Stepwise Functional Brain Architecture Correlates with Atrophy in Progressive Supranuclear Palsy.

BACKGROUND: Stepwise functional connectivity (SFC) detects whole-brain functional couplings of a selected region of interest at increasing link-step topological distances. OBJECTIVE: This study applied SFC to test the hypothesis that stepwise architecture propagating from the disease epicenter would shape patterns of brain atrophy in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). METHODS: Thirty-six patients with PSP-RS and 44 age-matched healthy control subjects underwent brain magnetic resonance imaging on a 3-T scanner. The disease epicenter was defined as the peak of atrophy observed in an independent cohort of 13 cases with postmortem confirmation of PSP pathology and used as seed region for SFC analysis. First, we explored SFC rearrangements in patients with PSP-RS, as compared with age-matched control subjects. Subsequently, we tested SFC architecture propagating from the disease epicenter as a determinant of brain atrophy distribution. RESULTS: The disease epicenter was identified in the left midbrain tegmental region. Compared with age-matched control subjects, patients with PSP-RS showed progressively widespread decreased SFC of the midbrain with striatal and cerebellar regions through direct connections and sensorimotor cortical regions through indirect connections. A correlation was found between average link-step distance from the left midbrain in healthy subjects and brain volumes in patients with PSP-RS (r = 0.38, P < 0.001). CONCLUSIONS: This study provides comprehensive insights into the topology of functional network rearrangements in PSP-RS and demonstrates that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP-RS. Our findings support the view of a network-based pathology propagation in this primary tauopathy. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Integrated evaluation of a panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: This study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters in a large cohort of patients with amyotrophic lateral sclerosis (ALS). METHODS: One hundred forty-three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45 healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array. RESULTS: NfL correlated with disease progression rate (p < 0.001) and with the measures of upper motor neuron burden (p < 0.001). NfL was higher in the ALS patients with classic and pyramidal phenotype. GFAP was raised in ALS with cognitive-behavioral impairment compared with ALS with normal cognition. NfL displayed the best diagnostic performance in discriminating ALS from HC (area under the curve [AUC] = 0.990), DEG (AUC = 0.946), and ALSmd (AUC = 0.850). UCHL1 performed well in distinguishing ALS from HC (AUC = 0.761), whereas it was not helpful in differentiating ALS from DEG and ALSmd. In multivariate analysis, NfL (p < 0.001) and UCHL1 (p = 0.038) were independent prognostic factors. Survival analysis combining NfL and UCHL1 effectively stratified patients with lower NfL levels (p < 0.001). CONCLUSIONS: NfL is a useful biomarker for the diagnosis of ALS and the strongest predictor of survival. UCHL1 is an independent prognostic factor helpful in stratifying survival in patients with low NfL levels, likely to have slowly progressive disease. GFAP reflects extramotor involvement, namely cognitive impairment or frontotemporal dementia.

Action Observation and Motor Imagery Improve Dual Task in Parkinson's Disease: A Clinical/fMRI Study.

BACKGROUND: Action observation training and motor imagery may improve motor learning in Parkinson's disease (PD). OBJECTIVES: The objectives of this study were to assess mobility and balance (performing motor and dual tasks) and brain functional reorganization following 6 weeks of action observation training and motor imagery associated with dual-task gait/balance exercises in PD patients with postural instability and gait disorders relative to dual-task training alone. METHODS: Twenty-five PD-postural instability and gait disorder patients were randomized into 2 groups: the DUAL-TASK+AOT-MI group performed a 6-week gait/balance training consisting of action observation training-motor imagery combined with practicing the observed-imagined exercises; the DUAL-TASK group performed the same exercises combined with watching landscape videos. Exercises were increasingly difficult to include the dual task. At baseline and at 6 weeks, patients underwent: mobility, gait, and balance evaluations (also repeated 2 months after training), cognitive assessment, and functional MRI, including motor and dual tasks. RESULTS: Dual-task gait/balance training enhanced mobility, during both single- and dual-task conditions, and executive functions in PD-postural instability and gait disorders, with a long-lasting effect at 14 weeks. When exercises were preceded by action observation training-motor imagery, PD-postural instability and gait disorders showed greater improvement of balance and gait velocity both with and without the dual task, particularly during the turning phase. After training, the DUAL-TASK+AOT-MI group showed reduced recruitment of frontal areas and increased activity of cerebellum during functional-MRI motor and dual task, correlating with balance/turning velocity and executive improvements, respectively. The DUAL-TASK group showed reduced activity of supplementary motor area and increased recruitment of temporo-parietal areas during the dual task and decreased cerebellar activity during the motor task correlating with faster turning velocity. Functional MRI results were not corrected for multiple comparisons and should be interpreted carefully. CONCLUSIONS: Adding action observation training-motor imagery to dual-task gait/balance training promotes specific functional reorganization of brain areas involved in motor control and executive-attentive abilities and more long-lasting effects on dual-task mobility and balance in PD-postural instability and gait disorders. © 2021 International Parkinson and Movement Disorder Society.

