Development of perampanel in epilepsy.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors play a key role in mediating glutamatergic transmission in the cortex. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile) is a potent, orally active, highly selective, non-competitive AMPA-type glutamate receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories. Development of perampanel as adjunctive therapy for the treatment of partial-onset seizures was planned in keeping with regulatory guidance and guidelines on antiepileptic drug (AED) development. This is the first AED with a specific action on glutamate-mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment-refractory partial-onset seizures in Phase III clinical trials. Perampanel (Fycompa(®)) has been approved in the EU and the United States for adjunctive treatment of partial-onset seizures.

Psychosis of Alzheimer's disease: Gender differences in regional perfusion.

We sought to determine whether the presence of psychotic symptoms in patients with Alzheimer's disease is associated with abnormal regional cerebral function. Perfusion single photon emission computed tomography images from 51 AD patients with psychotic symptoms were compared to images of 52 AD patients without such symptoms. Group comparisons were made with a voxel-based method, Statistical Parametric Mapping. We found that perfusion was lower in female patients with psychotic symptoms in right infero-lateral prefrontal cortex and in inferior temporal regions compared to female patients without such symptoms. In contrast, perfusion was higher in male patients with psychotic symptoms in the right striatum compared to male patients without such symptoms. Comparison groups did not differ in age or in dementia severity, as estimated by the Mini-Mental State Examination (MMSE). These results support the role of right hemisphere prefrontal and lateral temporal cortex in the psychosis of AD in women but not in men, and raise the possibility that these dysfunctional processes have a gender-specific regional pathophysiology in AD.

Sundowning and circadian rhythms in Alzheimer's disease.

OBJECTIVE: The goal of this study was to determine changes of circadian rhythms induced by Alzheimer's disease and to explore relationships among rhythm disturbances, sundowning, and sleep disturbances in patients with Alzheimer's disease. "Sundowning" is the occurrence or exacerbation of behavioral symptoms of Alzheimer's disease in the afternoon and evening. METHOD: Circadian rhythms of core body temperature and motor activity were measured in 25 patients with diagnoses of probable Alzheimer's disease and in nine healthy individuals. The subjects with Alzheimer's disease were divided according to the occurrence of sundowning as determined by staff reports. RESULTS: The subjects with Alzheimer's disease had less diurnal motor activity, a higher percentage of nocturnal activity, lower interdaily stability of motor activity, and a later activity acrophase (time of peak) than did the healthy individuals. They also had a higher mesor (fitted mean) temperature, higher amplitude of the fitted cosine temperature curve, and later temperature acrophase than did the healthy subjects. The severity of sundowning was associated with later acrophase of temperature, less correlation of circadian temperature rhythm with a 24-hour cycle, and lower amplitude of temperature curve. CONCLUSIONS: These data indicate that Alzheimer's disease causes disturbances of circadian rhythms and that sundowning is related to a phase delay of body temperature caused by Alzheimer's disease.

Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration.

BACKGROUND: Caregiver exhaustion is a frequent consequence of sleep disturbance and rest-activity rhythm disruption that occurs in dementia. This exhaustion is the causal factor most frequently cited by caregivers in making the decision to institutionalize patients with dementia. Recent studies have implicated dysfunction of the circadian pacemaker in the etiology of these disturbances in dementia. METHODS: We studied the activity and core-body temperature rhythms in a cohort of 38 male patients with a clinical diagnosis of probable Alzheimer disease (AD) approximately 2 years before death. These patients were later given a confirmed diagnosis of AD (n = 23), frontotemporal degeneration (FTD) (n = 9), or diffuse Lewy body disease (DLB) with mixed AD or FTD pathologies (n = 6) after autopsy and neuropathological examination. Physiological rhythms of patients with AD and FTD were then compared with a group of normal, elderly men (n = 8) from the community. RESULTS: Alzheimer patients showed increased nocturnal activity and a significant phase-delay in their rhythms of core-body temperature and activity compared with patients with FTD and controls. The activity rhythm of FTD patients was highly fragmented and phase-advanced in comparison with controls and apparently uncoupled from the rhythm of core-body temperature. CONCLUSIONS: Patients with AD and patients with FTD show different disturbances in their rhythms of activity and temperature compared with each other and with normal elderly patients.

Abnormal erythrocyte anion exchange in Alzheimer disease.

