Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A role for innate immunity in neurodegenerative diseases is now widely accepted, although debate continues over the relative contributions of these processes to disease progression and/or to disease amelioration. The idea that microglia and cytokines are important in neurodegeneration arose from neuropathological observations, especially in Alzheimer's disease. Microglia are invariant components of the Abeta plaques of Alzheimer's disease, where they show a waxing and waning of numbers, activation state, and cytokine expression during plaque progression. This is in contrast to diffuse Abeta deposits sometimes found in abundance in the brain of non-demented elderly individuals, which do not contain activated microglia. In Alzheimer's disease, plaque-associated astrocytes, which also produce paracrine mediators, show a pattern similar to that of microglia; and the associated plaque progression is accompanied by progressive damage to and loss of adjacent neurons. Further, activated microglia and astrocytes show a progressive pattern of association with neurofibrillary tangles. These observations, together with known functions of the involved cytokines, originally suggested a central role for immunological phenomena in driving disease progression in Alzheimer's disease. Further observations have extended these ideas to alpha-synuclein-based diseases (Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy) as well as other neurodegenerative diseases and conditions.
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PMID:Neuropathology and the neuroinflammation idea. 1958 54

Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants, overproduction or incorporation of free radicals from environment to living system leads to serious penalty leading to neuro-degeneration. Neural cells suffer functional or sensory loss in neurodegenerative diseases. Apart from several other environmental or genetic factors, oxidative stress (OS) leading to free radical attack on neural cells contributes calamitous role to neuro-degeneration. Though, oxygen is imperative for life, imbalanced metabolism and excess reactive oxygen species (ROS) generation end into a range of disorders such as Alzheimer's disease, Parkinson's disease, aging and many other neural disorders. Toxicity of free radicals contributes to proteins and DNA injury, inflammation, tissue damage and subsequent cellular apoptosis. Antioxidants are now being looked upon as persuasive therapeutic against solemn neuronal loss, as they have capability to combat by neutralizing free radicals. Diet is major source of antioxidants, as well as medicinal herbs are catching attention to be commercial source of antioxidants at present. Recognition of upstream and downstream antioxidant therapy to oxidative stress has been proved an effective tool in alteration of any neuronal damage as well as free radical scavenging. Antioxidants have a wide scope to sequester metal ions involved in neuronal plaque formation to prevent oxidative stress. In addition, antioxidant therapy is vital in scavenging free radicals and ROS preventing neuronal degeneration in post-oxidative stress scenario.
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PMID:Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. 1972 19

alpha-Synuclein is the major component of pathological inclusions characteristic of diseases like Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. A role for alpha-synuclein in neurodegenerative diseases is further supported by point mutations and duplication and triplication of the alpha-synuclein gene (SNCA) that are causative of these disorders. The middle hydrophobic region of the alpha-synuclein protein, also termed the "non-Abeta component of Alzheimer's disease amyloid plaque (NAC)" domain, is required for alpha-synuclein to polymerize into amyloid filaments, which are the major components of alpha-synuclein pathological inclusions. In this study, we assessed the importance of specific stretches of hydrophobic residues in driving the intrinsic ability of alpha-synuclein to polymerize. Several small deletions, even one with as few as two amino acid residues (A76 and V77), dramatically impaired the ability of alpha-synuclein to polymerize into mature amyloidogenic fibrils, and instead, it preferentially formed oligomers. However, this inhibition of filament assembly was clearly dependent on the spatial context, since similar and larger hydrophobic deletions in other parts of the NAC domain reduced only the rate of fibril formation, without abrogating filament assembly. Further, mutation of residue E83 to an A rescued the ability of mutant Delta76-77 alpha-synuclein to polymerize. These findings support the notion that while both the location and hydrophobicity of protein segments are important elements that affect the propensity to form amyloid fibrils, the intrinsic ability of a polypeptide to fold structurally into amyloid is also critical.
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PMID:Characterization of hydrophobic residue requirements for alpha-synuclein fibrillization. 1972 99

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25%), tremor dominant (31%), non-tremor dominant (36%) and rapid disease progression without dementia (8%) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70% of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.
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PMID:A clinico-pathological study of subtypes in Parkinson's disease. 1975 3

The oral and dental health of patients with Parkinson's disease (PD) has not been well documented and the findings are conflicting. Patients with PD were invited to take part in a clinical and radiographic examination together with a comparison control group of persons who were a spouse or family member. Subjects (n = 67) and controls (n = 55) were examined and compared. Subjects with PD had more missing teeth, caries, dental plaque, and poorer periodontal health. Counts of cariogenic bacteria in saliva were significantly higher for subjects with PD. They did not consume more sweets or sugar, did not brush less frequently, used dental floss more than controls, and visited the dentist at least as often. Salivary flow levels were comparable between subjects with PD and controls. The lack of muscular control may explain the poorer oral health of patients with PD. Dentists and patients with PD may be reluctant to embark on complex dental procedures, and this may explain the increased number of missing teeth in persons with PD in this study.
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PMID:Dental health of patients with Parkinson's disease in Iceland. 1993 51

