Quantitative gait analysis value as a predictor of shunt surgery effectiveness in normal pressure hydrocephalus: A technical note.

INTRODUCTION: Shunt surgery (SS) remains the most effective treatment for idiopathic Normal pressure hydrocephalus (iNPH), but the selection of the patients with the greatest potential benefit remains elusive. OBJECTIVE: Identify gait features predictive of best response to SS in iNPH. METHODS: Eight patients with iNPH were assessed at baseline, after Cerebrospinal fluid tap-test (CSF-TT) and SS, with clinical scales (Clinical/Patient Global Clinical Impression, EuroQol-5D, Clinical Dementia Rating Scale(CDR), MoCA test, Hoehn-Yahr Scale) and gait analysis with inertial sensors. RESULTS: The 8 included iNPH patients had a mean age of 73 years(59-81), moderate cognitive (CDR-1.5 (0.5-2); MoCA-9.5 (3-21)) and motor impairment (Hoehn-Yahr-2.75(2-3)). After SS, patients had a significant improvement in cognition (MoCA, p = 0.001) and quality of life. At baseline, patients with lower improvement (no change/ minimally improved) (n = 2), in comparison to patient with higher improvement (much/very much improved) (n = 6), already had higher cognitive impairment (MoCa-3(3-3) vs. 11(7-21)). Patients with lower improvement had a lower % of change in gait performance at LP (mean 10.2 %) and were absent of additional benefit after SS(mean -0.8 %). In contrast, gait performance in patients with higher improvement consistently got better from baseline to LP (mean 23.1 %) and from baseline to SS (mean 82.9 %). A significant negative correlation was observed between CDR score and several gait variables: speed (rpb=-0.92,p = 0.009); stride length (rpb=-0.92,p = 0.009); lift-off angle (rpb=-0.96,p = 0.003); and maximum heel (rpb=-0.81,p = 0.049). CONCLUSION: The magnitude of gait improvement after CSF-TT, quantified by gait analysis, can be used as an integral variable in the multimodal clinical approach to the prediction of improvement after SS.

Discrimination of idiopathic Parkinson's disease and vascular parkinsonism based on gait time series and the levodopa effect.

Idiopathic Parkinson's disease (IPD) and vascular parkinsonism (VaP) present highly overlapping phenotypes, making it challenging to distinguish between these two parkinsonian syndromes. Recent evidence suggests that gait assessment and response to levodopa medication may assist in the objective evaluation of clinical differences. In this paper, we propose a new approach for gait pattern differentiation that uses convolutional neural networks (CNNs) based on gait time series with and without the influence of levodopa medication. Wearable sensors positioned on both feet were used to acquire gait data from 14 VaP patients, 15 IPD patients, and 34 healthy subjects. An individual's gait features are affected by physical characteristics, including age, height, weight, sex, and walking speed or stride length. Therefore, to reduce bias due to intersubject variations, a multiple regression normalization approach was used to obtain gait data. Recursive feature elimination using the linear support vector machine, lasso, and random forest were applied to infer the optimal feature subset that led to the best results. CNNs were implemented by means of various hyperparameters and feature subsets. The best CNN classifiers achieved accuracies of 79.33%±6.46, 82.33%±10.62, and 86.00%±7.12 without (off state), with (on state), and with the simultaneous consideration of the effect of levodopa medication (off/on state), respectively. The response to levodopa medication improved classification performance. Based on gait time series and response to medication, the proposed approach differentiates between IPD and VaP gait patterns and reveals a high accuracy rate, which might prove useful when distinguishing other diseases related to movement disorders.

Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation.

BACKGROUND: The common GLA gene mutation p.F113L causes late-onset phenotype of Fabry disease (FD) with predominant cardiac manifestations. A founder effect of FD due to this mutation was found in the Portuguese region of Guimarães. Our study aims to deepen the knowledge on the natural history of this late-onset variant. METHODS: 203 consecutive adult Fabry patients with p.F113L mutation (79 males; mean age 46 ± 18 years), from this region, were submitted at baseline to a predefined diagnostic protocol. The occurrence of FD manifestations was analyzed in each decade of age in both genders. RESULTS: In males, left ventricular hypertrophy (40.2%) and late gadolinium enhancement (21.4%) arose over 30 years; heart failure (HF) (21.9%), ventricular tachycardia (8.9%) and conduction disorders over 40 years; and bifascicular (13.1%) and complete atrioventricular blocks (5.9%) beyond 50 years of age. Cardiac manifestations occurred more commonly and 1-2 decades earlier in males; their frequency increased with age. Septum and posterior wall thickness, LV mass, QRS interval duration and pro-BNP levels increased with age in both genders. Mean survival free from HF (64 ± 1 vs. 76 ± 2 years) and pacemaker (71 ± 2 vs. 86 ± 1 years) was higher in females (p < .001). Albuminuria A2/A3 (33.7%), brain white matter lesions (50.3%) and sensorineural deafness (44.7%) arose before 30 years of age in both genders, increasing with age. Renal failure and stroke were rare. Lysosomal inclusions were demonstrated in podocytes of patients with proteinuria. CONCLUSION: This study improves the knowledge on natural history of late-onset variants of FD, carrying major impact on clinical decisions and guidelines.

