Anxiety and Depressive Symptoms and Cortical Amyloid-ß Burden in Cognitively Unimpaired Older Adults.

BACKGROUND: There is evidence of relationships between behavioral symptoms and increased risk for Alzheimer's Disease and/or Alzheimer's Disease biomarkers. However, the nature of this relationship is currently unknown. OBJECTIVES: To evaluate the relationship between anxiety and depressive symptoms and amyloid-ß deposition in cognitively unimpaired older adults, and to assess mediating effects of either objective or subjective cognitive skills. DESIGN: Cross-sectional analysis of screening data from participants enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study (ClinicalTrials.gov Identifier: NCT02008357). SETTING: Data analysis. PARTICIPANTS: 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. MEASUREMENTS: We used linear regression to estimate the associations between amyloid-ß standard uptake value ratio (SUVR) and Geriatric Depression Scale (GDS) and State Trait Anxiety Inventory (STAI) scores while adjusting for potential confounding factors as well as for Cognitive Function Index (CFI) or Preclinical Alzheimer's Cognitive Composite (PACC) scores as possible mediational variables. RESULTS: 4399 subjects with complete covariates were included (mean age: 71.3, 59% female), GDS ranged 0-13 (mean: 1.0), and STAI ranged 6-24 (mean: 9.9). Amyloid-ß SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.275 points higher (95% CI: 0.038, 0.526; p-value = 0.023) for each 0.5-point increase in cortical amyloid-ß SUVR. Subjective cognitive decline (CFI) attenuated the relationship between SUVR and STAI, while objective cognitive function (PACC) did not. No statistically significant relationship between SUVR and GDS was observed (p = 0.326). CONCLUSIONS: In cognitively unimpaired adults with low levels of depression and anxiety, cortical amyloid-ß deposition is associated with anxiety but not depressive symptoms. Attenuation of this relationship by subjective cognitive difficulties suggests that anxiety may be partly due to such a perception resulting from cortical amyloid-ß deposition.

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.

Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial.

Methylation has been implicated in the etiology of psychiatric illness. Parenteral S-adenosylmethionine, a methyl group donor, has been shown to be an effective antidepressant. The authors studied the antidepressant effect of oral S-adenosylmethionine in a randomized, double-blind, placebo-controlled trial for 15 inpatients with major depression. The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action. S-Adenosylmethionine induced mania in a patient with no history of mania. S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression.

A comparison of psychiatric symptoms in vascular dementia and Alzheimer's disease.

OBJECTIVE: Psychiatric symptoms account for much of the morbidity of vascular dementia and Alzheimer's disease. The goals of this study were to extend previous observations of the psychopathology and behavioral problems associated with vascular dementia and to compare the profile of symptoms in patients with vascular dementia to that in patients with Alzheimer's disease. METHOD: Twenty-eight pairs of patients (one with vascular dementia and one with Alzheimer's disease) were matched with respect to education, age, and severity of dementia. Their psychiatric symptoms were assessed with the Neurobehavioral Rating Scale, a 28-item observer-rated instrument, and the Hamilton Depression Rating Scale, and the symptoms in the two diagnostic groups were compared. RESULTS: Blunted affect, depressed mood, emotional withdrawal, motor retardation, low motivation, anxiety, unusual thoughts, and somatic concerns occurred in more than one-third of the patients with vascular dementia. There was no significant relation between severity of cognitive impairment and severity of these noncognitive symptoms. The patients with vascular dementia had more impairment than the patients with Alzheimer's disease, as indicated by the Neurobehavioral Rating Scale total scores and scores on the behavioral retardation, anxiety/depression, and verbal output disturbance factors. They also had a higher total score on the Hamilton depression scale and higher scores on 14 of the 17 Hamilton depression items. CONCLUSIONS: Patients with vascular dementia have more severe behavioral retardation, depression, and anxiety than those with Alzheimer's disease when the groups have similar levels of cognitive impairment. This probably reflects the contrasting brain regions typically involved in the two disorders.

Cortical abnormalities associated with subcortical lesions in vascular dementia. Clinical and position emission tomographic findings.

