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

We report the clinical and neuropathological manifestations of Alzheimer's disease (AD) in nine kindreds of German ancestry all originating from the same two adjacent villages on the West bank of the Volga River. There have been 89 known demented persons (53 male, 36 female). Mean age of onset is 57.6 +/- 8.4 years with a range of 40 to 84. Mean age at death is 66.5 +/- 7.6 years with a range of 50 to 80. Mean disease duration is 10.3 +/- 4.8 years with a range of 3 to 23. Detailed medical records were available on 50 individuals. Of these, 24% had a seizure, 72% language disturbance, 36% rigidity, 16% tremor and 12% myoclonus. There were 15 autopsies on demented persons from 6 of the kindreds. One brain suggested Creutzfeldt-Jakob disease (CJD) in a woman with the typical clinical course. The remaining 14 brains showed typical neuropathological characteristics of AD including neuritic amyloid plaques, neurofibrillary tangles, amyloid angiopathy and granulovacuolar change. Amyloid plaques were also seen in the cerebellum in all but one brain in which this region was available for review. Autopsy material from five brains in four families has been stained with antibody directed against the amyloid peptide; in all cases, the neuritic plaques stained positively. Many of the families share common surnames. It is likely that these Volga German kindreds carry the same genetic mutation leading to Alzheimer's disease; and thus, they are a valuable resource for genetic investigations of AD. Thus far, the disease in these kindreds does not show close linkage to either the D21S1 or beta amyloid gene loci on chromosome 21.
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PMID:Characteristics of familial Alzheimer's disease in nine kindreds of Volga German ancestry. 260 19

Aside from physiological tremor, essential tremor (ET) is by far the most common cause of tremor in humans, affecting large numbers of individuals in every human population. The crude prevalence of ET has been conservatively estimated to be between 0.4% and 3.9%, although some estimates of the prevalence of ET among the elderly are higher than 20%. Essential tremor is the most prevalent adult-onset movement disorder, and is also regarded as one of the most common neurological disorders of adults, with a prevalence that is similar to or greater than that of stroke, Alzheimer disease, migraine headache, and lumbosacral pain syndromes. Essential tremor is as much as 20 times more prevalent than Parkinson disease.
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PMID:A new twist for stopping the shakes? Revisiting GABAergic therapy for essential tremor. 1040 81

There are very few reports in the literature dealing with the neuropathology of infant head injury, and the question of whether diffuse traumatic brain damage [diffuse axonal injury (DAI)] occurs in such children has not yet been reliably established by detailed neuropathological studies. We report the findings in the brains of a series of 37 infants aged 9 months or less, all of whom died from inflicted head injuries, and 14 control infants who died of other causes. Axonal damage was identified using immunohistochemistry for beta-amyloid precursor protein. Full clinical details were available for each case, the most constant of which in the study cohort was an episode of significant apnoea at presentation, found to have been recorded in 75% of cases. Global hypoxic damage was the most common histological finding. Widespread axonal damage, interpreted as vascular, was present in 13 cases, but widespread traumatic axonal injury was found in only two children, both of whom had severe head injuries with multiple skull fractures. Epidural cervical haemorrhage and focal axonal damage to the brainstem and the spinal nerve roots, found in 11 cases but not in controls, indicate that the craniocervical junction is vulnerable in infant head injury, the neuropathology being that of stretch injury from cervical hyperextension/flexion. Damage to this region could account for the observed apnoea, which could in turn lead to hypoxic damage and brain swelling. The observation that the predominant histological abnormality in cases of inflicted head injury in the very young is diffuse hypoxic brain damage, not DAI, can be explained in one of two ways: either the unmyelinated axon of the immature cerebral hemispheres is relatively resistant to traumatic damage, or in shaking-type injuries the brain is not exposed to the forces necessary to produce DAI.
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PMID:Neuropathology of inflicted head injury in children. II. Microscopic brain injury in infants. 1187 23

