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.

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.

Prevalence and severity of akathisia in patients on clozapine.

The atypical antipsychotic clozapine is reported to have unique therapeutic effects and to produce minimal extrapyramidal side effects. However, in a blind survey, akathisia was observed to be similar in prevalence and severity in patients treated with clozapine and those receiving standard neuroleptic antipsychotic drugs. In addition, as with standard antipsychotic drugs, the presence of akathisia in patients receiving clozapine was associated with a worse overall clinical outcome. The results suggest that akathisia may be a common side effect of all antipsychotic drugs, that akathisia may be produced by a mechanism distinct from other locomotor effects of these medications, and that patients receiving clozapine, like patients receiving standard antipsychotic drugs, should be monitored for akathisia.

Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population.

This chart review study examined the serum vitamin B12 and folate status of 102 geriatric patients newly admitted to a private psychiatric hospital. Only 3.7% were B12 deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those with below-median values of both vitamins had significantly lower Mini-Mental State scores than patients higher in one or both vitamins. Patients with "organic psychosis" with a negative family history for psychiatric disorder had significantly lower B12 levels than those with a positive family history. In major depression, folate levels correlated negatively with age at onset of psychiatric illness and length of hospitalization. These data suggest that (1) biochemically interrelated vitamins such as B12 and folate may exert both a separate and a concomitant influence on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric disorders that begin at a later age and lack a familial predisposition.

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.

First-episode mania in late life.

Among 14 elderly patients (mean age = 74.6 years) with first-episode mania who were followed for 3 to 10 years, men had a higher risk of mortality. Compared to 36 elderly patients with multiple episodes of mania, patients with first-episode mania were twice as likely to have a comorbid neurological disorder (71% [N = 10] versus 28% [N = 10]). Mania in the elderly appears to be a heterogeneous disorder.

Undiagnosed vomiting in an older woman: unsuspected bulimia.

Bulimia, believed to occur primarily in young women, is rarely suspected in older individuals. The authors report on a 56-year-old woman with rapid cycling bipolar disorder, whose unexplained vomiting proved attributable to bulimia.

Mania compared with unipolar depression in old age.

OBJECTIVE: The goal of this study was to clarify the meaning and importance of mania in old age. METHOD: The authors conducted a retrospective study of 50 elderly patients consecutively admitted to a private mental hospital with an index episode of mania. As a comparison group, they used 50 age- and sex-matched patients with unipolar depression. They reviewed the charts of the 100 patients for family history, clinical course, and neurological disorders. Outcome was determined by contacting patients, families, physicians, institutional settings, and vital statistics records. Survival analysis compared mortality rates. RESULTS: The manic patients had a greater familial predisposition to affective disorder and were younger at first psychiatric hospitalization. For the 20 manic patients whose first affective episode was depression, an average of 15 years elapsed before mania became manifest. Eighteen of the manic patients, compared with only four of the depressed patients, had neurological disorders. The manic patients had a significantly higher mortality rate than the depressed patients; by the end of the follow-up, 25 of the manic patients, compared with 10 of the depressed patients, had died. CONCLUSIONS: Mania appears to have a poorer prognosis and to be a more severe form of affective illness than unipolar depression. The 18 manic patients with neurological disorders seemed to have "secondary mania." Subtle cerebral changes due to aging may have been responsible for the conversion to mania in the 20 patients who experienced a long latency from first depression to onset of mania. The low frequency of early-onset mania in this study group highlights the need to differentiate early- from late-onset mania.

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.

Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease.

OBJECTIVE: The authors tested the hypothesis that evening bright light pulses would improve sleep-wake patterns and reduce agitation in patients with Alzheimer's disease who have severe sundowning (a syndrome of recurring confusion and increased agitation in the late afternoon or early evening) and sleep disorders. METHOD: Ten inpatients with Alzheimer's disease on a research ward of a veterans' hospital were studied in an open clinical trial. All patients had sundowning behavior and sleep disturbances. After a week of baseline measurements, patients received 2 hours/day of exposure to bright light between 7:00 p.m. and 9:00 p.m. for 1 week. During the baseline week, the treatment week, and a posttreatment week, patients were rated by nurses for agitation, sleep-wake patterns, use of restraints, and use of prescribed-as-needed medication. On the last 2 days of each week, patients wore activity monitors. Activity counts were analyzed for circadian rhythmicity. RESULTS: Clinical ratings of sleep-wakefulness on the evening nursing shift improved with light treatment in eight of the 10 patients. The proportion of total daily activity occurring during the nighttime decreased during the light-treatment week. The relative amplitude of the circadian locomotor activity rhythm, a measure of its stability, increased during the light-treatment week. More severe sundowning at baseline predicted greater clinical improvement. CONCLUSIONS: Evening bright light pulses may ameliorate sleep-wake cycle disturbances in some patients with Alzheimer's disease. This effect may be mediated through a chronobiological mechanism.

