JNS.jpgThe April issue of the Journal of the Neurological Sciences Vol 399 is now available online.


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Issue highlights

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Diffuse Lewy body disease

  • The fourth consensus report of the DLB Consortium consensus added REM sleep behavior disorder as the core feature.
  • Polysomnography finding is one of the indicative biomarkers.
  • Intercellular propagation of alpha-synuclein, microglial activation, and genes mutation are new findings of DLB pathology.
  • The features distinguish DLB from PDD are cognitive dysfunction and visual hallucination in early stage.
  • Cholinesterase inhibitors are the first line drugs to manage cognitive dysfunction and visual hallucination.
  • Antipsychiatry agents, dopamine agonists, and anticholinergics should be avoided because of neuropsychiatric side effects.

Diffuse Lewy body disease, also called dementia with Lewy bodies (DLB), is defined as progressive dementia and pathological Lewy bodies distributed in the central and autonomic nervous systems.

The clinical features are dementia, cognitive fluctuations, visual hallucinations, parkinsonism, and REM sleep behavior disorder (RBD). Confirmatory techniques include dopamine transporter imaging, meta-iodobenzylguanidine (MIBG) myocardial scintigraphy, and polysomnography. The pathology finding in DLB is misfolded alpha-synuclein, the main component of Lewy bodies, propagating in the central nervous system. This may interrupt the acetylcholine pathway and activate an inflammatory response.

Mutations of several genes have been found in patients with DLB, including SNCA, GBA, and APOE. The differential diagnosis of DLB and Parkinson's disease with dementia (PDD) is a debated issue. Clinical features distinguishing DLB from PDD include the timing of dementia and visual hallucinations, responses to dopaminergic agents and anti-psychotics, and imaging findings. As to the management of DLB, cholinesterase inhibitors are the Level-A recommendation for treating dementia in DLB patients and also are beneficial for treating visual hallucinations and psychotic symptoms.

Dopamine agonists have the risk of inducing psychotic symptoms, while levodopa should be used carefully for motor symptoms. Melatonin and clonazepam are effective in controlling RBD.

Several other treatment methods are undergoing trials, including pimavanserine, nilotinib, psychological interventions, and behavior therapy.

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Neuropsychological and neuroimaging evidences of cerebral dysfunction in stroke-free patients with atrial fibrillation: A review

Atrial fibrillation (AF) is the most common heart arrhythmia, with the highest prevalence in the elderly. AF has been correlated with silent lesions and cognitive impairment, even in the absence of stroke. The cognitive impairment in AF represents a risk of functional decline, morbidity, mortality and high costs, constituting a public health problem due to the increasing prevalence of this arrhythmia.

Cognitive analysis of patients with AF without stroke has shown poor performance in executive, memory and learning functions. The greater loss occurs in speed processing and performance of instrumental tasks leading to functional dependence.

Neuroimaging studies have shown both structural and functional abnormalities in individuals with AF even in the absence of cognitive impairment. The mechanisms related to cognitive impairment and cerebral abnormalities in the AF are still a matter of discussion in the literature and, therefore, how to stop its progression is unknown.

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Genetics of amyotrophic lateral sclerosis: A review

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor pathways, invariably leading to death within a few years of onset.

Most cases of ALS are sporadic, but familial forms of the disease (FALS) constitute 10% of the cases. Since the first identification of a causative gene in the 1990s and with recent advances in genetics, more than twenty genes have now been linked to FALS. This increased number of genes led to a tremendous amount of research, clearly contributed to a better understanding of the pathophysiology of this disorder, and paved the way for the development of new therapeutics and new hope for this fatal disease.

  • Familial amyotrophic lateral sclerosis (FALS) represents <10% of the total ALS patients.
  • FALS are mainly due to the mutations of four genes: C9ORF72, SOD1, FUS and TDP-43.
  • The increased number of genes has clearly contributed to a better understanding of the pathophysiology of ALS.
  • This increased number of genes also risk to led to difficulties to their classification.
  • Gene therapy is probably a therapeutic way to explore in ALS.

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RP001 hydrochloride improves neurological outcome after subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) results in neurological damage, acute cardiac damage and has a high mortality rate. Immunoresponse in the acute phase after SAH plays a key role in mediating vasospasm, edema, inflammation and neuronal damage.

The S1P/S1PR pathway impacts multiple cellular functions, exerts anti-inflammatory and anti-apoptotic effects, promotes remyelination, and improves outcome in several central nervous system (CNS) diseases.

RP001 hydrochloride is a novel S1PR agonist, which sequesters lymphocytes within their secondary tissues and prevents infiltration of immune cells into the CNS thereby reducing immune response.

In this study, we investigated whether RP001 attenuates neuronal injury after SAH by reducing inflammation. S1PRs, specifically S1PR1, 3 not only exerts anti-inflammatory effects, but also decreases heart rate and induces atrioventricular conduction abnormalities. Therefore, we also tested whether RP001 treatment of SAH regulates cardiac functional outcome.

Male adult C57BL/6 mice were subjected to SAH, and neurological function tests, echocardiography, and immunohistochemical analysis were performed. SAH induces neurological deficits and acute cardiac dysfunction compared to sham control mice. Treatment of SAH with a low-dose of RP001 induces better neurological outcome and cardiac function compared to a high-dose of RP001. Low-dose-RP001 treatment significantly decreases apoptosis, white matter damage, blood brain barrier permeability, microglial/astrocyte activation, macrophage chemokine protein-1, matrix metalloproteinase-9 and NADPH oxidase-2 expression in the brain compared to SAH control mice.

Our findings indicate that low-dose of RP001 alleviates neurological damage after SAH, in part by decreasing neuroinflammation.

  • RP001 hydrochloride treatment of SAH decreases expression of MCP-1, MMP-9 and NOX-2 as well as reduces microglial activation.
  • RP001 hydrochloride treatment of SAH reduces brain apoptosis, white matter damage and BBB breakdown.
  • RP001 hydrochloride improves neurological outcome after SAH by mediating immune response.