Aggravated decrease in the activity of nucleus basalis neurons in Alzheimer’s disease is apolipoprotein E-type dependent

As reported before, the metabolic activity of nucleus basalis neurons is reduced significantly in Alzheimer patients. Because the apolipoprotein E (ApoE) 4 genotype is a major risk factor for Alzheimer’s disease (AD), we determined whether the decrease in metabolic activity in nucleus basalis neurons in AD is ApoE-type dependent. The size of the Golgi apparatus (GA) was determined as a measure of neuronal metabolic activity in 30 controls and 41 AD patients with a known ApoE genotype by using an image analysis system in the nucleus basalis of Meynert. A polyclonal antibody directed against MG-160, a sialoglycoprotein of the GA, was used to visualize this organelle. There was a very strong reduction in the size of the GA in the nucleus basalis of AD patients. Furthermore, a strong and significant extra reduction in the size of the GA was found in the nucleus basalis neurons of AD patients with either one or two ApoE 4 alleles compared with Alzheimer patients without ApoE 4 alleles. Our data show that the decreased activity of nucleus basalis neurons in AD is ApoE 4 dependent and suggest that ApoE 4 participates in the pathogenesis of AD by decreasing neuronal metabolism.     

Testosterone locally increases vasopressin content but fails to restore choline acetyltransferase activity in other regions in the senescent male rat brain

Age-related decreases have been reported in both vasopressinergic and cholinergic innervation in the rat brain. Since both systems are also sensitive to sex steroids, the effect of testosterone supplementation on vasopressin (AVP) levels and on choline acetyltransferase (ChAT) activity was investigated in the brains of young, middle-aged and aged male rats. Although no age-related changes in AVP levels were observed in the lateral septum or the medial amygdala (MA), peripheral testosterone administration raised AVP levels in the MA in all age groups. ChAT activity decreased with age in the medial preoptic area and was not restored by testosterone.     

The supraoptic and paraventricular nuclei of the human hypothalamus in relation to sex, age and Alzheimer's disease

Volume and total cell number were determined in the supraoptic (SON) and paraventricular (PVN) nuclei of 14 male and 16 female subjects ranging in age from 10 to 93 years. In addition, 4 male and 6 female subjects suffering from Alzheimer's disease (AD) and ranging in age from 46 to 97 years were studied. Subjects were divided into two age groups, viz., "young" for subjects up to 60 years, and "old" for subjects older than 60. No sex differences in volume and in total cell number were observed in the SON and PVN in either age group. In addition, no significant correlation was found between total cell number in the SON and PVN and brain weight. No significant differences in volume and total cell number were found in either the SON or PVN between young and old control subjects or between AD cases and controls, indicating that these nuclei are spared from degenerative changes in senescence and AD. Determination of neuron numbers in the SON supported this view. In contrast, volume and total cell counts in the suprachiasmatic decreased in senescence and were dramatically reduced in AD. The present results indicate the occurrence of differential patterns of cell loss within the human hypothalamus with aging and in AD, which are proposed to be related to functional differences between the hypothalamic nuclei.     

Increased expression of estrogen receptor alpha and beta in the nucleus basalis of Meynert in Alzheimer's disease

The human nucleus basalis of Meynert (NBM) is severely affected in Alzheimer's disease (AD). Since estrogens may reduce both the risk and severity of AD, possibly by an action on the cholinergic system, we determined whether estrogen receptors are present in the human NBM and what their changes are in normal aging and in AD. ERalpha was expressed to a higher degree than ERbeta and was localized mainly in the cell nucleus, while ERbeta was mainly confined to the cytoplasm. A significant positive correlation between the percentage of ERalpha nuclear positive neurons and age was found in men but not in women, whereas the proportion of ERbeta cytoplasm positive cells increased during aging in both sexes. In AD the proportion of neurons showing nuclear staining for both ERalpha and beta and cytoplasmic staining for ERbeta was markedly increased. The percentage of ERbeta nuclear positive neurons increased in AD only in women but not in men. The ApoE genotype had no effect on ER expression in the NBM in AD. In conclusion, whereas only minor sex- and age-related changes in both ERs were found in the human NBM, a clear upregulation of ERalpha and beta was observed in AD.     

Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial

Rixt F. Riemersma-van der Lek, MD; Dick F. Swaab, MD, PhD; Jos Twisk, PhD; Elly M. Hol, PhD; Witte J. G. Hoogendijk, MD, PhD; Eus J. W. Van Someren, PhD

JAMA. 2008;299(22):2642-2655.

Context  Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms.

Objective  To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin.

Design, Setting, and Participants  A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia.

Interventions  Random assignment by facility to long-term daily treatment with whole-day bright (± 1000 lux) or dim (± 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years).

Main Outcome Measures  Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months.

Results  Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (–0.5 points; 95% CI, –0.10 to –1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect).

Conclusions  Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light.

Trial Registration  controlled-trials.com/isrctn Identifier: ISRCTN93133646

     

The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome

This paper examines how COMT¹⁵⁸ genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer‐based test‐paradigms. Associations with COMT¹⁵⁸ genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMT^MET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMT^MET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT¹⁵⁸ genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.     

The epidemiology of lip cancer: a review of global incidence and aetiology

Lip cancer (140 ICD-9) is a form of oral cancer that has a distinctive global epidemiology. This review summarises global incidence rates for male and female lip cancer with the aid of cancer atlases. High male lip cancer rates are reported for regions of North America (12.7 per 100 000 per annum), Europe (12.0 per 100 000 per annum) and Oceania (13.5 per 100 000 per annum), while it is virtually unknown in parts of Asia. Factors commonly cited as important in the aetiology of lip cancer include solar radiation, tobacco smoking and viruses. An attempt is made to summarise the evidence for factors that may be important in lip carcinogenesis. While incidence rates are generally stable or falling among males worldwide, they are rising in many female populations. The aetiology of the disease is far from established and much information regarding its pathogenesis is based on anecdotal rather than case-controlled epidemiological evidence. The epidemiology of lip cancer supports the proposal that the lip should be considered as a distinct cancer site, rather than being included with other forms of intraoral cancer.     

Postmortem tracing reveals the organization of hypothalamic projections of the suprachiasmatic nucleus in the human brain

The suprachiasmatic nucleus (SCN) is a small structure considered to be the site of the major circadian pacemaker of the mammalian brain. Disturbances in human biological clock function may occur in several diseases, such as Alzheimer's disease, sleep problems, and seasonal depression. Since basic knowledge of the anatomical connections of the human SCN is limited due to the lack of suitable neuroanatomical tracing methods, the understanding of physiological mechanisms of human SCN function has obviously been hampered. In the present study, the hypothalamic connections of the human SCN were revealed for the first time with a newly developed in vitro postmortem anterograde tracing method. The human SCN was found to be connected with nuclei in the hypothalamus that are involved in hormone secretion, cardiovascular regulation, and behavior activity. These human SCN projections appear to follow the same general patterns as those in the rodent brain. This homology may indicate an evolutionary conservation of the SCN projections from rodent to human. Through these connections, the human SCN may transmit its circadian information to regulate hormone secretion, body temperature, and behavioral functions as it does in animal species. In addition, the postmortem tracing technique may be a valuable tool that will contribute to our understanding of anatomical connections in the human brain, and may have other applications in the research on the physiology and pathology of the human brain. J. Comp. Neurol. 400:87–102, 1998. © 1998 Wiley-Liss, Inc.