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BackgroundThe promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization.Methods and ResultsThe authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers–Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark.ConclusionsAlthough manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.

BackgroundCerebral vasogenic edema (VE) has been reported to occur during antiamyloid immunotherapy. VE may be associated with central nervous system pathology with blood–brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimer's disease (AD).MethodsFluid‐attenuated inversion recovery imaging sequences were obtained from four ongoing multicenter, randomized, double‐blind, placebo‐controlled, phase 3 trials in patients with mild‐to‐moderate AD. The first set of baseline scans was from patients in volumetric magnetic resonance imaging addenda in the Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of Amyloid PaThologY (IDENTITY) studies examining semagacestat, a γ‐secretase inhibitor (cohort 1, n = 621). The second set of baseline scans was from the EXPanding Alzheimer's Disease InvestigaTIONs (EXPEDITION) studies examining solanezumab, an anti‐Aβ monoclonal antibody (cohort 2, n = 2141). Readers were blinded to patient‐identifying information and future treatment. A third set of baseline scans was from the first 700 patients who underwent protocol‐specified magnetic resonance imaging before randomization in the EXPEDITION studies (cohort 3). The analysis used three neuroradiologists: two performed independent primary interpretations and the third was the adjudicator. Readers were blinded to patient information, treatment, protocol, and time point.ResultsFour cases of asymptomatic VE were detected at baseline/screening. Two VE cases were due to underlying extra‐axial mass lesions. The third VE case was associated with numerous microhemorrhages in keeping with cerebral amyloid angiopathy‐related inflammation or Aβ‐related angiitis. The final VE case demonstrated localized sulcal fluid‐attenuated inversion recovery imaging hyperintensity. No VE was detected in cohort 3 by readers blinded to patient baseline status.ConclusionsVE seems to be rare at baseline in patients with AD in clinical trials, 2 of 2762 associated with AD. Additional cohorts should be evaluated to support these findings.

The three factors other than age that are the most important determinants of stroke occurrence are (1) transient cerebral ischemic attacks (TIAs), (2) hypertension, and (3) cardiac disease. In the Rochester population study, a stroke developed during the period of observation in 36% of the patients with TIAs. Fifty-one percent of all the strokes occurred during the first year after the TIA, and 21% occurred during the first month after the first attack. Hypertensive persons have an increased incidence of each of the major atherothrombotic diseases as compared to normotensive persons. During the full 25 years of study of the Rochester population, there was a decrease from the earliest to the latest five-year period of 32% for all strokes in women and 20% in men. This may reflect treatment of this population.

This study has attempted to identify all patients in the population of Rochester, Minnesota, who had stroke during the period 1955 through 1969, and to determine the course and survival of patients who have had stroke. Cerebral infarction from all causes, including embolic infarction, accounted for 79% of all strokes. Intracerebral hemorrhage accounted for 10% of the cases, and subarachnoid hemorrhage accounted for 6%. The average annual incidence rate for the 15 years of the study was 164 per 100,000 population per year. The rates for all strokes and for cerebral infarction were significantly higher for men than for women, except in the youngest age group. After the end of an earlier study, 1945 through 1954, the average annual incidence rate for all strokes decreased in each succeeding five-year interval and reached 141 during the period 1965 through 1969. The decrease in rates is apparent for all strokes and for cerebral infarction, and is more apparent for women than for men. The prevalence rate on January 1, 1960, and January 1, 1965, of about 700 per 100,000 population was higher than the rate for January 1, 1970, reflecting decreasing incidence rates. A study of the functioning capacity of survivors of stroke after six months indicates that only 4% required total care and nearly 30% were functioning normally. Fifty-four percent had some neurological deficit that may have been benefited by rehabilitative care. Aphasia was an important residual incapacity in 10%. The first-year recurrence rate of stroke was 10%, and the five-year recurrence rate was 20%. Among patients with stroke who died, 38% died of the initial stroke, 10% of a subsequent stroke, and 18% of heart disease. During the 25-year period, 1945 through 1969, there has been a trend toward gradually increasing survival for cerebral infarction in this community.