CONTEXT: Several abnormalities have been described in red blood cells of patients with Alzheimer disease (AD), but to date none of these has been confirmed by a second, independent study. Erythrocyte anion exchange has been reported to be abnormal in AD; we have developed a new technique for measuring anion exchange. OBJECTIVES: To confirm the abnormality of erythrocyte anion exchange in AD and to determine whether the phenomenon has potential for clinical utility. DESIGN: Comparison of patients with probable AD to age-matched controls. SETTING: University hospital and ambulatory clinic. METHODS: Chloride-bicarbonate exchange was measured in erythrocyte ghosts resealed with a fluorescent probe of chloride concentration. RESULTS: Erythrocyte anion exchange is abnormal in AD. This difference appears in citrate but not EDTA anticoagulant. Mahalanobis's generalized distance between the 2 populations is 1.7, and a discriminant function derived from our technique classifies 82% of the study population in accordance with the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Receiver operating characteristic analysis demonstrates the possibility of choosing cutoffs with high sensitivity and specificity. CONCLUSIONS: Measurement of red blood cell anion exchange may be useful in classifying patients with AD. The dependence of this phenomenon on anticoagulant suggests the involvement of platelet activation or complement fixation.

Core body temperature and sleep of older female insomniacs before and after passive body heating.

The purpose of this study was to investigate the relationship between core body temperature and sleep in older female insomniacs and changes in that relationship as a result of passive body heating (PBH). An increase in body temperature early in the evening by way of PBH in older female insomniacs increased SWS in the early part of the sleep period and improved sleep continuity. Fourteen older female insomniacs (60-73 years old) participated in at least two consecutive nights of PBH involving hot (40-40.5 degrees C) baths 1.5-2 hours before bedtime. Hot baths resulted in a significant delay in the phase of the core body temperature rhythm compared to baseline nights. This delay in temperature phase paralleled the improvements in sleep quality.

Estrogen therapy and aggressive behavior in elderly patients with moderate-to-severe dementia: results from a short-term, randomized, double-blind trial.

The authors used a randomized, double-blind, placebo-controlled clinical trial study design to investigate the efficacy and safety of short-term estrogen therapy in decreasing aggressive behaviors in elderly patients with moderate-to-severe dementia. Estrogen therapy was associated with lower total aggression scores (P<0.030) and with decreased frequency of physical aggression (P<0.019) over the 4-week trial. Verbally aggressive behaviors were decreased relative to control subjects, although this effect was not statistically significant. No drug-vs.-placebo differences were found for resistive, sexual, or self-directed aggressive behaviors. No adverse effects from the estrogen were observed during the course of the study.

Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia.

Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), the putative site of the hypothalamic circadian pacemaker, to determine the nature and degree of pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheimer disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick disease and 2 had severe hippocampal sclerosis. Comparisons were made with a control group composed of 13 age-matched patients with no clinical or pathological evidence of dementia or other CNS disorders. To determine the pathologic involvement within the SCN, human hypothalami were stained with: Nissl, Bielchowsky silver, thioflavin S and specific antibodies directed against vasopressin (VP), neurotensin (NT), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neurofibrillary tangle formation. Only rare diffuse plaques were noted. The pathologic changes within the SCN were less severe than in the other brain regions. Morphometric analysis was accomplished using a stereological approach to sample the average total number of positively stained neurons and astrocytes in 10 different 0.1mm2 microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrease in vasopressin (9.75 vs 16.7, p < 0.001) and neurotensin (6.82 vs 9.63, p < 0.002) neurons, as well as a corresponding increase in the GFAP-stained astrocyte/Nissl-stained neuron ratio (0.54 vs 0.10, p < 0.009). These studies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable indicator of disease-related pathology within the SCN. Taken collectively, our data support the hypothesis that damage to the SCN may be an underlying anatomical substrate for the clinically observed changes in circadian rhythmicity that have been observed in Alzheimer patients.

Dynamic susceptibility contrast MR imaging of regional cerebral blood volume in Alzheimer disease: a promising alternative to nuclear medicine.

