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Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42). Higher ratios of CSF tau/Aβ42, ptau181/Aβ42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving., Competing Interests: Possible Conflicts of Interest: Dr. Roe has no conflicts of interest. Dr. Barco has no conflicts of interest. Dr. Head has no conflicts of interest. Dr. Ghoshal has no conflicts of interest. Ms. Selsor reports no disclosures and has no conflicts of interest. Dr. Babulal has no conflicts of interest. Ms. Fierberg reports no disclosures and has no conflicts of interest. Ms. Vernon reports no disclosures and has no conflicts of interest. Mr. Shulman reports no disclosures and has no conflicts of interest. Ms. Johnson reports no conflicts of interest. Mr. Fague has no conflicts of interest. Dr. Xiong has no conflicts of interest. Dr. Grant has no conflicts of interest. Ms. Campbell reports no disclosures and has no conflicts of interest. Dr. Ott reports no conflicts of interest. Dr. Holtzman has no conflicts of interest. Dr. Benzinger has no conflicts of interest. Dr. Fagan has no conflicts of interest. Dr. Carr has no conflicts of interest. Dr. Morris has no conficts of interest.

Background: Cross-sectional studies suggest that the cognitive impact of Alzheimer disease pathology varies depending on education and brain size., Objective: To evaluate the combination of cerebrospinal fluid biomarkers of β-amyloid(42) (Aβ(42)), tau, and phosphorylated tau (ptau(181)) with education and normalized whole-brain volume (nWBV) to predict incident cognitive impairment., Design: Longitudinal cohort study., Setting: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri., Participants: A convenience sample of 197 individuals 50 years and older with normal cognition (Clinical Dementia Rating of 0) at baseline observed for a mean of 3.3 years., Main Outcome Measure: Time to Clinical Dementia Rating ≥ 0.5., Results: Three-factor interactions among the baseline biomarker values, education, and nWBV were found for Cox proportional hazards regression models testing tau (P = .02) and ptau (P = .008). In those with lower tau values, nWBV (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.31-0.91; P = .02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (P = .01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment in those with higher ptau values (P = .02)., Conclusion: In individuals with normal cognition and higher levels of cerebrospinal fluid tau and ptau at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.

Universally accepted neuropathologic criteria for differentiating Alzheimer disease (AD) from healthy brain aging do not exist. We tested the hypothesis that Bielschowsky silver stained total, cored, and neuritic senile plaques (TSPs, CSPs, and NSPs, respectively), rather than neurofibrillary tangles (NFTs), best discriminate between the 2 conditions using rigorously defined nondemented (n = 7) and AD (n = 35) subjects with no known co-morbidities. We compared lesions in 3 neocortical regions, in hippocampal CA1, and in entorhinal cortex in 19 men and 13 women between 74 and 86 years at death. The Clinical Dementia Rating (CDR) was used to assess degree of cognitive impairment within a year of demise. Neocortical TSP measures provided the highest correlation with expiration CDR: area under the curve (AUC) = 0.986 with 97.8% sensitivity at 90% specificity with an estimated cut-point of 6.0 TSP/ mm2. All SP measures yielded higher estimated AUC and sensitivity for 90% specificity compared to NFTs. Derived TSP cut-points applied to 149 persons with clinical AD regardless of their neuropathologic diagnosis yielded a sensitivity of 97% and specificity of 84% for TSPs in the 3 neocortical areas. Thus cut-points based on both diffuse and neuritic SP in neocortical regions distinguished nondemented and AD subjects with high sensitivity and specificity.

The presence of senile plaques in the neocortex of apparently nondemented elderly persons often is accepted as part of "normal" aging. Alternatively, because cerebral deposition of beta-amyloid may be a key mechanism in the development of Alzheimer's disease (AD), the presence of beta-amyloid-containing plaques may represent very early AD. To examine the relationships of cognitively normal aging, very mild dementia of the Alzheimer type, and the presence of neocortical senile plaques, we performed clinicopathologic correlation in 21 longitudinally studied healthy elderly subjects (84.5 +/- 6.6 years old at death). Nine subjects had strikingly high plaque densities in the neocortex; two of these subjects died of head injury before which there was no evidence of cognitive impairment. The other seven subjects with high plaque densities had clinical evidence for very mild cognitive impairment (Clinical Dementia Rating score of 0.5) at some time during their course and mildly impaired psychometric performance at last assessment before death. The remaining 12 subjects had no clinical or psychometric impairment and had few or no neocortical AD lesions. These results suggest that senile plaques may not be part of normal aging but instead represent presymptomatic or unrecognized early symptomatic AD. The high density of senile plaques (predominately of the diffuse subtype) in the cortex of subjects just at the threshold of detectable dementia is consistent with the hypothesis that beta-amyloid deposition is an initial pathogenetic event in the development of AD.

Magnetic resonance imaging detects blood-brain barrier disruption after gadolinium-DTPA enhancement of central nervous system lesions of multiple sclerosis. Experimental allergic encephalomyelitis has many clinical and pathological features in common with multiple sclerosis including alterations in the integrity of the blood-brain barrier. We have compared T2-weighted cranial MR images with Gd-DTPA dimeglumine-enhanced T1-weighted images of myelin basic protein-induced acute (Days 8-42 postimmunization) and central nervous system-induced chronic-progressive (Days 70-95 postimmunization) forms of experimental allergic encephalomyelitis in the guinea pig. Although animals from both groups had abnormal T2-weighted images, only the myelin basic protein-acute-EAE animals (Days 14-24 postimmunization) showed enhancement on postcontrast MR studies. The different responses of the acute and chronic diseases may result from different immunogens, severity of disease, or different permeability of the blood-brain barrier. Therefore, gadolinium-DTPA-enhanced, T1-weighted MR images distinguish acutely active and chronic inflammatory lesions in experimental allergic encephalomyelitis.

Volumetric indexes of cerebral atrophy obtained by using computed tomography (CT) were measured longitudinally in patients with senile dementia of the Alzheimer type (SDAT) and in healthy elderly control subjects. Measurements were made three times over a 51-month period. Of the original 44 patients with SDAT, five were available for CT examination at the last time of assessment (51 months); in contrast, 41 of the original 58 control subjects were still available for study at 51 months. As a group, scans of SDAT subjects showed greater atrophy than those of control subjects in all volumetric indexes at each time of testing and demonstrated greater progression of atrophy during the study period. However, the overlap of indexes between the patients with SDAT and the control subjects indicates that CT data cannot be used alone to predict the presence or progression of dementia in individual cases.