Pilot therapeutic education program in multiple system atrophy: Safety, quality of life and satisfaction from a national registry based longitudinal study.

BACKGROUND: Therapeutic education programs are effective in several chronic conditions. However, evidence is lacking in multiple system atrophy (MSA). We aimed to assess efficacy and safety of a comprehensive therapeutic education program in people with MSA (PwMSA) and their caregivers. METHODS: In this prospective longitudinal study we included 16 PwMSA and their main caregivers in 4 groups of 4 dyads each. The program consisted of eight 60-min interdisciplinary sessions: introduction, orthostatic hypotension, speech therapy, gait and respiratory physiotherapy, psychological support, urinary dysfunction, occupational therapy/social work. UMSARS, NMSS, PDQ39, EQ5 and Zarit scales were administered at baseline and 6 months later. After each session participants filled-out a modified EduPark satisfaction questionnaire and a Likert scale. Educational material was generated for each session after suggestions by participants. RESULTS: At baseline PwMSA and caregivers were comparable in age and sex, with significant correlation between UMSARS-IV (disability) and PDQ39 (quality of life). Adherence to sessions was of 94,92 %. Total modified EduPark scores and Likert scales did not differ in PwMSA vs. caregivers, mild-moderate vs. severe-advanced cases or between genders. The significant difference in satisfaction across sessions (p = 0.03) was driven by higher scores in speech, respiratory and occupational therapy sessions. Longitudinally there was no significant worsening in any scale, nor a significant increase post-vs. pre-program in the number of consultations. CONCLUSIONS: The healthcare education program in MSA was feasible, satisfactory, and safe for patients and caregivers. The educational material of the program is being forwarded to incident MSA cases attending our clinic.

Midbrain and pons MRI shape analysis and its clinical and CSF correlates in degenerative parkinsonisms: a pilot study.

OBJECTIVES: To conduct brainstem MRI shape analysis across neurodegenerative parkinsonisms and control subjects (CS), along with its association with clinical and cerebrospinal fluid (CSF) correlates. METHODOLOGY: We collected demographic and clinical variables, performed planimetric and shape MRI analyses, and determined CSF neurofilament-light chain (NfL) levels in 84 participants: 11 CS, 12 with Parkinson's disease (PD), 26 with multiple system atrophy (MSA), 21 with progressive supranuclear palsy (PSP), and 14 with corticobasal degeneration (CBD). RESULTS: MSA featured the most extensive and significant brainstem shape narrowing (that is, atrophy), mostly in the pons. CBD presented local atrophy in several small areas in the pons and midbrain compared to PD and CS. PSP presented local atrophy in small areas in the posterior and upper midbrain as well as the rostral pons compared to MSA. Our findings of planimetric MRI measurements and CSF NfL levels replicated those from previous literature. Brainstem shape atrophy correlated with worse motor state in all parkinsonisms and with higher NfL levels in MSA, PSP, and PD. CONCLUSION: Atypical parkinsonisms present different brainstem shape patterns which correlate with clinical severity and neuronal degeneration. In MSA, shape analysis could be further explored as a potential diagnostic biomarker. By contrast, shape analysis appears to have a rather limited discriminant value in PSP. KEY POINTS: • Atypical parkinsonisms present different brainstem shape patterns. • Shape patterns correlate with clinical severity and neuronal degeneration. • In MSA, shape analysis could be further explored as a potential diagnostic biomarker.

Combined CSF α-SYN RT-QuIC, CSF NFL and midbrain-pons planimetry in degenerative parkinsonisms: From bedside to bench, and back again.

