Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging and various neurodegenerative disorders, its incidence and topographic pattern were examined in 260 brains of elderly patients, including 116 autopsy-proven cases of Alzheimer disease (AD), 71 cases of clinically and autopsy-proven Parkinson disease (PD), 38 of dementia with Lewy bodies (DLB), 8 patients with progressive supranuclear palsy (PSP), one with senile tremor, and 26 age-matched controls without neuropsychiatric disorders. Using immunohistochemistry, alpha-synuclein (AS) positive lesions were assessed semiquantitatively. For technical reasons, the olfactory system was not systematically studied. All PD-brains showed AS-positive lesions in medullary, pontine and mesencephalic nuclei, with involvement of the nucleus basalis (90.1%), limbic cortex (58.9%), cingulate cortex (46%), amygdala, CA 2/3 hippocampal region (36.2%), neocortex (28.8%), and striatum (11%). 88% of clinical PD cases corresponded to LB pathology stages 4-6, 12% to stage 3 according to Braak et al. (2003). 84% of DLB brains were PD stage 5 or 6 and 17% stage 4, without significant differences between DLB with and without neuritic AD pathology, suggesting morphologic similarities betwee these disorders. 6/8 PSP and senile tremor cases, 49.1% of AD and 69% of aged controls were negative. AS-positive lesions in AD showed decreasing incidence from midbrain (24-28%), limbic cortex and amygdala (17-18%), nucleus basalis and medullary nuclei (13-17%), cingulate cortex (12%), CA 2/3 region (8%) to neocortex (2%), without gender differences or relationship to the severity of AD pathology (mean Braak stage 5.1). AD cases with AS positive lesions, particularly those with AS pathology in the amygdala, were older at death than negative ones (86.6 vs 83.3 yrs), but this difference was not statistically significant. 15 AD cases (seven of them with mild PD symptoms) and 3 aged controls without parkinsonian signs but LB pathology stages 3 (n=5) and 4 (n=13) were considered "incidental LB disease". 16 AD brains without parkinsonian symptoms had AS positive lesions in various areas without medullary involvement, suggesting deviation from the proposed stereotypic expansion pattern. Located AS-pathology in the midbrain and limbic cortex was seen in 31% of asymptomatic aged controls. These data 1. largely confirm Braak's staging of LB-pathology in PD; 2. suggest morphologic and pathogenic relations between PD (brainstem type) and DLB with and without coexistent AD pathology; 3. the occurrence of LB-related alpha-synucleinopathy in about 50% of AD brains and about 30% of aged controls. However, the basic mechanisms of LB-related AS-pathology and their pathogenic and clinical relevance in aged brain and neurodegenerative disorders await further elucidation.
 ...
PMID:Lewy body-related alpha-synucleinopathy in the aged human brain. 1548 Aug 35

Parkinson's disease (PD) is a common neurodegenerative disorder of adulthood characterized clinically by rigidity, bradykinesia, resting tremor, and postural instability. The annual incidence of PD ranges between 16 and 19 individuals per 100,000 (Twelves et al., Mov Disord 2003;18:19-31). Historically, PD has been commonly viewed as an idiopathic or environmentally triggered condition. However, as is true with most common conditions, there have been several families reported with PD who demonstrate a classic Mendelian pattern of inheritance. To date, nine genetic loci have been reported and four pathogenic genes have been identified: alpha-synuclein, parkin, DJ1, and PINK1. Families with alterations in these genes or linked sites demonstrate either recessive or dominant inheritance patterns and may have typical and/or atypical symptoms, with an age of onset extending from the second to the sixth decade. Commercial tests for parkin and alpha-synuclein mutations are now available. We predict that physicians, particularly neurologists, increasingly will be approached for information and referrals regarding genetic testing. To assist patients and their families, physicians will not only need to know when such testing is likely to yield a meaningful result but also be aware of the possible social and emotional consequences of testing. The following is a review of what is currently known about the genetics of PD within this context. We discuss what is known about genetic testing for Huntington's disease, a well-described model for genetic testing in a neurodegenerative disorder. We explore the utility, appropriateness, and possible implications of genetic testing for diagnostic and presymptomatic purposes.
 ...
PMID:Genetic testing in Parkinson's disease. 1550 1

PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including alpha-synuclein, parkin, ubiquitin C-terminal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable alpha-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.
 ...
PMID:Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease. 1604 50

