Structure‐oriented review of 14‐3‐3 protein isoforms in geriatric neuroscience

This review focuses on the possible relevance of 14‐3‐3 proteins in geriatric neuroscience. 14‐3‐3 proteins are mainly localized in the synapses and neuronal cytoplasm. These proteins regulate intracellular signal cascades for differentiation, development, growth, apoptosis and survival. Seven isoforms have so far been identified in mammals. The binding motifs and potential functions of 14‐3‐3 proteins are now recognized to have a wide range of functional relevance. First, we provide a brief summary of the molecular structure and multiple functions of 14‐3‐3 proteins. Second, we review the involvement of 14‐3‐3 proteins in common diseases of geriatric neurology, such as Alzheimer's disease and tauopathies, Parkinson's disease and α‐synucleinopathies, Huntington's disease and polyglutamine diseases, Creutzfeldt–Jakob disease and prion diseases, cerebral infarction, and atherosclerosis. Finally, we discuss the immunohistochemical localization of 14‐3‐3 proteins and its isoforms during the postnatal development of rat brains as a basis for understanding adult neurogenesis. The elucidation of the isoform‐dependent functions of 14‐3‐3 proteins with regard to brain development might be promising for the future development of novel therapeutic interventions for common diseases of geriatric neurology. Geriatr Gerontol Int 2012; ??: ??–??.     

Amyloid‐ß‐directed immunotherapy for Alzheimer's disease

Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid‐ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti‐amyloid immunotherapy remains one of the most promising emerging strategies for developing disease‐modifying treatments for AD. In this review, we examine the presently ongoing Aß‐directed immunotherapies that have passed clinical development Phase IIa.     

Montefiore‐Einstein Center for the Aging Brain: Preliminary Data

Given the multifaceted nature of dementia care management, an interdisciplinary comprehensive clinical approach is necessary. We describe our one‐year experience with outpatient based dementia care at the Montefiore‐Einstein Center for the Aging Brain (CAB) involving an multispecialty team of geriatricians, neurologists, and neuropsychologists, supported by geriatric psychiatrists, physiatrists, and social services. The goals of the CAB is to maximize dementia outcomes, including regular monitoring of patient's health and cognition, education and support to patients, their families and caregivers; initiation of pharmacological and non‐pharmacological treatments as appropriate, and the facilitation of access to clinical trials . The CAB follows a consultative model where patients referred to the center receive a comprehensive three step evaluation and management plan from Geriatric, Neuropsychology and Neurology specialists that is shared with patient, caregivers and primary care physicians. Of the 366 patients seen for cognitive complaints in our first year, 71% were women with a mean age of 74 years. Self‐identified ethnicity of patients included Caucasian (26%), African‐American (25%), Hispanic (18%) and multiracial (5%). Common final diagnoses assigned at the CAB included mild cognitive impairment syndromes (31%), Alzheimer's disease (20%), mixed dementia (11%), vascular dementia (9%), Frontotemporal dementia (4%) and dementia with Lewy bodies (4%). Our one‐year progress report indicates that an interdisciplinary clinical dementia care model is feasible in the outpatient setting as well as highly accepted by patients, caregivers and referring physicians.     

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Age‐Varying Association Between Statin Use and Incident Alzheimer's Disease

OBJECTIVES: To determine whether risk reduction of statins for Alzheimer's disease (AD) varies by age or presence of apolipoprotein E (APOE) ?4 allele. DESIGN: A cohort of cognitively intact elderly participants was assessed biennially for dementia and AD. SETTING: Community based. PARTICIPANTS: Three thousand three hundred ninety‐two members of a health maintenance organization (HMO) aged 65 and older and without dementia. MEASUREMENTS: Statin use was identified from the HMO pharmacy database, and proportional hazards models were applied with statin use as a time‐dependent covariate to assess the association between statins and AD and the modifying effects of age and the APOE ?4 allele. RESULTS: Over an average of 6.1 years of follow‐up of 3,099 participants, 263 participants developed probable AD. The adjusted hazard ratio (aHR) for statin use was 0.62 (95% confidence interval (CI)=0.40–0.97) for AD in models including demographic characteristics and vascular risk factors as covariates. The strength of the association between statins and AD diminished with age (statin‐by–age at entry interaction P=.04); the aHR in those younger than 80 was 0.44 (95% CI=0.25–0.78), versus 1.22 (95% CI=0.61–2.42) for aged 80 and older. The interaction term for statin use–by–APOE ?4 was not significant (P=.65). CONCLUSION: This enlarged study confirms earlier findings that statin therapy in early old age, but not in late age, may be associated with a lower risk of AD. The relationship between statin use and AD was consistent across APOE genotypes.     

