Skin reactions at the application site of rivastigmine patch (4.6 mg/24 h, 9.5 mg/24 h or 13.3 mg/24 h): a qualitative analysis of clinical studies in patients with Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Rivastigmine patch is approved for the treatment of all stages of Alzheimer's disease (AD). Application site reactions may be a concern to clinicians and we used two large clinical trial databases to investigate the incidence of skin reactions in patients receiving rivastigmine patch. METHODS: Data from a 24-week, randomised, double-blind (DB) evaluation of 13.3 vs. 4.6 mg/24 h rivastigmine patch in severe AD (ACTION) and a 72- to 96-week study comprising an initial open-label (IOL) phase followed by a 48-week randomised, DB phase (13.3 vs. 9.5 mg/24 h rivastigmine patch) in declining patients with mild-to-moderate AD (OPTIMA) were analyzed. The incidence, frequency, severity, management and predictors of application site reactions were assessed. RESULTS: Application site reactions were mostly mild or moderate in severity and reported by similar proportions in each treatment group ( ACTION: 13.3 mg/24 h, 24.5% and 4.6 mg/24 h, 24.2%; OPTIMA: IOL 9.5 mg/24 h, 22.9%; DB 13.3 mg/24 h, 11.4% and 9.5 mg/24 h, 12.0%); none were rated serious. In both studies, <9% of patients required treatment for application site reactions. Application site reactions led to discontinuation of 1.7% and 2.5% of the 13.3 mg/24 h and 4.6 mg/24 h groups, respectively, in ACTION, 8.7% in OPTIMA IOL and 1.8% and 3.5% of the 13.3 mg/24 h and 9.5 mg/24 h groups, respectively, in OPTIMA DB. CONCLUSIONS: Application site reactions were experienced by <25% of patients in both studies, with no notable effect of dose. No reactions qualified as serious and skin reactions were uncommon as a reason for study discontinuation.

Activation of innate anti-viral immune response genes in symptomatic benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the most common urologic disease in men over age 50. Symptoms include acute urinary retention, urgency to urinate and nocturia. For patients with severe symptoms, surgical treatment is used to remove the affected tissue. Interestingly, the presence of histologic BPH does not always correlate with symptoms. The molecular basis of symptomatic BPH and how it differs from asymptomatic BPH is unknown. Investigation into the molecular players involved in symptomatic BPH will likely give insight into novel therapeutic, and potentially preventative, targets. We determined the expression of genes involved in the innate anti-viral immune response in tissues from patients undergoing surgery to alleviate the symptoms of BPH, and compared the results with prostate tissue with histologic BPH, but from patients with few urinary issues (asymptomatic BPH). We found that expression of complement factor I, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like protein 3G, oligoadenylate synthetase 2 and interferon-induced tetratricopeptide 1, four genes whose protein products are involved in the innate anti-viral immune response, was significantly transcriptionally upregulated in symptomatic BPH. Additionally, we observe hypomethylation and concomitant expression of ancient retroviral-like sequences, the long interspersed nuclear element 1 retrotransposons, in symptomatic BPH when compared with normal prostate tissue. These findings merit further investigation into the anti-viral immune response in symptomatic BPH.

Dual Task Performance Is Associated with Amyloidosis in Cognitively Healthy Adults.

BACKGROUND: Preclinical Alzheimer's disease (AD) provides an opportunity for the study and implementation of interventions and strategies aimed at delaying, mitigating, and preventing AD. While this preclinical state is an ideal target, it is difficult to identify efficiently and cost-effectively. Recent findings have suggested that cognitive-motor dual task paradigms may provide additional inference. OBJECTIVES: Investigate the relationship between dual task performance and amyloidosis, suggestive of preclinical Alzheimer's disease and whether dual task performance provides additional information beyond a cognitive composite, to help in the identification of amyloidosis. DESIGN: Cross-sectional. SETTING: Outpatient specialty brain health clinical research institution in the United States. PARTICIPANTS: 52 cognitively healthy adults. MEASUREMENTS: The data included demographics, amyloid standardized uptake value ratio obtained via florbetapir-PET, neuropsychological testing, apolipoprotien E genotype, and dual task performance measures. Data were analyzed via hierarchal multiple linear regression or logistic regression, controlling for age, education, and apolipoprotien E genotype. Receiver operating characteristic curves were plotted, and sensitivity and specificity calculated via 2x2 contingency tables. RESULTS: There was a moderate relationship (rs>.30) between motor and cognitive dual task effects and amyloid standardized uptake value ratio (ps<.042). A strong relationship (r=.58) was found between combined dual task effect, a measure of automaticity derived from dual task performance, and amyloid standardized uptake value ratio (p<.001). Additionally, combined dual task effect showed promise in its unique contributions to amyloid standardized uptake value ratio, accounting for 7.8% of amyloid standardized uptake value ratio variance beyond cognitive composite scores (p=.018). Additionally, when incorporated into the cognitive composite, combined dual task effect resulted in improved diagnostic accuracy for determining elevated amyloid standardized uptake value ratio, and increased the sensitivity and specificity of the cognitive composite. CONCLUSSION: Dual task performance using the combined dual task effect, a measure of automaticity, was a moderate predictor of cerebral amyloidosis, which suggests that it has utility in the screening and diagnosis of individuals for preclinical AD. Additionally, when combined with the cognitive composite, the combined dual task effect improves diagnostic accuracy. Further research is warranted.

