Editorial Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2016, Vol. 10, No. 1 1
Editorial
Endocrine Disorders and Cognitive Function in the Elderly
Giuseppe Pasqualetti, Valeria Calsolaro and Fabio Monzani
*A direct link between cognition and endocrine function has been established at several levels, from preclinical models to large clinical surveys. In this regard, international guidelines suggest performing a screening test for thyroid function (circulat-ing TSH level) in subjects with cognitive impairment in order to exclude a possible reversible cause of dementia [1]. Moreover, marked cognitive changes have been observed in patients with severe hypercortisolism [2]. Apart from the full-blown manifes-tations of hypothyroidism and hypercortisolism that may account for secondary causes of dementia, either subclinical thyroid dysfunction or mild adrenal hyper-function along with several other endocrine diseases including testosterone deficit, obesity and glucose metabolism alterations, have been observed in patients with neurodegenerative diseases, suggesting a potential role of these clinical entities on Alzheimer (AD) or Parkinson Disease (PD) development [3-8]. Moreover, we have to mention the possible link between cognition and neuro-endocrine alterations associated with cardiovascular dysfunction. In this regard, the adrenergic system seems to play a key role in the cognitive alterations observed in heart failure [9]. However, given that all these clinical conditions increase the cardiovascular risk and the consequent risk of vascular dementia, it is very difficult to dis-tinguish their possible direct role on the neurodegenerative process from that consequent to chronic cerebrovascular disease. In any case, when analyzing the scientific literature regarding the association between mild endocrine or metabolic disorders and neurodegeneration, conflicting results are still present making the interpretation of reported results very complex. In fact, we have to consider different settings and different age ranges of the available studies along with the time of onset and the duration of the analyzed endocrine dysfunction. An increasing body of evidence suggests a possible concurrent effect of several en-docrine disorders and the ageing process on the pathophysiology of neurodegenerative diseases and, in general, on cognitive function [3, 4-8, 10]. This thematic issue of the Journal “Recent Patents on Endocrine, Metabolic & Immune Drug Discovery” is aimed to explore these complex relationships and provide an updated review of the literature reporting also on most recent patents that may have an impact on the development and progress of neurodegenerative diseases.
Both mild and overt thyroid dysfunction have been associated with cognitive impairment and AD, although apparent contra-dictory results have been reported in case of mild thyroid failure, in which cognitive function seems to be altered only in people younger than 75 years while, a continuum increasing risk with increasing age exists in patients with either subclinical hyperthy-roidism or high normal thyroid function [4, 11, 12]. Apart from the complex relationship between hypothyhyperthy-roidism and cogni-tion, an important aspect to be considered is when starting treatment of patients with mild thyroid failure. In this regard, the de-velopment of new thyroid hormone (TH) analogues will improve the safety profile of TH replacement therapy, especially in the elderly in whom the risk of excess therapy is considerable. The new indole derivative and heterocyclic compounds represent promising therapies for the treatment of hypothyroid patients with cognitive impairment, considering their potential favourable pharmacokinentic and pharmacodynamic properties: better penetration on the active site at central nervous system (CNS) and a more selective action on specific TH receptors [13, 14]. Also adrenal diseases, especially those related to steroid hormone ex -cess, may contribute to the development of cognitive dysfunction via multi-factorial processes such as a direct hormone effect on CNS interplay. In this regard, several functional studies showed a relationship between hypercortisolism and CNS alter-ations similar to that observed in AD, including cerebral atrophy [15]. Keeping in mind the neuroendocrine alteration of the adrenergic system as a possible link between HF and AD in the elderly, several efforts have been carried out with the aim of obtaining effective treatments for both conditions. Interestingly, several patents have been developed proposing adrenergic sys-tem as a target for both HF and AD [16, 17]. In this setting, new compounds modulating guanilate cyclase have been recently patented as treatments of HF, while few compounds have been developed for cognitive impairment [16-19].
Recently, an increased scientific interest raised regarding the relationship between glucose metabolism alteration, especially type II diabetes mellitus, and the pathophysiology of AD and PD, mainly for the link with neuroinflammation [20]. Interest-ingly, taking into account different endocrine and metabolic markers, new approaches are being developed with the aim to iden-tify subjects at risk of developing AD [21, 22]. Moreover, some trials are currently on going on new anti-diabetic drugs in AD development and progression and, the use of chromium has been proposed, due to its ability to increase GLUT activity and improve brain glucose metabolism [23, 24]. Considering the association between fatness and type 2 diabetes mellitus, it is not sur prising the reported link between lipid alterations, obesity and neurodegenerative diseases. Moreover, obesity has been associ ated with lowgrade systemic inflammation that may favour CNS neuroinflammation and neurodegeneration [20]. In this set -ting, new anti-obesity drugs have been tested for reducing binge episodes and eating-related obsessions and compulsions with consequent weight reduction [25-27]. In men also sexual hormones, especially testosterone, seem to have a key role in modulat-ing some brain functions such as those involved in sexual orientation, depression and cognitive abilities (especially learnmodulat-ing, memory and spatial cognitions) [28]. However, the role of testosterone deficit in the pathogenesis of dementia remains uncer-tain considering its complex effects on neurogenesis [29].
All these considerations confirm that the pathogenesis of neurodegenerative diseases is a very complex process that presents many players concurring in disease development. Among them, alterations of the endocrine system may have an important role
2 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2016, Vol. 10, No. 1 Editorial
in neuroinflammation and neurodegeneration, participating in the highly complex mechanism of these processes. In the recent future, new potential diagnostic tools and treatment will be available for improving the quality of care of people with CNS dys-function and dementia.
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Fabio Monzani M.D.
Geriatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56 126 - Pisa, Pisa Italy Tel: +39 050 997363 Email: fabio.monzani@med.unipi.it
