DHEA and cognitive function in the elderly.

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Contents lists available at ScienceDirect

Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb

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DHEA and cognitive function in the elderly

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Marcello Maggio a,b,∗ , Francesca De Vita a , Alberto Fisichella a , Elena Colizzi a , Sandra Provenzano a , Fulvio Lauretani a , Michele Luci a , Graziano Ceresini a,b , Elisabetta Dall’Aglio b , Paolo Caffarra c,d , Giorgio Valenti b , Gian Paolo Ceda a,b a

Geriatric Rehabilitation Department, University Hospital of Parma, Via Gramsci, 14, 43126 Parma (PR), Italy Department of Clinical and Experimental Medicine, Section of Geriatrics, Food Sciences Unit and Endocrinology of Aging Unit, University of Parma, Via Gramsci, 14, 43126 Parma (PR), Italy c Department of Neuroscience, University of Parma, Parma (PR), Italy d Outpatient Clinic for the Diagnosis and Therapy of Cognitive Disorders, AUSL, Parma (PR), Italy b

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Article history: Received 31 January 2014 Received in revised form 20 March 2014 Accepted 27 March 2014 Available online xxx

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Keywords: DHEA Cognitive function Older subjects

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The adrenal prohormone dehydroepiandrosterone (DHEA) and its sulphate conjugate (DHEAS) steadily decrease with age by 10% per decade reaching a nadir after the age of 80. Both DHEA and DHEAS (DHEA/S) exert many biological activities in different tissues and organs. In particular, DHEA and DHEAS are produced de novo in the brain, hence their classification as neurosteroids. In humans, the brain-to-plasma ratios for DHEA and DHEAS are 4–6.5 and 8.5, respectively, indicating a specific neuroendocrine role for these hormones. DHEA/S stimulates neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion. Together with antioxidant, anti-inflammatory and anti-glucocorticoid properties, it has been hypothesized a neuroprotective effect for DHEA/S. We conducted an accurate research of the literature using PubMed. In the period of time between 1994 and 2013, we selected the observational human studies testing the relationship between DHEA/S and cognitive function in both sexes. The studies are presented according to the cross-sectional and longitudinal design and to the positive or neutral effects on different domains of cognitive function. We also analysed the Clinical Trials, available in the literature, having cognitive domains as the main or secondary outcome. Although the cross-sectional evidence of a positive association between DHEA/S and cognitive function, longitudinal studies and RCTs using DHEA oral treatment (50 mg/day) in normal or demented adult–older subjects, have produced conflicting and inconsistent results. In summary, the current data do not provide clear evidence for the usefulness of DHEA treatment to improve cognitive function in adult–older subjects. This article is part of a Special Issue entitled ‘Essential role of DHEA’. © 2014 Elsevier Ltd. All rights reserved.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Physiology: Notes on DHEA/S secretion and changes during lifetime . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Biological actions of DHEA and DHEAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The neuroprotective role of DHEA/S in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . In vitro and animal Studies addressing the role of DHEA/S on cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: University of Parma, Clinical and Experimental Medicine, via Gramsci 14, Parma (PR), Italy. Tel.: +0039 0521703916/+0039 3313534235; fax: +0039 0521987562. E-mail addresses: [email protected], [email protected] (M. Maggio). http://dx.doi.org/10.1016/j.jsbmb.2014.03.014 0960-0760/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: M. Maggio, et al., DHEA and cognitive function in the elderly, J. Steroid Biochem. Mol. Biol. (2014), http://dx.doi.org/10.1016/j.jsbmb.2014.03.014

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Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Observational studies testing the relationship between DHEA/S and cognitive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Cross-sectional studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Longitudinal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The role of cortisol/DHEAS molar ratio in dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Intervention studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Inclusion criteria and the choice of dosage in men and women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Effects of DHEA treatment in pre and postmenopausal women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Effects of DHEA treatment in adult and older men and in both sexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.4. The role of DHEA in cerebrospinal fluid and mild cognitive impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.5. Effects of DHEA in acute stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Limitations and strengths of RCTs on DHEA treatment in cognitive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction 1.1. Physiology: Notes on DHEA/S secretion and changes during lifetime The adrenal prohormone dehydroepiandrosterone (DHEA) and its sulphate conjugate (DHEAS) are the most abundant steroid hormones in men, secreted innermost by the reticularis zone of the adrenal gland [1]. In an intracrine fashion, DHEA and DHEAS (DHEA/S) are metabolically inter-convertible by sulfo-transferase and sulfatase enzymatic activities in many peripheral tissues. DHEA is bound to albumin, less firmly than DHEAS. DHEA, but not DHEAS, is also weakly bound to Sex Hormone Binding Globulin [2]. Thus, DHEA is more rapidly cleared (half-life of 1 to 3 h) than DHEAS (half-life 10 to 20 h) and its blood levels (the typical circadian pattern of DHEA secretion) reflect the circadian secretion of the adrenocorticotrophic hormone (ACTH), which is the main regulator of DHEA concentration. However, there is no negative feedback of DHEA on ACTH [3]. Labrie and colleagues described for the first time that DHEA and DHEAS are adrenal precursors of sex steroids, after conversion into androstenedione, in the liver and other target organs [4]. DHEA/S accounts for 50% of androgens in men and 75% of estrogens in premenopausal women. After menopause, adrenal DHEA, DHEAS and androstenedione become the major precursors for both extragonadal estrogens and androgens [5,6]. These transformations are under control of tissue steroidogenic and metabolising enzymes such as 3␤-hydroxysteroid dehydrogenase/5-4-isomerase, 17␤-hydroxysteroid dehydrogenase, 5␣-reductase, and aromatase [7]. DHEAS levels vary profoundly throughout life in both sexes. Due to the immaturity of the 11␤-hydroxylase enzyme in utero, the 4 pathway within the adrenal gland remains inactive, shifting to the cholesterol metabolites production towards the 5 pathway, resulting in high DHEA levels. After birth, the zona glomerulosa becomes more active, and both the activity of the 5 pathway and DHEA levels decrease. DHEA concentrations start to rise at ‘adrenarche’, i.e. between 8 and 10 years of age, reaching a peak at the middle or at the end of the second decade of life [8] when DHEA/S starts to steadily decrease (10% per decade reaching a nadir after the age of 80) [9]. In both sexes at older age, the typical circadian pattern of DHEA secretion is completely lost [10]. Adrenopause is a generic term that highlights the significant decline in DHEAS production throughout the lifetime, and the major stability of glucocorticoids and mineralocorticoids. One of the potential underlying causes of DHEA/S decline is the progressive apoptosis of the cells of the zona reticularis. As consequence, there is an impaired activity of the enzyme 17,20-desmolase, which is fundamental in the conversion of 17-hydroxypregnenolone into DHEA [3,11].

