Recent advances in imaging in Parkinson disease

Despite recent knowledge on the pathophysiology of Parkinson disease, the precise and early diagnosis of this condition remains difficult. Advances in imaging techniques have enabled the assessment of in vivo structural, neurometabolic, and neurochemical changes in Parkinson disease, and their role as biomarkers have assumed greater importance in recent years. We presently review the various approaches with these imaging techniques for the study of Parkinson disease. Voxel-based morphometry studies with structural MRI showed a characteristic pattern of gray matter loss, and fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) studies have indicated latent network abnormalities in Parkinson disease. Moreover, radiotracer imaging with dopaminergic markers facilitates the assessment of pre- and postsynaptic nigro-striatal integrity, and other radiotracers have been used in the studies of nondopaminergic neurotransmitter systems, such as the cholinergic, noradrenergic, and serotonergic systems. These imaging techniques can be used to detect presymptomatic disease and to monitor disease progression. Thus, imaging data provide meaningful insights into the pathological process in Parkinson disease.     

Recent advances in understanding the pathogenesis of Huntington's disease.

Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder that is characterized by abnormal involuntary movements (chorea), intellectual impairment and selective neuronal loss. The expansion of a polymorphic trinucleotide repeat (the sequence CAG that codes for glutamine) to a length that exceeds 40 repeat units in exon 1 of the gene, HD, correlates with the onset and progression of the disease. The protein encoded by HD, huntingtin, is normally localized in the cytoplasm, whereas the mutant protein is also found in the nucleus, suggesting that its translocation to this site is important for the pathogenesis of HD. Although several proteins that interact with huntingtin have been identified in vitro, the significance of these interactions with the mutant protein in the pathogenesis of HD has yet to be determined. Recent progress in the development of cellular and animal models for the disease have provided invaluable insights and resources for studying the disease mechanisms underlying HD, and will be useful for screening and evaluating possible therapeutic strategies.     

Recent advances on the pathogenesis of Huntington's disease

We review recent advances regarding the pathogenesis of Huntington's disease (HD). This genetic neurodegenerative disorder is caused by an expanded CAG repeat in a gene coding for a protein, with unknown function, called huntingtin. There is selective death of striatal and cortical neurons. Both in patients and a transgenic mouse model of the disease, neuronal intranuclear inclusions, immunoreactive for huntingtin and ubiquitin, develop. Huntingtin interacts with the proteins GAPDH, HAP-1, HIP1, HIP2, and calmodulin, and a mutant huntingtin is specifically cleaved by the proapoptotic enzyme caspase 3. The pathogenetic mechanism is not known, but it is presumed that there is a toxic gain of function of the mutant huntingtin. Circumstantial evidence suggests that excitotoxicity, oxidative stress, impaired energy metabolism, and apoptosis play a role.     

Recent advances in the genetics of autism.

Autism is a strongly genetic disorder, with an estimated heritability of greater than 90%. Nonetheless, its specific genetic etiology remains largely unknown. Over the past several years, the convergence of rapidly advancing genomic technologies, the completion of the human genome project, and successful collaborative efforts to increase the number of deoxyribonucleic acid samples available for study have led to the first solid clues regarding the genetic origins of autism spectrum disorders. This article addresses the obstacles that have confronted gene discovery efforts and reviews recent linkage, cytogenetic, and candidate gene association studies relevant to autism spectrum disorders. In addition, promising avenues for future research and the potential contribution of emerging genomic technologies are considered.     

The genetics of Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder. In most instances, PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare monogenic forms of the disease do exist. Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been shown to cause familial parkinsonism. In addition, common variation in 3 genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA have been well-validated as susceptibility factors for PD. The function of these genes and their contribution to PD pathogenesis remain to be fully elucidated. The prevalence, incidence, clinical manifestations, and genetic components of PD are discussed in this review.     

Recent advances in the biochemistry and genetics of sphingolipidoses

Sphingolipidoses are a subgroup of lysosomal storage diseases. They are defined as disorders caused by a genetic defect in catabolism of sphingosine-containing lipids. Catabolism of these lipids involves enzymes and activator proteins. After the discovery of lysosomes by de Duve and the demonstration of the first defective lysosomal enzyme by Hers in 1963, the first enzyme deficiency for sphingolipidoses was characterized in 1965 and all the defective enzymes were demonstrated in the last three decades. In 1984, the first activator protein was found and it expanded the concept of sphingolipidoses. In the following years, many researches have been undertaken to understand the molecular basis of these diseases, the mechanism of pathogenesis, the mechanism of lysosomal digestion of glycosphingolipids (GSLs) and the functional domains of lysosomal enzymes. New hypotheses and theories have been put forward for the mechanism of lysosomal digestion and pathogenesis. However, although much has been done, the pathogenesis of sphingolipidoses has not been fully elucidated. Mouse models of these diseases have facilitated the elucidation of pathogenesis and the development of therapeutic strategies for these diseases, which are not treatable at present except for Fabry and type 1 Gaucher disease.