Founder effect of Fabry disease due to p.F113L mutation: Clinical profile of a late-onset phenotype.

BACKGROUND: Knowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region. METHODS AND RESULTS: FD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a predefined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria>30 mg/24 h 36.1%, chronic kidney disease≥G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations. CONCLUSION: A founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.

Gait stride-to-stride variability and foot clearance pattern analysis in Idiopathic Parkinson's Disease and Vascular Parkinsonism.

The literature on gait analysis in Vascular Parkinsonism (VaP), addressing issues such as variability, foot clearance patterns, and the effect of levodopa, is scarce. This study investigates whether spatiotemporal, foot clearance and stride-to-stride variability analysis can discriminate VaP, and responsiveness to levodopa. Fifteen healthy subjects, 15 Idiopathic Parkinson's Disease (IPD) patients and 15 VaP patients, were assessed in two phases: before (Off-state), and one hour after (On-state) the acute administration of a suprathreshold (1.5 times the usual) levodopa dose. Participants were asked to walk a 30-meter continuous course at a self-selected walking speed while wearing foot-worn inertial sensors. For each gait variable, mean, coefficient of variation (CV), and standard deviations SD1 and SD2 obtained by Poincaré analysis were calculated. General linear models (GLMs) were used to identify group differences. Patients were subject to neuropsychological evaluation (MoCA test) and Brain MRI. VaP patients presented lower mean stride velocity, stride length, lift-off and strike angle, and height of maximum toe (later swing) (p < .05), and higher %gait cycle in double support, with only the latter unresponsive to levodopa. VaP patients also presented higher CV, significantly reduced after levodopa. Yet, all VaP versus IPD differences lost significance when accounting for mean stride length as a covariate. In conclusion, VaP patients presented a unique gait with reduced degrees of foot clearance, probably correlated to vascular lesioning in dopaminergic/non-dopaminergic cortical and subcortical non-dopaminergic networks, still amenable to benefit from levodopa. The dependency of gait and foot clearance and variability deficits from stride length deserves future clarification.

Safinamide: a new hope for Parkinson's disease?

The loss of dopaminergic neurons (DAn) and reduced dopamine (DA) production underlies the reasoning behind the gold standard treatment for Parkinson's disease (PD) using levodopa (L-DOPA). Recently licensed by the European Medicine Agency (EMA) and US Food and Drug Administration (FDA), safinamide [a monoamine oxidase B (MOA-B) inhibitor] is an alternative to L-DOPA; as we discuss here, it enhances dopaminergic transmission with decreased secondary effects compared with L-DOPA. In addition, nondopaminergic actions (neuroprotective effects) have been reported, with safinamide inhibiting glutamate release and sodium/calcium channels, reducing the excitotoxic input to dopaminergic neuronal death. Effects of safinamide have been correlated with the amelioration of non-motor symptoms (NMS), although these remain under discussion. Overall, safinamide can be considered to have potential antidyskinetic and neuroprotective effects and future trials and/or studies should be performed to provide further evidence for its potential as an anti-PD drug.

Compensatory Postural Adjustments in an Oculus Virtual Reality Environment and the Risk of Falling in Alzheimer's Disease.

BACKGROUND/AIMS: Alzheimer's disease (AD) patients have an impaired ability to quickly reweight central sensory dependence in response to unexpected body perturbations. Herein, we aim to study provoked compensatory postural adjustments (CPAs) in a conflicting sensory paradigm with unpredictable visual displacements using virtual reality goggles. METHODS: We used kinematic time-frequency analyses of two frequency bands: a low-frequency band (LB; 0.3-1.5 Hz; mechanical strategy) and a high-frequency band (HB; 1.5-3.5 Hz; cognitive strategy). We enrolled 19 healthy subjects (controls) and 21 AD patients, divided according to their previous history of falls. RESULTS: The AD faller group presented higher-power LB CPAs, reflecting their worse inherent postural stability. The AD patients had a time lag in their HB CPA reaction. CONCLUSION: The slower reaction by CPA in AD may be a reflection of different cognitive resources including body schema self-perception, visual motion, depth perception, or a different state of fear and/or anxiety.

Application of Machine Learning in Postural Control Kinematics for the Diagnosis of Alzheimer's Disease.

