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Objective: To determine how the advent of extrapyramidal signs influences the progression of Alzheimer disease as measured by standard clinical measures. Design: We applied growth curve models to prospective data to characterize patients' cognitive and functional changes over time. To detect changes in disease course related to extrapyramidal signs, their onset was treated as a time-dependent covariate. Setting: Three research medical centers. Participants: Patients (n=217) with probable Alzheimer disease. Intervention: Patients were followed up semiannually for 5 years. Main Outcome Measures: Scores on the modified Mini-Mental State Examination and measures of basic and instrumental activities of daily living from the Blessed Dementia Rating Scale. Results: For basic and instrumental activities of daily living, disease course was more rapid once extrapyramidal signs developed. Decline in the modified Mini-Mental State Examination score was greater at the time the signs developed, but not at subsequent visits. Conclusions: The point at which extrapyramidal signs emerge is associated with measurable acceleration in the progression of Alzheimer disease. This may in part explain why extrapyramidal signs are associated with a poorer prognosis. The differential influence of extrapyramidal signs on cognitive and functional measures suggests that the pathological changes underlying these disease features may vary.

• Objective. —To compare cognitive changes in the dementias of Parkinson's disease (PD) and Alzheimer's disease (AD). Design. —Case series, group comparisons. Setting. —Ambulatory care referral center. Patients. —Consecutive sample of 14 patients with PD dementia and 27 with probable AD matched for overall intellectual function using a mental status test, as well as 1 nondemented PD and 12 mild probable AD patients, similarly matched for overall intellectual function. All demented patients met Diagnostic and Statistical Manual, Revised Third Edition , criteria for dementia. Main Outcome Measures. —Performance on a battery of neuropsychological tests assessing verbal and nonverbal memory, verbal fluency, and constructional ability. Results. —Nondemented and demented patients with PD performed worse than their probable AD comparison groups on verbal fluency and visuospatial tasks. Cognitive changes attributable to dementia were similar in PD and probable AD but were not identical. The patients with probable AD demonstrated more marked change in memory performance with delay. Conclusions. —Our findings suggest that when dementia occurs in PD it is overlaid on cognitive changes that already exist in nondemented patients but that the dementing process in PD involves systems other than those responsible for cognitive change in nondemented PD patients. We hypothesize that in most cases, dementia in PD involves changes in a nondopaminergic neurotransmitter system but is not due to concomitant AD.

