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The renin-angiotensin system and antihypertensive drugs Angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor antagonists (ARAs), prevent Ang II-mediated inhibition of acetylcholine release, interrupt the upregulation of deleterious inflammatory pathway, that drive amyloid-β deposit, hyperphosphorylated Tau-mediated damage, mitochondrial dysfunction, brain atrophy, impaired cerebral blood-flow, and cerebrovascular disease38

Key points . Potent vasoconstrictor Ang II may offer broad

benefits in AD. In addition to helping to ameliorate comorbid hypertension, these drugs are also likely improve diminished cerebral blood-flow, which can contribute to focal Amyloid-β pathology.

Thyroid and Alzheimer’s disease Low and high levels of TSH are associated with an increased risk of AD in women, but not in men39

. Indeed,

most studies suggest that AD is more frequent in women than men40

. In preschool children, a TSH value over 2.2 m U/ml can

result in lower scores in neurodevelopmental skills, and a higher risk of attention deficit and hyperactivity/ impulsivity symptoms41

. Hyperactivity disorder will

disappears in 70% of this population group at the age of 18 years, but can persist in the remainder. The consequence of this is a permanence in attention deficit and hyperactivity syndrome throughout adult life. This is more common in girls than boys42


Oestrogen and neurodegenerative disease The main factor for the development of AD is cerebrovascular disease (CVD). Despite this, AD is a different and separate condition. AD combined with CVD is associated with progressive decline, with CVD impacting AD onset and the severity of progression. Oestrogen can improve vascular flow, prevent vascular disease, and increase blood-flow in areas of the brain affected by AD43

effect on the central nervous system in particular44 Oestrogen exerts its influence on almost all systems of

. Furthermore, oestrogen has a profound .

the body, including the brain. Brain scanning studies have shown that oestrogen has a fundamental influence on the brain organisation patterns in post-menopausal women and profound effects on cognitive function, especially with regard to short-term or working memory and visual memory. Oestrogen appears to potentiate the effect of cholinesterase inhibitors used in treating AD. If the symptoms and clinical manifestations are

recognised early in the disease process, hormone replacement therapy (HRT), as well as other medication therapies, can be used as a treatment and preventive method for migraine and AD44, 45

. Oestrogens have a direct

effect on neuronal function (preservation) and repair neurons damaged by the disease process43


HRT and Alzheimer’s disease Women who receive oestrogen or hormone therapy at the time of menopause and continue for 10 years have a

52 ❚ June 2012 |

■ The mutations observed in different neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, are caused by different proteins

■ Approximately 30% of cases of Alzheimer's disease can be attributed to genetic factors. A positive family history and the ApoE4 gene are the strongest risk factors for late-onset Alzheimer’s disease

■ Glucagon-like peptide-1 (GLP-1) influences glucose- dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation. GLP-1 acts on neuronal proliferation and differentiation to produce neurite outgrowth

■ Women who receive hormone replacement therapy (HRT) at the time of menopause, and continue the regimen for 10 years, have a three-fold lower risk of developing Alzheimer’s disease

three-times lower risk of developing AD46 . A plethora of

in vitro and in vivo studies have supported the neuroprotective role of oestrogens and their impact on the neurotransmitter systems implicated in cognition. Recent HRT trials in non-demented post-menopausal women suggest a temporary positive effect, and meta-analyses converge to suggest a possible protective effect in relation to AD (reducing risk to 44%)47

. However,

data from the only large randomised controlled trial published to date, the WomenÕs Health Initiative Memory Study48

, did not confirm these observations and have

even suggested an increase in dementia risk for women using HRT. Apart from methodological differences, a key short-coming of this trial was perhaps the focus on late-onset hormonal changes. Further studies are thus required to clarify the role of hormonal risk factors, or protective factors, for cognitive dysfunction and dementia49

. HRT should begin as soon as symptoms of menopause

manifest, and before the onset of disease. The relationship between HRT and AD can be compared with that of HRT and osteoporosis. In both cases, HRT has a role in primary prevention45


Erythropoietin and neurodegenerative disease Chronic treatment with asialo-erythropoietin (ASIALO-EPO) or carbamylated erythropoietin (CEPO) can improve motor behaviour, reduce motoneuron loss and astrocyte and microglia activation in animal models and without effects in the blood50

. CEPO and, to a lesser

extent, ASIALO-EPO, could exert neuroprotective effects in a model of chronic motor neuron degeneration and reduce inflammation in the anterior horn of the spinal cord without increasing hematocrit levels. The mechanism by which these compounds act is still not fully clarified, but study results indicate that these molecules could offer a potentially important therapeutic approach for amyotrophic lateral sclerosis (ALS), for example50

. Although the molecular mechanisms associated with

the therapeutic action of erythropoietin remain unclear, it is known that cerebral inflammation, excitotoxicity, and oxidative stress play an important role on the pathogenesis of secondary brain injury after TBI52


levels of NF-κB, proinflammatory cytokines and ICAM-1 are markedly increased in injured animals53

. Rats

receiving recombinant human erythropoietin (RhEpo) post-TBI showed a considerable decrease of NF-κB, IL-1β, TNT-α and ICAM-1 levels compared with control. Furthermore, administration of RhEpo also reduces brain oedema, bloodÐ brain barrier permeability and apoptotic cells in the injured brain52


SERMs and neurodegenerative diseases Selective oestrogen receptor modulators (SERMs) are used in the treatment of osteoporosis, breast cancer and

. CEPO and ASIALO-EPO are equally effective

at enhancing spatial learning and promoting neural plasticity after traumatic brain injury (TBI)51

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