The purpose of this review is to collect information on the recent researches related to sphingolipidoses. The review includes the hydrolysis of GSLs in lysosome, mechanism of hydrolysis, pathogenesis and genetics of sphingolipidoses, a brief mouse model and therapeutic strategies of these diseases.     

Recent advances in the genetics of obsessive-compulsive disorder

This article reviews recent developments in understanding the genetic etiology of obsessive-compulsive disorder (OCD). Family studies provide further support for the familial aggregation of OCD. Genome-wide linkage studies indicate that specific chromosomal regions are linked to OCD. Moreover, results from recent molecular genetic studies suggest that several candidate genes are associated with OCD. However, specific genes causing OCD have not been conclusively identified, and the molecular pathogenesis of the disorder has not been elucidated. The search for genes is complicated by the clinical and etiologic heterogeneity of OCD, as well as the possibility of gene-gene and gene-environment interactions. Despite this complexity, further refinement of the phenotype and developments in molecular and statistical genetics hold promise for further deepening our genetic understanding of OCD in the future.     

Recent advances in the genetics of spastic paraplegias

Hereditary spastic paraplegias (HSPs) are genetically heterogeneous mendelian disorders characterized by weakness and spasticity in the lower limbs associated with additional neurologic signs in “complex” or “complicated” forms. Major advances have been made during the past two decades in our understanding of their molecular bases. The mapping of 34 genes (17 of which have been identified) involved in this clinically diverse group of disorders has highlighted their great genetic heterogeneity. From the combined genetic and clinical information obtained, a new classification is now emerging that will help to better diagnose this condition, evaluate disease progression, guide follow-up, and permit genetic counselling. Evidence is now accumulating that at least part of the physiopathology results from abnormal intracellular trafficking, as well as from altered cell recognition and signaling, oligodendroglial dysfunction, mitochondrial defects, and impaired cholesterol and/or neurosteroid metabolism.     

Recent advances in the pathogenesis of diabetic neuropathy

Recent advances in the understanding of the pathogenesis of diabetic neuropathy have been made in six areas. There is support for the notion that a reduction in nerve free myoinositol may be responsible in part for the nerve conduction slowing in diabetic neuropathy. There is further evidence of microvascular abnormalities, including morphometric evidence of multifocal fiber loss and of capillary changes in biopsied sural nerve. There is evidence of endoneurial hypoxia, including the findings of reduced nerve blood flow and endoneurial oxygen tensions in chronic experimental diabetic neuropathy (EDN). The major mechanisms of resistance to ischemic conduction failure (RICF) is the marked increase in nerve energy substrates. Recent studies provide certain insights into clinical characteristics of human diabetic neuropathy (HDN), including the asymmetric pattern of HDN, the paradox between liability to pressure palsies and RICF, and insulin-related acute painful neuropathy. The suggested pathogenetic scheme incorporates the notion that once hypoxia is established, it may start a vicious cycle of further capillary damage and escalating hypoxia.     

Molecular pathogenesis of Parkinson disease

Parkinson disease (PD), the most common neurodegenerative movement disorder, is characterized by an extensive and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of Lewy bodies, intracellular inclusions of aggregated alpha-synuclein. Although the cause and pathogenesis of selective loss of dopamine neurons and the accumulation of alpha-synuclein in PD remain elusive, growing lines of evidence from environmental risk factors and early-onset genetics point to a convergence between energy metabolism and the disposal of damaged proteins in the development of PD. These findings suggest that impairments in mitochondrial and ubiquitin-proteasome system function can significantly contribute to the pathogenesis of PD. This review will summarize recent insights gained from genetic and environmental studies of PD that underscore this association.     

