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.

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.

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.

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.

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.

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.

The natural history of Alzheimer's disease: a brain bank study.

OBJECTIVE: To define the natural history of Alzheimer's Disease (AD), from time of clinical (presumptive) diagnosis and/or onset of symptoms to death and to describe demographic and clinical characteristics of patients with AD. DESIGN: Retrospective medical records review. SETTING: Regional brain bank operated by a university hospital. PARTICIPANTS: One-hundred randomly selected, autopsy-confirmed Alzheimer's Disease patients. MEASUREMENTS: All information pertaining to family and clinical history (diagnoses, office visits, hospitalizations), medication use, nutritional status, and clinical testing (laboratory testing, imaging, diagnostics, and psychometric testing) was abstracted. Time of onset for behavioral symptoms (e.g., anxiety, wandering, agitation) and deficits in cognitive function (e.g., recent memory, concentration, language) and activities of daily living (ADL) were also abstracted. Data was collected on-site using a laptop computer and a series of customized data entry spreadsheets. Upon completion of the data abstraction process, data was converted to a database program for query and analysis. RESULTS: A complete natural history timeline was constructed based on the mean values observed in order to demonstrate important clinical endpoints, namely, diagnosis, institutionalization, and death. The mean time between onset of symptoms and clinical diagnosis was 32.1 months (standard deviation = 37.9 months). The interval between symptom onset and AD diagnosis was longer for patients who were less than 65 at time of diagnosis (mean = 37.6 months), female patients (mean = 34.9 months), and patients with a positive family history of dementia (mean = 37.5 months). The mean age at diagnosis was 74.7 years (standard deviation = 8.6 years), with a range of 52 to 89 years. Most patients were diagnosed between the ages of 70 and 79. Males were diagnosed at an earlier age, 72.8 years, on average, than females, 75.4 years. The mean time to institutionalization from time of clinical diagnosis was 23.9 months (standard deviation = 33.6 months). The average age at institutionalization was 77.6 years, with a minimum of 60 years and a maximum of 92.5 years. Institutionalization occurred 56.5 months after symptom onset, on average. This interval was shorter among patients with a negative family history (mean = 53.1 months) and patients diagnosed after age 65 (mean = 51.6 months). Patients diagnosed before age 65 experienced a significantly greater average time to institutionalization, 94 months (P = .01). Disease duration was measured as time from symptom onset until death. Mean disease duration was 101.3 months, or nearly 8.5 years (standard deviation = 59.2 months). Subgroup analysis showed that disease duration was prolonged in younger onset patients (mean = 129.1 months), females (mean = 107.9 months), and patients with a positive family history of dementia (mean = 106.3 months). CONCLUSIONS: These data suggest that the typical AD patient is diagnosed 32 months after symptom onset, at the age of 75 years. This patient is institutionalized 25 months after diagnosis, or approximately 57 months after symptom onset at age 78. The patient remains institutionalized for 44 months or, in actuality, until death. Total disease duration for this typical AD patient is just over 101 months, or approximately 8.5 years.

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.

Vasopressin response to dehydration in Alzheimer's disease.

Alzheimer's disease is a progressive deterioration of neuropsychological functioning. One of the main neuropathological correlates of the disease is a drop-out of cholinergic neurons within the central nervous system. The neuropeptide that is responsible for water homeostasis and defense against dehydration, vasopressin, is also under direct cholinergic control. Several studies have suggested that in Alzheimer's disease there has been a trend toward lower vasopressin levels than in age-matched controls. In order to improve discrimination of normal from diminished vasopressin levels, nine subjects with Alzheimer's disease (mean age 65 +/- 2 years) and nine age- and sex-matched controls (68 +/- 3 years) underwent a mild provocative challenge of overnight fluid restriction. Individuals with Alzheimer's disease had a greater degree of dehydration, with overnight serum osmolality of 313 +/- 4 vs 300 +/- 3 Mosmol/kg, P = .01, and diminished "thirst" as measured by water ingested in one hour of ad libitum water intake. Eight of the nine with Alzheimer's disease had levels of vasopressin which, by extrapolation, appear to be subnormal for their serum osmolalities, whereas seven of the nine control subjects has vasopressin levels within or above the reference range (P less than .05). Elderly individuals with Alzheimer's disease may be at increased risk of dehydration during periods of fluid restriction due to the loss of normal physiological responses of "thirst" and vasopressin secretion.

The use of psychotropic medication in the management of problem behaviors in the patient with Alzheimer's disease.

Although a variety of potential alternatives to the neuroleptics in the management of agitated behavior in Alzheimer's disease exist, more large, well-controlled studies are needed. At present, neuroleptics remain the standard treatment for this problem. It is also important for the clinician to investigate thoroughly underlying instigators of behavior change in Alzheimer's patients, such as delirium, anxiety, depression, or environmental factors, and target treatment to these disorders.

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.

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.

Drug-induced seizures in the elderly. Causative agents and optimal management.