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The overall result of these changes is the reduction in circulating DHEA/S levels and the blunted response to ACTH stimulation, with a normal cortisol response [12]. However, in conditions accompanied by chronic ACTH stimulation, DHEA/S levels may remain normal or decreased [13]. Lastly, some authors have suggested that the impairment of DHEA secretion may be realized through the inhibition of adrenal steroid synthesis as consequence of the age-associated insulin-resistance and hyperinsulinemia [14]. 1.2. Biological actions of DHEA and DHEAS Although DHEA/S is able to exert many biological actions, the precise mechanism is largely unknown. The activities of DHEA/S are thought to be mainly mediated by both a specific G protein coupled plasma membrane receptor [15] and a nuclear DHEA specific receptor binding complex [16]. DHEA seems to bind estrogen receptors exerting some estrogenlike activities, independent of its conversion to estradiol [17]. DHEA/S biological actions may also be realized through 7␣hydroxy-DHEA [18]. Some skeletal muscle binding sites can explain specific influence of DHEA/S on muscle function [19]. The specific G protein coupled plasma membrane receptor can influence the endothelial nitric oxide synthase activity [15]. In cultured human vascular smooth muscle cells (VSMCs), DHEA seems able to inhibit the cell proliferation by a mechanism independent of either androgen or estrogen receptors [20]. The unique mechanism by which DHEA induces the restoration of nitric oxide levels seems to be due to the increase and the stabilization of endothelial nitric oxide synthase expression within vascular epithelial cells [21]. Another DHEA specific receptor-binding complex has also been found in murine and human T cells. In this model, DHEA binding to this receptor complex led to an increased interleukin 2 production, supporting the beneficial influence of DHEA on immune system [5,22,23]. 2. The neuroprotective role of DHEA/S in the brain DHEA and DHEAS are produced de novo in the brain, hence their classification as neurosteroids [24,25]. In humans, the brain-toplasma ratios for DHEA and DHEAS are 4–6.5 and 8.5, respectively, indicating a neuroendocrine specific role for these hormones [26]. The major biological actions of DHEA/S in the brain (Fig. 1) involve neuroprotection [27,28], neurite growth [29,30], neurogenesis and neuronal survival [31,32], stimulation of apoptosis [33,34], catecholamine synthesis and secretion [35], as well as antioxidant [36], anti-inflammatory [37] and anti-glucocorticoid effects [38]. In humans, all these actions explain the potential beneficial effects of DHEA on mood, well-being and cognition, in particular as


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Fig. 1. Potential molecular mechanisms by which DHEA/S affects cognitive function.

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memory enhancing, antidepressant, anxiolytic and anti-aggressive agent [39]. DHEA/S exerts anti-amnesic effects through the stimulation of ␴-1 receptor [40]. In fact, ␴-1 receptor ligands have been reported to affect learning and memory processes via the long-term potentiation (LTP) of the N-methyl d-aspartate (NMDA) receptors [41]. LTP is a form of activity-dependent plasticity which results in a persistent enhancement of synaptic transmission. Data from animal studies support the induction of LTP after DHEA chronic treatment, which is blocked by the ␴-1 receptor antagonist [42]. DHEA may also act as anti-amnesic factor via calcium–phospholipid-dependant protein kinase C (PKC), which is also involved in the induction and maintenance of the LTP of NMDA. The activity of PKC is impaired in the brain of aging male animals and is reversed after DHEA treatment [43]. In addition, DHEA might be directly implicated in the modulation of the neuronal excitability both by NMDA receptor stimulation and ␥-aminobutyric acid (GABA) receptor inhibition [44,45]. DHEAS seems also to have a more potent antagonistic activity at NMDA receptor than DHEA. DHEAS is capable to enhance the

neuronal response to NMDA, to increase free intracellular calcium and to protect neuronal cells from NMDA-induced excitotoxicity [28]. However, some of DHEA/S actions might be realized through its conversion into sex steroids and the activation of androgen and estrogen receptors at tissue level, including central nervous system (CNS). Although most of the current data show that estradiol and testosterone have positive effects on cognitive performance [46–49], data at this regard are not conclusive. The age-related decline in DHEA/S levels is also accompanied by the reduction of insulin like growth factor (IGF)-1 levels [50]. IGF-1 is highly expressed within the brain, where it exerts neurotrophic and neuroprotective effects [51]. Low serum IGF-1 levels have been associated with deterioration of cognitive function [52]. DHEAS indirectly influences the production of IGF-1 and might modify its systemic and neurotrophic biological activities by inducing changing in IGF-binding proteins (IGFBPs). In fact, IGFBP-3 concentration has been positively correlated with DHEAS levels [53,54]. In both men and women, DHEA replacement therapy is capable to increase serum IGF-1 levels and IGF-1/IGFBP-1 ratio and may