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people that has only been recognized in the past decade and that remains widely underdiagnosed. At postmortem examination, affected patients show numerous alpha-synuclein-positive Lewy bodies (LB) in many parts of the cerebral cortex, particularly neocortical and limbic areas in addition to the nigral LB degeneration characteristic of Parkinson's disease (PD). Clinical presentation, unlike PD, is with progressive cognitive decline with particular deficits of visuospatial ability as well as frontal executive function accompanied by usually only mildly to moderately severe parkinsonism, which is often akineto-rigid without the classical parkinsonian rest-tremor. Further accompanying features include spontaneous recurrent visual hallucinations and conspicuous fluctuations in alertness and cognitive performance. The two main differential diagnoses are Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). To improve the differential diagnosis of DLB, consensus criteria have been developed that establish possible and probable levels of clinical diagnostic accuracy. Generally, their sensitivity is variable and low but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. Using operationalized criteria, DLB can be diagnosed clinically with an accuracy similar to that achieved for AD or PD. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. We review the present state of the best practice in the clinical diagnosis of DLB. Future modifications of diagnostic criteria would ideally include the full range of clinical presentations that can be associated with LB disease.
 ...
PMID:How to diagnose dementia with Lewy bodies: state of the art. 1609 75

We report a 73-year-old woman who had depression, dementia, and parkinsonism. She had postural tremor since her fortics. She was losing her weight since age 66 years. She noted difficulty in walk at age 72 (2001). She could not stand without assistance on July 2001, and she became hypobulic. On admission to our hospital on November 2001, she had dementia and revised Hasegawa dementia scale (HDS-R) was 8/30. She had mild limitation of the upward gaze, and rigidity in the neck, but not in the limbs. Postural tremor was seen. No muscle weakness was noted and tendon reflexes were normal. She was treated with levodopa/carvidopa, but she did not improve. She did not eat much. She was transferred to another hospital and she suddenly died on January 2002. The patient was discussed in a neurological CPC, and a chief discussant arrived at a conclusion that the patient had Parkinson disease with dementia. Some participants thought the diagnosis was progressive supranuclear palsy or diffuse Lewy body disease. The examination at autopsy revealed mild neuronal loss and Lewy bodies in the substantia nigra. Many Lewy bodies were observed in the cerebral cortex which corresponded to the neocortical type of DLB, and Lewy neurites were seen in the CA2 of the hippocampus by immunohistochemistry for alpha-synuclein. Spongy change was seen in the parahippocampus. Pathological diagnosis was diffuse Lewy body disease.
 ...
PMID:[A 73-year-old woman with depression, dementia, and parkinsonism]. 1627 38

Parkinson disease (PD) targets dopaminergic neurons in the substantia nigra, resulting in motor disturbances such as resting tremor, bradykinesia, and rigidity. Pathogenic processes likely occur over several decades, in that an overwhelming percentage of neurons are already dead at the time of clinical diagnosis. For this reason, the usage of animal model systems to discover the early steps in the pathologic cascade is required. These include exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively kills dopamine neurons in the substantia nigra, and genetic models incorporating mutations in the alpha-synuclein gene that cause disease in human patients. Through the evaluation of these models at multiple time points, it is possible to discover novel gene expression changes that may underlie disease pathogenesis. Specifically, the authors hypothesize that animal models of PD and human PD brains share a gene expression profile that signifies certain aspects of pathogenesis and/or recovery-resistance. To test this and similar hypotheses, the authors and others have utilized new microarray technology that enables the sampling of thousands of genes' expression level in one assay. Because the technology is fairly new and results can vary depending on methods used, results must be evaluated with care. Multiple array and data-mining options can be used to make the most accurate inferences as to differentially expressed genes in each set of samples. The authors developed a fusion classifier approach whereby individual data-mining algorithms generate lists of significant genes. The lists are subsequently queried, and only genes unanimously called significant are retained for further validation. Although the authors' approach identified hundreds of differentially expressed genes in each of three PD systems, only a few were common between the human and animal substantia nigra. These were related to dopamine phenotype, synaptic function, and the mitochondrial metabolism, implicating the presynaptic terminal as a primary site of injury. The time course of the authors' experiments indicates that if the synaptic changes could be prevented, this may alleviate some cell death, in that these changes precede neuronal loss.
 ...
PMID:Altered gene expression profiles reveal similarities and differences between Parkinson disease and model systems. 1628 95

