Expanding the Clinical and Mutational Spectrum of the PLP1-Related Hypomyelination of Early Myelinated Structures (HEMS)

the PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. mutations in PLP1 cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel PLP1 mutations in exon 3B detected by targeted next-generation sequencing. patients experienced psychomotor delay or nystagmus in the first year of age and then developed ataxic-spastic or ataxic syndrome, compatible with a phenotype of intermediate severity in the spectrum of PLP1-related disorders. regression occurred at the beginning of the third decade of the eldest patient. extrapyramidal involvement was rarely observed. brain MRI confirmed the involvement of structures that physiologically myelinate early, although the pattern of abnormalities may differ depending on the age at which the study is performed. these new cases contribute to expanding the phenotypic and genotypic spectrum of HEMS. additional studies, especially enriched by systematic functional evaluations and long-term follow-up, are welcome to better delineate the natural history of this rare hypomyelinating leukodystrophy

Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia

Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia. Although limited by the sample size, the absence of a placebo-controlled group, the poor compliance of enrolled population to the original experimental design and the partial accuracy of outcome measures in pediatric subjects, we suggest that NIFMV by WS could support locomotion of patients with childhood slow/non-progressive cerebellar ataxia with preserved sensory system and no signs of peripheral neuropathy. Future studies are definitely necessary to confirm these preliminary results and define criteria for successful NIFMV-based treatmen

Artificial Intelligence for Alzheimer’s Disease: Promise or Challenge?

Decades of experimental and clinical research have contributed to unraveling many mechanisms in the pathogenesis of Alzheimer’s disease (AD), but the puzzle is still incomplete. Although we can suppose that there is no complete set of puzzle pieces, the recent growth of open data-sharing initiatives collecting lifestyle, clinical, and biological data from AD patients has provided a potentially unlimited amount of information about the disease, far exceeding the human ability to make sense of it. Moreover, integrating Big Data from multi-omics studies provides the potential to explore the pathophysiological mechanisms of the entire biological continuum of AD. In this context, Artificial Intelligence (AI) offers a wide variety of methods to analyze large and complex data in order to improve knowledge in the AD field. In this review, we focus on recent findings and future challenges for AI in AD research. In particular, we discuss the use of Computer-Aided Diagnosis tools for AD diagnosis and the use of AI to potentially support clinical practices for the prediction of individual risk of AD conversion as well as patient stratification in order to finally develop effective and personalized therapies

Cannabinoids in Parkinson's Disease

The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson's disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies

Expanding the Clinical and Mutational Spectrum of the PLP1-Related Hypomyelination of Early Myelinated Structures (HEMS)

The PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. Mutations in PLP1 cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel PLP1 mutations in exon 3B detected by targeted next-generation sequencing. Patients experienced psychomotor delay or nystagmus in the first year of age and then developed ataxic–spastic or ataxic syndrome, compatible with a phenotype of intermediate severity in the spectrum of PLP1-related disorders. Regression occurred at the beginning of the third decade of the eldest patient. Extrapyramidal involvement was rarely observed. Brain MRI confirmed the involvement of structures that physiologically myelinate early, although the pattern of abnormalities may differ depending on the age at which the study is performed. These new cases contribute to expanding the phenotypic and genotypic spectrum of HEMS. Additional studies, especially enriched by systematic functional evaluations and long-term follow-up, are welcome to better delineate the natural history of this rare hypomyelinating leukodystrophy

Mild brain ischemia increases cerebral lipid peroxidation and activates leukocytes in the peripheral blood of rats

This study evaluated local and systemic leukocyte changes, respectively in the jugular and femoral veins, after an acute reduction of cerebral blood flow (oligoemia) in rats submitted either to permanent bilateral carotid occlusion (BCO) (no. = 36) for 5 hours or to sham operation (no. = 33). In a subgroup of rats (no. = 13) the extent of neural damage was histologically assessed. As a marker of biochemical brain changes the entity of the iron-ascorbate induced lipid peroxidation of synaptosomes was assessed in vitro by measuring malondialdehyde (MDA) reactive products. Five hours after surgery, the percentage of aggregated leukocytes and of activated neutrophils reducing the NBT were significantly higher in BCO rats (p < 0.05). However, leukocyte changes did not differ significantly between the jugular and the femoral districts. The brains of BCO rats showed tiny foci of neuronal necrosis. Synaptosomes obtained from the BCO animals showed a small but highly significant increase of MDA production (p < 0.01). Long-lasting brain oligoemia increases the production of lipid peroxidative metabolites, and causes the occurrence of tiny foci of neuronal necrosis in different brain regions. The lack of a significant gradient in aggregated leukocytes and activated neutrophils between the jugular and femoral venous districts demonstrates that leukocytes are stimulated in the peripheral blood by even mild biochemical and morphological brain damage

Intensive Postural and Motor Activity Program Reduces Scoliosis Progression in People with Rett Syndrome