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represent a precious physiological regulator of the IGF-1 system [55]. DHEA/S may act as neuroprotective agent by increasing or maintaining IGF-1 secretion. Animal studies confirm that DHEA may influence brain function other than binding to NMDA receptors [22] and can also favour the cortical-thalamic projection growth in the embryo [29]. DHEA/S exerts antagonistic activity at GABA receptor [56] and stimulates serotonin synthesis in the hypothalamus [57]. In brain slices, DHEAS inhibits GABA A-induced chloride ion transport currents in a dose-dependent manner leading to hypothesize the involvement of DHEA/S in the GABA A receptor antagonism [58,59]. DHEAS could be implicated in the modulation of different neurotransmitters release, such as glutamate and acetylcholine (ACh). In the hippocampus, the mechanism by which DHEAS stimulates spontaneous glutamate release is linked to the activation of presynaptic ␴-1 receptors [60]. The promoting effect of DHEAS on glutamate release in the hippocampus might explain its influence on learning and memory [61]. However, in the prefrontal cortex, the ␴-1 receptor antagonist, is capable to partially block the effect of DHEAS [62], suggesting the involvement of more complicated mechanisms to justify the effect of DHEAS on glutamate release in the prefrontal cortex. DHEAS promotes ACh release in the hippocampus [63] and augments cholinergic function in animal models [64]. All these effects may also contribute to explain its memory enhancing activity. There is also strong evidence that DHEA/S and its highly active steroid derivatives serve as anti-inflammatory pool. They can both modulate pro-inflammatory molecules, such as interleukin-6, tumor necrosis factor˛, nuclear factor-k B and the immune states, shifting the immune profile from Th2 to Th1 response [65,66]. This is of importance since increased inflammation and elevated levels of inflammatory cytokines have been associated with physical and cognitive decline [67,68]. Subsequently, the reduction in DHEA/S levels observed with age might contribute to shift the immunologic and inflammatory mechanisms toward a pro-inflammatory status, at both systemic and tissue (CNS) levels. However, this mechanism has been questioned by a very recent study posing serious doubts about the role of sex hormones, inflammation, and glucose metabolism as efficient pathways to explain the effects of DHEA/S on cognitive function [69]. Finally, the decrease in DHEA/S levels is also a potential trigger of the onset of cognitive impairment, including Alzheimer disease (AD), in older persons [70]. DHEA/S could exert neuro-protective actions against amyloid ␤ protein toxicity [71] and lipid peroxidation in human brain tissue. These effects have been observed in patients affected by AD [72]. DHEA/S seems also to decrease the b-site amyloid ␤ precursor protein-cleaving enzyme (BACE), that initiates the production of amyloid in the senile plaques found in brain tissue [36].

3. In vitro and animal Studies addressing the role of DHEA/S on cognition Several in vitro and animal studies support a role for DHEA/S in memory processes and other domains of cognitive function. In mice, DHEAS seems to prevent the memory impairments induced by the ACh receptor antagonist scopolamine [73]. A number of in vivo and in vitro studies have tested the effects of DHEAS on neuronal excitability and synaptic plasticity. Acute exposure to DHEAS rapidly facilitates the basal synaptic transmission in hippocampal CA1 through a non-competitive negative modulation of the GABA A receptor [56,74], known to have binding sites for DHEAS [45,74]. This data is confirmed by pharmacological studies showing that GABA A receptor antagonists inhibit the facilitation

of synaptic transmission induced by DHEAS [56]. However, the chronic effect of DHEAS on GABA A receptors has not fully been evaluated [75]. DHEAS could also affect cognitive function by enhancing spontaneous glutamate release in hippocampal neurons [60]. Acute administration of DHEAS facilitates primed-burst potentiation, but not the induction of LTP [76], which is stimulated by chronic administration of DHEAS [42]. As already described, DHEAS causes a chronic activation of the ␴-1 receptor, which leads to a certain priming status of postsynaptic neurons for LTP induction. However, ␴-1 receptor is not involved in the LTP induction. An enhancing effect of DHEAS on learning process is abolished by co-administration of the ␴-1 receptor antagonist [77]. High levels of ␴-1 receptor are distributed in the hippocampus, hypothalamus and cerebellum in rodents [78], in a similar fashion to what observed in humans [79]. A ligand binding subunit of the ␴-1 receptor is detected in the endoplasmic reticulum and in the postsynaptic membrane [80]. Intra-cerebroventricular infusion of a 16-mer antisense oligo-deoxynucleotide against the cloned ligand binding protein of endoplasmic reticulum type blocks the antiamnesic effect of DHEAS [81], indicating an interaction between DHEAS and the ␴-1 receptor in vivo. In hippocampal cell cultures, DHEA attenuates the neurotoxic exposure to glucocorticoids [82], excitatory amino acids [83] and oxidative stress [72], without any effect on the cell number. Interestingly, administration of DHEA seems to significantly improve the cognitive status of old mice [84]. However, we have to acknowledge significant differences between rodent and human adrenal endocrine systems. Most of DHEA/S in humans is synthesized from the adrenal glands, while in rodents active DHEA/S is locally produced in different tissues [85]. Moreover, rodents do not experience the age-related decrease in DHEA/S production observed in humans. In addition, the circulating DHEA/S levels in mice and rats are often unmeasurable [24], making any exogenous dose of DHEA/S supraphysiological. Thus, the rodent model cannot be considered the ideal one to be translated in primates or humans [85].