Recruitment into the Alzheimer Prevention Trials (APT) Webstudy for a Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD).

BACKGROUND: The Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy. OBJECTIVES: To remotely enroll a cohort of individuals into a web-based longitudinal observational study. Participants are followed quarterly with brief cognitive and functional assessments, and referred to Sites for in-clinic testing and biomarker confirmation prior to enrolling in the Trial-ready Cohort (TRC). DESIGN: Participants are referred to the APT Webstudy from existing registries of individuals interested in brain health and Alzheimer's disease research, as well as through central and site recruitment efforts. The study team utilizes Urchin Tracking Modules (UTM) codes to better understand the impact of electronic recruitment methods. SETTING: A remotely enrolled online study. PARTICIPANTS: Volunteers who are at least 50 years old and interested in Alzheimer's research. MEASUREMENTS: Demographics and recruitment source of participant where measured by UTM. RESULTS: 30,650 participants consented to the APT Webstudy as of April 2020, with 69.7% resulting from referrals from online registries. Emails sent by the registry to participants were the most effective means of recruitment. Participants are distributed across the US, and the demographics of the APT Webstudy reflect the referral registries, with 73.1% female, 85.0% highly educated, and 92.5% Caucasian. CONCLUSIONS: We have demonstrated the feasibility of enrolling a remote web-based study utilizing existing registries as a primary referral source. The next priority of the study team is to engage in recruitment initiatives that will improve the diversity of the cohort, towards the goal of clinical trials that better represent the US population.

TRC-PAD: Accelerating Recruitment of AD Clinical Trials through Innovative Information Technology.

BACKGROUND: The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's Disease (TRC-PAD) Informatics Platform (TRC-PAD IP) was developed to facilitate the efficient selection, recruitment, and assessment of study participants in support of the TRC-PAD program. OBJECTIVES: Describe the innovative architecture, workflows, and components of the TRC-PAD IP. DESIGN: The TRC-PAD IP was conceived as a secure, scalable, multi-tiered information management platform designed to facilitate high-throughput, cost-effective selection, recruitment, and assessment of TRC-PAD study participants and to develop a learning algorithm to select amyloid-bearing participants to participate in trials of early-stage Alzheimer's disease. SETTING: TRC-PAD participants were evaluated using both web-based and in-person assessments to predict their risk of amyloid biomarker abnormalities and eligibility for preclinical and prodromal clinical trials. Participant data were integrated across multiple stages to inform the prediction of amyloid biomarker elevation. PARTICIPANTS: TRC-PAD participants were age 50 and above, with an interest in participating in Alzheimer's research. MEASUREMENTS: TRC-PAD participants' cognitive performance and subjective memory concerns were remotely assessed on a longitudinal basis to predict participant risk of biomarker abnormalities. Those participants determined to be at the highest risk were invited to an in-clinic screening visit for a full battery of clinical and cognitive assessments and amyloid biomarker confirmation using positron emission tomography (PET) or lumbar puncture (LP). RESULTS: The TRC-PAD IP supported growth in recruitment, screening, and enrollment of TRC-PAD participants by leveraging a secure, scalable, cost-effective cloud-based information technology architecture. CONCLUSIONS: The TRC-PAD program and its underlying information management infrastructure, TRC-PAD IP, have demonstrated feasibility concerning the program aims. The flexible and modular design of the TRC-PAD IP will accommodate the introduction of emerging diagnostic technologies.

The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD): Experience from the First 3 Years.

