Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

The Rapid Cognitive Screen (RCS): A Point-of-Care Screening for Dementia and Mild Cognitive Impairment.

OBJECTIVES: There is a need for a rapid screening test for mild cognitive impairment (MCI) and dementia to be used by primary care physicians. The Rapid Cognitive Screen (RCS) is a brief screening tool (< 3 min) for cognitive dysfunction. RCS includes 3-items from the Veterans Affairs Saint Louis University Mental Status (SLUMS) exam: recall, clock drawing, and insight. Study objectives were to: 1) examine the RCS sensitivity and specificity for MCI and dementia, 2) evaluate the RCS predictive validity for nursing home placement and mortality, and 3) compare the RCS to the clock drawing test (CDT) plus recall. METHODS: Patients were recruited from the St. Louis, MO Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Medical Center (VAMC) hospitals (study 1) or the Saint Louis University Geriatric Medicine and Psychiatry outpatient clinics (study 2). Study 1 participants (N=702; ages 65-92) completed cognitive evaluations and 76% (n=533/706) were followed up to 7.5 years for nursing home placement and mortality. Receiver operator characteristic (ROC) curves were computed to determine sensitivity and specificity for MCI (n=180) and dementia (n=82). Logistic regressions were computed for nursing home placement (n=31) and mortality (n=176). Study 2 participants (N=168; ages 60-90) completed the RCS and SLUMS exam. ROC curves were computed to determine sensitivity and specificity for MCI (n=61) and dementia (n=74). RESULTS: RCS predicted dementia and MCI in study 1 with optimal cutoff scores of ≤ 5 for dementia (sensitivity=0.89, specificity=0.94) and ≤ 7 for MCI (sensitivity=0.87, specificity=0.70). The CDT plus recall predicted dementia and MCI in study 1 with optimal cutoff scores of ≤ 2 for dementia (sensitivity=0.87, specificity=0.85) and ≤ 3 for MCI (sensitivity=0.62, specificity=0.62). Higher RCS scores were protective against nursing home placement and mortality. The RCS predicted dementia and MCI in study 2. CONCLUSIONS: The 3-item RCS exhibits good sensitivity and specificity for the detection of MCI and dementia, and higher cognitive function on the RCS is protective against nursing home placement and mortality. The RCS may be a useful screening instrument for the detection of cognitive dysfunction in the primary care setting.

Dose effects associated with rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease.

AIM: The cholinesterase inhibitor rivastigmine is available in both oral and transdermal forms. The efficacy of oral rivastigmine appears to be dose-dependent. The current analysis investigates the effect of dose on the efficacy of the rivastigmine transdermal patch. METHODS: This was a retrospective analysis of a large, international, 24-week, randomised, placebo- and active-controlled trial (IDEAL, CENA713D2320) of rivastigmine in patients with mild-to-moderate Alzheimer's disease (AD). Patients received the 9.5 mg/24 h rivastigmine patch, the 17.4 mg/24 h rivastigmine patch, 12 mg/day rivastigmine capsules or placebo. Changes from baseline at week 24 on the AD Assessment Scale-cognitive subscale (ADAS-cog), AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) scale were calculated based on the patient's mode and last prescribed patch dose. The analysis included the 4.6 mg/24 h and 13.3 mg/24 h patch doses, for which efficacy data have not previously been reported. RESULTS: Significant differences (p<0.05 vs. placebo) were seen on the ADAS-cog and ADCS-ADL for all mode rivastigmine patch doses (except 4.6 mg/24 h) and all last prescribed rivastigmine patch doses (except 4.6 mg/24 h and 13.3 mg/24 h). Patients with a last prescribed/mode patch dose of 9.5 mg/24 h and 13.3 mg/24 h showed significant improvements (p<0.05 vs. placebo) on the ADCS-CGIC. CONCLUSION: Rivastigmine patch doses higher than 9.5 mg/24 h may offer additional benefits. The 13.3 mg/24 h patch is worthy of further investigation.

Rivastigmine transdermal system for the treatment of mild to moderate Alzheimer's disease.