4. Human studies 4.1. Observational studies testing the relationship between DHEA/S and cognitive function 4.1.1. Cross-sectional studies The parallel and marked reduction in DHEA/S levels and cognitive ability with age, together with the above-mentioned neuroprotective actions, has led to hypothesize a beneficial role for DHEA/S, especially in older subjects [85]. The cross-sectional relationship between DHEA/S levels and cognitive impairment has been largely investigated in adult and older populations (Table 1). In demented patients both hippocampal volume (assessed by magnetic resonance imaging) [86] and perfusion [87] have been directly related to DHEAS levels. By using data of the InCHIANTI Study, Valenti and co-workers showed a positive and independent association between baseline serum DHEAS levels and cognitive function, assessed by MiniMental State Examination (MMSE) test [88]. These data were confirmed by another cross-sectional study, conducted in 124 African American younger men (aged 50–65 years), where DHEAS was positively associated with MMSE scores [89]. In a recent study evaluating three cognitive domains (working memory, executive function and word processing speed) in a group of 49 men and 54 women, aged 60–88 years, with low serum DHEAS concentrations (3.8 ␮mol/L, 140 ␮g/dL), there was a positive association of serum DHEAS and working memory [69]. However,


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Table 1 Observational Studies Testing the Relationship between DHEAS and Cognitive function selected according to significant findings. Author reference

Year

Design

Population (number and age)

Follow-up (years)

Tests

Results

Test on cognition-executive function, working memory, and processing memory speed MMSE, TMT

DHEAS levels are positively associated with executive function in men DHEAS levels are positively associated with higher MMSE score DHEAS levels are positively associated with executive function, concentration and working memory

Positive association Hildret et al. [69]

2013

Cross sectional

49 m, 54 w, 60–88 y

–

Haren et al. [89]

2008

Cross Sectional

124 m, 50–65 y

–

Davis et al. [90]

2008

Cross sectional

295w, 21–77 y

–

Valenti et al. [88]

2009

Cross Sectional/Longitudinal

410 m, 345 w, >65 y

3

Goldman et al. [95]

2007

Longitudinal

472 m, 364 w, 54–91 y

3

Sanders et al. [96]

2010

Longitudinal

361 m, 628 w, >65 y

10

Fonda et al. [94]

2005

Cross sectional

981m, 48–80 y

–

Backward digit span test, DSST, figural relations test

Berr et al. [97]

1996

Longitudinal

266 m, 356 w, >65 y

4

Yaffe et al. [98]

1998

Longitudinal

394 w, >65 y

4–6

MMSE, Benton’s visual retention test, Weschler’s paired associates test, Isaac set test, Zazzo’s test, Weschler’s digit test, similarities test of the Weschler’s memory scale Modified MMSE, trials B, digit symbol, and GDSS

Moffat et al. [99]

2000

Longitudinal

883 m, 22–91 y

31

Barrett-Connor et al. [100]

1994

Longitudinal

270 m, 167 w, >65 y

16-–19

Kalmijin et al. [101]

1998

Longitudinal

189 m, and w, 55–80 y

4

BVRT, free and cued selective reminding test, MMSE, the blessed information-memoryconcentration test, the trail-making test Mini-mental status examination, Buschke selective reminding test, trails B, category fluency, and Heaton visual reproduction test MMSE

Mazat et al. [102]

2001

Longitudinal

119 m, 171 w, >70 y

8

MMSE

California verbal learning test immediate, Wechsler memory scale-third edition, FAS, Stroop, TMT(B), Wechsler memory scale-third edition MMSE

Short portable mental status questionnaire, the modified rey auditory verbal learning test, the modified digits backward test Modified MMSE, DSST

Higher DHEAS levels are associated and predictors of MMSE score DHEAS levels are predictors of physical and cognitive decline in men, but not in women

Low DHEAS is a marker of psychomotor speed and working memory decline in women

No significant relationship No significant effects of DHEAS on working memory, speed/attention and spatial ability No change in DHEAS levels in cases of incident dementia

DHEAS is not a sensitive predictor of cognitive performance or decline in women DHEAS is not predictor of cognitive decline

Baseline DHEAS is not associated with 4 of 5 tests of cognitive function

No significant association of DHEAS with cognitive impairment or decline No relationship between changes in DHEAS levels and mental status

Legend of the table: m = men; w = women; y = years; MMSE = mini-mental state examination; BVRT = Benton visual retention test; TMT = trail-making test; FAS = controlled oral word association test; Stroop = stroop color-naming interference test; DSST = digit symbol substitution test.

