Sandra A. Jacobson

Introduction: Longitudinal assessment of cognitive decline in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) often involves the use of both informant-based and objective cognitive assessments. As efforts have focused on identifying individuals in pre-clinical stages, instruments that are sensitive to subtle cognitive changes are needed. The Alzheimer’s Questionnaire (AQ) has demonstrated high sensitivity and specificity in identifying aMCI and AD; however its ability to measure longitudinal change has not been assessed. The aims of this study are to assess the sensitivity to change of the AQ and to determine whether the AQ predicts change in global cognition and function in cognitively normal (CN), aMCI, and AD subjects. Methods: Data from 202 individuals participating in a brain and body donation program were utilized for this study (101 CN, 62 aMCI, 39 AD). AD and aMCI individuals were matched on age, education, and gender to CN individuals. Sensitivity to change of the AQ was assessed in addition to the AQ’s ability to predict change in global cognition and function. The Mini Mental State Exam (MMSE) and Functional Activities Questionnaire (FAQ) were used as gold standard comparisons of cognition and function. Sample size calculations for a 25% treatment effect were also carried out for all three groups. Results: The AQ demonstrated small sensitivity to change in the aMCI and CN groups (d = 0.33, d = 0.23, respectively) and moderate sensitivity to change in the AD group (d = 0.43). The AQ was associated with increases in the Clinical Dementia Rating Global Score (OR = 1.20 (1.09, 1.32), P <0.001). Sample size calculations found that the AQ would require substantially fewer subjects than the MMSE given a 25% treatment effect. Conclusions: Although the AQ demonstrated small sensitivity to change in aMCI and CN individuals in terms of effect size, the AQ may be superior to objective cognitive tests in terms of required sample size for a clinical trial. As clinicians and researchers continue to identify and treat individuals in earlier stages of AD, there is a need for instruments that are sensitive to cognitive changes in these earlier stages.

Background Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption. Aims To characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms. Methods A longitudinal, observational study of 51 subjects with FM (range 55–95 years) and 81 control subjects (58–95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment. Results Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin. Discussion In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated. Conclusions Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.

Carriers of the ApoE ϵ4 allele are at a greater risk for developing Alzheimer’s disease (AD) and those who do develop AD tend to have a much greater neuropathological disease burden. Although several studies have shown significant differences in AD pathology among ϵ4 carriers and non-carriers, few have characterized these differences in terms of brain region and neuropathological score frequency. 566 pathologically-confirmed AD cases who were followed prospectively with antemortem dementia diagnoses (312 ApoE ϵ4 carriers and 254 ApoE ϵ4 non-carriers) were compared on the frequencies of neuropathological frequency scores (none, sparse, moderate, frequent) among several different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal) using the CERAD scoring system. Pathology score frequencies were analyzed by carrier status (ϵ4 carrier vs. ϵ4 non-carrier) and by genotype (2/3, 3/3, 2/4, 3/4, 4/4). Both analyses investigated pathology score frequencies among different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal). ϵ4 carriers had a significantly lower age at death (p <0.001) and significantly higher Braak scores (p <0.001) than ϵ4 non-carriers. Genotype comparison revealed that plaque and tangle pathologies increased in the following pattern, 2/3<3/3<2/4<3/4<4/4, for several brain regions. When stratified by age and ApoE ϵ4 carrier status, ϵ4 carriers tended to have significantly more frequent scores across most cortical areas. However, non-carriers age 90 and older tended to have greater plaque pathology than carriers. For tangle pathology, ϵ4 carriers tended to have significantly more “frequent” scores than non-carriers, except for the hippocampal and entorhinal areas in individuals age 90 and older. ApoE ϵ4 carriers had a significantly higher percentage of “frequent” scores for plaques and tangles when compared to ApoE ϵ4 non-carriers for several brain regions. However, ϵ4 non-carriers age 90 and older tended to have less plaque and tangle pathology in certain brain regions. These results demonstrate that AD pathology may manifest itself differently based on ApoE genotype and suggest that ApoE carriers and non-carriers may have different patterns of AD neuropathology location and density.

Background: Normal pressure hydrocephalus (NPH) is considered to be potentially treatable with the placement of a cerebrospinal fluid (CSF) shunt. However, the procedure has been reported to have variable success, particularly with respect to improving the cognitive impairment in NPH. The presence of neurologic comorbidities, particularly Alzheimer's disease (AD), may contribute to shunt responsiveness. Uncovering the extent to which AD and NPH co‐occur has implications for diagnosis and treatment of NPH. Autopsy studies of patients with NPH during their lifetime would elucidate the frequency of such comorbidities.Methods: A search of the Sun Health Research Institute Brain Donation Program database was conducted between January 1, 1997 and April 1, 2009 to identify all cases with neuropathologic evidence of dementia as well as those of clinically diagnosed NPH. We reviewed the medical records and brain findings of each NPH case.Results: Of the 761 cases autopsied over the study interval, 563 were found to have neuropathologic evidence meeting criteria for a dementing illness. Of 563 cases, AD was found exclusively in 313 (56%), and 94 suffered from secondary diagnosis of dementia. Nine of 761 cases were identified with a clinical diagnosis of NPH, which were among the 563 cases with neuropathology of dementing illness at autopsy, representing 1.6% (9/563) of the cases. On review of brain autopsy reports of these nine patients, eight (89%) were found to have AD and one (11%) had progressive supranuclear palsy. Review of the medical records of the nine NPH cases revealed the following clinical comorbidities: five suffered from AD, one from Parkinson's Disease, one from mild cognitive impairment, and one from seizure disorder.Conclusions: Given the findings of the present study, we support the AD‐NPH theory and posit that AD is a common pathologic comorbidity in the setting of NPH and may preclude cognitive improvement postshunt placement. This may influence the selection of cases for shunting in the future.

Given the level of interest and activity in the race to find a treatment for Alzheimer's disease, it is expected that a reasonably safe and effective drug will be identified within the next decade. It may be worthwhile to pause periodically during the course of this race to take stock of what we have learned. Over the past few years, a number of trials have been conducted with promising new compounds (including some with novel mechanisms of action) that failed to meet primary endpoints and so were discontinued from clinical development. This article reviews a set of molecules with a range of mechanisms that have been trialed but with negative results. This article also examines the reasons for the negative findings and summarizes some of what we have learned from these experiences.

The receptor for advanced glycation end products (RAGE) has been demonstrated to play a central role in the pathogenic mechanisms of a growing number of important neurological diseases, including Alzheimer’s disease (AD) and stroke. Two functional types of RAGE have been associated with neurological diseases: cell membrane-bound (full length) and soluble. In general, ligand binding to full-length RAGE initiates sustained cellular activation and receptor-dependent signaling resulting in inflammation and cellular stress, and is ultimately associated with increased RAGE expression. By comparison, soluble forms of RAGE, generated either by alternative splicing or by proteolysis, can reduce the severity of the consequence of ligand–membrane RAGE interactions by preventing ligands from binding to the full-length RAGE. This can inhibit the neurotoxic or proinflammatory responses involved in disease states. This article reviews the pathobiology of RAGE, with emphasis on soluble forms of RAGE, and discusses its re...