BACKGROUND AND PURPOSE: The goal of our study was to evaluate the sensitivity and specificity for Alzheimer disease of semiquantitative dynamic susceptibility contrast (DSC) MR imaging as compared with results of qualitative single-photon emission computed tomography (SPECT) in the same patients and with previously published semiquantitative SPECT results. METHODS: Fifty subjects were studied: 19 patients with probable Alzheimer disease with moderate cognitive impairment, eight mildly impaired patients with possible or probable Alzheimer disease, 18 group-matched elderly healthy comparison subjects, and five elderly comparison patients with psychiatric diagnoses. Relative values of temporoparietal regional cerebral blood volume (rCBV) were measured as a percentage of cerebellar rCBV, and group classification was assessed with logistic regression. The DSC MR imaging results were compared with SPECT scans in these same subjects and with previously published semiquantitative SPECT data. RESULTS: Temporoparietal rCBV ratios were reduced 20% bilaterally in the patients with Alzheimer disease. Using left and right temporoparietal rCBV as index measures, sensitivity was 95% in moderately affected patients with Alzheimer disease and 88% in patients with mild cases. Specificity was 96% in healthy comparison subjects and in psychiatric comparison subjects. Sensitivity with DSC MR imaging was considerably better than with visual clinical readings of SPECT scans (74% in moderate and 50% in mild Alzheimer disease cases), and was similar to previous published SPECT temporoparietal measurements (90%). Specificity with SPECT was 100% visually and 87% based on previous temporoparietal measurements. CONCLUSIONS: DSC MR imaging of rCBV is promising as a safe, potentially lower-cost alternative to nuclear medicine imaging for the evaluation of patients with dementia.

Preclinical prediction of Alzheimer's disease using SPECT.

BACKGROUND: Regional cerebral perfusion measured by single photon emission computed tomography (SPECT) was examined as a preclinical predictor of the development of Alzheimer's disease (AD). METHODS: Singular value decomposition was used to produce 20 SPECT factors (known as vectors) (n=152). Vector scores were then computed for four groups (n=136), differing in cognitive status: Group 1--normal controls at both baseline and follow-up; Group 2--subjects with "questionable" AD at both baseline and follow-up; Group 3--subjects with questionable AD at baseline who converted to AD on follow-up (Converters); Group 4--subjects with AD at baseline. All SPECT data in the analyses were gathered at baseline. RESULTS: The four groups could be distinguished on the basis of their baseline SPECT data (p < or = 0.00005; hit rate=83%). Regional decreases in perfusion were most prominent among Converters in the hippocampal-amygdaloid complex, the posterior cingulate, the anterior thalamus, and the anterior cingulate. Inclusion of apolipoprotein E status did not significantly improve the discrimination. CONCLUSIONS: SPECT data gathered and analyzed in this manner may be useful as one aspect of the preclinical prediction of AD. Three of the four brain regions important for discriminating Converters from normal controls involve a distributed brain network pertaining to memory, suggesting that this network may be selectively affected in the earliest stages of AD.

Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer's disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist.

OBJECTIVE: Higher than normal cellular levels of the phospholipid catabolic intermediate glycerophosphocholine have been found in postmortem brain tissue of persons with Alzheimer's disease. Proton magnetic resonance spectroscopy (1H-MRS) can detect a choline resonance that is largely due to glycerophosphocholine. The authors tested the hypothesis that treatment with xanomeline, an M1 selective muscarinic cholinergic agonist, would be associated with a decrease in the 1H-MRS choline resonance. METHOD: Patients with mild to moderate Alzheimer's disease received placebo or xanomeline for 6 months. 1H-MRS spectra were collected at baseline and after treatment discontinuation for 12 patients, two taking placebo and 10 taking xanomeline at a dose of 25 mg t.i.d. (N = 4), 50 mg t.i.d. (N = 3), or 75 mg t.i.d. (N = 3). RESULTS: For the combined group of patients taking xanomeline, there was a significant decrease in the choline/creatine ratio from baseline to endpoint. CONCLUSIONS: Treatment of Alzheimer's disease with a cholinergic agonist is associated with a decrease in the MRS choline resonance. Xanomeline may reduce breakdown of cholinergic neuron membranes by reducing the cellular requirement for free choline for acetylcholine synthesis.

Late-life suicide: a review.