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the relationship was sex-specific, with a trend toward a better executive function only in men. Interestingly, the age strongly influenced the association between DHEAS, executive function and word processing speed [69]. In 295 older healthy Australian women (aged 21–77 years) living in the community, those with higher levels of DHEAS and at least 12 years of education, exhibited better performance in tests of cognitive abilities including verbal, visual, spatial and working memory, attention and concentration, speed, and accuracy [90]. Consistently, some studies conducted in frail elderly patients and nursing home residents found an inverse relationship between DHEAS levels and cognitive abilities [91–93].

By contrast, in the large older male cohort of Massachusetts Male Aging Study, Fonda et al. failed to find any significant association between endogenous levels of DHEA/S and working memory, speed/attention and spatial ability during late life [94].

4.1.2. Longitudinal studies There are several longitudinal studies focusing on the relationship between DHEA/S levels and development of cognitive impairment (Table 1). These studies were different in terms of age, race, duration of follow-up, and the cognitive domains analysed.


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Table 2 Intervention studies testing the effects of DHEA administration on different domains of cognitive function selected according to significant findings. Author reference

Year

Design

Population (number and age)

Dose and duration

Tests

Results

Recognition memory, perceptual identification test, digit span memory tests, visual attentional vigilance task MMSE and HDS-R

DHEA improves recognition memory status

Positive effects Hirshman et al. [114]

2003

Double blind RCT

30 w, 39–70 y

DHEA 50 mg/d, 4 weeks

Yamada et al. [131]

2010

No RCT

27 w, 65–90 y

DHEA 25 mg/d, 6 months

Stangl et al. [115]

2011

Double blind placebocontrolled crossover

24 w, 55–80 y


Cognitive tasks designed to measure visual–spatial processes and MMSE

DHEA supplementation may have beneficial effects on verbal fluency DHEA has a beneficial effect on performance in visual-spatial tasks

No beneficial effects Wolf et al. [119]

1997

Double blind RCT

25 m, 15 w, 69 y mean age


Wolf et al. [111]

1998

Double blind RCT

38 m, 37 w, 59–81 y


Wolf et al. [117]

1998

17 m, 59–81 y


Visual, spatial and semantic memory tests

Barnhart et al. [134]

1999

Double blind placebocontrolled crossover Double blind RCT

60 w, 45–55 y

DHEA 50 mg/d, 3 months

Buschke immediate recall and delayed recall tests, symbol copying, DSST

van Niekerk et al. [106]

2001

Double blind RCT

46 m, 60–80 y


Wolkowitz et al. [132]

2003

Double blind RCT

58 m–w 75 y mean age

DHEA 50 mg/d 6months

Ten-item word list memory, test of object location memory, small battery-operated machine assessing choice reaction time AD assessment scale-cognitive, MMSE

Kritz-Silverstein et al. [120]

2008

Double blind RCT

110 m, 115 w, 55–85 y

DHEA 50 mg/d 1 y

Merritt et al. [113]

2012

Double blind RCT

48 w, 55–80 y


Age concentration test, picture memory test, stroop, digit span, number connecting, auditory verbal learning test Tests designed on visual–verbal memory, selective-attention and spatial memory

MMSE, TMT(B), category fluency test, modified boston naming test, word list memory and word list recall Digit span performance, verbal span performance tests, modified Sternberg paradigm

DHEA replacement does not improve psychomotor speed, concentration and memory DHEA has no effect on spatial memory. Improves attention and worsens visual–verbal memory after stress No effect of DHEA replacement on visual, spatial, and semantic memory No significant difference between DHEA group and placebo after test on psychomotor speed and memory No benefit of DHEA on attention, speed of information processing and verbal episodic memory

DHEA does not significantly improve cognitive performance in AD No difference in MMSE and other tests between DHEA treatment and placebo

No beneficial effects on short-term memory

Legend of the table: RCT = randomized controlled trials; m = men; w = women; y = years; mg/d = mg per day; AD = Alzheimer disease; HDS-R = Hasegawa dementia scalerevised; TMT = trail-making test; Stroop = stroop color-naming interference test. Each dose of DHEA was orally administered.

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In older men and in women of the InCHIANTI Italian cohort, low DHEA/S levels were significant predictors of accelerated decline in MMSE score during the 3-year follow-up period [88]. Goldman and Glei [95] found a significant role for baseline DHEAS concentrations in predicting 3 year-physical and cognitive decline in men (n = 472, mean age 66 years) but not in women (n = 364, mean age 65 years). These data have not been confirmed by Sanders et al. in a study testing the role of DHEAS decline in the deterioration of physical and cognitive performance during 10 years of observation [96]. In this cohort of 989 participants aged 65 years and older, the decline in DHEAS levels was a significant

predictor of Modified MMSE score and digit symbol substitution test (DSST) score (measures of psychomotor speed and working memory) in women independent of baseline DHEAS levels [96]. Additional studies have similarly found no relationship or even negative association between DHEA/S concentrations and cognitive function [97–102]. In 622 older subjects, Berr and coworkers found no association between DHEAS and cognitive function measured by MMSE and other battery tests assessing visual memory (Benton’s Visual Retention test), verbal memory (Wechsler Paired Associates test), verbal fluency (Isaac Set test), visuo-spatial attention (Zazzo’s test),


