Higher-dose (23 mg/day) donepezil formulation for the treatment of patients with moderate-to-severe Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly. An estimated 5.4 million people in the United States have AD, and its prevalence is expected to increase rapidly in the coming years. Few US Food and Drug Administration (FDA)-approved treatment options for AD are currently available. Donepezil is 1 of only 2 therapies approved in the United States for the treatment of moderate-to-severe AD. In 2010, the FDA approved a higher daily dose of donepezil (23 mg/day) for the treatment of AD in the moderate-to-severe stages based on positive results from a large, global, phase 3 clinical trial that compared switching to donepezil 23 mg/day with continuing treatment with donepezil 10 mg/day. In that trial, no benefit was seen in the co-primary endpoint of global functioning; however, donepezil 23 mg/day provided a small but significant improvement in the cognitive endpoint compared with donepezil 10 mg/day. A subgroup analysis subsequently showed that the cognitive benefits were significant irrespective of concomitant memantine use. Adverse events were mainly gastrointestinal related and were more prevalent in patients receiving the donepezil 23-mg/day dose during the first month of therapy, but were relatively infrequent thereafter. These data indicate that once-daily donepezil 23 mg may be an effective treatment option for patients with moderate-to-severe AD with or without concomitant memantine. This article reviews the rationale for using higher-dose donepezil, the clinical data supporting its use, and some of the practical implications that should be considered by practicing physicians when using donepezil 23 mg/day for patients with AD.

The art of sharing the diagnosis and management of Alzheimer's disease with patients and caregivers: recommendations of an expert consensus panel.

OBJECTIVE: To develop a set of recommendations for primary care physicians (PCPs) suggesting how best to communicate with patients, caregivers, and other family members regarding the diagnosis and management of Alzheimer's disease (AD). PARTICIPANTS: A national roundtable of 6 leading professionals involved in treating or advocating for patients with AD was convened on March 14, 2008. This roundtable included 4 leading academic physicians with diverse backgrounds (a geriatric psychiatrist, a neuropsychiatrist, a neurologist, and a geriatrician) from geographically diverse regions of the United States, who were invited on the basis of their national reputation in the field and experience working with minority populations with dementia; the executive director of a national AD advocacy organization; the executive director of a national advocacy organization for caregivers; and a medical correspondent with expertise in interviewing and small group leadership. EVIDENCE: Expert opinion supported by academic literature (search limited to PubMed, English language, 1996-2008, search terms: Alzheimer's disease, primary care, diagnosis, management, caregiver, family, patient-physician relationship). CONSENSUS PROCESS: Moderated dialogue aimed at generating consensus opinion; only statements endorsed by all authors were included in the final article. CONCLUSIONS: Diagnosis and management of AD by PCPs, utilizing specialist consultation as needed, may contribute to earlier diagnosis and treatment, improved doctor-patient and doctor-caregiver communication, increased attention to caregiver needs, and better clinical and quality-of-life outcomes for patients and caregivers. A set of expert panel recommendations describing practical strategies for achieving these goals was successfully developed.

Creativity and dementia: emerging diagnostic and treatment methods for Alzheimer's disease.

Alzheimer's disease research is beginning to yield promising treatments and prevention strategies. Current Alzheimer's disease treatments benefit symptoms, but do not appreciably alter the basic disease process. The new generation of Alzheimer's disease medications, however, will likely include disease-modifying treatments, which will slow disease progression or stop it entirely. These new treatments pursue four points of intervention: increasing the clearance of amyloid-beta42 (Abeta42) proteins in the brain, blocking Abeta42 production, decreasing Abeta42 production, and decreasing Abeta42 aggregation. Neurogenerative therapies are being explored as well, suggesting future treatments may not only stop disease progression but also reverse it. Risk factors for developing Alzheimer's disease and factors associated with a lower risk of Alzheimer's disease have been identified. Future Alzheimer's disease management may come to resemble routine cardiovascular disease prevention and management, which involves the control of modifiable risk factors and the use of medications that decrease or stop underlying pathology. The hope is that such management will arrest the disease process before cognitive symptoms have begun. Like other neurologic illnesses, Alzheimer's disease has a profound impact on creativity. Alzheimer's disease attacks the right posterior part of the brain, which enables people to retrieve internal imagery and copy images. Alzheimer's disease patients may lose the ability to copy images entirely. However, people with Alzheimer's disease can continue to produce art by using their remaining strengths, such as color or composition instead of shapes or realism. Studying art and dementia is a model for identifying the strengths of psychiatric patients. Remarkably, art emerges in some patients even in the face of degenerative disease. In this expert roundtable supplement, Jeffrey L. Cummings, MD, offers an overview of recent advances in Alzheimer's disease research. Bruce L. Miller, MD, discusses creativity in patients with neurologic illnesses. Daniel D. Christensen, MD, discusses emerging Alzheimer's disease therapies. Debra Cherry, PhD, discusses the advocacy needs of Alzheimer's disease patients and their caregivers. In addition, Patricia Utermohlen, MA, provides a testimonial of the impact of Alzheimer's disease on an accomplished artist.

Changing the course of Alzheimer's disease: anti-amyloid disease-modifying treatments on the horizon.

