IR. Over-encapsulated oral medication (LC-IR or placebo) was administered every 2 h. We monitored plasmatic levels of levodopa, motor status (UPDRS-III), mood, anxiety, and frontal functions at baseline (0-h) and hourly after each oral challenge. RESULTS: Repeated-measures ANOVAs showed significant group by treatment interaction indicating more fluctuations of levodopa plasma levels with LC-IR. No significant interactions were seen in the temporal profile of motor status, anxiety, mood and cognition. However, point-to-point parametric and nonparametric tests showed a significant more marked and more sustained improvement in anxiety scores under LCIG. A significant improvement of mood and verbal fluency was seen a + 3-h only under LCIG. DISCUSSION: Our sample of advanced PD patients exhibited moderate but significant non-motor fluctuations. LCIG was associated with a more favorable profile of acute affective and cognitive fluctuations that was particularly expressed at the first part of the infusion curve.

The Free and Cued Selective Reminding Test in Parkinson's Disease Mild Cognitive Impairment: Discriminative Accuracy and Neural Correlates.

Introduction: Memory alterations are common in Parkinson's disease (PD) patients but the mechanisms involved in these deficits remain poorly understood. The study aims to explore the profile of episodic memory deficits in non-demented early PD patients. Methods: We obtained neurological, cognitive and behavioral data from 114 PD patients and 41 healthy controls (HC). PD participants were grouped as normal cognition (PD-NC) and mild cognitive impairment (PD-MCI) according to the Level II criteria of the Movement Disorders Society Task Force (MDS-TF). We evaluate the performance amongst groups on an episodic memory task using the Free and Cued Selective Reminding Test (FCSRT). Additionally, gray matter volume (GMV) voxel based morphometry, and mean diffusivity (MD) analyses were conducted in a subset of patients to explore the structural brain correlates of FCSRT performance. Results: Performance on all subscores of the FCSRT was significantly worse in PD-MCI than in PD-NC and HC. Delayed total recall (DTR) subscore was the best at differentiating PD-NC from PD-MCI. Using crosstabulation, DTR allowed identification of PD-MCI patients with an accuracy of 80%. Delayed free and cued recall was associated with decreased GMV and increased MD in multiple fronto-temporal and parietal areas. Conclusion: Encoding and retrieval deficits are a main characteristic of PD-MCI and are associated with structural damage in temporal, parietal and prefrontal areas.