BACKGROUND: The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD) aims to accelerate enrollment for Alzheimer's disease (AD) clinical trials by remotely identifying and tracking individuals who are at high risk for developing symptoms of AD, and referring these individuals to in-person cognitive and biomarker evaluation with the purpose of engaging them in clinical trials. A risk algorithm using statistical modeling to predict brain amyloidosis will be refined as TRC-PAD advances with a maturing data set. OBJECTIVES: To provide a summary of the steps taken to build this Trial-Ready cohort (TRC) and share results of the first 3 years of enrollment into the program. DESIGN: Participants are remotely enrolled in the Alzheimer Prevention Trials (APT) Webstudy with quarterly assessments, and through an algorithm identified as potentially at high risk, referred to clinical sites for biomarker confirmation, and enrolled into the TRC. SETTING: Both an online study and in-clinic non-interventional cohort study. PARTICIPANTS: APT Webstudy participants are aged 50 or older, with an interest in participation in AD therapeutic trials. TRC participants must have a study partner, stable medical condition, and elevated brain amyloid, as measured by amyloid positron emission tomography or cerebrospinal fluid analysis. Additional risk assessments include apolipoprotein E genotyping. MEASUREMENTS: In the APT Webstudy, participants complete the Cognitive Function Index and Cogstate Brief Battery. The TRC includes the Preclinical Alzheimer's Cognitive Composite, comprised of the Free and Cued Selective Reminding Test, the Delayed Paragraph Recall score on the Logical Memory IIa test from the Wechsler Memory Scale, the Digit-Symbol Substitution test from the Wechsler Adult Intelligence Scale-Revised, and the Mini Mental State Examination total score (1). RESULTS: During the first 3 years of this program, the APT Webstudy has 30,650 consented participants, with 23 sites approved for in person screening, 112 participants have been referred for in-clinic screening visits with eighteen enrolled to the TRC. The majority of participants consented to APT Webstudy have a family history of AD (62%), identify as Caucasian (92.5%), have over twelve years of formal education (85%), and are women (73%). Follow up rates for the first quarterly assessment were 38.2% with 29.5% completing the follow up Cogstate Battery. CONCLUSIONS: After successfully designing and implementing this program, the study team's priority is to improve diversity of participants both in the APT Webstudy and TRC, to continue enrollment into the TRC to our target of 2,000, and to improve longitudinal retention, while beginning the process of referring TRC participants into clinical trials.

Neuropsychiatric symptoms in patients with Parkinson's disease and dementia: frequency, profile and associated care giver stress.

OBJECTIVE: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson's disease (PDD). METHODS: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed. RESULTS: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score > or = 4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson's disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson's Disease Rating Scale and care giver distress scores. CONCLUSION: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.

Consensus statement on the upcoming crisis in geriatric mental health: research agenda for the next 2 decades.

It is anticipated that the number of people older than 65 years with psychiatric disorders in the United States will increase from about 4 million in 1970 to15 million in 2030. The current health care system serves mentally ill older adults poorly and is unprepared to meet the upcoming crisis in geriatric mental health. We recommend the formulation of a 15- to 25-year plan for research on mental disorders in elderly persons. It should include studies of prevention, translation of findings from bench to bedside, large-scale intervention trials with meaningful outcome measures, and health services research. Innovative strategies are needed to formulate new conceptualizations of psychiatric disorders, especially those given scant attention in the past. New methods of clinical and research training involving specialists, primary care clinicians, and the lay public are warranted.

Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.

BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.

Obsessive-compulsive disorder in Huntington's disease.

Two patients with Huntington's disease (HD) and obsessive-compulsive disorder (OCD) are reported. The OCD was manifested by repetitive, stereotyped, complex, egodystonic behaviors that were disabling. These cases and other neurological syndromes with OCD (Gilles de la Tourette syndrome, neuroacanthocytosis, postencephalitic parkinsonism, caudate infarction, carbon monoxide poisoning, manganese intoxication, anoxia, progressive supranuclear palsy, Sydenham's chorea, and frontal lobe lesions) indicate that the frontal lobe, caudate nucleus, and globus pallidus are members of a complex circuit that plays a key role in mediating the symptoms of OCD. Evidence of excitatory subcortical output to cortex is shared by many neurological disorders manifesting OCD.

Gilles de la Tourette syndrome and the neurological basis of obsessions and compulsions.

Gilles de la Tourette syndrome (GTS) is a chronic neurological disorder manifested by involuntary motor tics and vocalizations. Many GTS patients also suffer from obsessions and compulsions. The clinical similarities between GTS and obsessive-compulsive disorder (OCD), their occurrence among members of the same families, and the fact that both can be observed as symptoms of known basal ganglia disturbances suggest that GTS and OCD share common neurological mechanisms. It is hypothesized that the tics and vocalizations of GTS are aberrant manifestations of simple motor programs that are spontaneously generated by the basal ganglia and that obsessions and compulsions represent more complex motor plans initiated by similar anomalous activities.