Alzheimer disease (AD), a serious neurodegenerative illness characterized by cognitive impairment and functional in-capacity, is thought to affect more than 26 million people worldwide, a number projected to expand to 106 million over the next several decades. The costs associated with this disease are estimated to be $25 billion, costs largely associated with the loss of independence and the need for care of these patients. It is no wonder that search for treatments is vigorous, with more than 700 trials registered on clinicaltrials.gov since 1997. One of the most common targets for treatment for AD is the manipulation of amyloid, which accumulates in the brain of those with the disease. One mechanism for this manipulation is the modulation of the enzyme γ-secretase, which may favor the production of a less toxic form of β-amyloid (Aβ). Tarenflurbil has demonstrated such activity in vitro and in in vivo animal studies, and it has shown relative safety in human trials. Hence, it was considered a viable candidate for phase 3 clinical trials in AD. The randomized placebo-controlled trial of tarenflurbil in patients with mild AD reported by Green et al1 is a well-conducted study of more than 1600 subjects with AD recruited from 133 sites across the United States. These investigators used a rigorous design and a long exposure period of 18 months. During the trial protocol, modifications were made (based on reanalysis of phase 2 data) consisting of shifting from 2 doses to a single high dose and modifying entry criteria to include only very mildly impaired subjects (with Mini-Mental State Examination [MMSE] scores of 20-26 inclusive). In the face of these modifications and the relatively long exposure period, most subjects (97%) were available for the primary analysis and the mean medication compliance rate was higher than 90%. It is therefore quite disappointing to see the dramatic lack of effect in the primary and secondary outcomes, with the exception of the Clinical Dementia Rating sum of boxes scores, which favored placebo. While so many things could go wrong in one of the few long trials that have been published to date, it appears that this cohort was typical of all that we know about patients with AD, with standard use of prescriptive cognitive enhancers, predictable decline in the placebo group in cognition, function, and behavior, no unusual adverse events, and no unreasonable loss to follow-up. We can therefore conclude with conviction that there was no benefit of tarenflurbil in this very typical group of patients with very mild AD. So why did this fail? Were there any data that should have limited enthusiasm to move to a phase 3 study? Was there false enthusiasm that moved this trial beyond the apparent data? There are several things to consider. The intent-to-treat analysis of the phase 2 study in mild to moderate AD demonstrated no significant benefit on the primary outcomes.2 Additional analyses that examined subgroups defined by MMSE scores identified a benefit in the group with the highest MMSE scores and a significant negative effect in several outcomes in those with lower MMSE scores. The decision to focus on this subgroup (mild) of a subgroup (mild to moderate) was solidified based on an analysis that demonstrated a differential treatment effect for the subgroup defined by a specific cut point on the MMSE. This approach to defining disease severity ex post facto identified a mild subgroup that demonstrated a benefit and a moderate subgroup that actually worsened. Dramatic differences in the direction of effect in subgroups seem biologically implausible. Should one suspect that at the shift of 1 point in an MMSE score, a patient was at risk for significant adverse effects with the agent that was otherwise beneficial? Could the results of the current trial suggest mathematical regression to the mean? The literature in clinical trials for the treatment of AD has many similar cases of failures in large trials that have based subject selection on a result in a subgroup of previous trials including acetylcarnitine, propentofylline, and most recently bapineuzumab. It would seem that the preliminary studies provided important information that forewarned of questionable effect, and further phase 2 testing might have been advisable before embarking on the “largest phase 3 trial to date.”1

Objective To describe the spectrum of clinical symptoms, signs, and laboratory features associated with A3243G, a mitochondrial DNA point mutation that affects multiple organs with varying severity, making the diagnosis and treatment of these patients complex. Design Cohort study. Setting Columbia University Medical Center. Participants A cohort of 123 matrilineal relatives from 45 families, including 45 fully symptomatic patients with mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (syndrome), 78 carrier relatives, and 30 controls. Main Outcome Measures Data gathered from standardized medical history questionnaires, neurological and ophthalmological examination forms, and laboratory tests. We compared data between 3 groups. Results Mutation carriers' clinical and laboratory results frequently had many abnormalities. In addition to neurological symptoms, they often had cardiac, endocrine, gastrointestinal, and psychiatric symptoms. Conclusions The A3243G mutation carriers have multiple medical problems, suggesting that the A3243G mutation should be considered as an etiological factor in patients with multisystem clinical presentations or a family history compatible with matrilineal inheritance. Because some medical problems affecting A3243G mutation carriers are treatable, early detection and proactive management may mitigate the burden of morbidity.

• First-degree relatives of patients with Alzheimer's disease (AD) are at greater risk for dementia when compared with the relatives of their healthy peers, but not when compared with the relatives of patients with Parkinson's disease. This may indicate that the risk of dementia in these relatives is not specific to AD or that these studies are biased. We obtained a family history and vital status information on each first-degree relative of patients attending a clinic and in a group of recruited healthy elderly subjects. Patients formed two groups: probable AD and other forms of dementia or cognitive disorders without dementia. The odds of dementia in first-degree relatives did not differ between patient groups. The odds of dementia in relatives of patients with probable AD or other forms of dementia was six times that in the relatives of the healthy elderly subjects. The cumulative incidence of dementia increased with age in the first-degree relatives of all subjects. Approximately 50% of the first-degree relatives of patients with AD were demented by age 91 years, but almost the same number of the other patient group's relatives were demented as well. That figure was never reached in the healthy elderly subject's relatives. Because the risk of dementia in first-degree relatives of patients with AD was similar to that for patients with other disorders, we cannot exclude the possibility that this is the result of selection and information biases. Our investigation implies that the increased risk of dementia may not be specific to relatives of patients with AD; the risk may also be increased in first-degree relatives of patients with other neurologic disorders.

