Poikilothermia in a 38-year-old Fabry patient

A Fabry patient with poikilothermia is described. Laboratory investigations, neuro-imaging and autonomic function tests did not disclose a cause. Assessment of intra-epidermal nerve fibre density and quantitative sensory testing revealed small fibre neuropathy with a highly impaired cold sensation. We speculate that the poikilothermia is either caused by a vascular lesion in the hypothalamus not visible on MRI or by small fibre neuropathy leading to disturbed body temperature perception and therefore impaired thermoregulation

Candidate Screening of the TRPC3 Gene in Cerebellar Ataxia

The hereditary cerebellar ataxias are a diverse group of neurodegenerative disorders primarily characterised by loss of balance and coordination due to dysfunction of the cerebellum and its associated pathways. Although many genetic mutations causing inherited cerebellar ataxia have been identified, a significant percentage of patients remain whose cause is unknown. The transient receptor potential (TRP) family member TRPC3 is a non-selective cation channel linked to key signalling pathways that are affected in cerebellar ataxia. Furthermore, genetic mouse models of TRPC3 dysfunction display cerebellar ataxia, making the TRPC3 gene an excellent candidate for screening ataxic patients with unknown genetic aetiology. Here, we report a genetic screen for TRPC3 mutations in a cohort of 98 patients with genetically undefined late-onset cerebellar ataxia and further ten patients with undefined episodic ataxia. We identified a number of variants but no causative mutations in TRPC3. Our findings suggest that mutations in TRPC3 do not significantly contribute to the cause of late-onset and episodic human cerebellar ataxias

Dysphagia in multiple system atrophy consensus statement on diagnosis, prognosis and treatment.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure plus cerebellar syndrome and/or parkinsonism. Dysphagia is a frequent and disabling symptom in MSA and its occurrence within 5 years of motor onset is an additional diagnostic feature. Dysphagia can lead to aspiration pneumonia, a recognized cause of death in MSA. Guidelines for diagnosis and management of dysphagia in MSA are lacking. An International Consensus Conference among experts with methodological support was convened in Bologna to reach consensus statements for the diagnosis, prognosis, and treatment of dysphagia in MSA. Abnormalities of the oral and pharyngeal phases of swallowing, esophageal dysfunction and aspiration occur in MSA and worsen as the disease progresses. According to the consensus, dysphagia should be investigated through available screening questionnaires and clinical and instrumental assessment (videofluoroscopic study or fiberoptic endoscopic evaluation of swallowing and manometry) at the time of MSA diagnosis and periodically thereafter. There is evidence that dysphagia is associated with poor survival in MSA, however effective treatments for dysphagia are lacking. Compensatory strategies like diet modification, swallowing maneuvers and head postures should be applied and botulinum toxin injection may be effective in specific conditions. Percutaneous endoscopic gastrostomy may be performed when there is a severe risk of malnutrition and pulmonary complications, but its impact on survival is undetermined. Several research gaps and unmet needs for research involving diagnosis, prognosis, and treatment were identified

When light hurts: Comparative Morphometry of Human Brainstem in Traumatic Photalgia

Traumatic brain injury is an increasingly common affliction, although many of its serious repercussions are still underappreciated. A frequent consequence is the development of light-induced pain, or ‘photalgia’, which can often lead to prolonged debilitation. The mechanism underlying the sensitivity to light, however, remains unresolved. Since tissue oedema (swelling) is a common feature of traumatic brain injury, we propose that the brainstem oedema, in particular, might sensitize the brainstem trigeminal complex to signals from ocular mechanisms activated in bright light. To assess this hypothesis, we ran high-resolution Magnetic Resonance Imaging of the brainstems of concussion groups with mild and severe photalgia, without photalgia, and healthy controls. The 3D configuration of the brainstem was determined by Tensor-Based Morphometry (TBM) for each participant. The TBM revealed significant deviations in the brainstem morphology of all concussion groups, with a characteristic signature for each group. In particular, concussion without photalgia showed bilateral expansion at the pontine/medulla junction, whereas concussion with photalgia showed mid-pontine shrinkage, consistent with degeneration of nuclei of the trigeminal complex. These results support the hypothesis that brainstem shrinkage/degeneration represents a morphological substrate of the photalgic sensitization of the trigeminal pathway

A multinational consensus on dysphagia in Parkinson's disease: screening, diagnosis and prognostic value

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD. Objective: To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients. Methods: A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. Results: Eighty-five papers were used to inform the Panel’s statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions. Conclusions: The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD

The ventro-medial prefrontal cortex: a major link between the autonomic nervous system, regulation of emotion, and stress reactivity?