Validation of the Italian version of carers' quality-of-life questionnaire for parkinsonism (PQoL Carer) in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a rare, rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. Caring for a partner or relative who suffers from PSP entails a strenuous and demanding task, usually lasting for years that affects carers' everyday life routines and emotional and social well-being. The 26-item Parkinsonism Carers QoL (PQoL Carer) is a self-administered, concise instrument evaluating the quality of life of caregivers of patients with atypical parkinsonism (both PSP and multiple system atrophy). Here, the PQoL Carer was translated into Italian and validated in 162 carers of PSP patients (54.3% women; mean age (standard deviation), 62.4 (15.4)) diagnosed according to the Movement Disorder Society criteria and recruited in 16 third-level movement disorders centers participating in the Neurecanet project. The mean PQoL total score was 40.66 ± 19.46. The internal consistency was excellent (Cronbach's alpha = 0.941); corrected item-total correlation was > 0.40 for all the items. A correlation with other health-related quality of life measures as well as with behavioral assessments was shown suggesting adequate convergent validity of the scale. PQoL also correlated with patients' severity of disease. The discriminant validity of the scale was evidenced by its capacity to differentiate between carers with varying levels of self-reported health (p < 0.001). In conclusion, the Italian version of the PQoL Carer is an easy, consistent, and valid tool for the assessment of the quality of life in carers of PSP patients.

Validation of the Italian version of the PSP Quality of Life questionnaire.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. The use of health-related quality of life (HR-QoL) measures allows assessing changes in health status induced by therapeutic interventions or disease progress in neurodegenerative diseases. The PSP-QoL is a 45-item, self-administered questionnaire designed to evaluate HR-QoL in PSP. METHODS AND RESULTS: Here, the PSP-QoL was translated into Italian and validated in 190 PSP (96 women and 94 men; mean age ± standard deviation, 72 ± 6.5; mean disease duration, 4.2 ± 2.3) patients diagnosed according to the Movement Disorder Society criteria and recruited in 16 third level movement disorders centers participating in the Neurecanet project. The mean PSP-QoL total score was 77.8 ± 37 (physical subscore, 46.5 ± 18.7; mental subscore, 33.6 ± 19.2). The internal consistency was high (Cronbach's alpha = 0.954); corrected item-total correlation was > 0.40 for the majority of items. The significant and moderate correlation of the PSP-QoL with other HR-QoL measures as well as with motor and disability assessments indicated adequate convergent validity of the scale. Gender and geographic location presented a significant impact on the PSP-QoL in our sample with women and patients from the South of Italy scoring higher than their counterparts. CONCLUSION: In conclusion, the Italian version of the PSP-QoL is an easy, reliable and valid tool for assessment of HR-QoL in PSP.

Weight gain after subthalamic nucleus deep brain stimulation in Parkinson's disease is influenced by dyskinesias' reduction and electrodes' position.

Parkinson's disease is a common neurodegenerative disease that can be treated with pharmacological or surgical therapy. Subthalamic nucleus (STN) deep brain stimulation is a commonly used surgical option. A reported side effect of STN-DBS is weight gain: the aim of our study was to find those factors that determine weight gain, through one year-long observation of 32 patients that underwent surgery in our centre. During the follow-up, we considered: anthropometric features, hormonal levels, motor outcome, neuropsychological and quality of life outcomes, therapeutic parameters and electrodes position. The majority (84%) of our patients gained weight (6.7 kg in 12 months); more than a half of the cohort became overweight. At 12th month, weight gain showed a correlation with dyskinesias reduction, electrodes voltage and distance on the lateral axis. In the multivariate regression analysis, the determinants of weight gain were dyskinesias reduction and electrodes position. In this study, we identified dyskinesias reduction and distance between the active electrodes and the third ventricle as determining factors of weight gain after STN-DBS implantation in PD patients. The first finding could be linked to a decrease in energy consumption, while the second one could be due to a lower stimulation of the lateral hypothalamic area, known for its important role in metabolism and body weight control. Weight gain is a common finding after STN-DBS implantation, and it should be carefully monitored given the potential harmful consequences of overweight.