Objective: To determine the validity of new subjective memory complaints (MCs) from individuals who previously, when without dementia, denied having MCs. Design: Prospective cohort. Setting: Longitudinal, community-based study of aging and dementia. Patients: One hundred thirty-three communitydwelling elderly individuals who were part of a registry for the study of conditions related to aging in North Manhattan, NY. Patients were selected if they were initially without dementia and had completed at least 2 successive annual clinical and neuropsychological evaluations and provided their own medical history. Main Outcome Measures: Performance on memory tests—the Buschke Selective Reminding Test and a visual memory task—and global performance on a neuropsychological test battery and clinical evaluation, by which questionable dementia or dementia was diagnosed according to a well-defined paradigm. Results: Fifty-three subjects with MCs at the initial evaluation performed no worse on the memory test than the 80 subjects who denied MCs initially. There was a weak association between MCs and the diagnosis of questionable dementia at baseline ( P =.04), but this was nonsignificant after adjusting for age and education. At 1-year follow-up, 21 of the 80 without baseline MCs now reported MCs. At the follow-up evaluation, these 21 subjects performed significantly worse on the memory tests, were 5 times more likely to have significant cognitive impairment, and had shown significantly greater decline over the preceding year on several of the cognitive measures than the 59 who continued to deny MCs. Conclusion: New MCs from individuals, who when without dementia recently denied MCs, may suggest the presence of significant impairment of memory or cognition.

To develop an informant-based semistructured interview to determine the onset and duration of symptoms of Alzheimer's disease, and to use this instrument with informants to characterize a cohort of mildly impaired patients with Alzheimer's disease.In study 1, interrater and interinformant reliability was examined for the date of onset and the order of appearance for specific symptoms that were elicited by the semistructured onset interview. In study 2, the instrument was used to characterize disease onset in a cohort of patients with Alzheimer's disease who were participating in a large multicenter study.Informants of patients with Alzheimer's disease.In study 1, interrater reliability for duration of illness was excellent (intraclass correlation coefficient = .99, P.001), and interinformant reliability was good (intraclass correlation coefficient = .86, P.001). Agreement for the presence of a given symptom was highest for those that were most commonly reported (eg, memory and performance difficulty). In study 2, 89% of the cohort had memory problems, and 63.9% had performance difficulties as the first or second symptom. Depression and language problems were less commonly reported. Psychosis and behavioral disturbances were rarely reported as the first problem.This instrument provides a reliable procedure for standardizing the estimation of duration of illness based on retrospective report.

To estimate the incidence rate and predictors of seizures in patients with mild to moderate Alzheimer disease (AD).Cohort study of patients with mild to moderate AD in clinical trials. Risk factors for potential seizures were evaluated by stratified descriptive statistics and univariable and multivariable Cox proportional hazards regressions.Pooled patient-level data from 10 Alzheimer Disease Cooperative Study clinical trials in mild to moderate AD from 1995 to 2010.Three thousand seventy-eight subjects randomized to the treatment or placebo arms of 10 AD clinical trials. Screening Mini-Mental State Examination scores ranged between 10 and 28.Eighteen seizures were reported in 3078 randomized subjects, with an incidence rate of 484 per 100 000 person-years (95% CI, 287-764). Statistically significant independent risk factors for seizure were younger age (adjusted hazard ratio, 0.80; 95% CI, 0.69-0.93 per every 5 years of age), greater cognitive impairment at baseline (adjusted hazard ratio, 2.79; 95% CI, 1.06-7.33 for Mini-Mental State Examination scores18 compared with Mini-Mental State Examination scores ≥18), and antipsychotic use at baseline (adjusted hazard ratio, 3.47; 95% CI, 1.33-9.08).Seizure rates in patients with mild to moderate AD in clinical trials are similar to rates observed in longer observational cohort studies, but they are greater than expected in the general elderly population. Younger age, greater degree of cognitive impairment, and history of antipsychotic use were independent risk factors for new-onset seizures in AD.