INTRODUCTION: Differential diagnosis between Parkinson's disease (PD) and atypical parkinsonisms (APs: multiple system atrophy[MSA], progressive supranuclear palsy[PSP], corticobasal degeneration[CBD]) remains challenging. Lately, cerebrospinal fluid (CSF) studies of neurofilament light-chain (NFL) and RT-QuIC of alpha-synuclein (α-SYN) have shown promise, but data on their combination with MRI measures is lacking. OBJECTIVE: (1) to assess the combined diagnostic ability of CSF RT-QuIC α-SYN, CSF NFL and midbrain/pons MRI planimetry in degenerative parkinsonisms; (2) to evaluate if biomarker-signatures relate to clinical diagnoses and whether or not unexpected findings can guide diagnostic revision. METHODS: We collected demographic and clinical data and set up α-SYN RT-QuIC at our lab in a cross-sectional cohort of 112 participants: 19 control subjects (CSs), 20PD, 37MSA, 23PSP, and 13CBD cases. We also determined CSF NFL by ELISA and, in 74 participants (10CSs, 9PD, 26MSA, 19PSP, 10CBD), automatized planimetric midbrain/pons areas from 3T-MRI. RESULTS: Sensitivity of α-SYN RT-QuIC for PD was 75% increasing to 81% after revisiting clinical diagnoses with aid of biomarkers. Sensitivity for MSA was 12% but decreased to 9% with diagnostic revision. Specificities were 100% against CSs, and 89% against tauopathies raising to 91% with diagnostic revision. CSF NFL was significantly higher in APs. The combination of biomarkers yielded high diagnostic accuracy (PD vs. non-PD AUC = 0.983; MSA vs. non-MSA AUC = 0.933; tauopathies vs. non-tauopathies AUC = 0.924). Biomarkers-signatures fitted in most cases with clinical classification. CONCLUSIONS: The combination of CSF NFL, CSF RT-QuIC α-SYN and midbrain/pons MRI measures showed high discriminant ability across all groups. Results opposite to expected can assist diagnostic reclassification.

Hierarchical cluster analysis of multimodal imaging data identifies brain atrophy and cognitive patterns in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a heterogeneous condition. Cluster analysis based on cortical thickness has been used to define distinct patterns of brain atrophy in PD. However, the potential of other neuroimaging modalities, such as white matter (WM) fractional anisotropy (FA), which has also been demonstrated to be altered in PD, has not been investigated. OBJECTIVE: We aim to characterize PD subtypes using a multimodal clustering approach based on cortical and subcortical gray matter (GM) volumes and FA measures. METHODS: We included T1-weighted and diffusion-weighted MRI data from 62 PD patients and 33 healthy controls. We extracted mean GM volumes from 48 cortical and 17 subcortical regions using FSL-VBM, and the mean FA from 20 WM tracts using Tract-Based Spatial Statistics (TBSS). Hierarchical cluster analysis was performed with the PD sample using Ward's linkage method. Whole-brain voxel-wise intergroup comparisons of VBM and TBSS data were also performed using FSL. Neuropsychological and demographic statistical analyses were conducted using IBM SPSS Statistics 25.0. RESULTS: We identified three PD subtypes, with prominent differences in GM patterns and little WM involvement. One group (n = 15) with widespread cortical and subcortical GM volume and WM FA reductions and pronounced cognitive deficits; a second group (n = 21) with only cortical atrophy limited to frontal and temporal regions and more specific neuropsychological impairment, and a third group (n = 26) without detectable atrophy or cognition impairment. CONCLUSION: Multimodal MRI data allows classifying PD patients into groups according to GM and WM patterns, which in turn are associated with the cognitive profile.

Cortical gray matter progression in idiopathic REM sleep behavior disorder and its relation to cognitive decline.