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simple logical reasoning (Wechsler Digit test), and abstractional abilities (Similarities Test of the Wechsler memory scale) during 4-year follow-up period [97]. Consistently, in a study of 394 community-dwelling women (aged 65 or older), the decline in serum DHEAS levels was not related, at 4–6 year follow-up, with cognitive function or change in cognitive performance assessed by modified MMSE, Trials B, Digit Symbol and the Geriatric Depression Scale-Shortened (GDSS) [98]. Moffat and co-authors by using data of the Baltimore Longitudinal Study of Aging, examined 883 community-dwelling men (aged 22–91 years) for 31 years. These authors found that neither mean DHEAS concentrations nor change in serum DHEAS concentrations were related to cognitive status or cognitive decline assessed by tests of verbal and visual memory, mental status, phonemic and semantic word fluency, and measures of visuomotor scanning and attention [99]. In a prospective study of 270 men and 167 women, Barrett–Connor and Edelstein [100] did not appreciate any association between baseline DHEAS levels and four of five standard screening tests of cognitive function, including MMSE. During a minimum of 14 and a maximum of 19 years follow-up period, DHEAS levels were significantly correlated with the Buschke test, only in women. Similarly, data from the Rotterdam Study, based on 189 participants aged 55–80 years, did not demonstrate a significant positive trend between baseline serum DHEAS levels and either cognitive impairment or cognitive decline (defined as a drop in the MMSE score of more than 1 point/year) in a quite short follow-up time (4 years, 1.9 on the average) [101]. Finally, Mazat et al. [102], in a cohort of 290 older participants, reported no significant role for DHEAS levels as predictor of any functional and psychological changes, and cognitive decline assessed by the MMSE. In conclusion, from the current available longitudinal studies, the relationship between DHEA/S serum levels and cognitive function is far to be well delineated.

4.2. The role of cortisol/DHEAS molar ratio in dementia The aging process is characterized by modifications of metabolic, anatomical pathways and steroid milieu inside CNS. Interestingly, the zona reticularis of the adrenal cortex undergo a selective impairment with age, probably because of the peculiar sensitivity of this area to microhemorrhagic events and vascular necrotic damage [103]. All these structural changes determine an imbalance between glucocorticoid and androgen secretions [103]. The two main actors of this hormonal imbalance have been identified in cortisol and DHEA/S. The ratio of these two hormones, cortisol/DHEAS molar ratio, has been considered a reliable marker of the balance between neurotoxic and neuro-protective factors. Not surprisingly, many studies have tried to show a relationship between blood cortisol levels, cortisol/DHEAS molar ratio and the severity of cognitive decline in adult subjects [104,105]. Indeed, 24-h cortisol/DHEAS molar ratio was found to be significantly higher in older persons, especially in those affected by dementia, compared to young controls. In older men, the ratio has been negatively associated with cognitive performance (subjects with MMSE score lower than 26 points had higher ratios) [101] and positively related to smaller hippocampal volume. Interestingly, the expected increase in cortisol/DHEAS molar ratio in centenarians has not been always reported [103]. In older men, lower morning salivary DHEA and higher salivary cortisol/DHEA ratio have been associated with more confusion and poorer visual–spatial memory performance [106]. Consistently, in a small study of senile dementia of Alzheimer type (sDAT) (mean age 66.9 ± 1.9 yr) there was a significant increase

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of cortisol/DHEAS molar ratio together with progressive higher levels from healthy to demented older patients [107]. Finally, an Italian case-control study performed in a limited number of AD subjects (5 men and 18 women 49–83 yr) has shown higher cortisol/DHEAS ratio without any relationship with the severity of dementia [108]. 4.3. Intervention studies Data coming from the majority of observational studies in humans and trials conducted in aged rodent models and primate model of Parkinson’s disease [109,110] have led to hypothesize a potential effect of exogenous DHEA supplementation in improving some cognitive domains. This neuroprotective effect has been tested in several human intervention studies (Table 2). 4.3.1. Inclusion criteria and the choice of dosage in men and women The ability of DHEA treatment to restore the normal DHEAS reference range and the bio-conversion rate of DHEA into testosterone and estrogens have been addressed in clinical trials conducted in both sexes. Most of the clinical trials used 50 mg of DHEA [111]. In older men, this dose has been shown to induce a significant increase in serum estradiol levels, without affecting testosterone and dihydrotestosterone concentrations [112]. In contrast, in older women, the same oral load was accompanied by an increase in serum testosterone levels, with minimal change in estradiol [55]. These data have been confirmed in a recent study in postmenopausal women (mean age of 63.5 years) where 50 mg oral DHEA resulted in a substantial increase of DHEA, DHEAS and testosterone, without any significant changes in estrone levels [113]. However, the characteristics of subjects enrolled in different clinical trials deserves some comments. DHEA replacement therapy was mostly tested in healthy older people with low serum DHEAS concentrations and/or where cognitive function was not the main outcome measure. However, we should also acknowledge that those intervention studies considering cognitive performance as the main outcome, did not recruit subjects according to DHEAS levels at entry. Therefore, the design and the quality of the current studies make very difficult the translation of their findings into the clinical practice. 4.3.2. Effects of DHEA treatment in pre and postmenopausal women Experimental studies exploring the effects of DHEA on cognition and memory performance in pre and post-menopausal women have reported mixed results, raising important questions about the opportunity of starting DHEA replacement therapy in this specific population. Hirshman et al., in a double-blind, randomized controlled trial (RCT) of 30 both pre- and post-menopausal women (ages 39–70) assigned to 4 week 50 mg/day oral DHEA or placebo, showed a marginal impact of DHEA on visual perception and memory [114]. The effects of DHEA treatment have been also tested in groups of only post-menopausal women. In a double-blind placebocontrolled crossover design study (24 women aged 55–80 yr), 50 mg of DHEA had beneficial effect only in few visual–spatial tasks [115]. In 48 women (mean age 63.8 years), with mean baseline DHEAS levels of 1.41 ␮mol/L, 4 week 50 mg oral DHEA administration did not affect short-term memory assessed by the digit and verbal tasks or modified Sternberg paradigm [113]. Surprisingly, 6 month treatment with 25 mg oral DHEA in 11 postmenopausal women (aged