Brain structural and functional connectivity in Parkinson's disease with freezing of gait.

OBJECTIVE: To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinson's disease and freezing of gait (PD-FoG). METHODS: T1-weighted, diffusion tensor (DT) MRI and RS functional MRI (fMRI) were obtained from 22 PD-FoG patients and 35 controls on a 3.0 T MR scanner. Patients underwent clinical, motor, and neuropsychological evaluations. Gray matter (GM) volumes and white matter (WM) damage were assessed using voxel based morphometry and tract-based spatial statistics, respectively. The pedunculopontine tract (PPT) was studied using tractography. RS fMRI data were analyzed using a model free approach investigating the main sensorimotor and cognitive brain networks. Multiple regression models were performed to assess the relationships between structural, functional, and clinical/cognitive variables. Analysis of GM and WM structural abnormalities was replicated in an independent sample including 28 PD-FoG patients, 25 PD patients without FoG, and 30 healthy controls who performed MRI scans on a 1.5 T scanner. RESULTS: Compared with controls, no GM atrophy was found in PD-FoG cases. PD-FoG patients showed WM damage of the PPT, corpus callosum, corticospinal tract, cingulum, superior longitudinal fasciculus, and WM underneath the primary motor, premotor, prefrontal, orbitofrontal, and inferior parietal cortices, bilaterally. In PD-FoG, right PTT damage was associated with a greater disease severity. Analysis on the independent PD sample showed similar findings in PD-FoG patients relative to controls as well as WM damage of the genu and body of the corpus callosum and right parietal WM in PD-FoG relative to PD no-FoG patients. RS fMRI analysis showed that PD-FoG is associated with a decreased functional connectivity of the primary motor cortex and supplementary motor area bilaterally in the sensorimotor network, frontoparietal regions in the default mode network, and occipital cortex in the visual associative network. CONCLUSIONS: This study suggests that FoG in PD can be the result of a poor structural and functional integration between motor and extramotor (cognitive) neural systems.

Dual-task gait training improves cognition and resting-state functional connectivity in Parkinson's disease with postural instability and gait disorders.

OBJECTIVES: To assess whether dual-task gait/balance training with action observation training (AOT) and motor imagery (MI) ameliorates cognitive performance and resting-state (RS) brain functional connectivity (FC) in Parkinson's disease (PD) patients with postural instability and gait disorders (PIGD). METHODS: 21 PD-PIGD patients were randomized into 2 groups: (1) DUAL-TASK + AOT-MI group performed a 6-week training consisting of AOT-MI combined with practicing observed-imagined gait and balance exercises; and (2) DUAL-TASK group performed the same exercises combined with landscape-videos observation. At baseline and after training, all patients underwent a computerized cognitive assessment, while 17 patients had also RS-fMRI scans. Cognitive and RS-FC changes (and their relationships) over time within and between groups were assessed. RESULTS: After training, all PD-PIGD patients improved accuracy in a test assessing executive-attentive (mainly dual-task) skills. DUAL-TASK + AOT-MI patients showed increased RS-FC within the anterior salience network (aSAL), and reduced RS-FC within the anterior default mode network (aDMN), right executive control network and precuneus network. DUAL-TASK patients showed increased RS-FC within the visuospatial network, only. Group × Time interaction showed that, compared to DUAL-TASK group, DUAL-TASK + AOT-MI cases had reduced RS-FC within the aDMN, which correlated with higher accuracy in a dual-task executive-attentive test. CONCLUSIONS: In PD-PIGD patients, both trainings promote cognitive improvement and brain functional reorganization. DUAL-TASK + AOT-MI training induced specific functional reorganization changes of extra-motor brain networks, which were related with improvement in dual-task performance.

Neural correlates of bradykinesia in Parkinson's disease: a kinematic and functional MRI study.

