Subject Review. p.17 Alzheimer s Disease: An Update. p.21 Diabetes Team and Glycemic Control DANIEL A. LLANO, MD, PHD

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1 Subject Review p.17 DANIEL A. LLANO, MD, PHD p.21 Diabetes Team and Glycemic Control MICHAEL JAKOBY, MD, MA, FACP ANN GAREY, NP ROBERT KIRBY, MD KINGSLEY ONYEMERE, MD, MPH JAMES KUMAR, MD RENATO ALCARAZ, MD NADIA MUSTAFA, MD MONICA HALL, RN, CDE LYNETTE MORRIS, RN DONNA ERICKSON, RD FAHAD SAEED, MD KAMRAN QURESHI, MD KIRITHIKA DORAIRAJ, MD LAURA WARDWELL, BS CHERYL SCHRAEDER, RN, PHD

2 SUBJECT REVIEW DANIEL A. LLANO, MD, PHD 1 1 Department of Neurology, Carle Hospital, Department of Molecular and Integrative Physiology, Neuroscience Program and Beckman Institute, University of Illinois at Urbana-Champaign INTRODUCTION Alzheimer Disease (AD) is the leading neurodegenerative disease of the elderly. It is characterized by synaptic loss, brain atrophy, loss of cholinergic innervation to multiple brain regions, extracellular de-position of amyloid beta and intraneuronal accumulation of hyperphosphorylated tau. AD typically leads to institutionalization and death by 10 years after diagnosis. Unfortunately, we have no treatments that are known to reverse the course of the illness, but multiple lines of investigation show promise. Herein, we review new developments in the diagnosis and treatment of AD. DIAGNOSIS Traditionally, AD was typically diagnosed based on clinical criteria ie, loss of cognitive function and the absence of competing alternative diagnoses. 1 However, clinical criteria may be quite insensitive to the early (and potentially more reversible) stages of the illness and, therefore, there has been great enthusiasm for incorporating biomarker data to achieve an earlier diagnosis. 2 In 2011, a proposal was introduced by the National Institute on Aging and Alzheimer Association workgroup to revise the diagnostic criteria to incorporate biomarker data, such as cerebrospinal fluid (CSF) analysis, fluorodeoxyglucose PET scanning or MRI scanning. 3 The effect of such revised criteria would likely expand the number of AD cases by including atypical cases of AD with positive biomarkers under the term Possible AD with evidence of AD pathophysiological process. New diagnostic criteria have also been proposed for mild cognitive impairment (MCI). MCI is a state where patients have had a decline in cognitive function, typically assessed via neuropsychological testing, that has not lead to impairment in their instrumental activities of daily living (eg, paying the bills, arranging their medications, etc). MCI, particularly amnestic MCI, where the cognitive deficits primarily involve episodic memory, is a known risk factor for AD, with an annual conversion rate to AD of 10 15%. 4 It has become clear over the past few years that the pathological hallmarks of AD are present during MCI, or even before. Therefore, the National Institute on Aging and Alzheimer Association workgroup in 2011 proposed to modify the definition of MCI to include biomarker data (eg, CSF, PET or MRI), and to report such patients as having MCI due to AD when biomarker data are positive, or MCI unlikely due to AD when biomarker data are negative. 5 These new diagnostic recommendations are being used in clinical trials for AD and MCI; however, it is not yet clear if or when these recommendations will be adopted in clinical practice. The widespread use of CSF and imaging biomarkers has been limited by their availability outside of academic centers. For example, though it is possible to send CSF for the measurement of amyloid beta and tau, there are still no universal standards for these markers. MRI of the brain is routinely done, but packages to quantify various volumetric measures are not standardized. FDG-PET is also routinely available, but currently is typically only reimbursed to distinguish frontotemporal dementia from AD. One of the more promising diagnostic technologies on the horizon is the use of radiotracers for amyloid plaque. It has been known for at least 10 years that Pittsburgh Compound B (commonly known as PIB) is a sensitive and specific marker for amyloid deposition, and can be used to assist the diagnosis of AD or MCI due to AD. 6 Unfortunately, since it is labeled with carbon-11, which has a very short half-life, it is limited for use in centers with a cyclotron onsite. Recently, several companies have moved forward with F18-labeled ~ p.17 ~

