Depression to Dementia

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  • (i) Individuals who develop depression at any point in their lives, sustain minimal or no depression-related neuropathology (eg, glucocorticoid neurotoxicity), and who have stable, normal cognitive functioning;
  • (ii) Individuals who develop depression at any point and who experience depression-related neuropathology that results in MCI that is stable (unless they experience additional depressive episodes);
  • (iii) Individuals who accumulate AD neuropathology over many years and who develop late-life depression (related or unrelated to AD pathology), that lowers brain reserve capacity, and results in expression of MCI earlier than otherwise would be the case, and given the underlying neuropathology, progress to AD;
  • (iv) Individuals who accumulate AD neuropathology over many years along with co-occurring cerebrovascular disease, which damages the frontostriatal circuitry, leading to late-life depression. The total neuropathologic burden, combined with depressed mood, lowers brain reserve capacity, leads to expression of MCI (eg, memory and executive dysfunction) earlier than otherwise would be the case, and, given the underlying neuropathology, progresses to AD along with co-occurring cerebrovascular disease;
  • and (v) Individuals who develop cerebrovascular disease (with variable neuropathologic burden), that damages the frontostriatal circuitry, leading to late-life depression and MCI (eg, executive dysfunction), that, will follow the course of the underlying cerebrovascular disease.
AD Alzheimer’s disease
CAD coronary artery disease
HPA hypothalamic-pituitary-adrenal
MCI mild cognitive impairment
MDE major depressive episode
WMH hyperintense white matter regions

ad-depGlucocorticoids contribute to hippocainpal atrophy and learning/episodic memory impairment

Depression is associated with neuroendocrine changes similar to those observed in animal models of chronic stress, including abnormalities within the hypothalamicpituitary-adrenal (HPA) axis. Most notably, depressed subjects have been shown to exhibit, increased HPA central drive with elevated corticotrophin-releasing hormone (CRH) and vasopressin production by cells of the hypothalamic paraventricular nucleus (PVN); impaired negative feedback regulation due to decreased expression of corticosteroid receptors in the hypothalamus and pituitary as well as upstream CNS regulatory centers; and adrenal hypertrophy (reviewed in ref 25). The net effect of these changes in HPA function is chronic elevation of adrenal glucocorticoid production with impaired negative feedback and abnormal homeostatic regulation. Such HPA dysregulation is clinically detectable (via dexamethasone nonsuppression or elevated 24-hour urinary Cortisol) in about, half of patients with major depression.2526 HPA dysregulation may be more common among older depressed individuals, as suggested by the finding of a significant correlation between age and post-dexamethasone Cortisol levels in individuals with late-life depression.27

Adrenal glucocorticoid/cortisol regulates HPA activity through both direct, negative feedback at the pituitary and hypothalamus and indirect, mechanisms involving higher central nervous system (CNS) centers. The human hippocampus, for example, contains large numbers of corticosteroid receptors and plays a critical role in downregulating CRH release via a multisynaptic pathway terminating in y-aminobutyric acid (GABA)-ergic output to the paraventricular nucleus (reviewed in ref 28). At. the same time, HPA disturbances causing prolonged hypercortisolemia may promote hippocampal atrophy and functional decline, such that HPA regulation is further compromised. ‘Iliis interaction may underlie the observed association between hypercortisolemic disease states such as Cushing’s syndrome and depression, and both hippocampal atrophy and impairment, in the verbal and spatial memory functions subserved by the hippocampus.29,30

Animal studies suggest that high-stress conditions or exogenous glucocorticoids can cause hippocampal neuronal damage31 and memory impairment.32 These changes have been observed concurrent with stress or exogenous glucocorticoid administration, and appear to progress over a lifetime of stress or glucocorticoid excess (see review in ref 33). Human studies in older adults likewise suggest that hippocampal size and function are diminished in the setting of elevated glucocorticoids,3435 and in proplemiaortion to duration of prior hypercortisolemia.36