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46–66, mean age 52.1 yr), produced negative effect on digit span memory [116]. 4.3.3. Effects of DHEA treatment in adult and older men and in both sexes The effects of DHEA treatment were also explored in middle-age and older men (age range 59–81 yr). In these 17 subjects 2-week DHEA treatment (50 mg daily) did not induce any change in memory or mood [117]. Similarly, van Niekerk and co-authors [106], showed no benefit of 13 week 50 mg DHEA daily treatment on attention, speed of information processing and verbal episodic memory in 46 middle-aged older men. Arlt and co-workers [118], in healthy older men, with serum DHEAS levels at entry below 4.1 ␮mol/L, and aged between 50–70 yr, noted that the restoration of DHEAS to adult normal reference range did not lead to a significant improvement in well-being or mood. However, no information was collected on cognitive function. Studies conducted in both sexes have shown similar results. In 25 healthy subjects (mean age 69.4 yr) Wolf et al. failed to detect any improvement in 6 cognitive tests assessing psychomotor speed, concentration, short and long term memory after 2-week of 50 mg daily DHEA treatment [119]. In the DHEA and Well-Ness (DAWN) Study, conducted in more than 200 healthy middle-aged and older men and women without signs of cognitive impairment, 1 year DHEA supplementation (50 mg/day) did not produce any beneficial effect on cognitive function [120]. Consistently, the examination of randomised, placebo-controlled clinical trials by Legrain et al. did not show any significant effect of DHEA replacement therapy in healthy individuals aged 60 years and over [121]. 4.3.4. The role of DHEA in cerebrospinal fluid and mild cognitive impairment DHEA/S concentrations and their changes in the cerebrospinal fluid (CSF) have been reported in some diseases. For instance AD and/or multi-infarct demented subjects had decreased [122–124], as well as increased or unchanged [125–127], serum and CSF DHEA/S levels. These results highlight the complexity of DHEA/S metabolism in the CNS. Patients with AD or vascular dementia showed increased DHEA levels along with reduced level of DHEAS in CSF and unmodified levels of 7␣-hydroxy-DHEA, 7␤-hydroxy-DHEA and 16␣-hydroxy-DHEA [128,129]. The authors speculated that elevated DHEA concentrations in CSF arose from either an overproduction via an alternate synthetic pathway [130] or reduced sulfation and hydroxylation. Thus, the assessment of DHEA levels could be useful during the prodromal phase of the mild cognitive impairment (MCI) in the elderly. Surprisingly, few studies have been performed in this specific group. Yamada et al. in their open, non-randomized controlled study showed beneficial effects of DHEA in elderly women with mild to moderate cognitive impairment. Participants randomized to oral DHEA (25 mg daily) or placebo for 6 months experienced both an improvement in cognitive function (verbal fluency) and an independence in basic activities of daily living (ADL) [131]. An open-label study with DHEA at higher doses (200 mg/day intravenously for 4 weeks) showed in more than 50% of multiinfarct demented patients a significant better psychometric performance test [122]. Finally, although an improvement of cognition (evaluated by the AD Assessment Scale-Cognitive) was observed after 3 months of DHEA supplementation in a small-scale randomized double-blind placebo-controlled study of AD subjects, this beneficial effect was no longer significant after 6 months [132]. 4.3.5. Effects of DHEA in acute stress The use of DHEA has also been evaluated in the response to acute stress. Wolf et al. [111], in a placebo-controlled trial of 75 older men

and women, tested the effects of 2-week DHEA administration on cognitive performance, before and after a laboratory psychological stressor (a free speech and mental arithmetic, during 5 min, in front of an audience). In DHEA group these authors found a lesser cognitive deterioration in the selective attention after the psychosocial stressor. However, acute DHEA administration, when compared to placebo, seemed to induce a significant impairment in the visual memory test. 4.4. Limitations and strengths of RCTs on DHEA treatment in cognitive function Current evidence from clinical trials testing the effects of DHEA treatment on cognitive function, has several limitations, mostly of whom arose from the Cochrane Collaboration meta-analysis [133]. This systematic review of controlled trials by the Cochrane Database [133] has identified only three controlled trials that adequately addressed the effects of DHEA administration (50 mg/day) on cognitive performance in healthy individuals [106,111,134]. Barnhart et al. enrolled 60 peri-menopausal women (age range: 45–55) with decreased well-being. Three cognitive measures (attention, speed of processing and verbal memory) were assessed by standardized tests. These authors found no significant effect of DHEA compared with placebo at 3 months [134]. The conclusions of this systematic review were against the opportunity to adopt DHEA treatment to improve cognitive function, well-being, in nondemented, middle-aged or older persons. In most of the current trials, cognitive domains have not always been considered the main study outcome. RCTs investigated the effects of DHEA supplementation in reversing cognitive decline, but did not examine the efficacy of DHEA in maintaining the “youthful” circulating DHEA/S levels. Moreover, several studies could have been underpowered to detect significant changes in cognitive outcomes, given both the small sample size and the different subset of the individuals enrolled (normal to cognitively impaired). It should be also pointed out that tests of cognitive function was often characterized by poor psychometric properties (with floor and ceiling effects and without a good range of scores) and low sensitivity to changes. In addition, baseline DHEAS levels highly differed between studies. It should be also underlined the inconsistent evidence of a beneficial effect of DHEA supplementation on cognitive function in non-demented middle-aged or older people. In summary, there are no elements to justify the growing public enthusiasm for DHEA supplementation, and the theoretical possibility of long-term neuroprotective effects of DHEA administration [135]. High quality controlled trials, in which the duration of DHEA treatment should be at least of 12 months, are needed to definitively answer to the question about the opportunity of starting DHEA treatment. 5. Conclusions In the recent years, the fascinating hypothesis that the neurosteroid DHEA/S plays an important role in cognitive performance, has been tested in a large number of animal models and few human studies. The relevant beneficial effects of DHEA treatment in animals have not confirmed in humans. This should be not surprising, given the significant differences in terms of adrenal physiology and DHEAS circulating levels, existing between rodents and humans, making the translation of the animal results such difficult. Epidemiological studies are not consistent in revealing an important role of DHEA/S decline in the onset of cognitive