We report a sporadic case of unusual cerebral amyloid angiopathy (CAA) with prominent capillary involvement. A 67-year-old doctor developed gait disturbance, resting tremor and rigidity. He was diagnosed to have Parkinson's disease, for which the treatment with levodopa was effective. Four years later he began to exhibit progressive cognitive decline and behavioral abnormalities consisting of hallucination and agitation. Subsequently, his condition steadily worsened and became bedridden with severe dementia, and he died eight years after the disease onset. During the clinical course, there had been no episode of stroke. Postmortem examinations revealed the typical pathology of Parkinson's disease with frequent cortical Lewy bodies in the amygdala. The most striking pathological feature of this patient was widespread CAA where prominent beta-amyloid (A beta) deposition was observed in the capillaries of the neocortex, most pronouncedly in the occipital lobe, as well as leptomeningeal and cerebral medium-sized and small vessels. Further, perivascular plaques were found in half of the amyloid-laden capillaries. Tau-positive dystrophic neurites were only sparsely detectable within a few perivascular plaques. Despite the severe A beta pathology, there was no microaneurysmal dilatation, fibrinoid necrosis or vascular occlusion. There was only one small ischemic lesion in the brain. The cerebral white matter was unremarkable. Senile plaques of neuritic type and neurofibrillary tangles were mostly limited to the hippocampal regions and, to a lesser degree, in the amygdaloid nucleus, which did not meet the neuropathological criteria of Alzheimer's disease. On the gene analyses, his apolipoprotein E (ApoE) genotyping was verified to be heterozygous epsilon 3/epsilon 4, and no mutation was seen in exons 16 and 17 of the amyloid precursor protein gene. Severe A beta capillary angiopathy as seen in our patient is exceptional in sporadic CAA. Further, A beta angiopathy of this patient was notable in the absence of an associated cerebrovascular disease despite prominent A beta deposition in the vessel walls. Regarding the development of his severe dementia, the limbic pathology of Lewy body disease might be one of the potential causes, but A beta angiopathy appears more likely because of its severity. We speculate that widespread A beta deposition disregulates the blood-brain barrier of the capillaries leading to a disturbance of the microcirculation throughout the cerebral cortex without obvious ischemic disintegration of the neuropil. We should take into consideration that A beta angiopathy can present as progressive dementia without cerebrovascular disease.
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PMID:[Sporadic cerebral amyloid angiopathy presenting with dementia and prominent capillary beta-amyloid deposition: a case report]. 1260 81

The mechanism by which amyloid peptide (Abeta(1-40)) produces effects on neurotransmission is currently unresolved. In initial experiments, using the patch-clamp technique, we found that 11.5 microM of preaggregated Abeta(1-40) altered the hippocampal neuron resting membrane potential and inhibited action potential firing. To identify the toxic species, the effects of Abeta(1-40) on sodium (I(Na)), calcium (I(Ca)), and potassium (I(K)) currents in hippocampal neurons were examined as a function of peptide aggregation state in a specially designed miniature recording chamber. Aggregation reactions were induced by constant shaking, starting with 50 microM monomeric peptide. At 10- to 30-min intervals, the ionic currents were examined on a single neuron suspended in control saline and then in a 100-microl sample of the aggregating peptide. We found that samples of the peptide taken 60-120 min into the aggregation process contained species that exhibited maximal inhibitory effects over a broad potential range in the rank ordering of I(Na) > I(Ca). I(K) was inhibited only slightly at depolarized potentials. Inhibition of APF through blockade of these channels would inhibit normal neuronal activity and directly contribute to cognitive dysfunction. In previous studies on SH-EP cells, we showed that neither monomeric nor fibrillar peptide had significant effect on cell viability except during exposure to the 60-120 minute aggregation product when cell death was recorded. Our kinetic model demonstrated that the toxic species was a slowly formed transient conformer (activated monomer), which was the only aggregating species that passed through a maximum concentration during aggregation. This species amounted to only a small fraction of the total amount of aggregating peptide. We conclude that, for both the native neurons in the present study as well as SH-EP1 cells, the activated monomeric conformer of the peptide is the toxic species.
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PMID:A slowly formed transient conformer of Abeta(1-40) is toxic to inward channels of dissociated hippocampal and cortical neurons of rats. 1467 72

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.
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PMID:[Clinical molecular genetics for PARK8 (LRRK2)]. 1771 20