Cumulative risks of developing extrapyramidal signs, psychosis, and myoclonus in the course of Alzheimer's disease (AD) were estimated in 72 patients with probable AD by the Kaplan-Meier survival method. The cumulative risk functions were found to increase at different rates for different signs as AD progressed. Comparisons of the cumulative risk functions revealed that in the early stages of AD, extrapyramidal signs and psychosis were more likely to develop than myoclonus. As AD progressed, the risk of developing myoclonus became as great as that of developing the other two signs. This study suggests that extrapyramidal signs, psychosis, and myoclonus represent developmental features that mark the progression of AD, rather than indicators of disease subtypes. The estimated cumulative risk functions set a reasonable expectation for the timing and likelihood of the emergence of the clinical signs. This, in turn, might aid in disease prognosis because the biological bases of these signs have been established and they have been shown to be predictive of other markers of disease course.

Background Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. Objective To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. Design Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. Setting Memory disorder centers in the United States and Canada. Patients A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. Main Outcome Measures Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. Results Mean ± SD Alzheimer's Disease Assessment Scale–Cognitive Subscale scores were 5.6 ± 3.3 for controls, 11.3 ± 4.4 for patients with MCI, 18.0 ± 6.2 for the AD CDR 0.5 group, and 25.2 ± 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E ϵ4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. Conclusions Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

Objective: To explore the functional significance of incident neuropsychologic impairment among initially asymptomatic subjects infected with human immunodeficiency virus. Design: Prospective, observational cohort study of homosexual and bisexual men to examine the incidence of work disability related to the onset of neuropsychologic impairment. Setting: A university clinical and behavioral research site in New York City. Participants: Sample of 207 homosexual and bisexual men; 123 were seropositive and 84 were seronegative. Principal Outcome Measures: Incident work disability in the course of 4.5 years of follow-up, with disability defined as a persistent (≥24 months) change in work hours (from 20 or more to less than 20 h/wk). Results: Compared with seronegative control subjects (n=72), the relative risk of work disability among initially asymptomatic seropositive men (n=44) was 2.76 (95% confidence interval, 1.2 to 6.5), nearly a threefold increase. Proportional hazards models show that this increased risk is attributable to the development of major neuropsychologic impairment in a subset (eight of 44) of the initially asymptomatic men, which is significantly associated with incident work disability (6/8 [75%]). Adjusting for symptom status and CD4 + cell count at the time of disability did not eliminate the increased risk associated with neuropsychologic impairment. Conclusions: In this cohort, the increased risk of work disability among initially asymptomatic human immunodeficiency virus—positive men was related to incident neuropsychologic impairment; such impairment predicted work disability independently of symptom status and CD4 + cell count over the follow-up period. Neuropsychologic impairment in the course of human immunodeficiency virus infection may indicate increased risk for poor outcomes over and above that associated with systemic disease.

• Objective. —Eight asymptomatic patients with sickle-cell disease (SCD) with magnetic resonance imaging (MRI) abnormalities consistent with cerebral infarcts (group 1) and eight asymptomatic patients with SCD with normal MRI scans (group 2) were followed up to assess the neurological correlates and the clinical outcome. Design. —Patients in the two cohorts underwent clinical evaluations and xenon 133 regional cerebral blood flow (rCBF) studies within 1 month of the entry MRI. This study sequence was repeated up to 5 years later. Neuropsychological studies also were performed in six group 1 patients and eight group 2 patients at the end of the study. Setting. —The patients were recruited from the Comprehensive Sickle Cell Center at Columbia University, New York, NY. Patients. —All patients had SCD, hemoglobin SS, and normal findings on clinical evaluation at entry. The group 1 cohort had clinically silent MRI abnormalities consistent with cerebral infarction. The group 2 cohort was age matched to group 1 and had normal MRI studies. Interventions. —None. Main Outcome Measure. —The natural history of MRI abnormalities and the neurological correlates were assessed to determine the predictive value of subclinical MRI lesions as a risk factor for clinically apparent stroke. Results. —The mean duration of MRI follow-up was 3.7 years. In group 1, four patients (50%) demonstrated progressive MRI abnormalities and three patients (38%) became clinically symptomatic. In group 2, findings for all patients remained normal on clinical and radiological examination. Both groups had markedly elevated rCBF values. Individual rCBF differences correlated with the specific MRI abnormalities. The psychometric study results were similar in the two cohorts. Eighty-three percent of group 1 and 88% of group 2 patients had defective scores in one or more areas of cognitive functioning. Three patients met cognitive criteria for dementia. Conclusions. —Cranial MRI abnormalities have important prognostic implications even when detected in clinically asymptomatic patients. Cognitive abnormalities exist in patients with SCD even in the absence of MRI abnormalities or clinical stroke.