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.

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 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.

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.

Circadian locomotor activity rhythms in Alzheimer's disease.

Circadian motor activity rhythms in 19 severely demented, institutionalized patients with Alzheimer's disease (AD) were evaluated with small, waist-worn electronic monitors which recorded 5-minute epochs for 48 to 72 hours. Controls were eight normal subjects of the same age (71 to 73 years) in a similar environment. As expected, computer-assisted analysis indicated more than twofold average increases in nocturnal activity and in the proportion of nocturnal to total daily activity in the AD patients. In patients (n = 8) with virtually constant pacing, daytime activity was markedly increased over that of normal controls; these "pacers" also had a significantly decreased amplitude of the circadian activity rhythm compared with controls. Moreover, AD patients showed a marked phase-delay, with individual afternoon maxima (acrophases) averaging 2.1 hours later than in controls (p less than 0.005). These findings quantitatively document clinical observations that AD patients, and especially a subgroup with pacing behavior, have markedly disturbed levels and modulation of daily locomotor activity. They accord with reports of altered circadian rhythms of endocrine and other physiologic parameters in such patients. Activity monitoring may represent a relatively simple, objective measure with which to characterize demented patients and to assess responses to treatment.

The scintigraphic appearance of Alzheimer's disease: a prospective study using technetium-99m-HMPAO SPECT.

Alzheimer's disease produces regional abnormalities in brain blood flow and metabolism that may result in recognizable scintigraphic patterns. We determined the predictive value of 99mTc-HMPAO SPECT for the presence of Alzheimer's disease based on a prospective study of 132 consecutive patients coming to our nuclear medicine clinical unit for evaluation of their memory loss or cognitive abnormalities. During clinical follow-up averaging 10.1 mo, a final diagnosis was established in 113 patients, 52 of which had Alzheimer's disease. The probability of Alzheimer's disease was determined for seven scintigraphic patterns. The probability was 19% that patients with memory loss and normal perfusion had Alzheimer's disease. For abnormal perfusion patterns, the probability of Alzheimer's disease was 82% with bilateral temporoparietal defects, 77% with bilateral temporoparietal defects with additional defects, 57% with unilateral temporoparietal defects, 43% with frontal defects only, 18% with other large defects and 0% with multiple small cortical defects. We conclude that for 99mTc-HMPAO SPECT the predictive value of bilateral temporoparietal defects for Alzheimer's disease is high, while the perfusion patterns of unilateral temporoparietal perfusion defects and frontal defects only, which occur in 20% of patients with Alzheimer's disease, are not predictive of that disease.

Quantitative brain SPECT in Alzheimer's disease and normal aging.

To improve the diagnostic utility of brain single-photon emission computed tomography (SPECT) in Alzheimer's disease (AD), we have developed and evaluated an objective method of differentiating patients and healthy elderly controls using a quantitative image analysis protocol. HMPAO-SPECT image datasets from 29 patients with probable AD and 78 age-matched controls were registered to a common anatomic frame of reference. Activity levels within 120 standardized cortical volumes were determined by an automated procedure. Subjects were classified into normal and AD groups by quadratic discriminant analysis using two features: global average activity level and average normalized activity levels within the two clusters of standardized volumes identified as most significantly different in AD by analysis of covariance. The classification used split-half replication to ensure valid results. Classification performance quantified by the area under a binormal ROC curve fitted to the data was 0.923 +/- 0.036; at a threshold likelihood ratio of 1, the sample sensitivity was 91% and specificity was 86%. We conclude that quantitative SPECT accurately distinguishes AD patients from elderly controls.

A neural network classifier for cerebral perfusion imaging.

UNLABELLED: Artificial neural networks have been applied to a variety of pattern recognition tasks in medical imaging and have been shown to be a powerful classification tool. The potential usefulness to discriminate normal from abnormal cerebral perfusion patterns was investigated. METHODS: Cerebral perfusion imaging with 99mTc-labeled hexamethylpropyleneimine oxime was performed on 52 normal control subjects, 29 patients with clinically diagnosed Alzheimer's disease (AD) and 25 patients with chronic cocaine polydrug abuse. Each study was registered and scaled to a common anatomic coordinate system, yielding 120 standardized cortical regions. A back-propagation neural network classifier based on regional perfusion was used to classify normal and abnormal perfusion patterns. The neural network was trained to discriminate patients with AD from age-matched normal controls and cocaine polydrug abuse patients from normal controls. The performance of the neural network in these two tasks was evaluated quantitatively by receiver operating characteristic (ROC) analysis using cross-validation. RESULTS: For patients with AD, the area under the ROC curve was 0.93 +/- 0.04. When testing with the cocaine polydrug abuser data, the area under the ROC curve was 0.89 +/- 0.04. CONCLUSION: Neural networks provide a potentially useful tool in the decision-making task to discriminate patients with AD and cocaine abuse from normal controls.

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.

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.