Salivary Cortisol and Memory Function

Researchers writing in the medical journal Neurobiology of Aging say their “results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.”

From the study abstract
Li G, Cherrier MM, Tsuang DW, Petrie EC, Colasurdo EA, Craft S, Schellenberg GD, Peskind ER, Raskind MA, Wilkinson CW. Salivary cortisol and memory function in human aging. Neurobiol Aging. 2006 Nov;27(11):1705-14. Epub 2005 Nov 4

OBJECTIVE: To examine the association of salivary cortisol with cognitive changes in a 3 year longitudinal study. Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition.

METHODS: Salivary cortisol samples were collected at home by 79 cognitively intact older persons (mean age 78+/-7 years) at 08:00, 15:00 and 23:00h, and collections were repeated annually for 3 years. Cognitive function was also assessed annually.

RESULTS: The mean cortisol level of samples taken at three times of day and the cortisol concentration at 23:00h were significantly associated with poorer performance on tasks of declarative memory and executive function. Of 46 subjects who completed the entire 3 year study, higher initial cortisol concentration at 23:00h predicted a decline in performance of delayed paragraph recall.

CONCLUSION: These results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.

Midlife Obesity Raises Risk of Alzheimer’s Disease Later

Researchers reporting at the American Academy of Neurology 58th Annual Meeting in San Diego this week say that midlife obesity raises the risk for Alzheimer’s.

From the American Academy of Neurology press release:
“People who are overweight or obese in their 40s have a greater risk of developing Alzheimer’s disease later in life, according to research that will be presented at the American Academy of Neurology 58th Annual Meeting in San Diego, Calif., April 1 – 8, 2006.

For the study, researchers followed nearly 9,000 people over a period of up to 30 years. The study participants were evaluated for overweight and obesity by measuring skinfold thickness below the shoulder and at the back of the upper arm. Those with higher skinfold measurements in their 40s were more likely to develop Alzheimer’s disease than those with smaller skinfold measurements.

Those in the highest group of shoulder skinfold measurements were nearly three times as likely to develop Alzheimer’s disease as those in the lowest group. For the arm measurements, those in the highest group were 2½ times as likely to develop Alzheimer’s as those in the lowest group.”

Read the entire press release at the American Academy of Neurology website

Alzheimer’s Disease Research

Insulin and Aging
A new study, to be published, says that high insulin levels, among both diabetics and non-diabetics, may contribute to Alzheimer’s disease.

To quote the authors of the study “Although this model has obvious relevance for diabetes mellitus, hyperinsulinemia and insulin resistance are widespread conditions that affect many nondiabetic adults with obesity, impaired glucose tolerance, cardiovascular disease, and hypertension. Our results provide a cautionary note for the current epidemic of such conditions, which, in the context of an aging population, may provoke a dramatic increase in the prevalence of AD (Alzheimer’s).”

You can read the entire article at the Journal of Neurology

Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease.
Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Arch Neurol. 2005 Oct;62(10):1556-60.

From the abstract: “Obesity at midlife is associated with an increased risk of dementia and AD (Alzheimer’s Disease) later in life. Clustering of vascular risk factors increases the risk in an additive manner. The role of weight reduction for the prevention of dementia needs to be further investigated.”
Read the abstract

Brain Estrogen Deficiency and Alzheimer’s Disease
Writing in the Proceedings of the National Academy of Sciences (USA), researchers studied the effects of estrogen deficiency and Alzheimer’s Disease. They wrote: “Much evidence indicates that women have a higher risk of developing Alzheimer’s disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor….Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.”

Yue X, Lu M, Lancaster T, Cao P, Honda SI, Staufenbiel M, Harada N, Zhenyu Z, Shen Y, Rena Li R Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer’s disease animal model Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0505203102

Melatonin and Alzheimer-like neurodegeneration
Writing in the medical journal Acta Pharmacologica Sinica, researchers studied the effect of melatonin and cognitive impairment. They wrote: “Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients.” Wang JZ, Wang ZF. Acta Pharmacol Sin. 2006 Jan;27(1):41-9.

Read the abstract here

Obesity and Alzheimer’s Disease
Researchers say that obesity can lead to higher risk of Alzheimer’s disease.

From the press release issued by Thomas Jefferson University Hospital: “A team led by researchers at the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and Edith Cowan University in Joondalup, Western Australia has shown that being extremely overweight or obese increases the likelihood of developing Alzheimer’s. They found a strong correlation between body mass index and high levels of beta-amyloid, the sticky protein substance that builds up in the Alzheimer’s brain and is thought to play a major role in destroying nerve cells and in cognitive and behavioral problems associated with the disease.”

Exercise Delays Onset of Dementia and Alzheimer’s
Larson EB, Wang L, Bowen JD,McCormick WC, Teri L, Crane P, Kukull W. Exercise Is Associated with Reduced Risk for Incident Dementia among Persons 65 Years of Age and Older. Annals of Internal Medicine January 17, 2006 Volume 144 Issue 2 Pages 73-81.

A new study reports a reduced incidence rate of dementia for people who exercised 3 or more times a week compared with those who exercised fewer than 3 times per week.

Say the study authors: “We believe these findings may be useful if they are confirmed because Alzheimer disease is one of the most feared illnesses of aging and is frequently cited as a reason for not wanting to “get old”: People do not want to lose their independence and quality of life as a consequence of aging.”

They conclude: “These results suggest that regular exercise is associated with a delay in onset of dementia and Alzheimer disease, further supporting its value for elderly persons.”