Background: A scoliosis prevalence of 94% was reported in the population with Rett syndrome (RTT), with an annual progression rate of 14 to 21° Cobb which may result in pain, loss of sitting balance, deterioration of motor skills, and lung disfunction. This paper describes the efficacy of an intensive conservative individualized physical and postural activity program in preventing scoliosis curvature progression in patients with RTT. Methods: Twenty subjects diagnosed with RTT and scoliosis were recruited, and an individualized intensive daily physical activity program was developed for each participant. Each program was conducted for six months by participants’ primary caregivers in their daily living environment. Fortnightly remote supervision of the program implementation was provided by an expert therapist. Pre- and post-intervention radiographs and motor functioning were analyzed. Results: An averaged progression of +1.7° ± 8.7° Cobb, over one year (12.3 ± 3.5 months) was observed in our group, together with motor function improvements. A relation between curve progression and motor skill improvement was observed. Conclusions: The intervention prevented scoliosis progression in our group. The achievement of functional motor improvements could enable better body segment control and muscle balancing, with a protective effect on scoliosis progression. The intervention was effective for individuals with RTT across various ages and severity levels. Individual characteristics of each participant and the details of their activity program are described

WHICH IS THE BEST WAY TO PERFORM THE PHYSIOLOGICAL COST INDEX IN ACTIVE INDIVIDUALS WITH UNILATERAL TRANS-TIBIAL AMPUTATION?

BACKGROUND: Physiological Cost Index (PCI) is a simple method used to estimate energy expenditure during walking. It is based on a ratio between heart rate and self-selected walking speed. Previous studies reported that PCI is reliable in individuals with lower limb amputation but only if there is an important walking impairment. No previous studies have investigated the correlation of PCI with the Energy Cost Walking (ECW) in active individuals with traumatic unilateral trans-tibial amputation, considering that this particular category of amputees has an ECW quite similar to healthy individual without lower limb amputation. Moreover, it is important to determine if PCI is also correlated to ECW in the treadmill test so as to have an alternative to over-ground test. OBJECTIVES: The aim of this study was to evaluate the correlation between PCI and ECW in active individuals with traumatic trans-tibial amputation in different walking conditions. The secondary aim was to evaluate if this correlation permits to determine ECW from PCI values. METHODOLOGY: Ninety traumatic amputees were enrolled. Metabolic data, heart rate and walking speed for the calculation of ECW and for PCI were computed over-ground and on a treadmill with 0% and 12% slopes during a 6-minute walking test. FINDINGS: There is a significant correlation between ECW and PCI walking over-ground (p=0.003; R2=0.10) and on treadmill with 12% slopes (p=0.001; R2=0.11) but there is only a poor to moderate correlation around the trendline. No significant correlation was found walking on treadmill with 0% slope. The Bland-Altman plot analysis suggests that is not possible to evaluate ECW directly from PCI. CONCLUSIONS: PCI is a reliable alternative measure of energy expenditure during walking in active individuals with trans-tibial amputation when performing over-ground or at high intensity effort on treadmill. PCI is therefore useful only for monitoring a within subject assessment. Layman’s Abstract: The knowledge of the energy cost of walking in disabled people is important to improve strategies of rehabilitation or fitness training and to develop new prosthetic and orthotic components. The “gold standard” for the evaluation of the energy cost of walking is the oxygen consumption measurement with a metabolimeter, but the testing procedure is expensive and time consuming, hardly practicable in many rehabilitation centers. The Physiological Cost Index (PCI) is an indirect tool that evaluates the oxygen consumption during walking. PCI considers heart rate during walking, in relation to the speed, as an indicator of energy expenditure. The formula is “walking heart rate – resting heart rate /speed”. PCI is widely used in literature but there is not a solid evidence of a direct correlation between PCI and energy cost of walking. In particular, for individuals with unilateral trans-tibial amputation without comorbidities, no previous studies have been conducted about this correlation. It has to be noticed that individuals with unilateral trans-tibial amputation have an energy cost of walking quite similar to healthy people. Previous studies reported that in healthy people such correlation does not exist. For this reason, the aim of this study was to evaluate if and in which walking condition a linear correlation exists between PCI and Energy Cost Walking in individuals with unilateral trans-tibial amputation. Oxygen consumption measurement with a metabolimeter and PCI were computed over-ground and on a treadmill with 0% and 12% slopes during a 6-minute walking test in 90 participants. We have found that PCI is an alternative measure of energy cost of walking when performing over-ground or with high intensity effort on treadmill (12% slope). These findings could be useful when PCI is used for monitoring a fitness training or for evaluation tests. Article PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/32953/25717 How To Cite:: Brunelli S, Sancesario A, Iosa M, Delussu A.S, Gentileschi N, Bonanni C, Foti C, Traballesi M. Which is the best way to perform the Physiological Cost Index in active individuals with unilateral trans-tibial amputation? Canadian Prosthetics &amp; Orthotics Journal. 2019, Volume2, Issue1, No.5. https://doi.org/10.33137/cpoj.v2i1.32953. Corresponding Author:Dr. Stefano Brunelli,Fondazione Santa Lucia, IRCCS, Via Ardeatina 306, 00179 Rome, Italy.ORCID: https://orcid.org/0000-0002-5986-1564Tel. +39 0651501844; Fax +39 0651501919E-MAIL: [email protected]