Bradykinesia is defined as a "complex" of motor alterations including decreased movement amplitude and/or speed and tendency to reduce them with movement repetition (sequence effect). This study aimed at investigating the neural and kinematic correlates of bradykinesia during hand-tapping in people with Parkinson's disease (pwPD) relative to healthy controls. Twenty-five pwPD and 25 age- and sex-matched healthy controls underwent brain functional MRI (fMRI) during a hand-tapping task: subjects alternatively opened and closed their right hand as fully and quickly as possible. Hand-tapping kinematic parameters were objectively measured during the fMRI task using an optical fibre glove. During the fMRI task, pwPD showed reduced hand-tapping amplitude (hypokinesia) and a greater sequence effect. PwPD relative to healthy controls showed a reduced activity of fronto-parietal areas, middle cingulum/supplementary motor area (SMA), parahippocampus, pallidum/thalamus and motor cerebellar areas. Moreover, pwPD showed an increased activity of brain cognitive areas such as superior temporal gyrus, posterior cingulum, and cerebellum crus I. The decreased activity of cerebellum IV-V-VI, vermis IV-V, inferior frontal gyrus, and cingulum/SMA correlated with hypokinesia and with the sequence effect. Interestingly, a reduced activity of areas involved in motor planning and timing correlated both with hypokinesia and with the sequence effect in pwPD. This study has the major strength of collecting objective motor parameters and brain activity simultaneously, providing a unique opportunity to investigate the neural correlates of the "bradykinesia complex".

Family History in Parkinson's Disease: A National Cross-Sectional Study.

BACKGROUND: Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect. OBJECTIVES: We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD). METHODS: A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected. RESULTS: Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group. CONCLUSIONS: fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD.

Proteomic identification of aldolase A as an autoantibody target in patients with atypical movement disorders.

We tried to identify the target/s of autoantibodies to basal ganglia neurons found in a patient with hyperkinetic movement disorders (HMD) characterized by rapid, rhythmic involuntary movements or spasms in both face and neck. Patient and control sera were used in Western blot to probe mouse brain homogenates. Two-dimensional gel electrophoresis (2-DE) SDS-PAGE protein spots recognized by the patient's antibodies were excised and sequenced by mass spectrometry analysis, and the glycolytic enzyme aldolase A was identified as the antigen recognized by the patient's autoantibodies. To assess relevance and specificity of these antibodies to the identified targets as biomarkers of autoimmunity in movement disorders, autoantibody responses to the identified target were then measured by ELISA in various diseases of the central nervous system. Anti-aldolase A autoantibodies were associated mainly with HMD (7/17, 41%) and Parkinson's disease (4/30, 13%) patients, and undetectable in subjects with other inflammatory and non-inflammatory central nervous system diseases. We, thus, identified aldolase A as an autoantigen in a sub-group of patients with HMD, a clinically ill-defined syndrome. Anti-aldolase A antibodies may represent a useful biomarker of autoimmunity in HMD patients.

Cerebellar alterations in Parkinson's disease with postural instability and gait disorders.

BACKGROUND: Few studies interrogated the involvement of cerebellum in modulating gait in Parkinson's disease (PD) patients with postural instability and gait disorders (PD-PIGD). This study aimed at assessing cerebellar atrophy and activity alterations during functional MRI (fMRI) gait-simulating motor- and dual-tasks in PD-PIGD. METHODS: Twenty-one PD-PIGD and 23 healthy controls underwent clinical assessment, structural MRI, and fMRI including a motor-task (foot anti-phase movements) and a dual-task (foot anti-phase movements while counting backwards by threes). Grey matter cerebellar volumes were assessed using SUIT atlas. FMRI activations were extracted from each cerebellar lobule, and we correlated cerebellar and basal ganglia activity. RESULTS: PD-PIGD patients had reduced volumes of cerebellar motor and non-motor areas relative to controls. During fMRI motor-task, patients showed greater activation of cognitive cerebellar areas (VI and Crus I-II) vs controls. During fMRI dual-task, PD-PIGD patients showed increased activity of cognitive areas (Crus II) and reduced activity of motor areas (I-IV). Cerebellar structural alterations correlated with increased fMRI activity of cerebellar cognitive areas and with lower executive-attentive performance. The increased activity of Crus I during the motor-task correlated with a better motor performance in PD-PIGD. Moreover, the increased activity of cerebellum correlated with a reduced activity of putamen. CONCLUSIONS: In PD-PIGD, the increased activity of non-motor cerebellar areas during gait-simulating tasks may be a consequence of grey matter atrophy or an attempt to compensate the functional failure of cerebellar motor areas and basal ganglia. Cerebellar MRI metrics are useful to characterize brain correlates of motor and dual-task abilities in PD-PIGD patients.