BACKGROUND: Idiopathic Rapid eye movement sleep behavior disorder (IRBD) is recognized as the prodromal stage of the alpha-Synucleinopathies. Although some studies have addressed the characterization of brain structure in IRBD, little is known about its progression. OBJECTIVE: The present work aims at further characterizing gray matter progression throughout IRBD relative to normal aging and investigating how these changes are associated with cognitive decline. METHODS: Fourteen patients with polysomnography-confirmed IRBD and 18 age-matched healthy controls (HC) underwent neuropsychological, olfactory, motor, and T1-weighted MRI evaluation at baseline and follow-up. We compared the evolution of cortical thickness (CTh), subcortical volumes, smell, motor and cognitive performance in IRBD and HC after a mean of 1.6 years. FreeSurfer was used for CTh and volumetry preprocessing and analyses. The symmetrized percent of change (SPC) of the CTh was correlated with the SPC of motor and neuropsychological performance. RESULTS: IRBD and HC differed significantly in the cortical thinning progression in regions encompassing bilateral superior parietal and precuneus, the right cuneus, the left occipital pole and lateral orbitofrontal gyri (FWE corrected, p < 0.05). The Visual form discrimination test showed worse progression in the IRBD relative to HC, that was associated with gray matter loss in the right superior parietal and the left precuneus. Increasing motor signs in IRBD were related to cortical thinning mainly involving frontal regions, and late-onset IRBD was associated with cortical thinning involving posterior areas (FWE corrected, p < 0.05). Despite finding olfactory identification deficits in IRBD, results did not show decline over the disease course. CONCLUSION: Progression in IRBD patients is characterized by parieto-occipital and orbitofrontal thinning and visuospatial loss. The cognitive decline in IRBD is associated with degeneration in parietal regions.

Disruption of posterior brain functional connectivity and its relation to cognitive impairment in idiopathic REM sleep behavior disorder.

BACKGROUND: Resting-state functional MRI has been proposed as a new biomarker of prodromal neurodegenerative disorders, but it has been poorly investigated in the idiopathic form of rapid-eye-movement sleep behavior disorder (IRBD), a clinical harbinger of subsequent synucleinopathy. Particularly, a complex-network approach has not been tested to study brain functional connectivity in IRBD patients. OBJECTIVES: The aim of the current work is to characterize resting-state functional connectivity in IRBD patients using a complex-network approach and to determine its possible relation to cognitive impairment. METHOD: Twenty patients with IRBD and 27 matched healthy controls (HC) underwent resting-state functional MRI with a 3T scanner and a comprehensive neuropsychological battery. The functional connectome was studied using threshold-free network-based statistics. Global and local network parameters were calculated based on graph theory and compared between groups. Head motion, age and sex were introduced as covariates in all analyses. RESULTS: IRBD patients showed reduced cortico-cortical functional connectivity strength in comparison with HC in edges located in posterior regions (p <0.05, FWE corrected). This regional pattern was also shown in an independent analysis comprising posterior areas where a decreased connectivity in 51 edges was found, whereas no significant results were detected when an anterior network was considered (p <0.05, FWE corrected). In the posterior network, the left superior parietal lobule had reduced centrality in IRBD. Functional connectivity strength between left inferior temporal lobe and right superior parietal lobule positively correlated with mental processing speed in IRBD (r = .633; p = .003). No significant correlations were found in the HC group. CONCLUSION: Our findings support the presence of disrupted posterior functional brain connectivity of IRBD patients similar to that found in synucleinopathies. Moreover, connectivity reductions in IRBD were associated with lower performance in mental processing speed domain.

Diagnostic Accuracy, Item Analysis and Age Effects of the UPSIT Spanish Version in Parkinson's Disease.

OBJECTIVE: The University of Pennsylvania Smell Identification Test (UPSIT) is the most commonly used test to detect olfactory impairment in Parkinson's disease (PD), but the cut-off score for clinical purposes is often difficult to establish because of age and sex effects. The current work aims to study the sensitivity and specificity of the UPSIT Spanish version and its accuracy in discriminating PD patients at different age groups from healthy controls (HC), and to perform an item analysis. METHOD: Ninety-seven non-demented PD patients and 65 HC were assessed with the UPSIT Spanish version. Sensitivity, specificity, and diagnostic accuracy for PD were calculated. Multiple regression analysis was used to define predictors of UPSIT scores. RESULTS: Using the normative cut-off score for anosmia (≤18), the UPSIT showed a sensitivity of 54.6% with a specificity of 100.0% for PD. We found that, using the UPSIT cut-off score of ≤25, sensitivity was 81.4% and specificity 84.6% (area under the receiver operating characteristic curve = 0.908). Diagnosis and age were good predictors of UPSIT scores (B = -10.948; p < .001; B = -0.203; p < .001). When optimal cut-off scores were considered according to age ranges (≤60, 61-70, and ≥71), sensitivity and specificity values were >80.0% for all age groups. CONCLUSIONS: In the Spanish UPSIT version, sensitivity and specificity are improved when specific cut-off scores for different age groups are computed.