OBJECTIVE: To examine the effects of subcortical lesions on cortical metabolic rate and clinical symptoms in patients with vascular dementia. METHOD: Eleven elderly patients with vascular dementia who demonstrated no lesion involving the cerebral cortex on magnetic resonance imaging underwent 18F-fluorodeoxyglucose positron emission tomography to assess global cortical metabolism and metabolic activity in each cortical lobe. Subcortical lesions on magnetic resonance imaging (periventricular hyperintensities, deep white matter hyperintensities, and subcortical lacunar infarcts) were measured using a graded scale of severity. Cognitive and noncognitive symptoms were assessed with the Neurobehavioral Rating Scale. RESULTS: Reduced cortical metabolism was generally associated with the severity of subcortical pathologic changes, but there was substantial heterogeneity in the relationship between subcortical lesions and cortical metabolic activity. Mean global cortical metabolism was lower in patients with periventricular hyperintensities in anterior subcortical regions than in those without such lesions. The metabolic rate in the frontal cortex was lower in patients with a lacunar infarct of the basal ganglia or thalamus than in those without. Neurobehavioral Rating Scale total score, the Verbal Output Disturbance factor score, and the Anxiety/Depression factor score were correlated with the severity of white matter lesions. CONCLUSIONS: Cortical metabolic dysfunction is related to ischemic subcortical lesions in patients with vascular dementia. Metabolism in the frontal cortex may be particularly dependent on pathologic alterations of subcortical nuclei. Anxiety, depression, and the overall severity of neuropsychiatric symptoms in vascular dementia are associated with the extent of white matter ischemia.

Effect of carbon monoxide on atherogenesis in normal pigs and pigs with von Willebrand's disease.

The extent of coronary and aortic atherosclerosis was examined in pigs following balloon-catheter injury of coronary arteries and subsequent feeding of an atherogenic diet for 4 months. The pigs were either exposed intermittently to 100 ppm carbon monoxide or to ambient air alone. Three types of pigs were used: normals, homozygotes for von Willebrand's disease (bleeders), and heterozygotes (carriers). The 3 types of pigs developed coronary artery intimal lesions of similar thickness. Aortic lesions, quantified as percent of aortic surface involved with sudanophilia and raised fibrous plaques, were slightly less extensive in bleeder pigs than in normals. Carbon monoxide exposure did not increase the thickness of coronary artery intimal lesions, nor did it increase the percent of aortic surface involved with sudanophilia or raised fibrous lesions. These results suggest that exposure to low levels of carbon monoxide does not perceptibly enhance atherogenesis induced by hypercholesterolemia. None of 14 bleeder pigs showed evidence of myocardial infarction, despite significant coronary artery narrowing. Of the 24 normal and carrier pigs, 5 showed myocardial infarction. Four of these 5 pigs were exposed to carbon monoxide, while 1 was not exposed. These findings suggest that exposure to low levels of carbon monoxide may increase the incidence of myocardial infarction and that the absence of von Willebrand factor may be protective.

Assessment of cognitive, psychiatric, and behavioral disturbances in patients with dementia: the Neurobehavioral Rating Scale.

OBJECTIVE: To assess the validity of the Neurobehavioral Rating Scale (NRS) in patients with Alzheimer's disease (AD) or multi-infarct dementia (MID) and to characterize the cognitive, psychiatric, and behavioral disturbances that occur in these patients. DESIGN: Cross-sectional evaluation. SETTING: West Los Angeles VAMC Geropsychiatry Inpatient Unit, Neurobehavior Inpatient Unit, and Dementia Clinic; UCLA Alzheimer's Disease Clinic. PATIENTS: Convenience sample of 61 patients with AD and 22 patients with MID. MAIN OUTCOME MEASURE: The NRS, a 27-item observer-rated instrument that measures cognitive, psychiatric, and behavioral disturbances. RESULTS: The NRS demonstrated content and convergent validity in this patient group. Principal components analysis of the NRS ratings identified a six-factor solution, and each factor contained clinically related symptoms. The factors were Cognition/Insight, Agitation/Disinhibition, Behavioral Retardation, Anxiety/Depression, Verbal Output Disturbance, and Psychosis. Among the patients with AD, agitation, disinhibition, hostility, poor insight, poor motivation, suspiciousness, and delusions were more severe in patients with more advanced dementia. Depressive symptoms occurred with equal severity in patients with mild and advanced dementia, but depressed mood was more severe in patients with earlier age of onset of AD. CONCLUSION: The NRS is a useful instrument for structured assessment of a broad range of cognitive, psychiatric, and behavioral disturbances in patients with dementia.

Does behavioral improvement with haloperidol or trazodone treatment depend on psychosis or mood symptoms in patients with dementia?