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disease associated with the accumulation of very long-chain fatty acids. Mutations in the ABCD1 gene encoding ALD protein (ALDP) cause this clinically heterogeneous disorder, ranging from adrenocortical insufficiency and neurodegeneration to severe cerebral inflammation and demyelination. ALDP-deficient mice replicate metabolic dysfunctions and develop late-onset axonopathy but lack histological signs of cerebral inflammation and demyelination. To test the hypothesis that subtle destabilization of myelin may initiate inflammatory demyelination in Abcd1 deficiency, we generated mice with the combined metabolic defect of X-ALD and the mild myelin abnormalities of myelin-associated glycoprotein (MAG) deficiency. A behavioural phenotype, impaired motor performance and tremor, developed in middle-aged Mag null mice, independent of Abcd1 genotype. Routine histology revealed no signs of inflammation or demyelination in the CNS, but immunohistochemical analyses of spinal cord neuropathology revealed microglia activation and axonal degeneration in Mag and Abcd1/Mag double-knockout (ko) and, less severe and of later onset, in Abcd1 mutants. While combined Abcd1/Mag deficiency showed an additive effect on microglia activation, axonal degeneration, quantified by accumulation of amyloid precursor protein (APP) in axonal spheroids, was not accelerated. Interestingly, abnormal APP reactivity was enhanced within compact myelin of Abcd1/Mag double-ko mice compared to single mutants already at 13 months. These results suggest that ALDP deficiency enhances metabolic distress in oligodendrocytes that are compromised a priori by destabilised myelin. Furthermore, the age at which this occurs precedes by far the onset of axonal degeneration in Abcd1-deficient mice, implying that oligodendrocyte/myelin disturbances may precede axonopathy in X-ALD.
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PMID:Lack of adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency. 1782 4

Reduced telomere length has recently been reported in T lymphocytes of individuals with trisomy 21 Down syndrome (DS) and dementia. Shorter telomeres also have been documented in dyskeratosis congenita, cell senescence, Alzheimer disease, and neoplastic transformation. These observations suggest that similar shortening may occur in people with fragile X-associated tremor/ataxia syndrome (FXTAS), which frequently is accompanied by dementia. To test this hypothesis, telomere length has been quantified in T lymphocytes from older male carriers of premutation FMR1 alleles, with or without FXTAS, and FXTAS with dementia. Shorter telomeres (relative to age-matched controls) were observed in 5/5 individuals with FXTAS and dementia, in 2/2 individuals with FXTAS without dementia, and in 3/3 individuals with the fragile X premutation only (P values ranged from <0.001 to <0.05; Student's t-test), indicating that telomere shortening is associated with the premutation expansion of the FMR1 gene. The current study design allowed simultaneous comparisons among control, premutation, FXTAS, and FXTAS with dementia samples, and showed nearly equal degrees of shortening relative to controls among the three premutation sample groups. Thus, telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS.
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PMID:Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene. 1847 92

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.
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PMID:Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems. 1868 48

Autonomic dysfunction is common in Lewy body disorders (Parkinson's disease, Dementia with Lewy Bodies, Pure Autonomic Failure, and REM sleep disorder). The loss of post-ganglionic myocardial sympathetic nerve fibers is a prominent feature of autonomic dysfunction in such disorders. (123)I-metaiodobenzylguanidine (MIBG) scintigraphy that visualizes catecholaminergic terminals in vivo is a biomarker used to detect cardiac sympathetic degeneration. Abnormal MIBG uptake has been consistently reported in Lewy body disorders. Some studies agree in the notion that increasing bradykinesia is related with an incremental cardiac sympathetic denervation, whereas tremor is not closely linked to cardiac denervation. "Atypical" parkinsonian syndromes, including Multiple System Atrophy, Progressive Supranuclear Palsy, and others, show modest reductions of cardial MIBG uptake. MIBG scintigraphy is moderately sensitive and specific in differentiating Parkinson's disease from such syndromes. Conversely, its sensitivity and specificity might be better in cognitively impaired patients, helping differential diagnosis between Dementia with Lewy Bodies, and Alzheimer disease. Confounding factors (comorbidities, comedications) should be carefully controlled before analyzing MIBG scintigraphy.
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PMID:123I-metaiodobenzylguanidine scintigraphy in Parkinson's disease and related disorders. 1987 2


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