Cortical thinning correlates of changes in visuospatial and visuoperceptual performance in Parkinson's disease: A 4-year follow-up.

BACKGROUND: Growing evidence highlights the relevance of posterior cortically-based cognitive deficits in Parkinson's disease (PD) as possible biomarkers of the evolution to dementia. Cross-sectional correlational studies have established a relationship between the degree of atrophy in posterior brain regions and visuospatial and visuoperceptual (VS/VP) impairment. The aim of this study is to address the progressive cortical thinning correlates of VS/VP performance in PD. METHODS: Forty-four PD patients and 20 matched healthy subjects were included in this study and followed for 4 years. Tests used to assess VS/VP functions included were: Benton's Judgement of Line Orientation (JLOT), Facial Recognition (FRT), and Visual Form Discrimination (VFDT) Tests; Symbol Digit Modalities Test (SDMT); and the Pentagon Copying Test (PCT). Structural magnetic resonance imaging data and FreeSurfer were used to evaluate cortical thinning evolution. RESULTS: PD patients with normal cognition (PD-NC) and PD patients with mild cognitive impairment (PD-MCI) differed significantly in the progression of cortical thinning in posterior regions. In PD-MCI patients, the change in VS/VP functions assessed by PCT, JLOT, FRT, and SMDT correlated with the symmetrized percent change of cortical thinning of occipital, parietal, and temporal regions. In PD-NC patients, we also observed a correlation between changes in FRT and thinning in parieto-occipital regions. CONCLUSION: In this study, we establish the neuroanatomical substrate of progressive changes in VS/VP performance in PD patients with and without MCI. In agreement with cross-sectional data, VS/VP changes over time are related to cortical thinning in posterior regions.

Lewy- and Alzheimer-type pathologies in midbrain and cerebellum across the Lewy body disorders spectrum.

AIMS: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are pathologically characterized by intraneuronal α-synuclein aggregates and thus labelled as Lewy body disorders (LBD). Conjoint cortical α-synuclein, tau and amyloid-ß (Aß), and striatal Aß aggregates, have been related to dementia in LBD. Interpretation of current and emerging in vivo molecular imaging of these pathologies will need of precise knowledge of their topographic distribution. We aimed to assess these pathologies further down the encephalon across the LBD-spectrum. METHODS: Semiquantitative rating of α-synuclein, Aß and hyperphosphorylated tau aggregates in midbrain (and cerebellum in the case of Aß as it represents the last ß-amyloidosis stage) sections from cases representative of the LBD-spectrum (PD non-dementia, PD-dementia, DLB; n = 10 each) compared to controls (n = 10) and Alzheimer's disease (AD; n = 10). RESULTS: α-synuclein midbrain scores rose from controls to AD and then LBD irrespective of dementia. Aß and tau were more prominent in the tectum/tegmentum, increasing from controls to LBD (mostly in dementia cases in the case of Aß), and then peaking in AD. By contrast, cerebellar Aß scores were marginal across the LBD-spectrum, as opposed to AD, only showing a trend towards greater involvement in LBD cases with dementia. CONCLUSIONS: Frequency and severity of Aß and tau pathologies in the midbrain across the LBD-spectrum were midway between controls and AD, with Aß in the tectum/tegmentum being associated with dementia. These findings might have potential implications in the eventual interpretation of regional uptake of in vivo molecular imaging of these pathologies.

Structural MRI correlates of the MMSE and pentagon copying test in Parkinson's disease.

