Jack, Clifford R

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.

Intracerebral hematoma may complicate treatment of acute myocardial infarction in patients treated with fibrinolytic agents. We studied the clinical presentation and computed tomographic characteristics. We studied eight patients with lobar intracerebral hematomas after fibrinolytic treatment of acute coronary occlusion. All patients had electrocardiographic and laboratory evidence of acute myocardial infarction and were treated with tissue plasminogen activator or streptokinase followed by heparin infusion to prevent reocclusion. Computed tomography scans of 17 patients with cerebral hemorrhage from other causes were used for comparison. For most patients, outcome was fatal within hours of the ictus. Computed tomography scans showed superficially large lobar hematomas in six patients. One patient had a putaminal hemorrhage, and one had a vermis hemorrhage. Multiple sites of intracerebral hemorrhage were noted in three patients. Fluid levels inside the hematoma suggesting continuing hemorrhage into multiple compartments were common. Radiologically, fluid levels in hematomas, multiple hematomas, and blood in multiple compartments served to differentiate fibrinolysis-induced hemorrhage from hemorrhage of other causes. Severe amyloid angiopathy was found in one patient who was operated on. Hemorrhages in multiple compartments and the presence of fluid levels inside the hematoma suggest fibrinolysis-associated cerebral hematomas. Severe amyloid angiopathy may be a crucial factor in this clinical entity. Outcome is poor, and a high proportion of patients have rapid progression to brain death. Therefore, emergency neurosurgical evacuation will probably be unsuccessful.

Antiphospholipid antibodies are known to be associated with increased risk of venous and arterial thrombotic events, including cerebral venous thromboses. Pseudotumor syndrome can be produced by cerebral venous thrombosis. A patient with cerebral venous thrombosis associated with antiphospholipid antibodies who exhibited pseudotumor syndrome is reported. A 49-year-old man who noted visual blurring and persistent vertical wavy lines in his fields of vision was found to have papilledema. Cerebrospinal fluid values were normal except for an opening pressure increase to 510 mm of fluid. His visual symptoms improved with lumbar puncture and the use of acetazolamide. Imaging studies showed that the transverse sinus was occluded completely on the left and partially on the right and that there was a small left cerebellar cortical venous infarction. Antiphospholipid syndrome should be considered in the differential diagnosis of pseudotumor syndrome related to cerebral venous thrombosis.

Background Criteria for the clinical diagnosis of Alzheimer's disease (AD) were established in 1984. A broad consensus now exists that these criteria should be revised to incorporate state‐of‐the‐art scientific knowledge. Methods The National Institute on Aging (NIA) and the Alzheimer's Association sponsored a series of advisory round table meetings in 2009 whose purpose was to establish a process for revising diagnostic and research criteria for AD. The recommendation from these advisory meetings was that three separate work groups should be formed with each assigned the task of formulating diagnostic criteria for one phase of the disease: the dementia phase; the symptomatic, pre‐dementia phase; and the asymptomatic, preclinical phase of AD. Results Two notable differences from the AD criteria published in 1984 are incorporation of biomarkers of the underlying disease state and formalization of different stages of disease in the diagnostic criteria. There was a broad consensus within all three workgroups that much additional work is needed to validate the application of biomarkers for diagnostic purposes. In the revised NIA‐Alzheimer's Association criteria, a semantic and conceptual distinction is made between AD pathophysiological processes and clinically observable syndromes that result, whereas this distinction was blurred in the 1984 criteria. Conclusions The new criteria for AD are presented in three documents. The core clinical criteria of the recommendations regarding AD dementia and MCI due to AD are intended to guide diagnosis in the clinical setting. However, the recommendations of the preclinical AD workgroup are intended purely for research purposes.

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all‐cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease‐modifying therapies may be most efficacious.

Hippocampal atrophy is a marker of disease state and progression in Alzheimer's disease. The gold standard to measure hippocampal volume is through manual segmentation. A number of protocols to measure hippocampal volume through manual segmentation have been developed, but the marked heterogeneity of anatomical landmarks has given rise to wide variability of volume estimates. With the aim of fostering the use of hippocampal volume in routine clinical settings, an international task force is currently working on developing a harmonized protocol that will resolve and reduce the present heterogeneity. The task force will then validate the harmonized protocol, develop harmonized probabilistic hippocampal maps, and develop illustrative and educational material on the use of the harmonized protocol and maps.