3 CARLE SELECTED PAPERS 2012 VOL. 55, NO. 1 compounds that bind amyloid, which would greatly increase the availability of this technology. The most advanced compound, florbetapir, see Figure 1, being developed by Eli Lilly and Avid, was initially rejected by the FDA in early 2011 based on lack of educational programs to train radiologists on the use of this technology. 7 It is widely suspected that the FDA will approve this diagnostic modality in It is still not clear exactly how florbetapir would impact clinical practice. Currently, it is not possible to riskstratify patients with MCI. With the use of amyloid imaging, it will be possible to categorize those patients as having a high- or a low-risk of conversion to AD. Unfortunately, given the lack of proven interventions to prevent the conversion of MCI to AD, it is not clear exactly how such information would be used. Further, it is not known whether third parties will pay for the use of such tests, which are likely to come with a substantial cost. Figure 1. Taken from 7 Florbetapir PET images. Top: 77-y-old woman with mild AD with MMSE of 24 (top) and Bottom: 82-y-old cognitively healthy man with MMSE of 30. Experimental conditions and imaging and computational parameters were identical for the 2 subjects. TREATMENT One of the pathologic hallmarks of AD is the loss of acetylcholine-containing neurons in the basal forebrain. This finding led to the development of drugs that increase acetylcholine levels in the central nervous system the cholinesterase inhibitors. These drugs have become the mainstay of AD therapy. The first of these, tacrine, is still available, but rarely used due to its propensity to cause liver function test elevations. Donepezil (Aricept) was approved by the FDA in 1996 and is by far the most widely prescribed drug in this class. Generic donepezil became available in Unfortunately, the efficacy of this drug, and drugs in this class, are modest. On average, donepezil can increase the score on the Mini-Mental State Exam by about 1 2 p oints relative to placebos, and approximately 30 40% of patients who take the drug will notice any benefit (data taken from the FDA-approved label). ~ p.18 ~

4 SUBJECT REVIEW In 2010 a non-generic 23 mg dosing formulation of donepezil became available. The approval of this formulation was based on a single clinical trial of patients with advanced AD. The benefits of this dose were quite small and the approval process for this dose has been met with controversy. 8 Given its costs and marginal benefits, many AD specialists (including me) rarely prescribe it. Two other cholinesterase inhibitors, rivastigmine and galantamine, are also available. Overall, the magnitudes of benefit across all of the cholinesterase inhibitors are similar, and since donepezil is the only QD dosed of these drugs, it has become the market leader. In 2007, a transdermal formulation of rivastigmine became available. Because of its stable pharmacokinetic profile, it causes less peak-dose effects and, in general, is better tolerated than donepezil. This is particularly true for the gastrointestinal side effects (diarrhea, nausea, anorexia), all of which are less common in the rivastigmine patch than donepezil. The other mainstay of therapy is memantine. The mechanism of action of this drug is not entirely clear, though it is thought to work by diminishing NMDA receptor activation. Overall, like the cholinesterase inhibitors, this drug has a modest benefit and a mild side effect profile. Initially, this drug was approved for moderate to severe AD, but clinical studies have borne out its benefit in all stages of AD, and it has been shown to have an additive benefit when given with donepezil. 9,10 Unfortunately, neither the cholinesterase inhibitors nor memantine has been shown to alter the course of AD, and consequently, they are only used for symptomatic therapy. Currently, there are at least a dozen ongoing phase II or phase III trials that will assess the potential for new drugs to alter the course of AD. Most of these drugs target the deposition of amyloid beta. The most advanced of these compounds, bapineuzumab, is a monoclonal antibody that targets amyloid beta. This drug has been in phase III for several years, and the outcome of its pivotal trials are expected to be available later this year. There are also at least 5 10 other monoclonal antibodies in clinical development, all with the potential to remove amyloid plaques, or prevent their deposition, and therefore have the potential to alter the course of AD. One particularly promising approach, the inhibition of the beta- or gamma-secretase enzymes that produce the amyloid beta compound, failed in more than one clinical trial, and their development has been halted. Other approaches are also in development. These include intranasal insulin, 5HT-6 receptor antagonists, nicotinic agonists and others. Therefore, given the large number of ongoing trials in this area, the next few years promise to be an exciting period for AD therapeutics. BEHAVIOR Behavioral symptoms (delusions, hallucinations, agitation) are very common in AD and represent a major cause of patient and caregiver distress. The most commonly used therapy for these symptoms had been the use of atypical antipsychotics. However, as of 2008, all antipsychotics (typical and atypical) have a black box warning from the FDA because of their potential to cause major adverse cardiac events and death. All recently approved antipsychotics also carry this warning. This warning was driven by a large meta-analysis showing a 60% increase in relative risk (absolute risk increase of 1%, or Number Needed to Harm of 100) across multiple different antipsychotics, even with short-term use. 11 This warning had a chilling effect on new research in this area, leaving physicians with few therapeutic options. Currently, many physicians use memantine for behavioral symptoms, for which there are supportive data. 12 For severe agitation which threatens either the patient s or caregiver s safety, judicious use of antipsychotics may be warranted. In my practice, I commonly start with low-dose risperidone since it is the most studied drug in this class and has been convincingly shown to diminish agitation. 13 It should be recognized that the antipsychotics typically diminish cognitive performance, and once on these drugs, one should clinical monitor frequently for side effects. It should be noted that for mild agitation, behavioral interventions (redirection, touch therapy, bed baths, building of behavioral routines) are preferred to the use of drugs. SUMMARY AD is growing in prevalence with the aging of our population and new therapies are needed for this illness. The current state-of-the-art approach to treat our patients is a combination of cholinesterase inhibitors, memantine as well as psychosocial interventions to improve our patients well-being. Other interventions, such as exercise (both physical and cognitive) also show promise to improve the symptoms of AD. The next few years will likely bring new diagnostic tools to uncover AD at earlier stages and new drugs to treat the illness. Our challenge will be to understand how to use these tools to enhance our patients lives. ~ p.19 ~

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