Today patients with mild to moderate Alzhiemer's disease (AD) have a treatment approach choice: oral or transdermal delivery. The aim of this review was to provide a concise, comprehensive overview of the clinically relevant safety, tolerability and efficacy information available for the rivastigmine transdermal system. Relevant articles were identified through a MEDLINE search of publications in the past 3 years using the terms 'rivastigmine' and 'transdermal' or 'patch'. Efficacy, safety and tolerability of the rivastigmine patch vs. placebo were established in a large, international, 24-week, double-blind, randomised clinical trial and subsequent 28-week open-label extension study. Drug exposure with the 9.5 mg/24 h rivastigmine patch was not significantly different to that provided by an oral capsule dose of 12 mg/day. Most frequently observed adverse events were gastrointestinal. In the primary study, incidences of nausea, vomiting and diarrhoea were: 5%, 3% and 3% respectively in the placebo group; 7%, 6% and 6% in the 9.5 mg/24 h rivastigmine patch group; and 23%, 17% and 5% in the 12 mg/day capsule group. Most patients experienced no, slight or mild application-site skin reactions. De novo patients or those taking oral rivastigmine or donepezil may tolerate a switch to rivastigmine patch. By providing drug exposure that is not significantly different to the highest recommended rivastigmine capsule dose (12 mg/day), with less fluctuation over 24 h, rivastigmine patch offers similar efficacy with an improved tolerability profile. The rivastigmine patch provides a viable treatment option for patients with mild to moderate AD.

Generalized anxiety disorder in the elderly.

Anxiety disorders, especially GAD, are among the most prevalent psychiatric illnesses in the elderly. Unfortunately, research relative to late-onset anxiety syndromes and longitudinal studies of early-onset anxiety syndromes are sparse. Nonetheless, clinicians can properly assess and treat older adults with anxiety disorders and improve their quality of life. Additional research is needed to better elucidate the various presentations of GAD in the elderly and in developing safe, effective, nonpharmacologic and pharmacologic treatment approaches.

Differentiating between lewy body dementia and Alzheimer's disease: a retrospective brain bank study.

Recent research has shown that while Lewy body dementia. (LBD) may be the second most common form of dementia, it is difficult to confirm the disease before autopsy. Patients with LBD share many clinical signs and symptoms with patients diagnosed with Alzheimer's disease (AD), making it difficult to differentiate between the two diseases in patients who are still living. Still, our purpose in this study was to determine any clinical features which may differentiate between autopsy-confirmed cases of AD and cases of LBD. We compared 13 patients with autopsy-confirmed AD with 12 patients who had autopsy-confirmed LBD. Phone calls were made to family members of the deceased to help clarify and add any other information not documented in the patient's files. Significant differences were found in three areas, and trends approaching statistical significance were found in two other areas. Visual hallucinations were more prominent in the patients with LBD than in the patients with AD (10/12 LBD vs. 4/13 AD, P < 0.05). A nonspecific tremor was also found more often in the LB patients than in the Alzheimer's patients (8/12 LBD vs. 3/13 AD, P < 0.05). Finally, the LB patients were more prone to wandering, especially earlier in the disease course than were the patients with AD (10/12 LBD vs. 6/13 AD, P < 0.5). There was also a trend within the LB patients for higher use of anxiolytics (9/12 LBD vs. 6/13 AD, P = 0.14) as well as antidepressants (7/12 LBD vs. 4/13 AD, P = 0.16). Our data confirmed our hypothesis that LBD from a clinical perspective is indeed similar to AD. However, the higher incidence of visual hallucinations, tremor and wandering as well as the trend toward the use of anxiolytics and antidepressants among LB patients was noted. This gives hope that a clinical differentiation between these two diseases and more specific treatments may be possible in the future.

Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications.

