Jared R. Brosch

Immunotherapy for Alzheimer’s Disease

The immune system plays a significant role in Alzheimer disease (AD). β-Amyloid deposition in the cortex is thought to be an initiating event in AD and the widely believed amyloid hypothesis proposes removal of amyloid may delay disease progression. Human trials of active or passive immune agents have failed to show benefit and increased adverse events of vasogenic edema and microhemorrhages. Evidence suggests the illness may be too advanced by the time patients are symptomatic with dementia. Future directions include better understanding of how and where immunotherapies should be targeted and treating patients at earlier stages of the illness.

Tau Imaging in Alzheimer’s Disease Diagnosis and Clinical Trials

In vivo imaging of the tau protein has the potential to aid in quantitative diagnosis of Alzheimer’s disease, corroborate or dispute the amyloid hypothesis, and demonstrate biomarker engagement in clinical drug trials. A host of tau positron emission tomography agents have been designed, validated, and tested in humans. Several agents have characteristics approaching the ideal imaging tracer with some limitations, primarily regarding off-target binding. Dozens of clinical trials evaluating imaging techniques and several pharmaceutical trials have begun to integrate tau imaging into their protocols.

A case of natalizumab-associated progressive multifocal leukoencephalopathy with repeated negative CSF JCV testing

The development of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab is a well-known potential risk. Diagnosis of PML can be confounded in patients with multiple sclerosis (MS) if new demyelinating lesions develop, and the sensitivity of existing diagnostic tests is less than ideal. In the case presented here, four samples of cerebrospinal fluid tested negative for John Cunningham virus (JCV) DNA by polymerase chain reaction, yet brain biopsy eventually proved positive by immunohistochemistry. A review of the limitations of existing clinical diagnostic tests is addressed, and we review the most recent literature on the proper management of natalizumab-treated MS patients.

Journal Club: Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology

Advances in neuroimaging, biomarkers, and clinical data have led to the hypothesis that the pathologic process of Alzheimer dementia begins decades prior to functional decline and diagnosis.1–3 High-profile clinical trial results have shown that biomarker changes can be made via pharmacologic intervention; however, the timing of this intervention has likely been too late to affect the cascade of neurodegenerative changes.4,5 In “Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology” by Monsell et al.,6 neuropathologic and clinical data were used to determine the risk of developing clinically significant cognitive impairment. This work represents a significant contribution because it examines a large cohort of autopsy data, which includes patients with Alzheimer dementia neuropathology who were clinically normal or diagnosed with mild cognitive impairment and Alzheimer-type dementia. The authors report a 3-fold increase in the risk of cognitive symptoms in association with quantifiable increases in neurofibrillary tangle pathology. In addition, several other factors, including APOE gene status, history of depression, and age, affected the clinical presentation. The ultimate goal of this investigation and similar studies is to facilitate the early and accurate identification of those at risk of developing Alzheimer dementia such that potentially disease-modifying therapies may be considered.

American Childhood Football as a Possible Risk Factor for Cerebral Infarction

Three adolescent football players who had ischemic stroke associated with football practice and play are described. The literature on stroke associated with childhood sports and football in particular is reviewed, and the multiple mechanisms by which football can contribute to ischemic stroke are discussed.

Comparison of Risk Factor Control in the Year After Discharge for Ischemic Stroke Versus Acute Myocardial Infarction

Background and Purpose— The Veterans Health Administration has engaged in quality improvement to improve vascular risk factor control. We sought to examine blood pressure (<140/90 mm Hg), lipid (LDL [low-density lipoprotein] cholesterol <100 mg/dL), and glycemic control (hemoglobin A1c <9%), in the year post-hospitalization for acute ischemic stroke or acute myocardial infarction (AMI). Methods— We identified patients who were hospitalized (fiscal year 2011) with ischemic stroke, AMI, congestive heart failure, transient ischemic attack, or pneumonia/chronic obstructive pulmonary disease. The primary analysis compared risk factor control after incident ischemic stroke versus AMI. Facilities were included if they cared for ≥25 ischemic stroke and ≥25 AMI patients. A generalized linear mixed model including patient- and facility-level covariates compared risk factor control across diagnoses. Results— Forty thousand two hundred thirty patients were hospitalized (n=75 facilities): 2127 with incident ischemic stroke and 4169 with incident AMI. Fewer stroke patients achieved blood pressure control than AMI patients (64%; 95% confidence interval, 0.62–0.67 versus 77%; 95% confidence interval, 0.75–0.78; P<0.0001). After adjusting for patient and facility covariates, the odds of blood pressure control were still higher for AMI than ischemic stroke patients (odds ratio, 1.39; 95% confidence interval, 1.21–1.51). There were no statistical differences for AMI versus stroke patients in hyperlipidemia (P=0.534). Among patients with diabetes mellitus, the odds of glycemic control were lower for AMI than ischemic stroke patients (odds ratio, 0.72; 95% confidence interval, 0.54–0.96). Conclusions— Given that hypertension control is a cornerstone of stroke prevention, interventions to improve poststroke hypertension management are needed.

Patient and Caregiver Assessment of the Benefits From the Clinical Use of Amyloid PET Imaging

Introduction: Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). Methods: A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. Results: We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. Discussion: Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.

Intra-arterial thrombolysis as an ideal treatment for inflammatory bowel disease related thromboembolic stroke: a case report and review.

ABSTRACT Thromboembolism, both venous and arterial, is a well-known complication of inflammatory bowel disease, with the risk of stroke highest when patients are less than 50 years of age. Because inflammatory bowel disease patients often have gastrointestinal bleeding, it is a challenge to treat their thromboembolic events with systemic therapy. In this case, a 42-year-old woman with Crohns disease developed a thromboembolism in her middle cerebral artery and was successfully treated with local intra-arterial thrombolysis. There is a growing trend to treat thromboembolic events in inflammatory bowel disease patients with local thrombolysis as it leads to better outcomes with regards to both the resolution of the thromboembolism and decreased secondary gastrointestinal bleeding.

A Review of Dementia with Lewy Bodies' Impact, Diagnostic Criteria and Treatment

Dementia with Lewy bodies is one of the most common causes of dementia. It is not as common as Alzheimer’s disease; the general publics awareness of the disease is poor in comparison. Its effects on caregivers and patients alike are not well known to the general population. There are currently no FDA-approved medications specifically for the treatment of DLB. Many of the medications that are approved for Alzheimer’s disease are widely used in the treatment of DLB with varying degrees of success. Treatment of DLB is life long and requires a dedicated team of physicians and caregivers to minimize the degree of morbidity and mortality experienced by the patients suffering from the disease as it progresses.

ANTICHOLINERGIC MEDICATION USE IS ASSOCIATED WITH REDUCED FMRI ACTIVITY DURING VISUAL EPISODIC ENCODING IN COGNITIVELY NORMAL OLDER ADULTS

responded ‘Never’, and for all but 2measures for this group tobe significantly different from every other one. As the frequency of reported usage increased, so did quality of performance, these improvements being incremental for measures from 7 tasks. On a pattern separation task, both speed and accuracywere significantly superior for the neurogenesis sensitive stimuli. The effect sizes of the differences between the 2 extreme scores were in the small tomedium range formeasures from 7 tasks. Conclusions: The frequency of word puzzle use is directly related to the quality of cognitive function on a range of major cognitive domains in this large population aged up to 96 years.