Accumulation and deposition of beta amyloid (Abeta) play a critical role in the pathogenesis of Alzheimer's Disease (AD), and numerous approaches to control Abeta aggregation are being actively pursued. Brain Abeta levels are controlled by the action of several proteolytic enzymes such as neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin. While up-regulation of these enzymes increased clearance of Abeta in transgenic mouse models of AD, these enzymes have other natural substrates and multiple cleavage sites in Abeta complicating their use for treating AD. Alternatively, immunotherapeutic approaches to clear Abeta are gaining interest. Active and passive immunization studies with Abeta can reduce plaque burden and memory loss, but clinical trials were stopped due to meningioencephalitis in some patients. Naturally occurring proteolytic antibodies have been shown to cleave Abeta, and their serum titers are increased in patients with AD reflecting a protective autoimmune response. These antibodies however cannot cross the blood brain barrier and depend entirely on peripheral clearance to clear Abeta. A potentially non-inflammatory approach to facilitate Abeta clearance and reduce toxicity is to promote hydrolysis of Abeta at its alpha-secretase site using affinity matured single chain antibody fragments (scFvs). Bispecific antibodies consisting of a proteolytic scFv and a targeting scFv can be engineered to selectively supplement and target extracellular alpha-secretase activity and to target toxic Abeta forms facilitating their degradation and clearance without generating an immune response. This strategy represents a suitable paradigm for treating other neurological diseases such as Parkinson's Disease, Lou Gehrig's Disease, and spongiform encephalopathies.
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PMID:Targeted hydrolysis of Beta-amyloid with engineered antibody fragment. 2008 8

Alois Alzheimer first pointed out that the disease which would later bear his name has a distinct and recognizable neuropathological substrate. Since then, much has been added to our understanding of the pathological lesions associated with the condition. The 2 primary cardinal lesions associated with Alzheimer's disease are the neurofibrillary tangle and the senile plaque. The neurofibrillary tangle consists of abnormal accumulations of abnormally phosphorylated tau within the perikaryal cytoplasm of certain neurons. The senile plaque consists of a central core of beta-amyloid, a 4-kD peptide, surrounded by abnormally configured neuronal processes or neurites. Other neuropathological lesions are encountered in cases of Alzheimer's disease, but the disease is defined and recognized by these 2 cardinal lesions. Other lesions include poorly understood changes such as granulovacuolar degeneration and eosinophilic rodlike bodies (Hirano bodies). The loss of synaptic components is a change that clearly has a significant impact on cognitive function and represents another important morphological alteration. It is important to recognize that distinguishing between Alzheimer's disease, especially in its early stages, and normal aging may be very difficult, particularly if one is examining the brains of patients who died at an advanced old age. It is also noted that instances of pure forms of Alzheimer's disease, in the absence of other coexistent brain disease processes, such as infarctions or Parkinson's disease-related lesions, are relatively uncommon, and this must be taken into account by researchers who employ postmortem brain tissues for research.
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PMID:Neuropathology of Alzheimer's disease. 2010 20

To identify the progression of pathology over the entire course of Parkinson's disease, we longitudinally followed a clinical cohort to autopsy and identified three clinicopathological phenotypes that progress at different rates. Typical Parkinson's disease has an initial rapid loss of midbrain dopamine neurons with a slow progression of Lewy body infiltration into the brain (over decades). Dementia intervenes late when Lewy bodies invade the neocortex. Older onset patients (> 70 years old) dement earlier and have much shorter disease durations. Paradoxically, they have far more alpha-synuclein-containing Lewy bodies throughout the brain, and many also have additional age-related plaque pathology. In contrast, dementia with Lewy bodies has the shortest disease course, with substantive amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that two age-related factors influence pathological progression in Parkinson's disease--the age at symptom onset and the degree and type of age-related Alzheimer-type pathology.
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PMID:The progression of pathology in Parkinson's disease. 2014 98

To investigate the relationships between age, the advanced clinical stages of Parkinson's disease and neuropathology, we surveyed 129 case records from donors with pathologically proven Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders. Cases were separated into five groups according to age at death, thus comparing patients who reached the advanced stage of the disease at different ages. Four milestones of advanced disease (frequent falls, visual hallucinations, dementia and need for residential care) occurred at a similar time from death in each group. There were no significant differences in disease duration across these age groupings, nor were there differences in the severity and distribution of Lewy body and other pathologies. The milestones of dementia (P < 0.0005) and visual hallucinations (P = 0.02) as well as the accumulation of multiple milestones (P < 0.0005) were associated with high cortical Lewy body scores. Demented cases also had significantly more Alzheimer neurofibrillary and amyloid-beta plaque pathology. Correlation analysis showed that the time intervals between disease onset and recording of milestones were strongly influenced by age at onset (P < 0.0001) and by total disease duration (P < 0.0001). The advanced disease phase plays out in a similar fashion at whatever age it occurs, with a common pathological endpoint. The clinico-pathological comparisons for the final stage of Parkinson's disease do support a staging system based on the rostral extent and severity of Lewy body pathology, although other pathologies may play a synergistic role in causing cognitive disability. The chief effects of age on the rate of progression are seen over the early-middle part of the disease. An exponential curve for clinical progression provides the best explanation for these observations about age and the disease course.
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PMID:Relationships between age and late progression of Parkinson's disease: a clinico-pathological study. 2037 10

Dementia is a highly prevalent problem causing considerable disability and mortality and exacting great costs to individuals, their families, and society. The 4 most common neurodegenerative disorders that cause dementia-Alzheimer disease, frontotemporal dementia, dementia with Lewy bodies, and dementia in Parkinson disease-have different underlying etiologies and pathogenetic mechanisms. There is a great need for early diagnostic markers; functional brain imaging may therefore assist in the detection and differential diagnosis of dementia due to neurodegenerative diseases. Functional imaging such as PET allows in vivo imaging of functional brain activity indicating cerebral blood flow and cerebral glucose metabolism, and PET allows imaging of neurotransmitter activity, including that of the cholinergic, dopaminergic, and serotonergic systems. New PET neuroimaging tracers are being developed for detecting pathologic parameters such as amyloid plaque and microglial activity. The development of molecular imaging is important for early diagnosis of dementia, selection of patients for therapies, and evaluation of therapies.
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PMID:Target-specific PET probes for neurodegenerative disorders related to dementia. 2081 Jul 58


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