The success of future neurodegenerative disease (ND) therapies depends partly on accurate antemortem diagnoses. Relatively few prior studies have been performed on large, multicenter-derived datasets to test the accuracy of final clinical ND diagnoses in relation to definitive neuropathological findings. Data were analyzed from the University of Kentucky Alzheimer's Disease Center autopsy series and from the National Alzheimer's Coordinating Center (NACC) registry. NACC data are derived from 31 different academic medical centers, each with strong clinical expertise and infrastructure pertaining to NDs. The final clinical diagnoses were compared systematically with subsequent neuropathology diagnoses. Among subjects meeting final inclusion criteria (N = 2,861 for NACC Registry data), the strength of the associations between clinical diagnoses and subsequent ND diagnoses was only moderate. This was particularly true in the case of dementia with Lewy bodies (DLB): the sensitivity of clinical diagnoses was quite low (32.1% for pure DLB and 12.1% for Alzheimer's disease (AD + DLB) although specificity was over 95%. AD clinical diagnoses were more accurate (85.0% sensitivity and 51.1% specificity). The accuracy of clinical DLB diagnoses became somewhat lower over the past decade, due apparently to increased “over-calling” the diagnosis in patients with severe cognitive impairment. Furthermore, using visual hallucinations, extrapyramidal signs, and/or fluctuating cognition as part of the clinical criteria for DLB diagnosis was of minimal utility in a group (N = 237) with high prevalence of severe dementia. Our data suggest that further work is needed to refine our ability to identify specific aging-related brain disease mechanisms, especially in DLB.

Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.

Objective: We assessed salience of subjective memory complaints (SMCs) by older individuals as a predictor of subsequent cognitive impairment while accounting for risk factors and eventual neuropathologies.Methods: Subjects (n 5 531) enrolled while cognitively intact at the University of Kentucky were asked annually if they perceived changes in memory since their last visit. A multistate model estimated when transition to impairment occurred while adjusting for intervening death. Risk factors affecting the timing and probability of an impairment were identified. The association between SMCs and Alzheimer-type neuropathology was assessed from autopsies (n 5 243).Results: SMCs were reported by more than half (55.7%) of the cohort, and were associated with increased risk of impairment (unadjusted odds ratio 5 2.8, p , 0.0001). Mild cognitive impairment (dementia) occurred 9.2 (12.1) years after SMC. Multistate modeling showed that SMC reporters with an APOE e4 allele had double the odds of impairment (adjusted odds ratio 5 2.2, p 5 0.036). SMC smokers took less time to transition to mild cognitive impairment, while SMC hormone-replaced women took longer to transition directly to dementia. Among participants (n 5 176) who died without a diagnosed clinical impairment, SMCs were associated with elevated neuritic amyloid plaques in the neocortex and medial temporal lobe.Conclusion: SMC reporters are at a higher risk of future cognitive impairment and have higher levels of Alzheimer-type brain pathology even when impairment does not occur. As potential harbingers of future cognitive decline, physicians should query and monitor SMCs from their older patients. Neurology ® 2014;83:1359-1365 GLOSSARY AD 5 Alzheimer disease; BRAiNS 5 Biologically Resilient Adults in Neurological Studies; CERAD 5 Consortium to Establish a Registry for Alzheimer's Disease; HRT 5 hormone replacement therapy; MCI 5 mild cognitive impairment; MTL 5 medial temporal lobe; NFT 5 neurofibrillary tangle; NP 5 neuritic plaque; NSI 5 no serious impairment; OR 5 odds ratio; SMC 5 subjective memory complaint.Subjective memory complaints (SMCs) may signal increased risk of progression into clinically recognized states of impairment, namely, mild cognitive impairment (MCI) and dementia. [1][2][3][4][5] Although prior studies use incident dementia as an endpoint, there is a need to consider the effect of SMC on the occurrence of MCI as well. 6 Little is known about risk factors associated with the occurrence of SMCs other than depression or poor psychological well-being.7 SMCs may reflect aspects of metamemory, as older adults monitor their own forgetting.8 Persons with SMC may show MRI-based hippocampal atrophy, a finding also seen in MCI.9 Finally, while Alzheimer disease (AD)-type neuropathologic changes occur years before clinical symptoms are detectable, only a few studies link SMC to neuropathology 10,11 or to biomarkers. 2We hypothesized that baseline cognitively intact subjects who declared an SMC would be at a higher risk of a cognitive impa...

The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimer’s disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P = 0.012), provoked hallucinations or delirium (P = 0.042), or the presence of any of these noncognitive symptoms of DLB (P < 0.0001). Letter fluency (P = 0.007) was significantly lower and Wechsler Logical Memory I (P = 0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD.