Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Blood biomarkers of Alzheimer’s disease:important considerations for use in clinical practice

Introduction:Fluid and positron emission tomography(PET)biomarkers that enable the detection of the hallmark proteins of Alzheimer’s disease(AD)(amyloid and tau)have revolutionized our approach to the diagnosis of AD.The evolution of AD diagnostic criteria to include biological characterization(Alzheimer’s Association Working Group,2023)provides an appropriate framework to reduce levels of clinico-pathologic mismatch and improve in-vivo diagnostic accuracy.As the therapeutic landscape for neurodegenerative disease evolves,it is increasingly incumbent on clinicians to provide timely,and pathologically precise diagnoses for patients.However,the expensive and invasive nature of these tests limits their scalability.

Treadmill training in Parkinson's disease:possible role of prefrontal modifications in the improved cortical-subcortical network function

Parkinson’s disease(PD)is a complex neurodegenerative disorder characterized by a range of motor symptoms such as bradykinesia,resting tremor,rigidity,and postural instability,as well as non-motor symptoms,such as depression,anxiety,sleep disturbances,and fatigue(Bloem et al.,2021).

Angiographic Features of Intracranial Aneurisms in Mali: A Preliminary Study of 105 Patients

Introduction: Rupture of intracranial aneurisms leads to severe morbidity and mortality. There are two modalities of treatment surgery and endovascular treatment. The diagnosis is made by angiography (DSA, CTA, RMA). The angiographic features used to assess the risk of the complications and choose the treatment modality are size, location and aneurism morphology. Materials and Methods: We reviewed and analyzed the computed tomographic angiography and magnetic resonance angiography of all patients admitted to the hospital of Mali with IAs from 2015 to 2021 either 7 years. Patients who were less than 18 years old, those with non-aneurysmal SAH, patients who request a discharge and those with an incomplete angiographic description of the IAs were excluded from the analysis. Results: We have collected 105 patients with 109 aneurysms. The sex ratio was 2/1 in favor of females. The mean age was 44.51 years with the range from 18 to 70 years. The presentation mode was subarachnoid hemorrhage (SAH) in 97% of cases. 76.19% had confirmed high blood pressure before the bleeding. 19.04% were diabetics. 98% of our patients have made a CT angiography and 2% have made MR angiography for the aneurysm diagnosis. 97.24% of aneurisms were located in the anterior part of the Willis circle. 39.44% of these aneurisms were the anterior communicating complex aneurysm. 27.52% of aneurysm had a small size, 42.20% had a medium size, 20.18% large size against 5.50% of the giant (Figure 3) and the middle cerebral artery was the most involved in the least. 95.41% of cases were saccular aneurysms against 4.59% fusiform. Conclusion: The angiographic feature of an intracranial aneurism in the Malian population may differ from other populations of the sub-region. The anterior communicating complex aneurysm is more common and the aneurism of the posterior part of the Willis circle is less common. We found the aneurism size ≥ 6 mm, ACA, MCA and Pcom more frequent.

Non-linear dynamic state-space network modeling for decoding neurodegeneration

Neurodegenerative disorders represent a pervasive global health challenge,yet therapeutic options remain conspicuously limited.These disorders are inherently dynamic processes within the central nervous system,unfolding across distinct sub-stages:initial structural neuronal alterations(sub-stage 1),functional impairment(sub-stage 2),and culminating in neuronal death(sub-stage 3).

Levodopa/Carbidopa Intestinal Gel for Treatment of Advanced Parkinson’s Disease: An Update on the Effects of Cognitive Functions

Cognitive impairment is a frequent non-motorsymptom of Parkinson’s disease (PD). In early disease stage, this takes the features of dysexecutive syndrome, and is mostly dependent on derangement of frontostriatal circuitries. In advanced stages, worsening of dysexecutive symptoms is accompanied by disorientation and memory deficit leading to dementia in 30% of cases, due to multiple neurotransmitter derangement. Dysexecutive symptoms in the early stages of PD may benefit from dopamine replacement therapy (DRT). Conversely, severe cognitive symptoms in more advanced stages are frequently aggravated by DRT. In particular, pulsatile stimulation of dopaminergic receptors by orally administered levodopa (LD) plays a significant negative role on cognitive and neuropsychiatric symptoms in advanced PD. The introduction of a gel of LD-carbidopa for continuous intestinal administration (LCIG) allows marked stabilization of plasma LD concentrations and provides benefit on motor fluctuations and dyskinesia of significantly greater magnitude than conventional oral administration in advanced PD patients. The results from several preliminary studies suggest that efficacy of LCGI on motor symptoms may be accompanied by good tolerability and potential benefit on several non-motor symptoms, including cognitive impairment. Future studies with longer observation period and larger cohorts are advised to confirm these preliminary observations.