The use of wearable devices to study gait and postural control is a growing field on neurodegenerative disorders such as Alzheimer's disease (AD). In this paper, we investigate if machine-learning classifiers offer the discriminative power for the diagnosis of AD based on postural control kinematics. We compared Support Vector Machines (SVMs), Multiple Layer Perceptrons (MLPs), Radial Basis Function Neural Networks (RBNs), and Deep Belief Networks (DBNs) on 72 participants (36 AD patients and 36 healthy subjects) exposed to seven increasingly difficult postural tasks. The decisional space was composed of 18 kinematic variables (adjusted for age, education, height, and weight), with or without neuropsychological evaluation (Montreal cognitive assessment (MoCA) score), top ranked in an error incremental analysis. Classification results were based on threefold cross validation of 50 independent and randomized runs sets: training (50%), test (40%), and validation (10%). Having a decisional space relying solely on postural kinematics, accuracy of AD diagnosis ranged from 71.7 to 86.1%. Adding the MoCA variable, the accuracy ranged between 91 and 96.6%. MLP classifier achieved top performance in both decisional spaces. Having comprehended the interdynamic interaction between postural stability and cognitive performance, our results endorse machine-learning models as a useful tool for computer-aided diagnosis of AD based on postural control kinematics.

Compensatory postural adjustments in Parkinson's disease assessed via a virtual reality environment.

Postural control is a complex dynamic mechanism, which integrates information from visual, vestibular and somatosensory systems. Idiopathic Parkinson's disease (IPD) patients are unable to produce appropriate reflexive responses to changing environmental conditions. Still, it is controversial what is due to voluntary or involuntary postural control, even less what is the effect of levodopa. We aimed to evaluate compensatory postural adjustments (CPA), with kinematic and time-frequency analyzes, and further understand the role of dopaminergic medication on these processes. 19 healthy subjects (Controls) and 15 idiopathic Parkinson's disease (IPD) patients in the OFF and ON medication states, wearing IMUs, were submitted to a virtual reality scenario with visual downward displacements on a staircase. We also hypothesized if CPA would involve mechanisms occurring in distinct time scales. We subsequently analyzed postural adjustments on two frequency bands: low components between 0.3 and 1.5 Hz (LB), and high components between 1.5 and 3.5 Hz (HB). Vertical acceleration demonstrated a greater power for discriminating IPD patients from healthy subjects. Visual perturbation significantly increased the power of the HB in all groups, being particularly more evident in the OFF state. Levodopa significantly increased their basal power taking place on the LB. However, controls and IPD patients in the ON state revealed a similar trend of the control mechanism. Results indicate an improvement in muscular stiffness provided by levodopa. They also suggest the role of different compensatory postural adjustment patterns, with LB being related to inertial properties of the oscillating mass and HB representing reactions to the ongoing visual input-changing scenario.

Role of the Visual and Auditory Systems in Postural Stability in Alzheimer's Disease.

BACKGROUND: Postural stability requires the integration of multisensory input information and translation into appropriate motor responses. Surprisingly, few previous studies have addressed the role of auditory input on postural stability in healthy subjects, and none has investigated this in Alzheimer's disease (AD). OBJECTIVE: To assess the influence of the visual and auditory systems on postural stability in patients with AD and healthy subjects. METHODS: Twenty-four patients with AD and healthy age-matched subjects were examined by kinematic postural analysis (inertia measurement units placed at the center of mass of the body) under four different conditions: stance with eyes open and eyes closed, with and without suppression of background noise (using ear defenders). The effects of visual and auditory influences were analyzed independently and in conjunction. RESULTS: In both groups, visual suppression had a negative impact on postural stability, while suppression of background noise, non-specifically and without spatial cues, significantly benefited postural stability. We also observed that in both groups, the positive effect of background noise suppression was insufficient to compensate for the negative effect of visual suppression, to which the patients were significantly more vulnerable. CONCLUSIONS: Audition, albeit less significant than vision, also plays a role in the multi-sensorial dynamic control of postural stability by the central nervous system. In everyday life, audition is likely to be a relevant factor in postural stability. This is especially relevant in AD in which, even when the peripheral sensory system is intact, the central processing is impaired and sensory dependence is re-weighted.

The effect of levodopa on postural stability evaluated by wearable inertial measurement units for idiopathic and vascular Parkinson's disease.