OBJECTIVES: Several previous studies have examined the effects of pharmacological interventions for agitated behavior in patients with dementia. However, the choice of medication in clinical practice continues to be directed largely by local pharmacotherapy culture rather than empirical treatment guidelines. We examined the relationship between behavioral improvement and co-occurring delusions and mood symptoms in patients with dementia who were treated with haloperidol, an antipsychotic medication, or trazodone, a serotonergic antidepressant. DESIGN: Randomized, double-blind, parallel-group, 9-week treatment trial. SETTING: Inpatient geropsychiatry unit. PARTICIPANTS: Twenty-eight patients with dementia and agitated or aggressive behaviors. INTERVENTION: Haloperidol 1 to 5 mg/day or trazodone 50 to 250 mg/day. MEASUREMENTS: Cohen-Mansfield Agitation Inventory (CMAI), Hamilton Depression Rating Scale (Ham-D), and delusional thoughts subscale and hallucinations subscale of the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). RESULTS: CMAI scores improved in each treatment group over the 9 weeks of treatment (P < .001 in each group). Within the haloperidol treatment group, CMAI improvement was not associated with baseline delusional thoughts score or with change in delusional thoughts score over the course of treatment. Within the trazodone treatment group, CMAI improvement was associated with baseline score on total Ham-D (r = -0.60, P = .02), Ham-D items measuring subjective mood symptoms (r = -0.50, P = .07), and Ham-D items measuring neurovegetative signs (r = -0.49, P = .08). CMAI improvement was also associated with improvement in Ham-D total score over the course of treatment (r = 0.62, P = .02). CONCLUSIONS: Mild depressive symptoms in patients with dementia and agitated behavior are associated with greater behavioral improvement by trazodone-treated patients. In contrast, the presence of delusions in concert with behavioral disturbance does not necessarily predict greater behavioral improvement with haloperidol treatment than in subjects without signs of psychosis.

The Neurobehavioral Rating Scale: reliability in patients with dementia.

Precise measurement of cognitive, psychiatric, and behavioral symptoms is essential to understanding clinical, pathophysiologic, and treatment aspects of Alzheimer's disease and other dementing illnesses. The Neurobehavioral Rating Scale (NRS) is a 28-item observer-rated instrument that measures a broad range of cognitive and noncognitive symptoms. The interrater reliability of the NRS was examined in 15 patients with dementia. The correlation coefficient for the NRS total scores was .93. Coefficients for NRS factor scores and individual item scores were also satisfactory. Correlations for measures of subjectively experienced symptoms were acceptable, but less robust than measures of cognition and observable behavior. These results support the reliability of the NRS for multidimensional assessment of patients with dementia.

p(C) analysis facilitates dementia diagnosis.

A modified receiver operating characteristic (ROC) analysis technique was applied to a sample of 161 consecutive volunteers seen in a dementia clinic. Clinical, imaging, neuropsychological, and laboratory evaluation guided experienced clinicians in clinical diagnosis, taken as the "gold standard." Two symptom inventories, the Hachinski Ischemic Score and the Dementia of the Alzheimer's Type Inventory, were obtained by clinicians who were blind to final clinical diagnosis; scores on these inventories correlate with the likelihoods of multi-infarct dementia and Alzheimer's disease, respectively. A disjunctive sequential testing strategy was analyzed such that subthreshold scores on the first test identified patients for whom the second test was considered. Both tests were analyzed at all possible cutoff-point combinations and in both possible testing sequences. Diagnoses based on these tests were compared with the clinical "gold standard" diagnoses to determine the accuracy of the testing procedures. The best strategy correctly classified 154/161 (95.6%) of the dementia patients and required cutoff points (5 for the HIS and 10 for the Dementia of the Alzheimer's Type Inventory) that were lower than those usually recommended for either test used alone (i.e., 7 and 14, respectively). The Hachinski Ischemic Score--then Dementia of the Alzheimer's Type Inventory testing sequence was superior to the reverse strategy. A sensitivity analysis (varying prevalences of Alzheimer's disease, multi-infarct dementia, and other dementias) revealed similar test performances across a wide range of prevalences. These data suggest that simple clinical tests that take approximately 30 minutes to administer can produce diagnostic classifications of dementia that are similar to those of clinicians experienced in dementia diagnosis.

Drug-induced mania--causative agents, clinical characteristics and management. A retrospective analysis of the literature.

128 case reports of drug-induced mania were reviewed. Steroids, levodopa and other dopaminergic agents, iproniazid, sympathomimetic amines, triazolobenzodiazepines and hallucinogens were the agents that most commonly induced manic syndromes. The most common characteristics of drug-induced manic episodes were increased activity, rapid speech, elevated mood, and insomnia. Patients who developed mania often had a prior history, family history, or current symptoms of mood disturbance. The episodes were most commonly treated by discontinuing or reducing the dose of causative agent. Discontinuation of the inciting drug and treatment with neuroleptic agents were equally efficacious: lithium treatment was less effective. The majority of agents that induce mania have an effect on monoaminergic systems.