Proximal-distal motor unit number estimationdynamic changes in patients with amyotrophic lateral sclerosis A one-year follow-up

BACKGROUND：Amyotrophic lateral sclerosis （ALS） is the most common of all the motor neuron diseases and the absence of a biologic marker has made both diagnosis and tracking evolution of the disease difficult, Electrodiagnostic tests play a fundamental role in quantifying pathological changes in the motor unit pool.OBJECTIVE：We assessed distal-proximal Motor Unit （MU） loss and changes using the method of motor unit number estimation （MUNE）.DESIGN, TIME AND SETTING：A case-control study was performed at the Department of Neuroscience, Pisa University Medical School, Italy from December 1999 to November 2009. PARTICIPANTS：A total of 50 ALS patients were recruited, 30 males：mean age （59.6 ± 13.3） years; 20 females：mean age （63.9 ± 11.7） years; range （30-82） years; all patients had probable or definite ALS. Thirty healthy volunteers were recruited from department staffs, including 20 males and 10 females; mean age （57.7 ± 13.8） years served as controls.METHODS：MUNE was performed for both the biceps brachii and abductor digiti minimi muscles of the same side. The technique used relayed substantially on manual incremental stimulation of the motor nerve, known as the McComas technique （50 ms sweep duration, a gain of 2 mV/Div for M wave, 0.5 mV/Div for each step; filters 10-20 kHz）.MAIN OUTCOME MEASURES：MUNE results were measured.RESULTS：Functioning MU numbers, measured by MUNE, decreased in the biceps brachii and abductor digiti minimi muscles over the entire one-year follow-up period （one assessment every three months） compared with baseline determination, the rate of MU decrease was similar in both muscles, but steeper distally.CONCLUSION：MUNE is a feasible method for ALS patients both proximally and distally to track changes over time in muscle MUs during the disease＇s evolution.

Impact of COVID-19 pandemic on the neuropsychiatric status of Wilson’s disease

We have read with interest the Letter to the Editor by Drs.Zhuang and Zhong,who presented the clinical data of 68 patients with Wilson’s disease(WD)who were admitted to the hospital before and during the coronavirus disease 2019(COVID-19)pandemic,and appreciated their findings on hepatic and some extrahepatic manifestations.Nevertheless,given the strong impact of the pandemic on patients with neurological and psychiatric disorders,we would have expected a worsening of the psychiatric and/or neurological impairments in these patients.In contrast,according to the authors,these manifestations remained,somewhat unexpectedly,unchanged.This finding is in contrast with most of the current literature that highlights not only an increased incidence of mental health disorders in the general population but also an exacerbation of neurological and psychiatric symptoms in patients with chronic diseases,especially in those with pre-existing neuropsychiatric disorders,such as WD.Although the study was mainly focused on the hepatic features of WD patients taking anti-copper treatment,a generic and cumulative definition of neurological and psychiatric manifestations,as in this study,does not allow for further considerations.Future studies during and after the pandemic are necessary to clarify the real impact,either direct or indirect,of the COVID-19 pandemic on the neurological and psychiatric symptoms of WD patients.

Experience of a Single Center in the Diagnosis and Classification of Cases of Left Ventricular Noncompaction

Objectives: To analyse the clinical profile of consecutive cases of Left Ventricular Non Compaction (LVNC) with particular interest in non-compacted segments valuation. Methods: There were 18,000 patients seen from 2007 to 2010, with a complete evaluation including family history and personal cardiac history, clinical examination and electrocardiography. Diagnosis was based on three published definitions. Results: The diagnosis of LVNC was placed in 1.4% of cases. Clinical and echo-cardiographic data for the 250 cases of LVNC are presented. Trabecular meshwork was observed predominantly at the apex (91.6%), in the lateral and inferior wall (40.4% and 38.0% respectively), and less frequently in the posterior and anterior wall (21.6% and 9.2% respectively). Conclusions: This study suggests that LVNC is a form of cardiomyopathy with higher prevalence and relatively better prognosis than previously reported.