BACKGROUND: Cognitive impairment in Parkinson's disease (PD) is common and recent studies have focused on addressing the most suitable screening tool for its assessment. MMSE is commonly used in clinical practice and longitudinal studies found a relationship between the MMSE pentagon copying item and progression to dementia, but its neuroanatomical correlates have been poorly investigated. The aim of this study is to investigate the MRI structural correlates of the global MMSE and the pentagon item scores in PD patients in the absence of dementia. METHODS: We selected a sample of 92 PD patients and 36 controls. MMSE was used as a global measure of cognitive status, and the pentagon copying test as a measure of visuospatial performance. FreeSurfer software was used to assess intergroup differences in cortical thickness (CTh) and global atrophy measures, as well as their relationship with cognitive performance. RESULTS: Compared to controls, patients showed significant differences in measures of global atrophy, which correlated with performance on MMSE and the pentagon item. Regional differences in CTh were seen between PD patients and controls bilaterally in the temporo-parietal-occipital region. Patients with impaired performance compared with those of normal performance also showed CTh reductions in these regions. CONCLUSION: Our results suggest MMSE and the pentagon item reflect brain changes which at a regional level involve mainly posterior regions. Correlates of the pentagon item were seen in the same regions where PD patients exhibited significant thinning, and involved more areas and bigger cluster sizes than the correlates of MMSE global scores.

123I-MIBG cardiac uptake, smell identification and 123I-FP-CIT SPECT in the differential diagnosis between vascular parkinsonism and Parkinson's disease.

UNLABELLED: Vascular parkinsonism (VP) may occur as a distinct clinicopathological entity but the comorbid presence of vascular damage in Parkinson's disease (PD) is very frequent too. This differential diagnosis has therapeutic and prognostic implications but remains challenging as the usefulness of a number of supporting tools is still controversial. OBJECTIVE: To ascertain the clinical value of cardiac (123)I-meta-iodobenzylguanidine ((123)I-MIBG) SPECT, olfactory function and (123)I-FP-CIT SPECT as supporting tools in the differential diagnosis between VP and PD. METHODS: Cross-sectional study of 15 consecutive patients with suspected VP, 15 PD patients and 9 healthy subjects. Cardiac (123)I-MIBG SPECT (heart-to-mediastinum ratio) and olfactory testing (University of Pennsylvania Smell Identification Test-UPSIT) were performed in all of them. (123)I-FP-CIT SPECT was performed in VP-suspected patients. RESULTS: Heart-to-mediatinum ratio was significant lower in suspected VP (mean 1.45) and PD (mean 1.16) compared to control group (mean 1.69) (p = 0.017 and p < 0.0001). VP patients presented a higher ratio than PD patients (p = 0.001). Control group presented a significant higher UPSIT score (mean 30.71) when compared to both VP (mean 18.33) and PD (mean 15.29) (p = 0.001 for both groups). Those VP with a cardiac (123)I-MIBG non suggestive of PD were more likely to have a higher UPSIT score (p = 0.006). (123)I-FP-CIT SPECT imaging was heterogeneous (7/15 VP normal, 3/15 abnormal suggestive of PD and 5/15 abnormal but atypical for PD). CONCLUSIONS: The use of cardiac (123)I-MIBG SPECT and to a lesser extent UPSIT could assist the differential diagnosis between VP and PD in subjects in which the diagnosis remains uncertain despite (123)I-FP-CIT SPECT imaging.

Prominent psychiatric symptoms in patients with Parkinson's disease and concomitant argyrophilic grain disease.

In Parkinson's disease (PD), cognitive decline and psychiatric symptoms may occur and very often co-exist, eventually leading to PD-dementia. We report three patients with PD who presented striking psychiatric manifestations along with mild cognitive decline not progressing to dementia across the course of disease and in which postmortem neuropathological study revealed, besides alpha-synuclein inmunoreactive Lewy-body pathology, concomitant four-repeat tau positive argyrophilic grain pathology. We consider that argyrophilic grains might have modulated the clinical presentation of PD in these patients, being the main substrate of their prominent psychiatric symptoms in the absence of definite dementia.

Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans.

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population.

Structural correlates of facial emotion recognition deficits in Parkinson's disease patients.

The ability to recognize facial emotion expressions, especially negative ones, is described to be impaired in Parkinson's disease (PD) patients. Previous neuroimaging work evaluating the neural substrate of facial emotion recognition (FER) in healthy and pathological subjects has mostly focused on functional changes. This study was designed to evaluate gray matter (GM) and white matter (WM) correlates of FER in a large sample of PD. Thirty-nine PD patients and 23 healthy controls (HC) were tested with the Ekman 60 test for FER and with magnetic resonance imaging. Effects of associated depressive symptoms were taken into account. In accordance with previous studies, PD patients performed significantly worse in recognizing sadness, anger and disgust. In PD patients, voxel-based morphometry analysis revealed areas of positive correlation between individual emotion recognition and GM volume: in the right orbitofrontal cortex, amygdala and postcentral gyrus and sadness identification; in the right occipital fusiform gyrus, ventral striatum and subgenual cortex and anger identification, and in the anterior cingulate cortex (ACC) and disgust identification. WM analysis through diffusion tensor imaging revealed significant positive correlations between fractional anisotropy levels in the frontal portion of the right inferior fronto-occipital fasciculus and the performance in the identification of sadness. These findings shed light on the structural neural bases of the deficits presented by PD patients in this skill.

Socio-demographic and clinical factors influencing the adherence to treatment in Parkinson's disease: the ADHESON study.

BACKGROUND: Symptoms of Parkinson's disease (PD) are usually controlled by a continuous titration of medication and addition of multiple therapies over the course of the disease. Therapeutic complex schemes, polymedication, comorbidities and the number of medications required contribute to non-adherence. METHODS: This cross-sectional survey was performed in 418 patients with PD on treatment with any antiparkinsonian medication. Patient adherence was assessed through physicians' subjective perception and the Morisky-Green test (MGT). Several social, demographic and clinical features were correlated through bivariate and multivariate analyses. RESULTS: According to the physician's opinion 93.7%, and according to the MGT 60.4% of patients were adherent to parkinsonian therapy. The bivariate analysis showed greater adherence in patients with a high level of knowledge about the disease (62.8%), good clinical control (63.6%), a spouse or life partner (63%) and higher incomes (66%). Negative correlation with psychiatric symptoms was found. In relation to the MGT, the logistic regression model showed a negative correlation between cognitive deterioration and psychiatric pathology and adherence to therapy. CONCLUSIONS: The physician's impression overestimated the compliance of patients when compared with an objective evaluation such as the MGT. Cognitive impairment and psychiatric symptoms are the clinical variables associated with a lower level of adherence.

[Neuroprotection in Parkinson's disease: analysis though group of experts' methodology]. / Neuroprotección en la enfermedad de Parkinson: análisis a través de la metodología de informadores clave.

INTRODUCTION: Currently used antiparkinsonian drugs neither stop nor slow-down the progressive nature of the disease. The final phase of PD is characterized by the presence of symptoms and signs resistant to dopaminergic agents, such as depression, dementia, freezing and falls. Therefore, it is urgent to develop therapies able to positively modify this outcome. Despite neuroprotection is a research priority in PD, no effective strategies have been found so far. METHOD: A key informants study was conducted. A group of experts in PD fulfilled a questionnaire of 10 questions to explore the most important topics related to neuroprotection. Afterwards a consensus about the current situation of neuroprotection in PD was established and future directions of development were suggested. RESULTS: Most of the answers emphasized the need of new concepts, the limitations of animal models and the difficulties in the difficulties in demonstrating a neuroprotective effects in humans owing to a lack of biomarkers. Some of the experts believe that we are already exerting a disease modifying effect. CONCLUSIONS: The concept of neuroprotection should be widened. Animal models should be improved. A reliable biomarker to start neuroprotective therapies long before the appearance of motor symptoms and to evaluate the neuroprotective effect of any therapy should be urgently developed.