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impairment occurring with age with a large number of observations showing no association and limited data documenting a positive effect of DHEA supplementation. Nevertheless, most of the RCTs did not find any effect of DHEA replacement on memory and other domains of cognitive function. It is also necessary to point out that most of the studies, summarized in this review, have considered groups of men and women heterogeneous in terms of age, DHEAS levels at entry, and baseline health status. Moreover, cognitive status has not been always considered the primary outcome of observational studies and RCTs. The negative results found by most of the studies could be due to the multi-factorial nature of the cognitive impairment. In addition, the contribution of low DHEA/S in cognitive impairment should be evaluated as part of the multiple hormonal dysregulation occurring during the aging process. In fact, the mild simultaneous decline in anabolic hormones (DHEAS, testosterone and IGF-1) is more frequently observed than a single hormonal derangement in aging model [51,136]. The role of multiple anabolic hormonal deficiency should be more appropriately taken into account as risk factor of cognitive impairment and mortality especially in older men [137]. Therefore, in our opinion, future studies should better address the need of rebalancing the ratio between anabolic and catabolic hormones, rather than correcting a single hormone concentration. In conclusion, the available data lead to reject the fascinating hypothesis of the usefulness of DHEA supplementation in improving or maintaining memory and other cognitive domains in older individuals.

5.1. Perspectives In the current state, human data are not strong enough to support a significant role of DHEA/S to counteract the age-related decline of cognitive function. DHEA supplementation could be confined to older persons with MCI, and increased vulnerability to stressors, and/or in the larger context of anabolic hormonal deficiency. An attractive marker of cognitive dysfunction might also be represented by the cortisol/DHEA/S ratio.

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McManus, Culture and regeneration of human neurons after brain surgery, J. Neurosci. Methods 107 (2001) 15–23. [32] K.K. Karishma, J. Herbert, Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression, Eur. J. Neurosci. 16 (2002) 445–453. [33] L. Zhang, Li Bs, W. Ma, J.L. Barker, Y.H. Chang, W. Zhao, D.R. Rubinow, Dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEAS) regulate apoptosis during neurogenesis by triggering the Akt signaling pathway in opposing ways, Brain Res. Mol. Brain Res. 98 (2002) 58–66. [34] I. Charalampopoulos, C. Tsatsanis, E. Dermitzaki, V.I. Alexaki, E. Castanas, A.N. Margioris, A. Gravanis, Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins, Proc. Nat. Acad. Sci. U.S.A. 101 (2004) 8209–8214. [35] I. Pérez-Neri, S. Montes, C. Ojeda-López, J. 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Cognitive Function and Salivary DHEA Levels in Physically Active Elderly African American Women.

Cognitive function in subclinical hypothyroidism in elderly.

Endogenous sex hormones and cognitive function in the elderly.

Relationship between mastication and cognitive function in elderly in L'Aquila.

Improvement of cognitive function after cochlear implantation in elderly patients.

Association between intake of B vitamins and cognitive function in elderly Koreans with cognitive impairment.

Correlation between physical function, cognitive function, and health-related quality of life in elderly persons.

Cognitive impairment in the elderly.

Cognitive impairment in the elderly.

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B vitamin supplementation improves cognitive function in the middle aged and elderly with hyperhomocysteinemia.

Developmental Patterns of Cognitive Function and Associated Factors among the Elderly in Taiwan.

Association between olfactory identification and cognitive function in community-dwelling elderly: the Shanghai aging study.

Tai chi improves cognitive and physical function in the elderly: a randomized controlled trial.

Correlation Between Vision and Cognitive Function in the Elderly: A Cross-Sectional Study.

Decreased motor function is associated with poorer cognitive function in elderly with type 2 diabetes.

Effects of art and music therapy on depression and cognitive function of the elderly.

Physical activity and cognitive function of community Chinese elderly in Hong Kong (HK) and Guangzhou (GZ).

Cross-sectional study of the association of cognitive function and hippocampal volume among healthy elderly adults.

Cerebral microbleeds are associated with worse cognitive function in the nondemented elderly with small vessel disease.

Screening for cognitive impairment in the elderly.

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Relationship between dietary pattern and cognitive function in elderly patients with type 2 diabetes mellitus.