Suicide ranked as the ninth leading cause of death in the United States in 1992, with persons over the age of 65 years being at the highest risk. Suicidologists predict a dramatic increase in both the rate and the total number of late-life suicides over the next three decades, highlighting the urgent need for prevention and treatment strategies specifically targeting at-risk older individuals. Comprehensive Medline and PsycLit searches of elderly suicide (and various synonyms thereof) were conducted for English-language publications dating back to 1989, and the bibliographies in these sources were examined for additional publications. An overview of the epidemiology, biology, psychopathology, and frequent medical concomitants of late-life suicide is presented here. Innovative preventive strategies are also briefly summarized. It is concluded that further investigation is needed in several areas: the neurobiology of aging, affective disorders, and suicide; the complex interactions between somatic and psychiatric illnesses; personality traits that may confer vulnerability to suicide in late life; and age-related variations in the prevalence and phenomenology of Axis I psychopathology in suicide victims.

Regional atrophy of the corpus callosum in subjects with Alzheimer's disease and multi-infarct dementia.

Regional areas of the corpus callosum (CC) were evaluated in subjects with dementia. The area of the CC and seven distinct subdivisions were measured in subjects with Alzheimer's disease (AD) (n = 162), multi-infarct dementia (MID) (n = 28), and in a healthy comparison group (n = 36). There were significant differences in the regional areas of the CC for both the AD and MID patients relative to values for the comparison subjects. When mildly demented (MMSE > or = 21), subjects with AD had significantly smaller posterior midbody, isthmus, and splenium and subjects with MID had significantly smaller genu relative to comparison subjects. This study reports different patterns of regional CC area loss in subjects with AD and MID.

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

OBJECTIVE: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). DESIGN: A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout. SETTING: Outpatients at 17 centers in the United States and Canada. PARTICIPANTS: A total of 343 men and women at least 60 years of age with mild to moderate AD. INTERVENTIONS: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. OUTCOME MEASURES: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). RESULTS: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P < or = .05), and CIBIC+ (high dose vs placebo; P < or = .02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P < or = .002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P < or = .02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. CONCLUSIONS: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.

Regional cerebral blood volume measured by dynamic susceptibility contrast MR imaging in Alzheimer's disease: a principal components analysis.

Dynamic susceptibility contrast (DSC) MRI is an alternative to positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the evaluation of cerebral hemodynamics in patients with Alzheimer's disease. DSC MRI allows the construction of high resolution images of cerebral blood volume (CBV) without the use of radionuclides or ionizing radiation. In this study, DSC MRI data were collected from 16 patients with probable Alzheimer's disease and 16 age-matched control subjects. Characteristic patterns of regional CBV variation were found using principal component analysis. Three such patterns were identified: a global variation pattern, an anterior-to-posterior CBV gradient, and a temporoparietal pattern. Group differences in the principal component scores associated with the global and temporoparietal patterns (P = .08 and P = .007, respectively) suggest that these deficits reflect characteristic CBV abnormalities in Alzheimer's disease. Using only these two scores, the Alzheimer's disease group was classified with a sensitivity of 81% and a specificity of 88%. Additionally, disease severity, as measured by the Mini-Mental State Examination (MMSE), was correlated significantly with the third principal component score (Pearson's r = .50, P = .05).

Dynamic susceptibility contrast MRI of regional cerebral blood volume in Alzheimer's disease.

OBJECTIVE: The purpose of this study was to investigate the potential effectiveness of dynamic susceptibility contrast magnetic resonance imaging (MRI) to discriminate elderly patients with Alzheimer's disease from normal matched comparison subjects. METHOD: Images of regional cerebral blood volume (CBV) were generated from echo-planar MRI with the dynamic susceptibility contrast method in 13 Alzheimer's disease patients and 13 comparison subjects group-matched on age and gender. RESULTS: Temporoparietal cerebral blood volume, expressed as a percentage of the cerebellum value, was reduced 17% bilaterally in the patients with Alzheimer's disease. Blood volume in sensorimotor regions was reduced only 8.5% in the patients. Discriminant function analysis based on left and right temporoparietal measures correctly classified 88.5% of the subjects as patients or comparison subjects. Temporoparietal CBV was reduced even in mildly affected Alzheimer's disease patients (Mini-Mental State scores > 24). CONCLUSIONS: Dynamic susceptibility contrast MRI of regional CBV is promising as a nonradioactive, potentially lower-cost alternative to other functional neuroimaging methods for evaluating Alzheimer's disease.

Effects of passive body heating on the sleep of older female insomniacs.