Read the full article here at the Annals of Internal Medicine

Obesity and Alzheimer’s
Midlife Obesity Raises Risk of Alzheimer’s Disease Later
Researchers reporting at the American Academy of Neurology 58th Annual Meeting in San Diego this week say that midlife obesity raises the risk for Alzheimer’s. Read more

Testosterone, Alzheimer’s, Mood and Quality of Life
A study suggets that that testosterone replacement therapy improved overall quality of life in patients with Alzheimers Disease.

Brain Estrogen Deficiency and Alzheimer’s Disease
Writing in the Proceedings of the National Academy of Sciences (USA), researchers studied the effects of estrogen deficiency and Alzheimer’s Disease. They wrote: “Much evidence indicates that women have a higher risk of developing Alzheimer’s disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor….Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.”

Yue X, Lu M, Lancaster T, Cao P, Honda SI, Staufenbiel M, Harada N, Zhenyu Z, Shen Y, Rena Li R Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer’s disease animal model Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0505203102

Melatonin and Alzheimer-like neurodegeneration
Writing in the medical journal Acta Pharmacologica Sinica, researchers studied the effect of melatonin and cognitive impairment. They wrote: “Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients.” Wang JZ, Wang ZF. Acta Pharmacol Sin. 2006 Jan;27(1):41-9.

Read the abstract here

Cortisol Concentrations Predict a Decline in Memory Function
Researchers writing in the medical journal Neurobiology of Aging say their “results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.” Read more

Pregnenolone Research

Sleep and Memory

George O, Vallee M, Le Moal M, Mayo W. Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes. Psychopharmacology (Berl). 2006 Jan 17;:1-12

Rationale: The neurosteroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3alpha,5alpha THPROG) have been implicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory.

Objective: To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems.

Conclusions: The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments.

Alzheimer’s
Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients.

Weill-Engerer S, David JP, Sazdovitch V, Liere P, Eychenne B, Pianos A, Schumacher M, Delacourte A, Baulieu EE, Akwa Y.Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients.J Clin Endocrinol Metab. 2002 Nov;87(11):5138-43

Abstract: “…To investigate the physiopathological significance of neurosteroids in Alzheimer’s disease (AD), we compared the concentrations of pregnenolone, pregnenolone sulfate (PREGS), dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), progesterone, and allopregnanolone…in individual brain regions of AD patients and aged nondemented controls, including hippocampus, amygdala, frontal cortex, striatum, hypothalamus, and cerebellum.

A general trend toward decreased levels of all steroids was observed in all AD patients’ brain regions compared with controls: PREGS and DHEAS were significantly lower in the striatum and cerebellum, and DHEAS was also significantly reduced in the hypothalamus. A significant negative correlation was found between the levels of cortical beta-amyloid peptides and those of PREGS in the striatum and cerebellum and between the levels of phosphorylated tau proteins and DHEAS in the hypothalamus. This study provides reference values for steroid concentrations determined by gas chromatography-mass spectrometry in various regions of the aged human brain. High levels of key proteins implicated in the formation of plaques and neurofibrillary tangles were correlated with decreased brain levels of PREGS and DHEAS, suggesting a possible neuroprotective role of these neurosteroids in AD.”

Pregnenolone main page

Testosterone and Cognitive Function

A study in the European Journal of Endocrinology says “Low endogenous levels of testosterone may be related to reduced cognitive ability, and testosterone substitution may improve some aspects of cognitive ability.”

Beauchet O. Testosterone and cognitive function: current clinical evidence of a relationship. Beauchet O. Eur J Endocrinol. 2006 Dec;155(6):773-81.

BACKGROUND: Testosterone levels decline as men age, as does cognitive function. Whether there is more than a temporal relationship between testosterone and cognitive function is unclear. Chemical castration studies in men with prostate cancer suggest that low serum testosterone may be associated with cognitive dysfunction. Low testosterone levels have also been observed in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). This paper reviews the current clinical evidence of the relationship between serum testosterone levels and cognitive function in older men.

METHODS: A systematic literature search was conducted using PubMed and EMBASE to identify clinical studies and relevant reviews that evaluated cognitive function and endogenous testosterone levels or the effects of testosterone substitution in older men.

RESULTS: Low levels of endogenous testosterone in healthy older men may be associated with poor performance on at least some cognitive tests. The results of randomized, placebo-controlled studies have been mixed, but generally indicate that testosterone substitution may have moderate positive effects on selective cognitive domains (e.g. spatial ability) in older men with and without hypogonadism. Similar results have been found in studies in patients with existing AD or MCI.

CONCLUSIONS: Low endogenous levels of testosterone may be related to reduced cognitive ability, and testosterone substitution may improve some aspects of cognitive ability. Measurement of serum testosterone should be considered in older men with cognitive dysfunction. For men with both cognitive impairment and low testosterone, testosterone substitution may be considered. Large, long-term studies evaluating the effects of testosterone substitution on cognitive function in older men are warranted.

Testosterone, Alzheimer’s, Mood and Quality of Life

Effects of Testosterone on Cognition and Mood in Male Patients With Mild Alzheimer Disease and Healthy Elderly Men. Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. Arch Neurol. 2005 Dec 12

From the study abstract: “There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD).

OBJECTIVE: To evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with mild AD and healthy elderly men.

RESULTS: For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale. No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo.

In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures. Testosterone treatment was well tolerated with few adverse effects relative to placebo.”

CONCLUSIONS: Results suggest that testosterone replacement therapy improved overall quality of life in patients with AD. Testosterone had minimal effects on cognition.

Read the abstract