Recent progress in neuroscience revealed diverse regions of the CNS which moderate autonomic and affective responses. The ventro-medial prefrontal cortex (vmPFC) plays a key role in these regulations. There is evidence that vmPFC activity is associated with cardiovascular changes during a motor task that are mediated by parasympathetic activity. Moreover, vmPFC activity makes important contributions to regulations of affective and stressful situations

The Central Clock Neurons Regulate Lipid Storage in Drosophila

A proper balance of lipid breakdown and synthesis is essential for achieving energy homeostasis as alterations in either of these processes can lead to pathological states such as obesity. The regulation of lipid metabolism is quite complex with multiple signals integrated to control overall triglyceride levels in metabolic tissues. Based upon studies demonstrating effects of the circadian clock on metabolism, we sought to determine if the central clock cells in the Drosophila brain contribute to lipid levels in the fat body, the main nutrient storage organ of the fly. Here, we show that altering the function of the Drosophila central clock neurons leads to an increase in fat body triglycerides. We also show that although triglyceride levels are not affected by age, they are increased by expression of the amyloid-beta protein in central clock neurons. The effect on lipid storage seems to be independent of circadian clock output as changes in triglycerides are not always observed in genetic manipulations that result in altered locomotor rhythms. These data demonstrate that the activity of the central clock neurons is necessary for proper lipid storage

Ceruloplasmin Protects Against Rotenone-Induced Oxidative Stress and Neurotoxicity

To clarify the neuroprotective property of ceruloplasmin and the pathogenesis of aceruloplasminemia, we generated ceruloplasmin-deficient (CP−/−) mice on the C57BL/10 genetic background and further treated them with a mitochondrial complex I inhibitor, rotenone. There was no iron accumulation in the brains of CP−/− mice at least up to 60 weeks of age. Without rotenone treatment, CP−/− mice showed slight motor dysfunction compared with CP+/+ mice, but there were no detectable differences in the levels of oxidative stress markers between these two groups. A low dose of rotenone did not affect the mitochondrial complex I activity in our mice, however, it caused a significant change in motor behavior, neuropathology, or the levels of oxidative stress markers in CP−/− mice, but not in CP+/+ mice. Our data support that ceruloplasmin protects against rotenone-induced oxidative stress and neurotoxicity, probably through its antioxidant properties independently of its function of iron metabolism

Delayed Postconditioning Protects against Focal Ischemic Brain Injury in Rats

We and others have reported that rapid ischemic postconditioning, interrupting early reperfusion after stroke, reduces infarction in rats. However, its extremely short therapeutic time windows, from a few seconds to minutes after reperfusion, may hinder its clinical translation. Thus, in this study we explored if delayed postconditioning, which is conducted a few hours after reperfusion, offers protection against stroke.Focal ischemia was generated by 30 min occlusion of bilateral common carotid artery (CCA) combined with permanent occlusion of middle cerebral artery (MCA); delayed postconditioning was performed by repetitive, brief occlusion and release of the bilateral CCAs, or of the ipsilateral CCA alone. As a result, delayed postconditioning performed at 3h and 6h after stroke robustly reduced infarct size, with the strongest protection achieved by delayed postconditioning with 6 cycles of 15 min occlusion/15 min release of the ipsilateral CCA executed from 6h. We found that this delayed postconditioning provided long-term protection for up to two months by reducing infarction and improving outcomes of the behavioral tests; it also attenuated reduction in 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG)-uptake therefore improving metabolism, and reduced edema and blood brain barrier leakage. Reperfusion in ischemic stroke patients is usually achieved by tissue plasminogen activator (tPA) application, however, t-PA's side effect may worsen ischemic injury. Thus, we tested whether delayed postconditioning counteracts the exacerbating effect of t-PA. The results showed that delayed postconditioning mitigated the worsening effect of t-PA on infarction.Delayed postconditioning reduced ischemic injury after focal ischemia, which opens a new research avenue for stroke therapy and its underlying protective mechanisms

Reduced cAMP, Akt Activation and p65-c-Rel Dimerization: Mechanisms Involved in the Protective Effects of mGluR3 Agonists in Cultured Astrocytes

In recent decades, astrocytes have emerged as key pieces in the maintenance of normal functioning of the central nervous system. Any impairment in astroglial function can ultimately lead to generalized disturbance in the brain, thus pharmacological targets associated with prevention of astrocyte death are actually promising. Subtype 3 of metabotropic glutamate receptors (mGluR3) is present in astrocytes, its activation exerting neuroprotective roles. In fact, we have previously demonstrated that mGluR3 selective agonists prevent nitric oxide (NO)-induced astrocyte death. However, mechanisms responsible for that cytoprotective property are still subject to study. Although inhibition of adenylyl cyclase by mGluR3 activation was extensively reported, the involvement of reduced cAMP levels in the effects of mGluR3 agonists and the association between cAMP decrease and the downstream pathways activated by mGluR3 remain neglected. Thus, we studied intracellular signaling mediating anti-apoptotic actions of mGluR3 in cultured rat astrocytes exposed to NO. In the present work, we showed that the cytoprotective effect of mGluR3 agonists (LY379268 and LY404039) requires both the reduction of intracellular cAMP levels and activation of Akt, as assessed by MTT and TUNEL techniques. Moreover, dibutyryl-cAMP impairs Akt phosphorylation induced by LY404039, indicating a relationship between mGluR3-reduced cAMP levels and PI3K/Akt pathway activation. We also demonstrated, by co-immunoprecipitation followed by western-blot, that the mGluR3 agonists not only induce per se survival-linked interaction between members of the NF-κB family p65 and c-Rel, but also impede reduction of levels of p65-c-Rel dimers caused by NO, suggesting a possible anti-apoptotic role for p65-c-Rel. All together, these data suggest that mGluR3 agonists may regulate cAMP/Akt/p65-c-Rel pathway, which would contribute to the protective effect of mGluR3 against NO challenge in astrocytes. Our results widen the knowledge about mechanisms of action of mGluR3, potential targets for the treatment of neurodegenerative disorders where a pathophysiological role for NO has been established