Late-Onset Alzheimer Disease.

The oldest-old represent the fastest growing segment of society, and the risk of developing dementia continues to increase with advancing age into the 9th and 10th decades of life. The most common form of dementia in the oldest-old is Alzheimer disease (AD), although there are often mixed pathologies contributing to dementia in addition to amyloid plaques and neurofibrillary tangles. Diagnosing AD in the oldest-old is challenging due to cognitive and physical changes associated with aging. Treatment remains supportive, with current approved medications able to provide modest symptomatic benefit but unable to slow the progression of disease.

Age of onset of hypertension and risk of dementia in the oldest-old: The 90+ Study.

INTRODUCTION: We investigated the association between age of onset of hypertension and dementia risk in an oldest-old cohort. METHODS: Participants are from The 90+ Study, a population-based longitudinal study of people aged 90+ who are survivors from the Leisure World Cohort Study. We estimated hypertension onset age using self-reported information from The 90+ Study and Leisure World Cohort Study, collected about 20 years earlier. A total of 559 participants without dementia were followed every 6 months for up to 10 years. RESULTS: A total of 224 participants developed dementia during follow-up (mean = 2.8 years). Compared with those without hypertension, participants whose hypertension onset age was 80 to 89 years had a lower dementia risk (hazard ratio = 0.58, P = .04) and participants with an onset age of 90+ years had the lowest risk (hazard ratio = 0.37, P = .004). DISCUSSION: Developing hypertension at older ages may protect against dementia. Understanding the mechanisms for this lower risk is important for determining ways to prevent dementia in the very elderly.

Sound Body Sound Mind? Physical Performance and the Risk of Dementia in the Oldest-Old: The 90+ Study.

OBJECTIVES: To examine the longitudinal association between physical performance and risk of dementia in individuals aged 90 and older without dementia. DESIGN: Population-based longitudinal study. SETTINGS: The 90+ Study, Laguna Woods, California. PARTICIPANTS: Men n = 176 and women n = 402 without dementia from The 90+ Study (n = 578, mean age 93.3). At baseline, 54% of participants were cognitively normal, and 46% had cognitive impairment, no dementia. MEASUREMENTS: Physical performance measures (4-m walk, 5 chair stands, handgrip, standing balance) were scored from 0 (unable to perform) to 4 (best performance). The outcome was dementia, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Hazard ratios (HRs) for dementia in relation to baseline physical performance were estimated using Cox regression after adjustment for potential confounders. HRs and P-values for the overall Wald chi-square are reported to show the magnitude of each physical performance measure and the strength of the association between each measure and incident dementia. RESULTS: Poor physical performance in most measures was associated with greater risk of incident dementia over a mean follow-up of 2.6 years (range 0.6-9.0 years). After controlling for potential confounders, standing balance had the strongest association with incident dementia (HRs = 1.9-2.5, overall P = .02), followed by 4-m walk (HRs = 1.1-1.8, overall P = .04) and handgrip (HRs = 1.0-2.0, overall P = .03). The association with five chair stands was not significant. In a subanalysis limited to cognitively normal participants, HRs were attenuated, but most remained in the same direction. CONCLUSION: Poor physical performance is associated with risk of developing dementia over an average 2.6-year follow-up in the oldest-old, indicating that poor physical performance may be an early sign of late-age dementia.

Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study.

OBJECTIVE: The purpose of this study was to examine the role of multiple pathologies in the expression of dementia in the oldest-old. METHODS: A total of 183 participants of The 90+ Study with longitudinal follow-up and autopsy were included in this clinical-pathologic investigation. Eight pathologic diagnoses (Alzheimer disease [AD], microinfarcts, hippocampal sclerosis, macroinfarcts, Lewy body disease, cerebral amyloid angiopathy, white matter disease, and others) were dichotomized. We estimated the odds of dementia in relation to each individual pathologic diagnosis and to the total number of diagnoses. We also examined dementia severity in relation to number of pathologic diagnoses. RESULTS: The presence of multiple pathologic diagnoses was common and occurred more frequently in those with dementia compared with those without dementia (45% vs 14%). Higher numbers of pathologic diagnoses were also associated with greater dementia severity. Participants with intermediate/high AD pathology alone were 3 times more likely to have dementia (odds ratio = 3.5), but those with single non-AD pathologies were 12 times more likely to have dementia (odds ratio = 12.4). When a second pathology was present, the likelihood of dementia increased 4-fold in those with intermediate/high AD pathology but did not change in those with non-AD pathologies, suggesting that pathologies may interrelate in different ways. CONCLUSIONS: In the oldest-old, the presence of multiple pathologies is associated with increased likelihood and severity of dementia. The effect of the individual pathologies may be additive or perhaps synergistic and requires further research. Multiple pathologies will need to be targeted to reduce the burden of dementia in the population.

Dementia in the oldest old.

