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Guo et al.1 report a landmark study in this issue of Neurology ® that illustrates the continuing importance of amyloidosis in both the conceptual understanding and clinical treatment of Alzheimer disease (AD). Using data from cognitively normal adults enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), they show that a high amyloid burden in the banks of the superior temporal sulcus (BANKSSTS) predicts memory decline over 4 years, even in those who are classified as β-amyloid (Aβ) negative by the ADNI-defined composite score, which represents the aggregation of amyloid combined across regions. In addition to memory, amyloid positivity in the BANKSSTS predicts decline in executive function, although the association is weaker. It is worth noting that the study is a model of state-of-the-art methodology, providing a template for best practices that should be broadly used by researchers to advance the field. We describe the conceptual, clinical, and methodologic strengths (and occasional weaknesses) of the study below.

Objective: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. Methods: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. Results: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies ( p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia ( p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD ( p ≤ 0.0003). Conclusions: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

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 = 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 = 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 = 2.8, p APOE e4 allele had double the odds of impairment (adjusted odds ratio = 2.2, p = 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 = 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.

Recent studies raised questions about the severity of cognitive impairment associated with dementia with Lewy bodies (DLB). However, there have been few analyses of large, multicenter data registries for clinical-pathologic correlation.We evaluated data from the National Alzheimer's Coordinating Center registry (n = 5,813 cases meeting initial inclusion criteria) and the University of Kentucky Alzheimer's Disease Center autopsy series (n = 527) to compare quantitatively the severity of cognitive impairment associated with DLB pathology vs Alzheimer disease (AD) and AD+DLB pathologies.Mini-Mental State Examination (MMSE) scores showed that persons with pure DLB had cognitive impairment of relatively moderate severity (final MMSE score 15.6 +/- 8.7) compared to patients with pure AD and AD+DLB (final MMSE score 10.7 +/- 8.6 and 10.6 +/- 8.6). Persons with pure DLB pathology from both data sets had more years of formal education and were more likely to be male. Differences in final MMSE scores were significant (p0.01) between pure DLB and both AD+DLB and pure AD even after correction for education level, gender, and MMSE-death interval. Even in cases with extensive neocortical LBs, the degree of cognitive impairment was most strongly related to the amount of concomitant AD-type neurofibrillary pathology.Dementia with Lewy bodies can constitute a debilitating disease with associated psychiatric, motoric, and autonomic dysfunction. However, neocortical Lewy bodies are not a substrate for severe global cognitive impairment as assessed by the Mini-Mental State Examination. Instead, neocortical Lewy bodies appear to constitute or reflect an additive disease process, requiring Alzheimer disease or other concomitant brain diseases to induce severe global cognitive deterioration.

Editors' Note: Discussing the study “Self-reported memory complaints: Implications from a longitudinal cohort with autopsies,” Jenkins et al. disagree with the conclusion that physicians should solicit and monitor subjective memory complaints from their older patients. The authors, Schmitt et al., respond. Yanofsky expresses his frustration with the current neurology practice, which is pushing him to retire early. In response, Busis suggests an alternative, more effective, solution. —Chafic Karam, MD, and Robert C. Griggs, MD Kryscio et al.1 concluded: “physicians should solicit and monitor …

Objective: Evaluate the association of frontal release signs (FRS) with cognitive decline in subjects with intact cognition (CI), mild cognitive impairment (MCI), and dementia. Background FRS are primitive reflexes that regress with brain maturation and reappear in the setting of brain injury or neurodegeneration. Despite their association with dementia, the diagnostic utility of FRS in the setting of early predementia cognitive decline is poorly understood. Design/Methods: We examined the prevalence and progression of FRS over 2,545 discrete annual visits in 689 subjects with CI, MCI, and dementia. Independent variables included diagnostic category and the absence or presence (> 1 positive) of FRS. Results: The prevalence of FRS at baseline assessment was 7.5% in CI, 28.6% in MCI, and 34.5% in demented subjects. FRS at baseline was significantly associated with older age (p Conclusions: FRS may have diagnostic utility in the earliest stages of cognitive decline that has not been previously appreciated. FRS should be included as an important component of the evaluation of cognitive decline in persons at risk for the development of a degenerative dementia. Supported by: NIA 1 P30 AG028383. Disclosure: Dr. Metcalf has nothing to disclose. Dr. Abner has nothing to disclose. Dr. Schmitt has nothing to disclose. Dr. Kryscio has nothing to disclose. Dr. Stiles has nothing to disclose. Dr. Jicha has received personal compensation for activities with Pfizer Inc, Janssen Immunotherapy, and Eli Lilly & Company. Dr. Jicha has received research support from Baxter, Janssen, Pfizer Inc, Medivation, and Danone.

Objective: Assess the correlations between antipsychotic medication use in elderly dementia persons with neuropathological outcomes data, including cerebrovascular disease (CVD) pathology. Background A 2006 FDA-issued black box indicated that elderly patients with dementia treated with antipsychotics are at an increased risk of death, primarily from vascular complications (myocardial infarction and stroke) and infections (pneumonia). Despite the profound impact this warning has had on the field, the cerebrovascular consequences of antipsychotic use in dementia remain poorly understood. Design/Methods: We identified all subjects with a history of dementia related psychosis treated with antipsychotic agents (DPAP; n=32) in the University of Kentucky Alzheimer9s Disease Center Brain Bank. Control subjects were placed in two cohorts matched for age, gender, apoe, education and MMSE including subjects with dementia but no psychosis or antipsychotic medication (DNPNAP group; n=32), and subjects with dementia and psychosis but no antipsychotic medication (DPNAP group; n=32). Demographic, clinical, genetic, and neuropathological features were compared between groups. Results: Comparative analysis of vascular risk factors (hypertension, hyperlipidemia, myocardial infarction, smoking, diabetes mellitus, cardiac arrhythmia, and Hachinski scores) revealed no significant between group differences. Clinical diagnoses including Alzheimer9s, Lewy-Body, frontotemporal, and vascular dementia did not differ between groups. Cause of death including myocardial infarction, stroke, and pneumonia did not differ between groups (p=0.73, χ2 test). Braak, CERAD, amyloid angiopathy, and Lewy body scores supported the diagnoses of moderate to severe dementia in the majority of cases (86%), but did not differ between groups. No statistically significant differences were found between the 3 groups for degree of atherosclerosis (p=0.25) or lacunar (p=0.34), micro- (p= 0.67), hemorrhagic (p= 0.81), or macro (p= 0.90) infarcts. Conclusions: Antipsychotic medication use is not associated with increased burden of cerebrovascular disease on neuropathological examination. Future studies investigating causal relationship between antipsychotic use and increased risk of death in dementia patients is warranted. Disclosure: Dr. Singhal has nothing to disclose. Dr. Abner has nothing to disclose. Dr. Schmitt has nothing to disclose. Dr. Nelson has nothing to disclose. Dr. Jicha has received personal compensation for activities with Pfizer Inc, Janssen Immunotherapy, and Eli Lilly & Company. Dr. Jicha has received research support from Baxter, Janssen, Pfizer Inc, Medivation, and Danone.