Intracranial volume and Alzheimer disease: evidence against the cerebral reserve hypothesis

Background: Total intracranial volume (TIV) measurement commonly is used to correct for variations in premorbid brain size in imaging studies of cerebral structures in Alzheimer disease (AD). This assumes no intrinsic difference in TIV between patients and control subjects and that TIV measurements are unaffected by cerebral atrophy. However, an autopsy study has suggested that a larger premorbid brain may protect against AD onset. A recent computed tomographic study lent support to this by finding a correlation between intracranial size and age at onset of AD in women. Objective: To investigate the relationship between TIV and sporadic and familial AD. Design: Retrospective case study. Setting: Specialist dementia clinic. Patients: Eighty-five patients with AD and 52 healthy volunteers. Main Outcome Measures: Age at symptom onset and TIV measured using a semiautomatic interactive thresholding technique on magnetic resonance imaging spanning the entire intracranial cavity. Results: Reproducibility measurement was high (intrarater coefficient of variation, 1.2%; interrater coefficient of variation, 0.7%). Unlike brain atrophy in the patients with AD, TIV did not vary over time. Mean TIV did not differ significantly between any of the subject groups. There was no association between TIV and age or age at symptom onset. The only significant predictor of TIV was sex. Conclusions: Measurements of TIV are independent of atrophy and can be used safely to adjust for differences in head size in studies of cerebral structure in AD. Premorbid brain size does not differ between patients with familial and sporadic AD and controls and does not delay disease onset.