PURPOSE OF REVIEW: This article discusses some of the unique features of dementia in the oldest old, including some of the most common diagnostic challenges, and potential strategies to overcome them. RECENT FINDINGS: Advances include new insight into the role of common risk factors and the effects of multiple underlying neuropathologic features for dementia in the oldest old. In addition, this article contains the latest age-specific normative data for commonly used neuropsychological tests for the oldest old. SUMMARY: The oldest old-people aged 90 years and older-are the fastest-growing segment of society and have the highest rates of dementia in the population. The risk factors, diagnostic challenges, and underlying neuropathologic features of dementia are strikingly different in the 90-years-and-older population compared to younger elderly. Special consideration of these unique features of dementia is necessary when evaluating oldest-old subjects with cognitive impairment.

Poor physical performance and dementia in the oldest old: the 90+ study.

OBJECTIVE: To examine the cross-sectional relationship between physical performance and dementia in the oldest old (those ≥ 90 years of age). DESIGN: Cross-sectional study. SETTING: The 90+ Study is a population-based, longitudinal, epidemiologic study of aging and dementia performed at the University of California, Irvine, from January 1, 2003, through November 30, 2009. PARTICIPANTS: A total of 629 participants from The 90+ Study were included in the study. The mean age was 94 years, and most (72.5%) were women. MAIN OUTCOME MEASURES: All-cause dementia, based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria, was the main outcome measure. The independent variables were physical performance measures, including 4-m walk, 5 chair stands, standing balance, and grip strength, each scored from 0 to 4 (0, unable to perform; 4, best performance). Odds of dementia in relation to the physical performance measures were estimated by logistic regression after adjustment for age and sex. RESULTS Poor physical performance in all measures was significantly associated with increased odds of dementia (P< .001). Odds ratios for every unit decrease in physical performance score were 2.1 for 4-m walk, 2.1 for chair stands, 1.9 for standing balance, and 1.7 for grip strength. CONCLUSIONS: We found a strong cross-sectional relationship between poor physical performance and dementia in people 90 years and older. Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition. Additional research is necessary to determine the temporal relationship between poor physical performance and cognitive dysfunction.

Amyloid imaging and cognitive decline in nondemented oldest-old: the 90+ Study.

BACKGROUND: The goal of this study was to examine cross-sectional and longitudinal associations between cognitive performance and beta amyloid (Aß) load determined by florbetapir F18 positron emission tomography (PET) in nondemented oldest-old. METHODS: Thirteen nondemented (normal or cognitively impaired nondemented) participants (median age, 94.2 years) from The 90+ Study underwent florbetapir-PET scanning within 3 months of baseline neuropsychological testing. Amyloid load was measured with a semi-automated quantitative analysis of average cortical-to-cerebellar standardized uptake value ratio (SUVr) and a visual interpretation (Aß- or Aß+). Neuropsychological testing was repeated every 6 months. RESULTS: At baseline, SUVr correlated significantly with tests of global cognition and memory. During follow-up (median, 1.5 years), the Aß+ group had steeper declines on most cognitive tests, particularly global cognitive measures. CONCLUSION: This preliminary study suggests that greater amyloid load is associated with poorer cognition and faster cognitive decline in nondemented oldest-old. Amyloid load may identify individuals at increased risk of developing Alzheimer's disease.

Genetically engineered T cells to target EGFRvIII expressing glioblastoma.

Glioblastoma remains a significant therapeutic challenge, warranting further investigation of novel therapies. We describe an immunotherapeutic strategy to treat glioblastoma based on adoptive transfer of genetically modified T-lymphocytes (T cells) redirected to kill EGFRvIII expressing gliomas. We constructed a chimeric immune receptor (CIR) specific to EGFRvIII, (MR1-zeta). After in vitro selection and expansion, MR1-zeta genetically modified primary human T-cells specifically recognized EGFRvIII-positive tumor cells as demonstrated by IFN-gamma secretion and efficient tumor lysis compared to control CIRs defective in EGFRvIII binding (MRB-zeta) or signaling (MR1-delzeta). MR1-zeta expressing T cells also inhibited EGFRvIII-positive tumor growth in vivo in a xenografted mouse model. Successful targeting of EGFRvIII-positive tumors via adoptive transfer of genetically modified T cells may represent a new immunotherapy strategy with great potential for clinical applications.

Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2: laboratory investigation.

OBJECT: Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. METHODS: Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. RESULTS: Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. CONCLUSIONS: These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM.

Aphasia: associated disturbances in affect, behavior, and cognition in the setting of speech and language difficulties.

Patients with disturbances in affect, behavior, and cognition present a variety of challenges to healthcare providers; their evaluation and treatment becomes especially problematic in the setting of speech and language difficulties. The authors present the case of a man who sustained a left-side cerebrovascular accident with aphasia and discuss the approach to his diagnosis and treatment. Moreover, since a variety of speech and language problems can arise after stroke and since patients and their treaters can become frustrated by impaired communication and diagnostic uncertainties, authors review the clinical manifestations, timing, and treatment of such conditions so that treatment can be improved.