Sano, Mary

Abstract Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p < 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.

The terrorist attacks on 11 September 2001 potentially exposed more than 400,000 responders, workers, and residents to psychological and physical stressors, and numerous hazardous pollutants. In 2011, the World Trade Center Health Program (WTCHP) was mandated to monitor and treat persons with 9/11-related adverse health conditions and conduct research on physical and mental health conditions related to the attacks. Emerging evidence suggests that persons exposed to 9/11 may be at increased risk of developing mild cognitive impairment. To investigate further, the WTCHP convened a scientific workshop that examined the natural history of cognitive aging and impairment, biomarkers in the pathway of neurodegenerative diseases, the neuropathological changes associated with hazardous exposures, and the evidence of cognitive decline and impairment in the 9/11-exposed population. Invited participants included scientists actively involved in health-effects research of 9/11-exposed persons and other at-risk populations. Attendees shared relevant research results from their respective programs and discussed several options for enhancements to research and surveillance activities, including the development of a multi-institutional collaborative research network. The goal of this report is to outline the meeting’s agenda and provide an overview of the presentation materials and group discussion.

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

AbstractWith increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long‐term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Background Observational studies and small clinical trials suggested that hormone replacement therapy (HRT) decreases risk of cognitive loss and Alzheimer's disease (AD) in postmenopausal women and may have value in primary prevention. Purpose A clinical trial was designed to determine if HRT delays AD or memory loss. This report describes the rationale and original design of the trial and details extensive modifications that were required to respond to unanticipated findings that emerged from other studies during the course of the trial. Methods The trial was designed as a multi-center, placebo-controlled primary prevention trial for women 65 years of age or older with a family history of dementia. Recruitment from local sites was supplemented by centralized efforts to use names of Medicare beneficiaries. Inclusion criteria included good general health and intact memory functioning. Participants were randomized to HRT or placebo in a 1:1 ratio. Assignment was stratified by hysterectomy status and site. The primary outcomes were incident AD and memory decline on neuropsychological testing. Results Enrollment began in March 1998. In response to the Women's Health Initiative (WHI) May 2002 report of increased incidence of heart disease, stroke, pulmonary embolism, and breast cancer among women randomized to HRT, participants were re-consented with a revised consent form. Procedural modifications, including discontinuation of study medication and a modification of the planned primary outcome based on a final enrollment below the target enrollment (N = 477), were enacted in response to the subsequent WHI Memory Study report of increased risk of dementia and poorer cognitive function with HRT. The mean length of treatment exposure prior to discontinuation was 2.14 years. Participants' mean age at baseline was 72.8; mean education was 14.2 years. Minority participation was 19% and 34% had a hysterectomy. The study continues to follow these participants for a total of 5 years blind to the original medication assignment. Limitations Results reported from the WHI during the course of this study mandated extensive procedural modifications, including discontinuing recruitment before completion and halting study medication. Alternative strategies for study redesign that were considered are discussed. Clinical Trials 2008; 5: 523—533. http://ctj.sagepub.com