Progression of clinical deterioration and pathological changes in patientswith Alzheimer disease evaluated at biopsy and autopsy

Objectives: To quantify the progression of senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, and microglial activation in the cort ex and white matter of patients with Alzheimer disease evaluated at both bi opsy and subsequent autopsy and correlate these changes with the progressio n of neurologic impairment. Setting: Academic referral center for patient with Alzheimer disease. Patients: Four patients meeting the clinical criteria for Alzheimer disease , enrolled in a pilot study for the evaluation of response to intracerebrov entricular administration of bethanechol chloride. The patients were follow ed up until death occurred and autopsy was performed. Results: all 4 patients had progressive deterioration from the time of biop sy to autopsy (9-11 years). Pathological investigations showed a striking i ncrease in the density of senile plaques and neurofibrillary tangles in 2 o f 4 patients from biopsy to autopsy, and a significant increase in microgli al activation in 1 of 4 cases. Severity of cerebral amyloid angiopathy vari ed significantly among patients, 1 of whom displayed striking amyloid depos ition with associated subcortical white matter atrophy. Conclusions: These unique data demonstrate that the progressive neurologic impairment in Alzheimer disease is accompanied by a significant increase in senile plaque and neurofibrillary tangle counts in the frontal cortex and, possibly in some patients, by increased microglial cell activation. Cerebr al amyloid angiopathy was associated with significant white matter disease.