Treatment strategies for multiple sclerosis:When to start,when to change,when to stop?

Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.

Longitudinal quantitative electroencephalographic study in mono-hemispheric stroke patients

The identification of individual factors modulating clinical recovery after a stroke is fundamental to personalize the therapeutic intervention to enhance the final clinical outcome.In this framework,electrophysiological factors are promising since are more directly related to neuroplasticity,which supports recovery in stroke patients,than neurovascular factors.In this retrospective observational study,we investigated brain neuronal activity assessed via spectral features and Higuchi's fractal dimension(HFD) of electroencephalographic signals in acute phase(2–10 days from symptom onset,T0) and sub-acute phase(2.5 months,T1) in 24 patients affected by unilateral middle cerebral artery stroke.Longitudinal assessment of the clinical deficits was performed using the National Institutes of Health Stroke Scale(NIHSS),together with the effective recovery calculated as the ratio between difference of NIHSS at T0 and T1 over the NIHSS value at T0.We observed that delta and alpha band electroencephalographic signal power changed between the two phases in both the hemispheres ipsilateral(ILH) and contralateral(CHL) to the lesion.Moreover,at T0,bilateral higher delta band power correlated with worse clinical conditions(Spearman's rs = 0.460,P = 0.027 for ILH and rs = 0.508,P = 0.013 for CLH),whereas at T1 this occurred only for delta power in ILH(rs = 0.411,P = 0.046) and not for CHL.Inter-hemispheric difference(ILH vs.CLH) of alpha power in patients was lower at T0 than at T1(P = 0.020).HFD at T0 was lower than at T1(P = 0.005),and at both phases,ILH HFD was lower than CLH HFD(P = 0.020).These data suggest that inter-hemispheric low band asymmetry and fractal dimension changes from the acute to the sub-acute phase are sensitive to neuroplasticity processes which subtend clinical recovery.The study protocol was approved by the Bioethical Committee of Ospedale San Giovanni Calibita Fatebenefretelli(No.40/2011) on July 14,2011.

An open-label pilot study with high-dose thiamine in Parkinson's disease

Parkinson’s disease（PD）is a progressive neurodegenerative disorder clinically characterized by motor symptoms（bradykinesia,tremor,rigidity,postural instability）and non-motor symptoms（hyposmia,sleep disorders,autonomic and sphincteric dysfunctions,fatigue,pain,depression,and cognitive disorders）（Sprenger and Poewe,2013）.

Alpha-Klotho in Parkinson’s disease: a perspective on experimental evidence and potential clinical implications

more than 20 years ago,and immediately emerged as a master regulator of aging-related processes,which basically operates as an anti-aging factor.It is expressed through the entire human body,representing the choroid plexus and the kidney as the most active sources at the central nervous system(CNS)and periphery level respectively.To a lesser extent,also the parathyroid gland,the adipose tissue,and the liver express KL.KL is a transmembrane protein serving as an essential co-receptor for fibroblast growth factor receptors,but,in general,it mediates a number of molecular pathways and biological functions at a multisystem level.In fact,even a soluble form exists,originated by the extracellular domain cleavage,which circulates in human fluids,allowing a sort of systemic signaling.Although all the tissue-specific actions have not been completely clarified,there is solid evidence that KL regulates basic mineral homeostasis and internal metabolism pathways.