OBJECTIVES: To review the amyloid hypothesis as the predominant mechanistic theory of Alzheimer's disease and update the status of new disease-modifying, anti-amyloid treatments in clinical development. DATA SOURCES: Governmental Web sites and those of professional Alzheimer's disease associations and drug manufacturers were searched for new drugs in development. An English-language search of PubMed (January 2003-January 2006) was conducted using the search terms Alzheimer's disease and amyloid hypothesis and each of the drugs and immunotherapies from the 4 identified classes of anti-amyloid, disease-modifying therapies. STUDY SELECTION AND DATA EXTRACTION: Studies and reports were selected on the basis of recent publication, adequate methodology, and completeness of data. DATA SYNTHESIS: Immunotherapy, γ-secretase inhibitors, selective neurotoxic aggregated 42-amino acid peptide subspecies of amyloid ß (Aß42)-lowering agents (tarenflurbil), inhibitors of amyloid aggregation (tramiprosate), and statins show promise in clinical trials. Safety remains an important factor. Disease-modifying drugs that specifically target the amyloid cascade and do not interact with essential biological pathways are expected to possess a lower rate of unintended adverse events.Agents that selectively target Aß42 production (e.g., tarenflurbil), block Aß aggregation (e.g., tramiprosate), or enhance alpha-secretase activity (statins) offer hope for disease modification and prevention and do not appear to interfere with other biological pathways. CONCLUSIONS: Discovery of safe and effective disease-modifying therapies will usher in a new age of Alzheimer's disease treatment.

Alzheimer's disease: progress in the development of anti-amyloid disease-modifying therapies.

The amyloid hypothesis--the leading mechanistic theory of Alzheimer's disease--states that an imbalance in production or clearance of amyloid beta (Abeta) results in accumulation of Abeta and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Abeta or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Abeta42-lowering agents; statins; anti-Abeta aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and gamma-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Abeta42 production (eg, tarenflurbil), enhance the activity of alpha-secretase (eg, statins), and block Abeta aggregation (eg, transiposate).

Practical treatment strategies for patients with Alzheimer's disease.

With the "baby boomers" entering retirement and beyond and the life expectancy of the entire population increasing, the burden of Alzheimer's Disease (AD) grows alarmingly greater. Over 5 million people in the United States currently have AD, and that number could triple by 2050. The financial impact of caring for these patients is substantial. Estimates of direct and indirect costs are as high as $148 billion per year. In addition to its substantial economic impact, AD has devastating effects on patients and their families. Alzheimer's disease begins with gradual memory loss and progresses to personality change, behavioral disturbance, loss of executive function, and loss of the ability to perform basic activities of daily living, including eating, walking, dressing, and grooming. These impairments strain families and caregivers and create challenges to the care and safety of the patient as well as threaten the health and well-being of the caregiver. As the number of patients diagnosed with AD increases, there is an ever-growing need for early diagnosis, which often is first observed in the primary care setting. While AD cannot be reversed or stopped, disease progression can be delayed and quality of life enhanced with early diagnosis and treatment. Early and accurate diagnosis has become increasingly important and will become even more so with the anticipated new generation of medications. Though several consensus statements on diagnosis and treatment of AD have been developed, few primary care physicians routinely follow evidence-based guidelines in their clinical practices. A 2006 survey conducted by the American Academy of Family Physicians identified a moderate to high level of need for education on AD in a majority of respondents. This article illustrates the primary care management of AD beginning with diagnosis and concluding with autopsy. Enhancing diagnostic and treatment skills in primary care will promote earlier diagnosis, improved patient management, and ongoing research into this increasingly important dilemma of aging.

Anterior capsulotomy for treatment of refractory obsessive-compulsive disorder: results in a young and an old patient.

The objective of this case report was to assess the effect of anterior capsulotomy for obsessive-compulsive disorder (OCD) in 2 patients beyond extremes of age ranges of published radiofrequency capsulotomy. The youngest patient developed OCD at age 10 with increasing symptoms of tension and worry. The symptoms were refractory to medications and behavioral therapy. He underwent anterior capsulotomy at age 18. The older patient was 64 at the time of surgery. His OCD began about age 17 with checking and counting rituals. His obsessions extended into other areas such as fear of injuring people while driving. His work performance was greatly compromised. Despite medication trials his rituals and obsessions intensified. After 47 years of severe symptoms he underwent surgery. The youngest patient returned to high school full-time and graduated. He was able to read and comprehend without obsessing about the meaning of words. His thinking and behavior became symptom free and he married 4.5 years after surgery. His score on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after surgery on no medication is zero. The older patient improved gradually without medication. He could play with and touch his grandchildren for the first time. He could drive a car again and his Y-BOCS dropped from 30 preoperatively to 8. Twenty-four months after surgery he is essentially free of obsessions, compulsions and anxiety. We conclude that treatment-refractory OCD may be alleviated by anterior radiofrequency capsulotomy in the young and the old patient. This study expands the documented age range of response from 18 to 64.

Practical Principles for the Management of Alzheimer's Disease.

Alzheimer's disease is a complex disorder that is particularly challenging to treat and manage. Early recognition of Alzheimer's disease is the first step toward providing patients with optimal therapy and the best opportunity for treatment response. Subsequently, physicians will need to address issues that emerge as the disease inevitably progresses. As the number of elderly patients with Alzheimer's disease increases, it becomes increasingly important for the primary care physician-usually the first line of patient contact-to diagnose Alzheimer's disease early, and initiate and manage appropriate long-term cholinesterase inhibitor therapy, which has been shown to provide significant benefits to Alzheimer's disease patients. In this article, discussions of individual patients illustrate commonly encountered situations in the primary care setting.