Howard Fillit

A call for transparent reporting to optimize the predictive value of preclinical research

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

Elevated circulating tumor necrosis factor levels in Alzheimer's disease

Recent investigations have demonstrated a local inflammatory response in Alzheimers disease (AD), including microglia and cytokines. Levels of the cytokine tumor necrosis factor alpha (TNF-alpha) in sera from patients with AD and age-matched controls were measured by an enzyme-linked immunoassay and a cytotoxicity bioassay. Significantly elevated levels of TNF were found in AD sera compared to controls. Elevated circulating TNF may be derived from the local CNS inflammatory reaction in AD, and may account for some systemic manifestations of AD such as weight loss. Future studies may determine if, in the absence of complicating disorders which may elevate TNF, circulating TNF could be a marker of AD inflammatory activity.

Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders

Alterations of the cerebral microvasculature have been reported in aging and in neurodegenerative disorders such as Alzheimers disease. However, the exact role of microvascular alterations in the pathogenesis of neurodegeneration remains unknown. In the present report, the cerebral cortex microvasculature was studied by immunohistochemistry using a monoclonal antibody against vascular heparan sulfate proteoglycan protein core in normal aging controls, Alzheimers disease, Down syndrome, Guam amyotrophic lateral sclerosis/parkinsonian dementia complex, Picks disease and dementia pugilistica. In all dementing illnesses, increased microvascular pathology was evident compared to normal controls. Decreased microvascular density and numerous atrophic vessels were the primary abnormalities observed in all dementing disorders. These microvascular abnormalities demonstrated regional and laminar selectivity, and were primarly found in layers III and V of frontal and temporal cortex. Quantitative analysis employing computer-assisted microscopy demonstrated that the decrease in microvascular density in Alzheimers disease was statistically significant compared to age-matched controls. In addition, extracellular heparan sulfate proteoglycan deposits were observed which colocalized with thioflavine S-positive senile plaques in Alzheimers disease, Down syndrome and selected Guam dementia cases. In some cases, heparan sulfate proteoglycan was seen in senile plaques that appeared to be diffuse or primitive plaques that stained weakly with thioflavine. Heparan sulfate proteoglycan-containing neurons were also observed in Alzheimers disease, as well as in Down syndrome and Guam cases. Glial staining for heparan sulfate proteoglycan was never observed. Our data support previous observations that microvascular pathology is found in aging and in Alzheimers disease. The changes in Alzheimers disease exceed those found in normal aging controls. We also found microvascular pathology in all other dementing disorders studied. Our studies further demonstrated that the microvascular pathology displays regional and laminar patterns which parallel patterns of neuronal loss. Finally, we also found that heparan sulfate proteoglycan is present in senile plaques and neurons not only as previously reported in Alzheimers disease, but also in Down syndrome and Guam cases. Heparan sulfate proteoglycan in senile plaques may be derived from either the degenerating microvasculature or from degenerating neurons. Further studies are necessary to determine the role of microvascular disease in the progression of Alzheimers disease and other dementing disorders.

Achieving and maintaining cognitive vitality with aging.

Cognitive vitality is essential to quality of life and survival in old age. With normal aging, cognitive changes such as slowed speed of processing are common, but there is substantial interindividual variability, and cognitive decline is clearly not inevitable. In this review, we focus on recent research investigating the association of various lifestyle factors and medical comorbidities with cognitive aging. Most of these factors are potentially modifiable or manageable, and some are protective. For example, animal and human studies suggest that lifelong learning, mental and physical exercise, continuing social engagement, stress reduction, and proper nutrition may be important factors in promoting cognitive vitality in aging. Manageable medical comorbidities, such as diabetes, hypertension, and hyperlipidemia, also contribute to cognitive decline in older persons. Other comorbidities such as smoking and excess alcohol intake may contribute to cognitive decline, and avoiding these activities may promote cognitive vitality in aging. Various therapeutics, including cognitive enhancers and protective agents such as antioxidants and anti-inflammatories, may eventually prove useful as adjuncts for the prevention and treatment of cognitive decline with aging. The data presented in this review should interest physicians who provide preventive care management to middle-aged and older individuals who seek to maintain cognitive vitality with aging.

