title: The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs.
abstract: BACKGROUND
  Extrapyramidal signs (EPS) are common in Alzheimer disease (AD) and increase in prevalence as AD advances. The neuropathologic substrate responsible for EPS in AD remains to be fully characterized.
  
  
  METHODS
  Subjects had a clinical diagnosis of AD confirmed by neuropathologic examination. EPS during life were documented by clinical methods assessing bradykinesia, cogwheel rigidity, rest tremor, and parkinsonian gait. Subjects with EPS and previous neuroleptic exposure were excluded. Twenty-eight subjects were in the EPS group and 104 subjects were without EPS. Neuron loss, alpha-synuclein (ASYN)-labeled pathology, and tau-labeled pathology in the substantia nigra were measured using semiquantitative techniques such that higher scores represented increased pathologic burden.
  
  
  RESULTS
  Presence of nigral ASYN-labeled pathology was more common (50 vs 28.9%; p < 0.05) in the EPS group than in those without EPS. There was more nigral neuron loss in the EPS group (1.50 vs 1.11 in no-EPS group; p < 0.05). Tau-labeled burden was not different by group comparisons; however, EPS onset at later stages of dementia severity was associated with increased tau-labeled pathology (Kendall tau-B = 0.48, p < 0.01) and this association remained after controlling for dementia severity at death. Additionally, moderate to severe tau burden was more common in the subgroup with "pure AD" (definite AD without other neuropathology) with EPS (81.8%) than cases without EPS (49.0%; p < 0.05). Four subjects with EPS (14.3%) had little to no significant nigral pathologic changes.
  
  
  CONCLUSIONS
  Clinically detected extrapyramidal signs (EPS) in Alzheimer disease (AD) are associated with substantia nigra pathology including alpha-synuclein aggregation, hyperphosphorylated tau accumulation, and neuron loss that may account for the increasing prevalence of EPS as AD progresses. In some cases, limited nigral pathology suggests extranigral factors in the clinical symptoms of EPS.
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO, USA. jburns2@kumc.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Burns
authors.forename: J E
authors.initials: JE
authors.lastname: Galvin
authors.forename: C M
authors.initials: CM
authors.lastname: Roe
authors.forename: J C
authors.initials: JC
authors.lastname: Morris
authors.forename: D W
authors.initials: DW
authors.lastname: McKeel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D001344:Autopsy; D005260:Female; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009483:Neuropsychological Tests; D020734:Parkinsonian Disorders / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D016875:tau Proteins