• We examined 99 human immunodeficiency virus (HIV)—negative and 122 HIV-positive intravenous drug users (IVDUs) without acquired immunodeficiency syndrome (AIDS) to determine whether HIV-positive IVDUs had more neurologic and neuropsychological impairment than their HIV-negative counterparts. Controlling for age, education, drug use, history of head injury, and interactions between head injury and HIV status and drug use, HIV-positive subjects had more extrapyramidal signs and frontal release signs. These findings persisted when asymptomatic HIV-positive subjects without systemic signs of infection and HIV-negative subjects were compared. Neurologic findings were more severe in those with more systemic illness. Among those reporting a history of head injury with loss of consciousness, neuropsychological performance was significantly worse in the HIV-positive subjects, and this increased with severity of illness. This was not true in the group without head injury, suggesting an interaction between history of head injury and the seropositive state. No relationship was noted between head injury and either drug use or HIV state. Therefore, subtle neurologic and neuropsychological abnormalities may precede clinical evidence of AIDS in IVDUs and may be more evident in those with head injury.

• A brief diagnostic battery of neuropsychological tests was developed for a large-scale epidemiological study of dementia. We operationally defined dementia as defective memory and defective performance in at least two other areas, including orientation, abstract reasoning, construction, and language. Criterion scores for defining defective performance on each test were developed. In a pilot study that used 51 different subjects with a working diagnosis based on physicians' assessment (ie, 32 demented and 29 nondemented subjects), the test-based diagnosis agreed with the working diagnosis in all but two cases. The test battery was then applied to 430 healthy elderly subjects. Eighteen percent of those with 8 or less years of education met criteria for dementia compared with 5% of those with more than 8 years of education. We computed educationcorrected scores for each test with the use of residuals from the regression of each test score on education. Based on corrected scores, 12 subjects were reclassified as nondemented and 11 as demented. Subjects who were reclassified as demented were significantly more impaired in activities of daily living than nondemented subjects who were not reclassified. Activities of daily living in subjects who were reclassified as nondemented did not differ from those in demented subjects who were not reclassified. These findings suggest that the neuropsychological battery may have utility in the diagnosis of dementia. However, neuropsychological performance may be influenced by education, and some form of adjustment, such as correction for activities of daily living, may be required in epidemiological studies.

• Dementia and depression in patients with Parkinson's disease have been reported separately, but their prevalence is controversial. This study examines the coexistence of these two problems and suggests a common underlying biochemical system. We examined these two entities by retrospective chart review and cerebrospinal fluid biochemistry. We found a prevalence of 10.9% for dementia, 51% for depression, and 5.4% for coincident depression and dementia. In a prospective study of patients with Parkinson's disease we found a continuum of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. Patients who were either depressed or demented had lower concentrations of this metabolite than other patients with Parkinson's disease, but patients who were depressed and demented had the lowest levels. These results suggest that the coexistence of dementia and depression represents a unique clinical entity in Parkinson's disease. The serotonergic system may be involved in depression and dementia because evidence of a cumulative effect on this biochemical system is present.