On the basis of these findings, many have hypothesized that glucocorticoids may promote hippocampal cell injury and death when chronically elevated, as in the setting of hypercortisolemica associated with major depression. Glucocorticoid-induced cellular damage may be mediated through effects on several biochemical substrates. Postulated mechanisms include decreased glucose uptake and ATP generation, elevated intracellular calcium with increased free radical production and degradative enzyme activity, and impaired uptake of glutamate from hippocampal synapses resulting in excitotoxicity.28,37 In addition, hypercortisolemia has been linked to a decrease in neurogenesis in the dentate gyrus.38 While the combination of cell death and decreased neurogenesis may theoretically contribute to hippocampal cell loss over time, recent, evidence suggests at. most a minor role for this mechanism in hypercortisolcmic human subjects in the absence of cooccurring insults.39 Animal and human studies support the idea that glucocorticoids contribute to hippocampal atrophy and functional deficits predominantly through more subtle alterations, including reduced synapse number,40 atrophy of pyramidal cell dendrites,41derangement, of glial cells,42 and other changes.

The loss of hippocampal volume and memory function observed in some elders with late -life depression suggests the possibility that depression may be a predispositional risk factor for AD in particular. Indeed, lower hippocampal volumes independently predict subsequent AD in groups of MCI and cognitively normal elderly subjects.52 Likewise, deficits in verbal learning and memory, similar to those described in cuthymic patients with history of major depression,30 also predict AD (eg, ref 53). While a primary causal role for depression in AD pathogenesis seems unlikely, depression-associated hypercortisolemia leading to decline in hippocampal size, connectivity and cognitive function may represent one of multiple links between depression and dementia as described below.

Brain and cognitive reserve are often used interchangeably, but in fact, have subtle but. distinct differences in meaning.119 Nevertheless, either may account, equally well for the relationship between depression and dementia. Tltic concept of brain reserve capacity, first proposed by Satz120 varies across individuals such that those with greater neuronal redundancy are able to tolerate more cell loss than those with less redundancy, before manifesting clinical symptoms. The concept of redundancy refers to the notion that, circuits contain more than the minimum number of neurons needed to perform an operation. Redundancy is evident when individuals incur substantial neuronal loss before the appearance of clinical symptoms. Thus, brain reserve capacity posits that individual differences in neural redundancy translate into differences in thresholds for vulnerability to or protection from clinical symptoms after brain damage. The concept of cognitive reserve developed by Stern (eg, refs 121 ,122) is similar but rather than being based on differences in brain size or neuronal count, emphasizes differences in the efficiency or manner in which tasks are performed or information is processed.

Both brain reserve and cognitive reserve explain the role of risk and protective factors for cognitive impairment (including progressive decline into dementia), associated with brain damage. For example, higher educational attainment, larger head size, larger brain volume,123 social engagement, 124 physical activity,125 and leisure cognitive activity126,127 may result in greater redundancy and/or efficiency and therefore reserve, thereby offering protection against exhibiting clinical symptoms of dementia. Similarly, lower levels of these protective factors may reduce neuronal or functional redundancy leading to earlier dementia symptom onset for a given level of CNS damage.

While certain mechanisms may alter an individual’s risk to develop (or change the rate of development of) ADrelated pathology (eg, P-amyloid deposition), other mechanisms alter the strength of association between these biological changes and the time to develop clinical disease. We propose that depression alters an individual’s risk of cognitive dysfunction, shortening the latent period between the development, of AD neuropathology and the onset, of clinical dementia, thus increasing the incidence and prevalence of AD among older adults with depression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872078/


About Glucocorticoids

Glucocorticoids (GCs) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor (GR),[1] that is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure (see structure to the right). A less common synonym is glucocorticosteroid.

GCs are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as reduction of inflammation. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over the counter.[2] They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. This includes: inhibitory effects on lymphocyte proliferation as in the treatment of lymphomas and leukemias; and the mitigation of side effects of anticancer drugs.

GCs affect cells by binding to the glucocorticoid receptor (GR). The activated GR complex, in turn, up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).[2]

Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. In technical terms, “corticosteroid” refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for “glucocorticoid.” Glucocorticoids are chiefly produced in the zona fasciculata of the adrenal cortex, whereas mineralocorticoids are synthesized in the zona glomerulosa.

Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.

https://en.wikipedia.org/wiki/Glucocorticoid

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