Cost of Alzheimer's disease and related dementia in managed-medicare.

BACKGROUND: Managed care organizations (MCOs) will have increased responsibility for the care of large numbers of persons with dementia. There are, however, few studies that inform about decisions of healthcare utilization and expenditures for individuals with dementia in managed care.

Alzheimer’s disease and related dementias increase costs of comorbidities in managed Medicare

Objectives: To analyze the relationship between comorbid conditions and costs for patients with AD and related dementias (ADRD) in a Medicare managed care organization (MCO). To derive implications for improving management of patients with ADRD. Methods: Retrospective analysis was carried out on administrative data for 3,934 patients with ADRD and 19,300 age/sex-matched control subjects enrolled in a large Medicare MCO. Patients with ADRD were identified from diagnoses on medical claims and encounter data for a 2-year period. Control subjects were selected from health plan members without dementia. Comorbid conditions were based on the diagnostic classifications from the Charlson comorbidity index. Health care costs and utilization for MCO-covered services for cases were compared with those of control subjects. Results: Prevalence of ADRD was 4.4%, substantially higher than reported in previous studies of Medicare managed care and similar to population-based estimates. After controlling for comorbid conditions, age, and sex, annual costs were

Cardiovascular risk factors and dementia

4,134 higher for ADRD patients, resulting in excess costs of

Improving dementia care: The role of screening and detection of cognitive impairment

16 million to the MCO. For the 10 most prevalent comorbidities in ADRD patients, adjusted costs were higher for ADRD patients compared with control subjects with the same condition. Higher costs were attributable to higher inpatient and skilled nursing facility utilization. Conclusions: In this study, prevalence rates for ADRD mirrored population estimates. Costs for patients with ADRD in this Medicare MCO varied considerably by comorbid condition and were substantially higher for patients with both AD and comorbid diseases commonly targeted for disease management, indicating that AD increases costs through effects on the management of comorbid illnesses. These findings indicate that better treatment and care management of AD could reduce the costs of comorbid illnesses commonly experienced by the frail elderly.

The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis

BACKGROUND Dementias, such as Alzheimers disease (AD) and vascular dementia, are disorders of aging populations and represent a significant economic burden. Evidence is accumulating to suggest that cardiovascular disease (CVD) risk factors may be instrumental in the development of dementia. OBJECTIVE The goal of this review was to discuss the relationship between specific CVD risk factors and dementia and how current treatment strategies for dementia should focus on reducing CVD risks. METHODS We conducted a review of the literature for the simultaneous presence of 2 major topics, cardiovascular risk factors and dementia (eg, AD). Special emphasis was placed on clinical outcome studies examining the effects of treatments of pharmacologically modifiable CVD risk factors on dementia and cognitive impairment. RESULTS Lifestyle risk factors for CVD, such as obesity, lack of exercise, smoking, and certain psychosocial factors, have been associated with an increased risk of cognitive decline and dementia. Some evidence suggests that effectively managing these factors may prevent cognitive decline/dementia. Randomized, placebo-controlled trials of antihypertensive medications have found that such therapy may reduce the risk of cognitive decline, and limited data suggest a benefit for patients with AD. Some small open-label and randomized clinical trials of statins have observed positive effects on cognitive function; larger studies of statins in patients with AD are ongoing. Although more research is needed, current evidence indicates an association between CVD risk factors--such as hypertension, dyslipidemia, and diabetes mellitus--and cognitive decline/dementia. CONCLUSIONS From a clinical perspective, these data further support the rationale for physicians to provide effective management of CVD risk factors and for patients to be compliant with such recommendations to possibly prevent cognitive decline/dementia.

Heparin Oligosaccharides that Pass the Blood‐Brain Barrier Inhibit β‐Amyloid Precursor Protein Secretion and Heparin Binding to β‐Amyloid Peptide

The value of screening for cognitive impairment, including dementia and Alzheimers disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimers Foundation of America and the Alzheimers Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient‐centered management of dementia.