Physostigmine ameliorates the delusions of Alzheimer's disease.

Alzheimer's disease (AD) patients frequently manifest delusions, and the cholinergic deficiency of AD may contribute to this aspect of the psychopathology of the disorder. In a double-blind, crossover study involving two patients, we compared the antidelusional efficacy of physostigmine, an acetylcholinesterase inhibitor, with haloperidol, a widely used neuroleptic agent. Physostigmine ameliorated the delusions and produced fewer side effects. These preliminary observations suggest that the cholinergic deficiency contributes to the occurrence of delusions in AD and cholinergic therapy may have a role in the treatment of the delusional symptoms.

Neuropsychiatric disturbances associated with idiopathic calcification of the basal ganglia.

A patient with idiopathic calcification of the basal ganglia (ICBG) manifested a schizophrenialike psychosis beginning at age 17 and later developed a complex movement disorder and mild dementia. Extensive calcification of the basal ganglia was demonstrated by computerized tomography. Review of reported cases of ICBG suggests that patients who become symptomatic early in adulthood are more likely to present with psychosis, whereas those presenting later in life typically manifest dementia and a motor system disorder. ICBG, like other conditions affecting subcortical structures, can produce schizophrenialike symptoms that may precede the onset of intellectual deterioration and extrapyramidal motor disturbances.

Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 allele confers significant risk for Alzheimer's disease and is associated with a greater amyloid burden in the brain. Future treatments may target molecular mechanisms associated with this allele, and it is important to define any phenotypic characteristics that correspond to this genotype. We sought to clarify the relationship between ApoE status and noncognitive symptoms in Alzheimer's disease patients. METHODS: Possible and probable Alzheimer's disease patients from a clinical trial (n = 605) were assessed with the 10-item Neuropsychiatric Inventory cross-sectionally prior to treatment, and their ApoE genotype was determined. Among the population studied, the following numbers with specific genotypes were studied: 23-2/3, 17-2/4, 209-3/3, 288-3/4, 68-4/4. RESULTS: When correlations were controlled for the patient's level of cognitive impairment, there was no relationship between epsilon 4 dose and any of the 10 noncognitive symptoms assessed, including psychosis, mood changes, and personality alterations. CONCLUSIONS: Among patients with comparable disease severity, the epsilon 4 allele does not confer additional psychiatric morbidity.

Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurobiological basis.

Alzheimer's disease (AD) is manifested by core features of progressive memory impairment, visuospatial decline, aphasia, and loss of executive function. In addition, patients may evidence a variety of other cognitive and behavioral features. The neurobiological basis for this clinical heterogeneity is uncertain but corresponding abnormalities on functional imaging suggest that variations in the distribution of the pathogenic changes in AD account for some of the observed clinical differences. Behavioral as well as cognitive variability has been correlated with disturbances on positron emission tomography and single photon emission computerized tomography. Functional imaging can reveal characteristic brain activity changes in AD, distinguish AD from other dementia syndromes, assess the integrity of transmitter systems in AD, determine the effect of cognitive enhancing and psychotropic drugs on metabolism and transmitter system function in AD, and possibly predict treatment responsiveness. Animal models of AD may improve our understanding of clinical variations in human AD. Thus far, development of cognitive tests for transgenic mice with AD pathology has been limited. Evaluations paralleling human neuropsychological tests are needed. In addition, technologies facilitating behavioral observations relevant to psychosis, depression, apathy, and agitation in AD have not been developed for transgenic models. Application of experiments inducing animal equivalents of depression and psychosis to determine the vulnerability of animal models of AD to these conditions may provide additional insights into human neuropsychiatric symptoms in AD. The efficacy of psychotropic drugs can be assessed in animal models of AD subjected to the provocative stimuli used in experimental models of psychopathology. There are a plethora of opportunities for basic scientists to offer insights, develop strategies, and provide techniques and technologies relevant to understanding the clinical manifestations of AD.

Telomere shortening in T cells correlates with Alzheimer's disease status.

Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, and therefore serve as markers of a cell's replicative history. In vivo, clonal expansion of T cells during immune responses to both foreign and autoantigens is associated with telomere shortening. To investigate possible immune alterations in Alzheimer's disease (AD) that might impact current vaccine-based therapeutic strategies, we analyzed telomere lengths in immune cell populations from AD patients. Our data show a significant telomere shortening in PBMC from AD versus controls (P=0.04). Importantly, telomere length of T cells, but not of B cells or monocytes, correlated with AD disease status, measured by Mini Mental Status Exam (MMSE) scores (P=0.025). T cell telomere length also inversely correlated with serum levels of the proinflammatory cytokine TNFalpha (a clinical marker of disease status), with the proportion of CD8+ T cells lacking expression of the CD28 costimulatory molecule, and with apoptosis. These findings suggest an immune involvement in AD pathogenesis.