Action observation and motor imagery improve motor imagery abilities in patients with Parkinson's disease - A functional MRI study.

INTRODUCTION: Motor imagery (MI) skills can be affected in Parkinson's disease (PD). We aimed at assessing MI and brain functional changes after action observation and MI training (AOT-MI) associated with gait/balance exercises in PD patients with postural instability and gait disorders (PD-PIGD). METHODS: Twenty-five PD-PIGD patients were randomized into two groups: DUAL-TASK + AOT-MI group performed 6-week gait/balance training combined with AOT-MI; DUAL-TASK group performed the same exercises without AOT-MI. Before and after training, MI was assessed using Kinesthetic-and-Visual-Imagery Questionnaire (KVIQ) and a MI functional MRI (fMRI) task. During fMRI, subjects were asked to watch first-person perspective videos representing gait/balance tasks and mentally simulate their execution. At baseline patients were compared with 23 healthy controls. RESULTS: PD groups did not differ in the MI scores. Both patient groups increased kinesthetic KVIQ score after training, while only DUAL-TASK + AOT-MI group improved visual and total KVIQ scores. At baseline, both PD groups showed reduced fMRI activity of sensorimotor, temporal and cerebellar areas relative to controls. After training, DUAL-TASK + AOT-MI patients increased activity of anterior cingulate, fronto-temporal and motor cerebellar areas, and reduced the recruitment of cognitive cerebellar regions. DUAL-TASK group showed increased recruitment of occipito-temporal areas and reduced activity of cerebellum crus-I. DUAL-TASK + AOT-MI relative to DUAL-TASK group had increased activity of cerebellum VIII-IX. In DUAL-TASK + AOT-MI group, KVIQ improvement correlated with increased activity of cerebellum IX and anterior cingulate, and with reduced activity of crus-I. CONCLUSIONS: AOT-MI improves MI abilities in PD-PIGD patients, promoting the functional plasticity of brain areas involved in MI processes and gait/balance control.

Brain activity of the emotional circuit in Parkinson's disease patients with freezing of gait.

OBJECTIVE: Emotional processes might influence freezing of gait (FoG) in Parkinson's disease (PD) patients. We assessed brain functional MRI (fMRI) activity during a "FoG-observation-task" in PD-FoG patients relative to healthy controls. METHODS: Twenty-four PD-FoG patients and 18 age- and sex-matched healthy controls performed clinical and neuropsychological evaluations, and fMRI experiments including: i) "FoG-observation-task" consisting of watching a patient experiencing FoG during a walking task (usually evoking FoG); ii) "gait-observation-task" consisting of watching a healthy subject performing similar walking tasks without experiencing FoG. RESULTS: During both tasks, PD-FoG patients showed reduced activity of the fronto-parietal mirror neuron system (MNS) relative to controls. In the "FoG-observation-task" relative to the "gait-observation-task", PD-FoG patients revealed an increased recruitment of the anterior medial prefrontal cortex and a reduced recruitment of the dorsomedial prefrontal cortex and hippocampus relative to controls. Healthy controls in the "FoG-observation-task" relative to the "gait-observation-task" showed increased recruitment of cognitive empathy areas and decreased activity of the fronto-parietal MNS. CONCLUSION: Our results suggest that when PD-FoG patients observe a subject experiencing FoG, there is an increased activity of brain areas involved in self-reflection emotional processes and a reduced activity of areas related to motor programming, executive functions and cognitive empathy. These findings support previous evidence on the critical role of the emotional circuit in the mechanisms underlying FoG.

A multiparametric MRI study of structural brain damage in dementia with lewy bodies: A comparison with Alzheimer's disease.