Efficient RT-QuIC seeding activity for α-synuclein in olfactory mucosa samples of patients with Parkinson’s disease and multiple system atrophy

Background:Parkinson’s disease(PD)is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms.PD is characterized by intraneuronal accumulation of abnormalα-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of eitherα-synuclein,as in the case of Multiple System Atrophy(MSA)or tau,as in the case of Corticobasal Degeneration(CBD)and Progressive Supranuclear Palsy(PSP),in other disease-specific brain regions.Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization ofα-synuclein or tau aggregates in the brain.Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues,including receptor neurons of the olfactory mucosa(OM).Methods:We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion(RT-QuIC)assay for OM analysis.In particular,by using human recombinantα-synuclein as substrate of reaction,we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induceα-synuclein aggregation,and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.Results:Our results showed that a significant percentage of MSA and PD samples inducedα-synuclein aggregation with high efficiency,but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect.Notably,the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.Conclusions:Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities forα-synuclein.Additional studies are required for(i)estimating sensitivity and specificity of the technique and for(ii)evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms.RT-QuIC analyses of OM and cerebrospinal fluid(CSF)can be combined with the aim of increasing the overall diagnostic accuracy of these diseases,especially in the early stages.

Hypodysfibrinogenemia in a young patient withrecurrent strokes

Stroke is a complex disease, but in some instances is the direct result of a monogenic disease. Here we report the case of a 44-year-old Italian man who experienced recurrent transitory ischemic attacks and strokes. He also had right fetal-type posterior cerebral artery. He was diagnosed with congenital hypodysfibrinogenemia due to a mutation leading to a truncated fibrinogen gamma chain. Further studies are needed to better elucidate the links between fibrinogen dysfunction and stroke. Hypodysfibrinogenemia should be included among the monogenic diseases associated with ischemic stroke. Physicians should be aware of this condition, which may be detectable on routine assays.

Neurological diseases associated with autoantibodies targeting the voltage-gated potassium channel complex:immunobiology and clinical characteristics

Voltage-gated potassium channels(VGKCs)represent a group of tetrameric signaling proteins with several functions,including modulation of neuronal excitability and neurotransmitter release.Moreover,VGKCs give a key contribution to the generation of the action potential.VGKCs are complexed with other neuronal proteins,and it is now widely known that serum autoantibodies directed against VGKCs are actually directed against the potassium channel subunits only in a minority of patients.By contrast,these autoantibodies more commonly target three proteins that are complexed with alpha-dendrotoxin-labeled potassium channels in brain extracts.These three proteins are contactin-associated protein-2(Caspr-2),leucine-rich,glioma inactivated 1(LGI-1)protein and the protein Tag-1/contactin-2.Neoplasms are detected only in a minority of seropositive patients for VGKC complex-IgG and do not significantly associate with Caspr-2 or LGI-1.Among all the cancers described in association with VGKC complex-IgG,lung carcinoma,thymoma,and hematologic malignancies are the most commonly detected.We will review all the major neurological conditions associated with VGKC complex-IgG.These include Isaacs’syndrome,Morvan syndrome,limbic encephalitis,facio-brachial dystonic seizures,chorea and other movement disorders,epilepsy,psychosis,gastrointestinal neuromuscular diseases,a subacute encephalopathy that mimics Creutzfeldt-Jakob prion disease both clinically and radiologically and autoimmune chronic pain.The vast majority of these conditions are reversible by immunotherapy,and it is becoming increasingly recognized that early diagnosis and detection of VGKC complex-IgG is critical in order to rapidly start the treatment.As a result,VGKC complex-IgG are now part of the investigation of patients with unexplained subacute onset of epilepsy,memory or cognitive problems,or peripheral nerve hyperexcitability syndromes.

Pulsed intravenous corticosteroids in chronic inflammatory demyelinating polyneuropathy: why not?

Chronic inflammatory demyelinating polyneuropathy(CIDP)is a remitting/relapsing and/or chronic autoimmune disorder,characterized by symmetrical,sensorimotor neuropathic involvement and a slowly progressive onset.

Is creatine kinase associated with outcome in COVID-19?

The new"severe acute respiratory syndrome"(SARS)-correlated coronavirus(SARS-CoV-2),first isolated from three patients from Wuhan(China),has been spreading worldwide since the end of 2019,emerging as an exceptional global crisis.This disorder was called"coronavirus disease 2019"or COVID-19.Clinical features are highly variable,and the clinical severity ranges from asymptomatic to fatal.The understanding of SARS-CoV-2 infection is ongoing.Several neurological symptoms were identified as part of the COVID-19 spectrum,including muscle pain,confusion,and headache[1].