BACKGROUND: Postural stability analysis has shown that postural control is impaired in untreated idiopathic Parkinson's disease (IPD), even in the early stages of the disease. Vascular Parkinson's disease (VPD) lacks consensus clinical criteria or diagnostic tests. Moreover, the levodopa effect on postural balance remains undefined for IPD and even less so for VPD. OBJECTIVE: To characterize postural stability, using kinematic analysis with wearable inertial measurement units, in IPD and VPD patients without clinical PI, and to subsequently analyze the response to levodopa. METHODS: Ten patients with akinetic-rigid IPD and five patients with VPD were included. Clinical and postural stability kinematic analysis was performed before and after levodopa challenge, on different standing tasks: normal stance (NS), Romberg eyes open (REO) and Romberg eyes closed. RESULTS: In the "off state", VPD patients had higher mean distances and higher maximal distance of p ostural sway on NS and REO tasks, respectively. VPD patients maintained a higher range of anterior-posterior (AP) postural sway after levodopa. In the absence of PI and non-significant differences in UPDRS-III, a higher mPIGD score in the VPD patients was mainly due to gait disturbance. Gait disturbance, and not UPDRS-III, influenced the degree of postural sway response to levodopa for VPD patients. CONCLUSION: Quantitative postural sway evaluation is useful in the investigation of Parkinsonian syndromes. VPD patients have higher AP postural sway that is correlated with their gait disturbance burden and also not responsive to levodopa. These observations corroborate the interconnection of postural control and locomotor networks.

Postural stability analysis with inertial measurement units in Alzheimer's disease.

BACKGROUND: The cause of frequent falls in patients with Alzheimer's disease (AD) is still not well understood. Nevertheless, balance control and sensory organization are known to be critical for moving safely and adapting to the environment. METHODS: We evaluated postural stability in 20 AD patients (11 fallers and 9 nonfallers) and 16 healthy controls with an inertial measurement unit (triaxial accelerometers and gyroscopes) attached to the center of mass (COM) in different balance conditions (Romberg on flat surface and frontward/backward-inclined surface, with or without visual suppression) in a motor lab. RESULTS: In AD patients, the group of fallers showed a different kinetic pattern of postural stability characterized by higher vulnerability to visual suppression, higher total/maximal displacement and a mediolateral/anteroposterior range of sway, and a consequent need for more corrections of COM pitch and roll angles. CONCLUSION: Further studies are needed to consolidate the normative values of the discriminatory kinetic variables with the potential of inclusion in a multifactorial analysis of the risk of falls. Nevertheless, these results highlight signs of impairment of central postural control in AD, which may require early therapeutic intervention.

Deep Brain Stimulation of the Subthalamic Nucleus for Parkinson's Disease in a Patient with HIV Infection: Dual Clinical Benefit.

As a result of the efficacy of highly active antiretroviral therapy (HAART), patients with human immunodeficiency virus (HIV) can survive longer and are thus naturally prone to ageing-related degenerative disorders such as Parkinson's disease (PD). Managing PD and HIV in the same patient may be challenging, as HAART and levodopa interact and may cause intolerable side effects. Concerns about the increased risk of hardware infection in immunocompromised patients submitted to deep brain stimulation of the subthalamic nucleus (STN-DBS) still persist. We report a PD patient with HIV infection who suffered peak-dose dyskinesias and intolerable gastrointestinal side effects while on HAART, prompting its suspension. STN-DBS allowed complete postoperative levodopa withdrawal and HAART restart, without infectious complications after 12 months of follow-up. STN-DBS seems to be a safe procedure in selected patients with both medically refractory PD and HIV infection, and may result in clinical optimization of both conditions.

Role of Tc-Sulesomab Immunoscintigraphy in the Management of Infection following Deep Brain Stimulation Surgery.

Infection constitutes a serious adverse event in patients submitted to deep brain stimulation, often leading to removal of the device. We set to evaluate the potential role of immunoscintigraphy with (99m)Tc-labelled antigranulocyte antibody fragments ((99m)Tc-sulesomab) in the management of infection following DBS. (99m)Tc-sulesomab immunoscintigraphy seems to correlate well with the presence and extent of infection, thus contributing to differentiate between patients who should remove the hardware entirely at presentation and those who could undergo a more conservative approach. Also, (99m)Tc-sulesomab immunoscintigraphy has a role in determining the most appropriate timing for reimplantation. Finally, we propose an algorithm for the management of infection following DBS surgery, based on the results of the (99m)Tc-sulesomab immunoscintigraphy.

Suicide attempts after subthalamic nucleus stimulation for Parkinson's disease.

A higher risk of suicidal attempt after subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) has been consistently reported. We retrospectively analyzed 3 PD patients with suicide attempts after STN-DBS. All patients had normal pre- and immediate postoperative psychopathological and cognitive evaluations, with STN-DBS yielding a good motor benefit. Levodopa medication was markedly reduced. Albeit there was a significant reduction in dopaminergic medication, there was also a considerable time lag to suicide attempt. Impulsive behavior could have played a higher role, going unnoticed in punctual psychopathological examinations. STN-DBS patients need a closer postoperative psychiatric and behavioral follow-up.