INTRODUCTION: Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is crucial for an adequate patients' management but might be challenging. We investigated with advanced MRI techniques gray (GM) and white matter (WM) damage in DLB patients compared to those with AD. METHODS: 24 DLB patients, 26 age- and disease severity-matched AD patients, and 20 age and sex-matched controls performed clinical and neuropsychological assessment, and brain structural and diffusion-tensor MRI. We measured GM atrophy using voxel-based morphometry, WM hyperintensities (WMH) using a local thresholding segmentation technique, and normal-appearing WM (NAWM) damage using tract-based spatial statistic. RESULTS: DLB and AD patients exhibited mild-to-moderate-stage dementia. Compared to controls, GM damage was diffuse in AD, while limited to bilateral thalamus and temporal regions in DLB. Compared to DLB, AD patients exhibited GM atrophy in bilateral fronto-temporal and occipital regions. DLB and AD patients showed higher WMH load than controls, with no differences among each other. WMH in DLB were diffuse with relative prevalence in posterior parietal-occipital regions. Compared to controls, both DLB and AD patients showed reduced microstructural integrity of the main supratentorial and infratentorial NAWM tracts. AD patients exhibited greater posterior NAWM damage than DLB. CONCLUSIONS: DLB showed prominent WM degeneration compared to the limited GM atrophy, while in AD both tissue compartments were severely involved. In DLB, NAWM microstructural degeneration was independent of WMH, thus revealing two possible underlying processes. Different pathophysiological mechanisms are likely to drive GM and WM damage distribution in DLB and AD.

Dual-task clinical and functional MRI correlates in Parkinson's disease with postural instability and gait disorders.

BACKGROUND: Dual-task is a challenge for Parkinson's disease patients with postural instability and gait disorders (PD-PIGD). OBJECTIVE: This study investigated clinical, cognitive and functional brain correlates of dual-task deficits in PD-PIGD patients using quantitative gait analysis, neuropsychological evaluations and functional MRI (fMRI). METHODS: Twenty-three PD-PIGD patients performed a clinical assessment of gait/balance abilities. Single and dual-task Timed-Up-and-Go tests were monitored using an optoelectronic system to study turning velocity. Patients underwent executive-attentive function evaluation and two fMRI tasks: motor-task (foot anti-phase movements), and dual-task (foot anti-phase movements while counting backwards by threes starting from 100). Twenty-three healthy subjects underwent neuropsychological and fMRI assessments. RESULTS: Dual-task in PD-PIGD patients resulted in worse gait performance, particularly during turning. Performing the dual-task relative to the motor-fMRI task, healthy subjects showed widespread increased recruitment of sensorimotor, cognitive and cerebellar areas and reduced activity of inferior frontal and supramarginal gyri, while PD-PIGD patients showed increased recruitment of inferior frontal gyrus and supplementary motor area and reduced activity of primary motor, supramarginal and caudate areas. Dual-task gait alterations in patients correlated with balance and executive deficits and with altered dual-task fMRI brain activity of frontal areas. CONCLUSIONS: This study suggested the correlation between dual-task gait difficulties, postural instability and executive dysfunction in PD-PIGD patients. FMRI results suggest that an optimized recruitment of motor and cognitive networks is associated with a better dual-task performance in PD-PIGD. Future studies should evaluate the effect of specific gait/balance and dual-task trainings to improve gait parameters and optimize brain functional activity during dual-tasks.

Long term follow-up in advanced Parkinson's disease treated with DBS of the subthalamic nucleus.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting both motor and non-motor systems. Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been an approved treatment for PD for more than 30 years, but few data are available regarding its long-term effectiveness. OBJECTIVE: The aim of this study is to evaluate patients' outcome, both from a motor and non-motor perspective, 9 to 14 years after DBS implantation. We have investigated patients with advanced PD and treated with STN-DBS, in relation to key clinical features of PD. METHODS: 18 patients were assessed both retrospectively and prospectively. They underwent motor examination, neuropsychological evaluation and questionnaires on the quality of life, preoperatively, as well as 1, 9 and 14 years after DBS surgery. All patients were implanted with STN-DBS at San Raffaele Hospital between 2004 and 2010. RESULTS: 13 males and five females underwent DBS implantation with a mean PD duration of 11 years. Stimulation significantly improved med-off/stim-on condition up to 9 years, compared to the preoperative off state, and med-on/stim-on condition at 14 years, compared to med-on/stim-off state. Long term improvement specifically involved tremor and rigidity, as well as dopaminergic daily dose. At the same time, STN-DBS had no long-lasting effect on axial symptoms and cognitive functions. CONCLUSIONS: STN-DBS remains an effective therapy for advanced PD, also over the years. Despite the underlying progression of the disease, this treatment extends the period in which the overall quality of life is still acceptable.

How to assess active contact coordinates in deep brain stimulation surgery? Comparison of three methods for determining the position of the active contact.