Depression and Parkinson's disease: a review.

OBJECTIVE: The purpose of this review is to provide an update of the research regarding depression in Parkinson's disease and to synthesize the information into a neurobiological model relating the structural and biochemical changes in this disorder to the behavioral manifestations. METHOD: The author used a computer-based search of the literature, augmented by extensive bibliography-guided article reviews, to find information on depression and Parkinson's disease. FINDINGS: Depression occurs in approximately 40% of patients with Parkinson's disease; depression in Parkinson's disease is distinguished from other depressive disorders by greater anxiety and less self-punitive ideation. Lower CSF levels of 5-hydroxyindoleacetic acid, a past history of depression, and greater functional disability are associated with a greater risk of depression in Parkinson's disease. Female gender, early age at onset of Parkinson's disease, and greater left brain involvement may also be risk factors. Approximately half of depressed patients with Parkinson's disease meet criteria for major depressive episodes; half have dysthymia. Depression is more common in Parkinson's disease with prominent bradykinesia and gait instability than in tremor-dominant syndromes. Depressed patients with Parkinson's disease have greater frontal lobe dysfunction and greater involvement of dopaminergic and noradrenergic systems than nondepressed patients with the disease. Mood changes in Parkinson's disease respond to treatment with conventional tricyclic antidepressants or ECT. CONCLUSIONS: Neurobiological investigations suggest that depression in Parkinson's disease may be mediated by dysfunction in mesocortical/prefrontal reward, motivational, and stress-response systems. Neuropsychological, metabolic, clinical, pharmacological, and anatomical studies support the involvement of frontal dopaminergic projections in patients with Parkinson's disease and depression.

Cholinesterase inhibitors: A new class of psychotropic compounds.

OBJECTIVE: This article reviews evidence indicating that acetylcholinesterase inhibitors have psychotropic properties. METHOD: The author reviewed the English-language literature pertinent to the response of neuropsychiatric symptoms in Alzheimer's disease and related conditions to cholinergic agents. RESULTS: The cholinergic system originates in the basal forebrain and projects diffusely to the cerebral cortex; the limbic and paralimbic regions receive the most abundant cholinergic projections. The basal forebrain nuclei are positioned at the interface of the limbic system and cerebral cortex, where they play a role in mediating emotional responses. The basal forebrain nuclei are atrophic in Alzheimer's disease, leading to a widespread cholinergic deficit. The cholinergic disturbance may contribute to neuropsychiatric manifestations of the disease. The treatment of patients with Alzheimer's disease with acetylcholinesterase inhibitors reduces neuropsychiatric symptoms, particularly apathy and visual hallucinations. In some studies, a variety of other neuropsychiatric symptoms have been reported to respond to treatment with acetylcholinesterase inhibitors. Response profiles vary among acetylcholinesterase inhibitors. CONCLUSIONS: Acetylcholinesterase inhibitors have psychotropic effects and may play an important role in controlling neuropsychiatric and behavioral disturbances in patients with Alzheimer's disease. These agents also may contribute to the management of other disorders with cholinergic system abnormalities and neuropsychiatric symptoms. The beneficial response is most likely mediated through limbic cholinergic structures.

Secondary mania with focal cerebrovascular lesions.

The authors describe two patients with secondary mania associated with right thalamic infarctions. Both patients exhibited hemisensory loss, denial of illness, and amnesia for the manic episode. One improved with lithium therapy and the other recovered without specific pharmacologic intervention. A review of reported cases reveals that most focal lesions associated with secondary mania involve the diencephalic region and that the majority of lateralized lesions are on the right side.

Mutism: review, differential diagnosis, and report of 22 cases.

Mutism is a common manifestation of both psychiatric and neurologic illness. Psychiatric disturbances associated with mutism include schizophrenia, affective disorders, conversion reactions, dissociative states, and dementias. Neurologic disorders producing mutism involve the basal ganglia, frontal lobes, or limbic system structures. In psychiatric and neurologic conditions, mutism is often associated with other signs of catatonia. The authors review the literature on mutism, including psychiatric, neurologic, toxic-metabolic, and drug-induced causes. Methods to discriminate among the many causes of mutism in the clinical setting are discussed, and 22 new cases of mutism are reported to emphasize the wide differential diagnosis.