Journal of neurology & neuromedicine最新文献

Long-distance intracellular axonal transport is predominantly microtubule-based, and its impairment is linked to neurodegeneration. Here we review recent theoretical and experimental evidence that suggest that near the axon boundaries (walls), the effective viscosity can become large enough to impede cargo transport in small (but not large) caliber axons. Theoretical work suggests that this opposition to motion increases rapidly as the cargo approaches the wall. However, having parallel microtubules close enough together to enable a cargo to simultaneously engage motors on more than one microtubule dramatically enhances motor activity, and thus decreases the effects due to such opposition. Experimental evidence supports this hypothesis: in small caliber axons, microtubule density is higher, increasing the probability of having parallel microtubules close enough that they can be used simultaneously by motors on a cargo. For transport toward the minus-end of microtubules, e.g., toward the cell body in an axon, a recently discovered force adaptation system can also contribute to overcoming such opposition to motion.

Malignant cerebral edema is a potential consequence of large territory cerebral infarction, as the resultant elevation in intracranial pressure may progress to transtentorial herniation, brainstem compression, and death. In appropriate patients, decompressive hemicraniectomy (DHC) reduces mortality without increasing the risk of severe disability. However, as the foundational DHC randomized, controlled trials excluded patients greater than 60 years of age, the appropriateness of DHC in older adults remains controversial. Recent clinical trials among elderly participants, including DESTINY II, reported that DHC reduces mortality, but may leave patients with substantial morbidity. Nationwide analyses have demonstrated generalizability of such data. However, what constitutes an acceptable outcome - the perspective on quality of life after survival with substantial disability - varies between clinicians, patients, and caregivers. Consequently, quality of life measures are being increasingly incorporated into stroke research. This review summarizes the impact of DHC in space-occupying cerebral infarction, and the influence of patient age on postoperative survival, functional capacity, and quality of life-all key factors in the clinical decision process. Ultimately, these data underscore the inherent complexity in balancing scientific evidence, clinical expertise, and patient and family preference when pursuing hemicraniectomy among the elderly.

The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue in vitro and in vivo. As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation.

Alzheimer's disease (AD) is characterized by neuronal death with an accumulaton of intra-cellular neurofibrillary tangles (NFT) and extracellular amyloid plaques. Reduced DNA repair ability has been reported in AD brains. In neurons, the predominant mechanism to repair double-strand DNA breaks (DSB) is non-homologous end joining (NHEJ) that requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kD DNA-PK catalytic subunit (DNA-PKcs) and its activator Ku, a heterodimer of p86 (Ku80) and p70 (Ku70) subunits. Upon binding to double-stranded DNA ends, Ku recruits DNA-PKcs to process NHEJ. In AD brains, reduced NHEJ activity as well as DNA-PKcs and Ku protein levels have been shown. Normal aging brains also show a reduction in both DNA-PKcs and Ku levels questioning a direct link between NHEJ ability and AD, and suggesting additional players/events in AD pathogenesis. Deficiency of Ku80, a somatostatin receptor, can disrupt somatostatin signaling thus inducing amyloid beta (Aβ) generation, which in turn can potentiate DNA-PKcs degradation and consequently loss of NHEJ activity, an additional step negatively affecting DSB repair. Trigger of these two different pathways culminating in genome instability may differentiate the outcomes between AD and normal aging.

Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system with a clinically heterogeneous presentation that includes progressive loss of dopaminergic (DA) neurons in the substantia nigra. A minority of PD cases are familial and are caused by mutations in single genes. Most cases, however, are idiopathic PD, a complex multifactorial disorder with environmental and genetic contributors to etiology. Here, we first briefly summarize published evidence that among environmental contributors is dietary deficiency of magnesium. We then review genetic data suggesting that mutations in genes encoding two proteins contributing to cellular magnesium homeostasis confer risk for PD or other Parkinsonian conditions. First, the gene encoding magnesium transporter SLC41A1 is, among others, a candidate for the causative gene in the PARK16 locus where variation is associated with risk for idiopathic Parkinsonian disease. Studies of the function of SLC41A1 in animal models are needed to test whether this protein has a role in maintenance of dopaminergic neurons. Second, in a small study, a hypomorphic variant of TRPM7, a magnesium-permeable channel, was over-represented in cases of amyotrophic lateral sclerosis/ Parkinson dementia complex versus controls from the same ethnic group. Although this association was not detected in a second study, in zebrafish Trpm7 is necessary for terminal differentiation and reduction of toxin-sensitivity in dopaminergic neurons. Overall, epidemiological results support the possibility that mutations in genes relevant to magnesium homeostasis would alter PD risk, but deeper genetic analyses of PD patients are necessary to confirm whether SLC41A1 and TRPM7 are among such genes.

Background: Cognitive impairment is common in multiple sclerosis (MS), and affects employment and quality of life. Large studies are needed to identify risk factors for cognitive decline. Currently, a MS-validated remote assessment for cognitive function does not exist. Studies to determine feasibility of large remote cognitive function investigations in MS have not been published.

Objective: To determine whether MS patients would participate in remote cognitive studies. We utilized the Modified Telephone Interview for Cognitive Status (TICS-M), a previously validated phone assessment for cognitive function in healthy elderly populations to detect mild cognitive impairment. We identified factors that influenced participation rates. We investigated the relationship between MS risk factors and TICS-M score in cases, and score differences between cases and control individuals.

Methods: The TICS-M was administered to MS cases and controls. Linear and logistic regression models were utilized.

Results: 11.5% of eligible study participants did not participate in cognitive testing. MS cases, females and individuals with lower educational status were more likely to refuse (p<0.001). Cases who did complete testing did not differ in terms of perceived cognitive deficit compared to cases that did participate. More severe disease, smoking, and being male were associated with a lower TICS-M score among cases (p<0.001). The TICS-M score was significantly lower in cases compared to controls (p=0.007).

Conclusions: Our results demonstrate convincingly that a remotely administered cognitive assessment is quite feasible for conducting large epidemiologic studies in MS, and lay the much needed foundation for future work that will utilize MS-validated cognitive measures.

Deep brain stimulation (DBS) has proven to be an effective treatment for neurologic disorders such as Parkinson's disease, and is currently being investigated as a therapy for psychiatric diseases such as addiction, major depressive disorder, and obsessive compulsive disorder. In this commentary, we review and discuss the findings presented in the Letter to the Editor entitled "Attitudes towards treating addiction with deep brain stimulation," written by Ali et al¹. The survey presented in this Letter reported general approval for examining the effects of DBS on addictive disorders in a clinical trial, but highlighted critical areas of concern including informed consent, patient autonomy, appropriate medical practice, passing of clinical trial milestones, and implications on law enforcement.

This review addresses the role that substance P (SP) and its preferred receptor neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, viral, parasitic, and neurodegenerative diseases of the central nervous system. The SP/NK1R complex is a key player in the interaction between the immune and nervous systems. A common effect of this interaction is inflammation. For this reason and because of the predominance in the human brain of the NK1R, its antagonists are attractive potential therapeutic agents. Preventing the deleterious effects of SP through the use of NK1R antagonists has been shown to be a promising therapeutic strategy, as these antagonists are selective, potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to clinical management of CNS inflammation.