Recent advances in the genetics of recurrent vertigo and vestibulopathy

PURPOSE OF REVIEW: To focus on recent advances in the genetics of recurrent vertigo, with an overview on episodic ataxia, benign recurrent vertigo (mainly migraine-associated vertigo), bilateral vestibulopathy, and Ménière's disease. RECENT FINDINGS: Since the identification more than a decade ago of the genetic causes of episodic ataxia type 1 with myokymia caused by KCNA1 mutations and episodic ataxia type 2 with nystagmus caused by CACNA1A mutations, the list of episodic ataxia syndromes with distinct clinical features and genetic loci is slowly expanding, now up to episodic ataxia type 7. There is growing recognition for a correlation between benign recurrent vertigo and migraine, and acceptance for vertigo as a manifestation of migraine; efforts to identify susceptibility loci for migraine and migraine-associated vertigo are underway. A handful of families with vestibulopathy spanning several generations have been identified. Although no gene has yet been found, vestibulopathy with normal hearing variably associated with migraine is likely monogenic and heterogeneous, similar to nonsydromic deafness. There is also continuing effort to identify genetic causes of familial Ménière's disease. SUMMARY: Overlapping clinical features among different familial syndromes of recurrent vertigo and strong association with migraine suggest shared mechanisms. Collaborative efforts in patient identification and recruitment will facilitate progress in understanding disease mechanisms to improve diagnosis and treatment of recurrent vertigo.     

Recent advances in the genetics of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with a low survival rate beyond 5 years from symptom onset. Although the genes that cause most cases of ALS are still unknown, several important genetic discoveries have been made recently that will bring substantial insight into some of the mechanisms involved in ALS. Mutations in two genes with related functions were recently reported in patients with familial ALS: the FUS/TLS gene at the ALS6 locus on chromosome 16 and the TARDBP gene at the ALS10 locus on chromosome 1. In addition, the first wave of genomewide association studies in ALS has been published. While these studies clearly show that there is no definitive and common highly penetrant allele that causes ALS, some interesting candidate genes emerged from these studies. The findings help to better delineate the types of genes and genetic variants that are involved in ALS and provide substantial material for future research.     

Parkinson病分子遗传研究的新动态

在过去的几年里 ,家族性Ｐａｒｋｉｎｓｏｎ病 (ＰＤ)的分子遗传研究取得了重大进展 ,α ｓｙｎｕｃｌｅｉｎ、Ｐａｒｋｉｎ等致病基因相继被定位及克隆。但对于原发性ＰＤ来说绝大多数是散发性的 ,尽管流行病学的证据表明该病有遗传倾向 ,但至今未能建立明确的遗传模式 ,遗传因素与环境因素究竟谁起着主导作用 ,它们之间又是如何相互作用最终导致ＰＤ发病的 ,尚未有定论。这里仅向大家介绍一些ＰＤ分子遗传学领域的新动态。近年来一种新的研究模式正在兴起 ,概括起来分为以下步骤 :收集大量家系并按临床特点进行分型 ,利用覆盖全基因组的大…     

Amyotrophic lateral sclerosis. Recent advances in pathogenesis and therapeutic trials

We reviewed the current status of pathogenesis and therapeutic trials in amyotrophic lateral sclerosis (ALS). Clinical studies have identified several rare but definable causes for apparent ALS. Certain clinical features previously considered unlikely to occur in ALS are found on careful examination. Epidemiologic surveillance and recent studies of neurotoxic plant seeds used in Guam have shed light on the pathogenesis of endemic ALS. Extensive analyses of biochemical, metabolic, immunologic, viral, and toxic factors have provided provocative results requiring further studies. Reflecting on some of these hypotheses, therapeutic trials have been performed more vigorously than ever. Amyotrophic lateral sclerosis is now investigated at the molecular genetic level. Human autopsy and experimental animal studies have expanded our understanding of basic mechanisms involving motoneuronal degeneration. In the future, we must continue a relentless search for the pathogenesis of ALS, prospective clinical studies to define the limits of ALS, and well-designed, controlled therapeutic trials.     

Recent advances in the pathogenesis and immunotherapy of multiple sclerosis

In this article recent advances in research on the pathogenesis of multiple sclerosis (MS) are summarized. New evidence from molecular histopathology is discussed focussing on neurodegenerative aspects. In addition findings with a direct effect on therapeutic decisions are presented which have contributed to improved immunotherapy. During the last decade important advances in immunotherapy have proven especially useful for patients with relapsing-remitting MS. Escalating algorithms are available for both relapses and long-term immunotherapy. Novel therapeutic approaches with monoclonal antibodies have increasing importance, yet side effects are not completely understood. The pathogenetic insights presented here may open new avenues for novel immunotherapies and lead to individualized MS therapy in the future. Limitations are given for primary progressive MS due to the lack of suitable tissue specimens and experimental models. Neuroprotective treatment strategies aiming at the protection of glial and neuronal cells are still in early stages of development.