The purpose of this study was to evaluate passive body heating (PBH) as a treatment for insomnia in older adults. Polysomnographic recordings of older adults routinely show an increase in sleep fragmentation and a substantial decrease in slow-wave sleep (SWS) consistent with complaints of "lighter" more disturbed sleep. An increase in body temperature in young adults early in the evening by way of PBH has been shown to produce an increase in SWS in the early part of the sleep period. In a crossover design, nine female insomniacs (aged 60-72 yr) participated in two consecutive nights of PBH, involving hot (40-40.5 degrees C) and luke-warm (37.5-38.5 degrees C) baths 1.5 hours before bedtime. Significant improvement in sleep continuity and a trend toward an increase in SWS occurred after hot baths. Results of subjective measures showed that subjects experienced significantly "deeper" and more restful sleep after hot baths. In addition, hot baths resulted in a significant delay of temperature nadir in comparison to baseline nights.

Depression in a long-term care facility: clinical features and discordance between nursing assessment and patient interviews.

OBJECTIVE: Nurses commonly observe more depression than is diagnosed and treated in nursing homes. Accordingly, we aimed to describe the clinical features of untreated nursing home residents whom nurses identify as depressed and to compare nurse ratings of depressed nursing home residents with ratings from direct interviews and patient self-reports. DESIGN: Cross-sectional survey followed by semi-structured diagnostic interviews of depressed patients and their nurses. SETTING: A large academic, multi-level, long-term care facility. PARTICIPANTS: Thirty-seven patients aged 74-99 (mean age 88.4) whom nurses identified as having daily symptoms of depression. Subjects had Mini-Mental State Exam (MMSE) scores > 10 (mean score 21.2), were not acutely or terminally ill, and were able to participate in an interview. MEASUREMENTS: DSM-III-R mood diagnoses and separate ratings of interviews with nurses and patients using the Cornell Scale for Depression. RESULTS: Nurses observed daily symptoms of depression in 110 of 495 (22%) long-term care residents on units not reserved for advanced dementia. Of these 110 patients, 58 (53%) were not receiving antidepressants. Of 37 patients eligible for interviews, nine met criteria for major depression, 20 met criteria for another non-major depression diagnosis, and eight did not have a diagnosable mood disorder. Cornell scale ratings derived exclusively from interviews of nurses were similar across the three diagnostic groups (12.5, 9.9, and 9.5, respectively; P = .31; mean 10.5), whereas Cornell scale ratings from patient interviews differed among groups (15.9, 6.9, and 4.1, respectively; P < .001; mean 8.4). Correlation between nurse Cornell ratings and patient Cornell ratings was poor (r = .27), especially for patients with non-major forms of depression (r = -.20). MMSE and Cumulative Illness Rating Scale (CIRS-G) scores were similar in the three groups. CONCLUSIONS: Nurses frequently observed symptoms of depression in a long-term care setting, and many symptomatic patients were not being treated with antidepressants. In these patients, nurse-derived symptom ratings did not vary across DSM-III-R diagnostic categories and correlated poorly with ratings from direct patient interviews. These findings suggest that nurse caregivers may contribute important diagnostic information about non-major depression and raise questions about the application of standard diagnostic categories to late-life depression in the nursing home.

Circadian locomotor activity and core-body temperature rhythms in Alzheimer's disease.

Sleep-wake cycle disturbances suggest that circadian rhythms may be disrupted in patients with Alzheimer's disease (AD). In this study, we examined the circadian rhythms of core-body temperature and locomotor activity in 28 patients with probable AD and 10 healthy controls. AD patients had higher percent nocturnal activity than controls, corresponding to the clinical picture of fragmented sleep. The amplitude of the activity cycle in the AD patients was lower than that of controls and the acrophase of this cycle in AD patients was 4.5 h later. There was no difference in the amplitude of the core-body temperature circadian rhythm, but AD patients had delayed temperature acrophases. A subgroup of AD patients with large mean time differences between the acrophases of their activity and temperature cycles had lower temperature amplitudes and greater activity during the night. These findings suggest that a subgroup of AD patients with impaired endogenous pacemaker function may have a diminished capacity to synchronize the rhythm of core-body temperature with the circadian cycle of rest-activity. This circadian rhythm dysfunction may partly explain the fragmented nocturnal sleep exhibited by these patients.