Parkinson's disease (PD) is a debilitating neurodegenerative disease, with clinical features of tremor, muscular rigidity and akinesia, occurring as a result of midbrain dopamine loss. The search for treatments has relied heavily on animal models of the disorder. The use of monkey models of PD plays a distinct role in the development and assessment of novel treatments. The common marmoset (Callithrix jacchus) is a popular New World monkey used in the search for new treatments. These monkeys are easy to handle and survive well in captivity. This review examines the advantages of using marmoset monkeys in PD research and examines the different models available with reference to their use in pre-clinical assessment for novel therapeutic treatments. The most common models involve the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA). Recently, selective cerebral transgenic over-expression of alpha-synuclein has also been attempted in marmosets as a potential model for PD. Each model has its advantages. The MPTP-based model in marmosets resembles the disease with regards to the neuroanatomy of neurotransmitter loss; the unilateral application of 6-OHDA allows for the assessment of more complex sensorimotor deficits due to the presence of an intact 'control' side; the over-expression of alpha-synuclein in the midbrain results in the slow onset of behavioural symptoms allowing for a pre-symptomatic time window. The appropriateness of each of these marmoset models for the assessment of treatments depends on several factors including the experimental aim of the study and whether emphasis is placed on the analysis of behavioural deficits.
 ...
PMID:Marmoset monkey models of Parkinson's disease: which model, when and why? 1632 13

Parkinson's disease (PD) is a significant neurodegenerative disease of the elderly, affecting 1 to 2% of those over 60 years of age. The disorder is characterized by resting tremor, bradykinesia, rigidity, postural instability, and pathologically by alpha-synuclein-positive Lewy bodies. For most, the etiology is unknown and it is likely due to a multifactorial interaction of genes and the environment. In a minority, a clear environmental, toxic, or genetic etiology is determined. Six genes have been identified to cause diseases often indistinguishable from sporadic PD. Although accounting for only 1 to 3% of PD, the identification of single genes that cause PD clearly indicate that PD can have solely genetic causes. In addition to single-gene mutations, large familial aggregation and twin studies demonstrate a modest genetic component in idiopathic PD.
 ...
PMID:Clinical implications of Parkinson's disease genetics. 1704 50

Parkinson's disease (PD) is an etiologically heterogeneous disorder characterized by parkinsonism (bradykinesia, resting tremor, rigidity, and postural instability) with good response to L-dopa. PD is the second most prevalent neurodegenerative disorder after Alzheimer disease. Although the majority of PD cases are sporadic, 5-10% of PD is monogenic form of PD as familial PD (FPD). Multifactorial genetic-environmental interaction has been thought in PD pathogenesis, although these interactions are still poorly understood. In 2004, LRRK2 was identified as the causative gene for PARK8 originally mapped in the large Japanese Sagamihara family with late-onset autosomal dominant PD (ADPD). Patients with LRRK2 mutations account for approximately 2-13% of ADPD and 0.5-3% of sporadic PD. Genetically, LRRK2 mutations have been distributed worldwide with some ethnic differences by single founder effect such as G2019S, R1441G, and G2385R variants. LRRK2 G2385R was reported to be a risk factor for sporadic PD in Asia. Clinically, most patients with LRRK2 mutations develop typical idiopathic PD, however, variable clinical features and pathologies such as diffuse Lewy body disease, multiple system atrophy, progressive supranuclear palsy, and amyotrophic lateral sclerosis have been reported. Although Lewy bodies have been considered as a pathological hallmark for sporadic PD classically, some FPD and sporadic PD patients with heterozygous LRRK2 mutations or homozygous parkin mutations have no Lewy bodies. On the other hand, LRRK2 was reported as a component of Lewy bodies. Based on the variability, multifunction of LRRK2 such as phosphorylation of other proteins, especially, alpha-synuclein and tau, have been suggested. As interaction of Parkin and LRRK2 was reported, interaction and intersection among the autosomal-recessive or autosomal-dominant PD proteins could be involved in some common pathways, and LRRK2 may play an important role as a key FPD gene product. Identification of PARK8 and LRRK2 has given meaningful insights in not only PD but also numerous neurodegenerative disorders such as synucleinopathies and tauopathies with or without Lewy bodies.
 ...
PMID:[Clinical molecular genetics for PARK8 (LRRK2)]. 1771 20

Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity. Current medications only provide symptomatic relief and fail to halt the death of dopaminergic neurons. A major hurdle in development of neuroprotective therapies are due to limited understanding of disease processes leading to death of dopaminergic neurons. While the etiology of dopaminergic neuronal demise is elusive, a combination of genetic susceptibilities and environmental factors seems to play a critical role. The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of disease (encoding alpha-synuclein, parkin, DJ-1, PINK-1 and LRRK2) and studies from experimental animal models has provided crucial insights into molecular mechanisms in disease pathogenesis and identified probable targets for therapeutic intervention. Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD. In this review we provide an overview of the most relevant findings made by the PD research community in the last year and discuss how these significant findings improved our understanding of events leading to nigrostriatal dopaminergic degeneration, and identification of potential cell survival pathways that could serve as targets for neuroprotective therapies in preventing this disabling neurological illness.
 ...
PMID:Parkinson's disease. 1791 Nov 61


<< Previous 1 2 3 4 5 6 7 8 Next >>