Hospitalization in Community‐Dwelling Persons with Alzheimer's Disease: Frequency and Causes

OBJECTIVES: To examine the rates of and risk factors for acute hospitalization in a prospective cohort of older community‐dwelling patients with Alzheimer's disease (AD). DESIGN: Longitudinal patient registry. SETTING: AD research center. PARTICIPANTS: Eight hundred twenty‐seven older persons with AD. MEASUREMENTS: Acute hospitalization after AD research center visit was determined from a Medicare database. Risk factor variables included demographics, dementia‐related, comorbidity and diagnoses and were measured in interviews and according to Medicare data. RESULTS: Of the 827 eligible patients seen at the ADRC during 1991 to 2006 (median follow‐up 3.0 years), 542 (66%) were hospitalized at least once, and 389 (47%) were hospitalized two or more times, with a median of 3 days spent in the hospital per person‐year. Leading reasons for admission were syncope or falls (26%), ischemic heart disease (17%), gastrointestinal disease (9%), pneumonia (6%), and delirium (5%). Five significant independent risk factors for hospitalization were higher comorbidity (hazard ratio (HR)=1.87, 95% confidence interval (CI)=1.57–2.23), previous acute hospitalization (HR=1.65, 95% CI=1.37–1.99), older age (HR=1.51, 95% CI=1.26–1.81), male sex (HR=1.27, 95% CI=1.04–1.54), and shorter duration of dementia symptoms (HR=1.26, 95% CI=1.02–1.56). Cumulative risk of hospitalization increased with number of risk factors present at baseline: 38% with zero factors, 57% with one factor, 70% with two or three factors, and 85% with four or five factors (P_trend<.001). CONCLUSION: In a community‐dwelling population with generally mild AD, hospitalization is frequent, occurring in two‐thirds of participants over a median follow‐up time of 3 years. With these results, clinicians may be able to identify dementia patients at high risk for hospitalization.     

Frequency and Correlates of Caregiver‐Reported Sleep Disturbances in a Sample of Persons with Early Dementia

OBJECTIVES: To identify sleep disturbances in participants with subtypes of dementia and explore clinical correlates. DESIGN: Cross‐sectional. SETTING: Outpatient clinics in western Norway and the Mayo Clinic Study of Aging, Olmsted County, Minnesota. PARTICIPANTS: One hundred fifty‐one community‐dwelling western Norway residents referred for geriatric medicine, geriatric psychiatry or neurology evaluation and 420 participants without dementia from the Mayo Clinic Study of Aging. MEASUREMENTS: Dementia was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. The Mayo Sleep Questionnaire, an interview to detect sleep disturbances, was administered to diagnose probable rapid eye movement (REM) sleep behavior disorder, probable periodic leg movements during sleep, probable restless legs syndrome, probable sleepwalking, probable sleep‐related leg cramps, probable obstructive sleep apnea, and excessive daytime sleepiness. Insomnia was assessed using the Neuropsychiatric Inventory, an interview to detect neuropsychiatric symptoms in dementia. RESULTS: Seventy‐one percent of the participants with dementia and 55.7% of control participants had sleep disturbances (P=.001). Most frequently reported in the mild dementia participants were insomnia (29.9%), probable sleep‐related leg cramps (24.1%), excessive daytime sleepiness (22.6%), probable restless legs syndrome (20.7%), and probable REM sleep behavior disorder (18.5%). There were more sleep‐related problems reported in participants with Lewy body dementias (LBD) (dementia with Lewy bodies and Parkinson's disease dementia) than in those with Alzheimer's disease (P=.008). Having any sleep disorder correlated with depression (P=.03) and anxiety (P=.02). CONCLUSION: Sleep problems are common in dementia, particularly in subjects with LBD, and are associated with psychiatric symptoms. Further research is needed to understand these associations and identify treatment strategies.