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The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs

From the Department of Neurology (Drs. Burns, Galvin, and Morris), Alzheimer Disease Research Center (Drs. Burns, Galvin, Roe, and Morris), Anatomy and Neurobiology (Dr. Galvin), Division of Biostatistics (Dr. Roe), Department of Pathology and Immunology (Drs. Morris and McKeel), and Program in Physical Therapy (Dr. Morris), Washington University, St. Louis, MO.

Address correspondence and reprint requests to Dr Burns, Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Blvd., MSN 2012, Kansas City, KS 66160; e-mail: jburns2{at}kumc.edu

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, -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 -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.

Received July 28, 2004. Accepted in final form January 7, 2005.

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