Alzheimer's disease (AD) is often associated with multiple comorbidities and subsequent polypharmacy. Treatment of AD with acetylcholinesterase (AChE) inhibitors can carry a risk of drug interaction with multiple medications often prescribed for other co-existing illnesses. Rivastigmine is an AChE inhibitor that is enzymatically cleaved by AChE, minimally metabolized by cytochrome P450 enzymes, has low protein binding, has a short plasma half-life, and a relatively short duration of action. Such properties make it ideal for use in this patient population. A pharmacodynamic analysis of rivastigmine administered concomitantly with other medications (22 different therapeutic classes) did not reveal any significant pattern of increase in adverse events that would indicate a drug interaction. In summary, rivastigmine was well tolerated and safely administered to a population receiving multiple medications for 'real-world' comorbidities.

The role of the psychiatrist in Alzheimer's disease.

Psychiatrists are uniquely qualified to provide a variety of important services to patients with Alzheimer's disease and their families and professional caregivers. This paper highlights the role of the psychiatric physician in the differential diagnosis of dementing illnesses. Psychiatrists are also uniquely trained to evaluate and treat the psychiatric symptoms and problem behaviors in Alzheimer's disease. The psychiatrist may be asked to utilize and monitor antidementia compounds as well as to orchestrate functional and competency evaluations. As the leader of the mental health team, the psychiatrist serves as educator and resource provider to patients and their families. Lately, the psychiatrist works closely with caregivers to monitor for and prevent burnout and depression.

Late-life onset of psychotic symptoms.

The authors retrospectively evaluated the etiology and clinical findings of patients with first manifestations of psychotic symptoms after the age of 65. Nearly 10% of over 1,700 consecutive geriatric patients admitted to an acute inpatient psychogeriatric unit had late-life onset psychotic symptoms. About three-fourths of these were women, usually in their seventies. Dementia of the Alzheimer's type was the most common cause of psychosis arising in late life, followed by major depression, medical/toxic causes, delirium, bipolar disorder, delusional disorder, schizophrenia, and schizoaffective disorder. Clinical manifestations consisted mostly of delusions and hallucinations.

Advance directives, competency evaluation, and surrogate management in elderly patients.

As patients age, their capacities for memory, judgment, reasoning, planning, and decision-making may erode. Preparing for the time when these losses occur involves three important strategies: advance directives, competency evaluation, and surrogate management. Advance directives allow currently competent patients to record the kind of medical procedures they desire if they become incompetent in the future. Competency evaluations determine the mental competence of a patient and require special training for the physician. The need for surrogate management increases as a patient's cognitive deficits worsen and often requires involvement of the legal system. This paper addresses these important strategies in detail.

Epidemiology of psychotherapeutic drug use in older adults.

Those over 65 years of age constitute nearly 13% of the United States population. This age group, however, consumes three times their number of prescribed and over-the-counter remedies. In fact, nearly 30% of all prescriptions and 40% of over-the-counter remedies are consumed by older adults. This is also the population most sensitive to the side effects of drugs and, in particular, to the mood- or mind-altering properties of commonly prescribed and over-the-counter remedies. This article discusses medication usage among older adults with a special focus on various classes of psychotherapeutic agents- their uses, potential abuses, and special hazards.

Estrogen as a psychotherapeutic agent.

This article provides information on the effects of estrogen as a psychotherapeutic agent. Estrogen has a positive effect on several neurotransmitter systems that are assumed to be involved in regulation of affect, behavior, and cognition. Clinical studies suggest that an important cause of nonresponsiveness to antidepressants in postmenopausal women may be inadequate hormone replacement. Potential uses of estrogen as a mood stabilizer or mood enhancer also are described in this article. In the area of behavior, estrogen regulates aggressivity, sexual drive, impulsivity, and hostility. In terms of cognition, evidence suggests the importance of estrogen in the prevention and treatment of Alzheimer's-type dementia. At the end of the article, future research directions are discussed.

The treatment of psychosis in late life.