Impaired insight in Alzheimer disease: association with cognitive deficits, psychiatric symptoms, and behavioral disturbances.

OBJECTIVE: The purpose of this study was to evaluate symptoms associated with impaired insight in patients with Alzheimer disease (AD). BACKGROUND: Although unawareness of deficits is common in AD, the relation of awareness to psychiatric and behavioral disturbances has not been extensively studied. METHOD: We conducted a cross-sectional investigation of 91 patients with probable AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. Awareness of cognitive and functional deficits was measured with the Inaccurate Insight item from the Neurobehavioral Rating Scale. Psychiatric and behavioral symptoms were measured using factor scores and individual items from the Neurobehavioral Rating Scale. Global cognitive deficits were measured using the Mini-Mental State Examination (MMSE). RESULTS: Stepwise regression analysis showed that insight was associated with MMSE score, depression/anxiety factor score, and agitation/disinhibition factor score. Variables not associated with awareness of deficits included patient age, behavioral retardation factor score, verbal output disturbance factor score, and psychosis factor score. Post hoc analyses showed a positive relation (i.e., greater insight, more symptomatology) between deficit awareness and symptoms of depressed mood and anxiety. There was a negative relation (i.e., greater insight, less symptomatology) between insight and symptoms of hostility, agitation, inattention, and tension. In a follow-up stepwise regression analysis, increased deficit awareness was associated with a higher MMSE score, greater depressed mood, and decreased agitation. CONCLUSIONS: These findings suggest that patients with AD may experience symptoms of depressed mood in relation to increased awareness of decrements in functioning. The data also indicate that patients with poor insight demonstrate greater agitated behavior. Consistent with previous research, impaired insight was higher in the later stages of the illness.

A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia.

The authors compared the efficacy and side effects of trazodone and haloperidol for treating agitated behaviors associated with dementia. Twenty-eight elderly patients with dementia and agitated behaviors were randomly assigned to double-blind treatment with either trazodone (50-250 mg/day) or haloperidol (1-5 mg/day) for 9 weeks. There was no significant difference in improvement between the medication groups. Adverse effects, however, were more common in the group treated with haloperidol. Improvement in individual areas suggested that repetitive, verbally aggressive, and oppositional behaviors responded preferentially to trazodone, whereas symptoms of excessive motor activity and unwarranted accusations responded preferentially to haloperidol. These results indicate that moderate doses of trazodone and haloperidol are equally effective for treatment of overall agitated behaviors in patients with dementia, but specific symptoms may respond preferentially to a particular agent.

Executive dysfunction in Alzheimer's disease: association with neuropsychiatric symptoms and functional impairment.

Relationships between measures of executive skills and neuropsychiatric and functional status were examined in a group of 31 patients with Alzheimer's disease. Deficits in four executive skills tests were significantly associated with the Agitation/Disinhibition factor score and Total Neuropsychiatric score on the Neurobehavioral Rating Scale, as well as the Activities subscore on the Blessed Dementia Scale. The majority of these associations remained significant after covariance for Mini-Mental State Examination scores. Executive dysfunction is associated with clinically relevant neuropsychiatric symptoms and functional impairment in Alzheimer's disease. These associations may be independent of other cognitive deficits such as memory, language, and visuospatial skills, and may not be appreciated on routine clinical evaluations. Executive skills deficits, neuropsychiatric symptoms, and functional disability may emerge from shared neurobiological mechanisms.

The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer's disease.

Cognitive and noncognitive psychiatric symptoms were systematically evaluated in 21 patients with Alzheimer's disease by using the Neurobehavioral Rating Scale. Regional cerebral metabolic activity was measured in each patient by [18F]fluorodeoxyglucose PET. Significant correlations emerged between global cortical metabolic activity and the Agitation/Disinhibition factor score, Cognition factor score, and total score. Relationships between noncognitive symptoms and metabolic activity were regionally specific, with significant correlations between Agitation/Disinhibition factor score and metabolism in the frontal and temporal lobes, between Psychosis factor score and metabolism in the frontal lobe, and between Anxiety/Depression factor score and metabolism in the parietal lobe. These results suggest that psychiatric symptoms are fundamental expressions of the cortical dysfunction of Alzheimer's disease.