We conducted a review of drugs that were most commonly associated with inducing seizures in the elderly population. The method for determining the risk of these agents includes evaluating the utilisation and the percentage of adverse events in previous studies and case reports. Classes of medications, such as anti-psychotics and antidepressants, are extensively reviewed to provide the clinician with treatment options in high risk patients. The risk of seizures secondary to the withdrawal of alcohol (ethanol) and benzodiazepines, and methods employed to minimise the risk are discussed. In addition, the management of patients with drug-induced seizures is delineated. Drug-induced seizures are a potentially serious adverse effect. It is important that clinicians are aware of which classes of medications and individual medications are associated with reducing seizure threshold.

Safety and efficacy of caffeine-augmented ECT in elderly depressives: a retrospective study.

Prior studies have shown that in younger depressives undergoing ECT whose seizure durations declined despite maximum settings on three different ECT devices, pretreatment with caffeine lengthened seizures and resulted in clinical improvement. Caffeine (half life, 140-270 minutes) was well tolerated even in patients with pre-existing cardiovascular disease. The purpose of this retrospective study was to determine the safety and efficacy of caffeine augmented ECT in elderly depressed patients. The charts of 14 elderly depressives (average age 75.6, range 59-83; 2 males, 12 females) who received caffeine-augmented ECT were reviewed. Patients pre- and post-ECT medications, blood pressure, pulse, and seizure times (cuff and EEG) for each ECT performed were noted. The following conclusions were drawn from our study: (1) Caffeine definitely increases the seizure length and was useful in our setting when the energy settings could not be increased anymore. (2) Caffeine augmentation inconsistently causes an increase in pulse rate, on average, in the elderly. (3) Caffeine inconsistently produces an increase in mean arterial pressure. (4) Caffeine did not consistently produce an increase in the maximum rate-pressure product. We conclude from this study that caffeine-augmented ECT is safe and effective in increasing seizure duration in the elderly. However, more research needs to be done to determine optimal dosing and tolerability.

Prevalence of delirium and urinary tract infection in a psychogeriatric unit.

A retrospective study involving 407 patients discharged over a 2-year period from a psychogeriatric unit found that 83 (20.4%) had urinary tract infection (UTI) and 54 (13.3%) had delirium diagnoses at admission. Of the 54 with delirium, 14 (25.9%) had UTI. Of these 14 patients, delirium cleared in nine (64.3%) after appropriate treatment of UTI, two (14.3%) improved with treatment of concomitant medical disorders, and three (21.4%) did not improve. Only six of the 14 (42.8%) showed symptoms of UTI, with only one of the 14 (7.1%) showing fever and leukocytosis. Urine analyses were abnormal in all cases with 13/14 (92.8%) having positive cultures. Dementia was an associated risk factor in 71.4% of the 14 patients with UTI and delirium. Clinicians need to have a high index of suspicion relative to the presence of UTI in the elderly, especially with pre-existing cognitive impairment, since it can precipitate delirium. Early recognition and appropriate treatment decreases morbidity.

The use of carbamazepine to treat benzodiazepine withdrawal in a geriatric population.

Rapid withdrawal of short to intermediate half-life benzodiazepines may be hazardous, particularly in the elderly. The use of carbamazepine to facilitate withdrawal has been reported in younger patients. We describe four elderly patients (average age, 72.5 years) who had each experienced at least one unsuccessful attempt at alprazolam withdrawal and who were subsequently successfully withdrawn via the use of carbamazepine over a period ranging from 2 to 6 days. These geriatric patients experienced no major withdrawal symptoms, but mild symptoms were common. There was no correlation between dose or duration of alprazolam use and extent of withdrawal symptoms. We recommend use of this treatment regimen in a hospital setting only, where close monitoring can occur.

A preliminary comparison of healthy elderly and young adults on the SUNYA Revision of the Psychosomatic Symptom Checklist.

Elderly (n = 30) and young (n = 30) subjects, equated in terms of general physical health, education and depression, were compared in terms of Total, Frequency and Intensity scores on the psychosomatic symptom checklist (PSC). Elderly subjects scored significantly lower than young subjects for both PSC Total and PSC Intensity scores. These results call into question the practice of aggregating PSC data from age heterogeneous samples and indicate the importance of reporting all three PSC scores.

The older patient with psychotic symptoms.

Literature of the past ten years is reviewed to examine psychosocial, psychiatric, organic, and general medical causes of psychotic symptoms in persons over age 65. Being bedfast with poor caretaker relationships and being socially isolated are risk factors for psychosis among elderly persons. A thorough history is essential to differential diagnosis. Psychiatric causes to be ruled out include schizophrenia; depression, including mania; dementia and delirium; paranoid state; and late-life delusional disorder. Perhaps the most common etiology is cognitive impairment, generally attributable to Alzheimer's disease or multi-infarct dementia. Organic or toxic etiologies need to be ruled out, especially in persons with visual hallucinations. Drug toxicity, a structural brain lesion, or a subtle seizure disorder should be considered. If symptoms are not alleviated when psychosocial triggers or underlying toxic, organic, or medical causes are addressed, patients may respond to supportive therapy and low doses of high-potency neuroleptics. The clinician should keep in mind that older adults are highly sensitive to the side effects of these agents.

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.