The authors emphasize the need for careful differential diagnosis when symptoms of psychosis arise in patients over the age of 65 years. Prevalence of psychotic disorders in the elderly ranges from 0.2%-4.7% in community-based samples to 10% in a nursing home population and as high as 63% in a study of Alzheimer's patients. Risk factors associated with the development of psychotic symptoms and common causes of delirium are reviewed. Because age-related changes affect the pharmacokinetics of neuroleptics, the authors' treatment recommendations, which include the use of traditional and novel antipsychotics, take into account the higher risk of side effects in the elderly.

Diagnosis and treatment of psychotic symptoms in elderly patients.

The diagnosis and treatment of psychotic symptoms in elderly patients requires more than extrapolation from studies of similar symptoms in the adult population. In comparison with early-onset psychosis, late-onset psychosis is characterised by differences in both its risk factors and typical signs and symptoms. Diagnosis may include psychotic disorders, mood disorders, delusional disorder, dementia or delirium. Several medications have also been associated with the development of psychotic symptoms in the elderly. There is a paucity of literature concerning psychotic symptoms specifically in elderly patients, and this complicates management. Treatment involves the resolution of any causative general medical condition, and/or symptomatic management with antipsychotic medication. The high-potency antipsychotics are typically better tolerated in the elderly than their low-potency counterparts. In addition, the newer atypical antipsychotics such as clozapine have shown early promise. It is important to consider the higher incidence of adverse effects and tardive dyskinesia in the elderly when choosing a drug and its dosage. Consideration of psychosocial factors completes the appropriate management of psychotic symptoms in older patients.

Issues involved in assessing competency.

A psychiatric competency assessment entails more than merely conducting a few clinical tests to diagnose the cause of a cognitive impairment. The psychiatrist may need to explore other aspects of the patient's life, including his or her interpersonal relationships and functional abilities. To provide a truly useful consult for other physicians, legal professional, family members, and the patient, the psychiatrist must be able to integrate the medical findings along with all relevant personal information and apply this information to the legal standards of the particular jurisdiction. By being able to apply both medical and legal knowledge of proxy decision making, the psychiatrist will be better prepared to make recommendations that will facilitate the proper care and services for the cognitively impaired patient.

The evolution of psychiatric symptoms in Alzheimer's disease: a natural history study.

OBJECTIVE: To characterize the natural history of Alzheimer's Disease (AD); in particular, to determine the prevalence and time of onset of psychiatric symptoms. DESIGN: Retrospective medical records review. SETTING: Regional brain bank operated by a university hospital. PARTICIPANTS: One hundred randomly selected autopsy-confirmed AD patients. MEASUREMENTS: The presence of psychiatric symptoms (e.g., anxiety, wandering, agitation) was documented, and the time of onset relative to diagnosis was measured. RESULTS: Irritability, agitation, and aggression were documented in 81 patients (81%) an average of 10 months after diagnosis. A total of 72% of patients experienced depression, changes in mood, social withdrawal, and suicidal ideation more than 2 years before diagnosis (26.4 months). Hallucinations, paranoia, accusatory behavior, and delusions were documented around the time of diagnosis (0.1 months after diagnosis) in 45% of patients. Patients with early-onset disease, more years of formal education, and male gender experienced psychiatric symptoms later, relative to diagnosis, than their counterparts. CONCLUSIONS: Psychiatric manifestations of depression may herald a diagnosis of AD, as such behaviors occurred more than 2 years before diagnosis, on average, in this cohort. Psychotic symptoms manifested around the time of diagnosis, perhaps even prompting diagnosis, whereas agitative symptoms occurred in the first year after diagnosis. The evolution of psychiatric symptoms in this cohort differed according to age at onset of disease, years of formal education, and gender.

Treating the agitated Alzheimer patient.

Dementia is a syndrome that consists of cognitive, psychiatric, and behavioral changes. Studies report from 42% to 62% of nursing home residents and at least 50% of outpatients with dementia exhibit behavioral disturbances. Agitation is a frequent behavioral disturbance associated with dementia. The Omnibus Budget Reconciliation Act (OBRA) regulations have made it imperative that physicians review and be familiar with alternative treatment options. We review and present strategies for the evaluation and treatment of agitation in demented patients.