David G. Harper

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.

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 Alzheimers 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.

Disturbance of Endogenous Circadian Rhythm in Aging and Alzheimer Disease

OBJECTIVE Normal sleep-wake regulation is dependent upon an oscillatory circadian rhythm promoting alertness and sleep at appropriate times of day. Circadian rhythms have been noted to be disturbed as a consequence of both normal aging and age-associated pathologies like Alzheimer disease (AD). However, the relationship between the consequences of normal versus pathological aging upon circadian regulation remains unclear. The authors evaluated the similarities and differences between the consequences of aging and AD on endogenous circadian rhythm. METHODS Authors measured locomotor activity and, with a constant routine protocol, core body temperature, examining differences and similarities in circadian disturbances in groups of normal elderly and patients with probable AD (pAD), as compared with a comparison group of young, normal volunteers, measuring endogenous circadian amplitude (ECA) and endogenous circadian phase (ECP) of core body temperature, and made parametric and nonparametric assessments of locomotor activity rhythms. RESULTS The ECP of core body temperature was delayed in patients with pAD versus both normal young and normal elderly subjects, whereas the ECA was reduced both in normal elderly and pAD subjects compared with a comparison group of young subjects. There was also disassociation of the activity and core body temperature rhythms in both age groups versus the young subjects. CONCLUSIONS Authors observed changes in endogenous circadian rhythm in pAD that were consonant with those seen in normal aging (amplitude reduction; loss of phase coordination) and also observed changes that were apparently discrete from those seen in normal aging (phase delay).

Dementia severity and Lewy bodies affect circadian rhythms in Alzheimer disease

Sleep disturbance is a symptom shared by all neurodegenerative, dementing illnesses, such as Alzheimers disease (AD) and dementia with Lewy bodies (DLB), and its presence frequently precipitates decisions to seek institutional care for patients. Although the sleep disturbances of AD and DLB are qualitatively similar, they appear to be more prominent in patients with DLB. Disturbance of the circadian rhythm has been noted and is a potential factor underlying the nocturnal sleep fragmentation and daytime sleepiness observed in these patients. We studied the circadian variation of core-body temperature and motor activity in a total of 32 institutionalized patients with probable AD by NINCDS-ADRDA criteria, 9 of whom also met pathologic criteria for DLB. Eight, healthy, elderly male controls were studied on a clinical research unit designed to simulate the hospital environment where the dementia patients were studied. Circadian variables generally had greater deviations from normal associated with increasing AD pathology, as measured by postmortem-determined Braak stage, supporting the hypothesis that central changes mediate circadian disturbances in AD and DLB. Patients with a postmortem diagnosis of DLB manifested greater disturbances of locomotor activity circadian rhythms than patients with AD, possibly reflecting the greater sleep disturbances seen in this population, but the differences from normal in the circadian rhythms of the AD and DLB patients were qualitatively similar.

Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia.

The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythm in humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain-behaviour relationships in the human.

Locomotor Activity in Depressed Children and Adolescents: I. Circadian Dysregulation

OBJECTIVE To determine whether circadian activity rhythms were altered in pediatric patients with depression. Evidence was sought for a shift in the timing of the rhythm, blunting of circadian amplitude, or emergence of noncircadian periodicities. METHOD Locomotor activity was quantified in 57 patients with major depressive mood disorders (mean age 12.4 years) and 16 normal controls (9.9 years). Activity was measured in 5-minute epochs during 72 hours using belt-worn electronic activity monitors. RESULTS Patients with mood disorders displayed a 15% decrease in the amplitude of their circadian rhythm, and a 52% increase in the magnitude of their twice-daily (hemicircadian) rhythm. No significant difference emerged in the timing of the circadian rhythm. Depressed inpatients and outpatients displayed comparable disturbances, which were most marked in adolescents. CONCLUSIONS Circadian activity rhythms were dysregulated in pediatric patients with major depression. These findings may have etiological and diagnostic significance.

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°C) and luke-warm (37.5–38.5°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.

Age‐related changes in brain energetics and phospholipid metabolism

Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus (31P) MRS. 31P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21–84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (−0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using 31P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non‐demented and psychiatrically stable older adults and specifically analyzed gray‐white matter differences in brain metabolism. Copyright

Neuropsychiatric correlates of white matter hyperintensities in Alzheimer's disease†

To investigate the association of behavioral and psychological symptoms of dementia (BPSD) in Alzheimers disease (AD) and magnetic resonance imaging (MRI) measures of brain atrophy and white matter hyperintensities (WMH).

31Phosphorus magnetic resonance spectroscopy study of tissue specific changes in high energy phosphates before and after sertraline treatment of geriatric depression

We investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12‐week treatment trial of sertraline.