Autopsy-Confirmed Parkinson Disease GWAS Consortium (APDGC)

The APDGC was formed to conduct a genome-wide association study in individuals with neuropathologically confirmed Parkinson Disease (PD) and neuropathologically normal controls. The rationale for the study is that including only cases and controls with neuropathologically confirmed disease status will reduce diagnostic misclassification and increase power to detect novel genetic associations.]]>
MINIMAL CLINICAL CRITERIA - PD Cases There must be an antemortem CLINICAL DIAGNOSIS OF PARKINSONISM. Ideally the cases would have been considered to have idiopathic Parkinson's disease, but given the imprecision of clinical diagnoses, if the case meets pathologic exclusion and inclusion criteria (see below), but was misdiagnosed as an atypical parkinsonian disorder, such as progressive supranuclear palsy or multiple system atrophy, such cases are acceptable. There must not have been a prominent dementia syndrome, particularly dementia occurring at the time of onset or within one year of parkinsonism. Given the prevalence of some degree of cognitive impairment in idiopathic Parkinson's disease (as much as 80% in some series), cases with later developing cognitive problems can be included, but they must meet all the pathologic inclusion criteria. PATHOLOGICAL EXCLUSION CRITERIA: There must be no other pathology that could reasonably be considered to be the structural substrate of parkinsonism. Excluded are cases with progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, frontotemporal degenerations and other disorders that can be associated with parkinsonism (e.g., normal pressure hydrocephalus, post-encephalitic parkinsonism, certain spinocerebellar atrophies or transmissible spongiform encephalopathies), even if they meet the minimal pathologic inclusion criteria. In other words, co-incidental Lewy bodies are not acceptable if they occur in an individual with another major pathologic process that could account for parkinsonism. Given that the age of many individuals to be included in the study is advanced, it is acceptable to have some age-related pathologies, such as cerebrovascular disease or argyrophilic grains. MINIMAL PATHOLOGICAL INCLUSION CRITERIA: There must be moderate-to-severe substantia nigra neuronal loss. There must be Lewy bodies. Ideally, Lewy bodies will have been assessed with a sensitive method for their detection, such as immunohistochemistry for α-synuclein or ubiquitin, but if Lewy bodies were readily detected with routine histological methods, such as hematoxylin and eosin stains, the case meets minimum criteria for presence of Lewy bodies. There must be minimal Alzheimer type pathology. In an effort to exclude genetic factors that associate with Alzheimer's disease, only cases in which Alzheimer type pathology has been evaluated and only those that meet criteria 3a and 3b are acceptable. Neuritic plaques must be no more than sparse in the neocortex. Neuritic plaques are defined according to the CERAD criteria, which requires assessment with either an appropriate silver stain or thioflavin S fluorescent microscopy. This criterion does not exclude cases with diffuse, non-neuritic plaques, which may be frequent, as long as the case also meets criterion 3b. Neurofibrillary tangle stage must be no more than Stage IV. MINIMAL CLINICAL CRITERIA - CONTROLS There must be NO antemortem clinical diagnosis of parkinsonism. PATHOLOGICAL CRITERIA: There must be NO OR MILD substantia nigra neuronal loss. There must be NO LEWY BODIES in all brain regions examined. Given the uncertainty of Lewy bodies as a biomarker for PD and wishing not to dilute the power of genetic association, presence of Lewy bodies in any region, including olfactory bulb, autonomic nervous system and the amygdala is an exclusion criterion. There must be minimal Alzheimer type pathology. In an effort to exclude genetic factors that associate with Alzheimer's disease, only cases in which Alzheimer type pathology has been evaluated and only those that meet criteria 3a and 3b are acceptable. Neuritic plaques must be no more than sparse in the neocortex. Neuritic plaques are defined according to the CERAD criteria (see figure), which requires assessment with either an appropriate silver stain or thioflavin S fluorescent microscopy. This criterion does not exclude cases with diffuse, non-neuritic plaques, which may be frequent, as long as the case also meets criterion 3b. Neurofibrillary tangle stage must be no more than Stage IV. ]]>