To date there is still no agreement in the literature on postoperative active contact coordinate (ACc) acquisition. The aim of the study is to test if the use of three methods commonly adopted in the literature for ACc acquisition (stereotactic X-rays (RXc), postoperative MRI (MRIc) and calculation of the expected ACc) for the same active contact (ACo) lead to significant differences. In our series of 176 ACo, mean euclidean distances were 1.2 +/- 0.3, 2.1 +/- 1.3, and 2.5 +/- 1.6 mm between MRIc and RXc, RXc and EXc, and MRIc and EXc, respectively. Statistically significant differences along the three axes were found. Our results indicate that final ACc depends on the method adopted to acquire them. MRI and X-rays lead to a similar ACc acquisition. The difference between the EXc and the direct visualization methods (X-rays and MRI) is significantly higher.

Brain activity during lower limb movements in Parkinson's disease patients with and without freezing of gait.

In this study, we assessed brain functional MRI (fMRI) activity during a foot movement task in Parkinson's disease patients with (PD-FoG) and without freezing of gait (PD-noFoG). Twenty-seven PD patients (17 PD-FoG) and 18 healthy controls (HC) were recruited. PD-FoG cases were divided into nine with mild and eight with moderate FoG according to the FoG questionnaire. Patients underwent motor and neuropsychological evaluations. Both patients and controls performed an fMRI task consisting of alternate dorsal/plantar foot flexion movements according to an auditory stimulus of 0.5 Hz. PD-FoG and PD-noFoG patients were similar for all motor variables (except for the presence of FoG). PD-FoG patients performed worse in executive, attention and working memory, visuospatial, language and memory cognitive tests relative to HC and in executive and language functions compared with PD-noFoG patients. While PD-noFoG patients showed an increased recruitment of the fronto-striatal circuit relative to HC during the fMRI task, PD-FoG subjects showed an increased activity of the parieto-occipital and cerebellar areas compared with HC and a reduced basal ganglia activity when compared with PD-noFoG patients. Within the PD-FoG group, patients with more severe FoG scores showed a decreased recruitment of fronto-parietal areas relative to less severe cases. fMRI modifications correlated with FoG severity and with executive-attentive and visuospatial deficits in PD-FoG patients. This study revealed the presence of two different patterns of brain activity during a foot movement task in PD-FoG and PD-noFoG patients, suggesting a possible compensatory role of parieto-occipital networks to overcome the fronto-striatal failure in PD-FoG cases.

Bilateral Repetitive Transcranial Magnetic Stimulation With the H-Coil in Parkinson's Disease: A Randomized, Sham-Controlled Study.

Background: Pilot open-label application of high-frequency repetitive transcranial magnetic stimulation (rTMS) with H-coil in Parkinson's Disease (PD) have shown promising results. Objective: To evaluate safety and efficacy of high-frequency rTMS with H-coil in PD in a double-blind, placebo-controlled, randomized study. Methods: Sixty patients with PD were randomized into 3 groups: M1-PFC (real stimulation on primary motor-M1 and pre-frontal cortices-PFC), M1 (real rTMS on M1, sham on PFC), Sham (apparent stimulation). Primary outcome was baseline-normalized percent improvement in UPDRS part III OFF-therapy at the end of treatment (12 rTMS sessions, 4 weeks). Secondary outcomes were improvement in UPDRS part III sub-scores, timed tests, and neuropsychological tests. Statistical analysis compared improvement following real and sham stimulation at the end of the protocol using either a t-test or a Mann-Whitney test. Results: All patients tolerated the treatment and concluded the study. One patient from M1-PFC group was excluded from the analysis due to newly discovered uncontrolled diabetes mellitus. No serious adverse effect was recorded. At the end of treatment, patients receiving real rTMS (M1-PFC and M1 combined) showed significantly greater improvement compared to sham in UPDRS part III total score (p = 0.007), tremor subscore (p = 0.011), and lateralized sub-scores (p = 0.042 for the more affected side; p = 0.012 for the less affected side). No significant differences have been oserved in safety and efficacy outcomes between the two real rTMS groups. Notably, mild, not-distressing and transient dyskinesias occurred in 3 patients after real rTMS in OFF state. Conclusions: The present findings suggest that high-frequency rTMS with H-coil is a safe and potentially effective procedure and prompt larger studies for validation as add-on treatment in PD.