Introduction

Improved medical, economic and socio-cultural conditions has increased life expectancy, especially for women. The incidence of disorders such as hypertension, diabetes mellitus, psychiatric and degenerative brain diseases, especially stroke and dementia such as Alzheimer’s disease, are more frequently seen in older people . Although it is not clear how age contributes per se to these disorders (compared with the state of health of these individuals), there is reason to believe that, in most cases, these are multi-factorial outcomes of antagonistic pleomorphism .

The key message in this chapter is that, in addition to disease processes such as vascular disease and neurodegenerative processes, the ageing brain may deteriorate as a result of apparently normal functional, structural and molecular changes that accompany ageing, the effects of common medications, or both. The latter may not be known as psycho-affective, but may clinically affect brain function in older individuals. Examples include thyroid hormone, non-steroidal anti-inflammatory drugs, dopaminergics, nitric oxide-active drugs, corticoids, and sex steroids. As each of these can separately, and in combination, result in similar signs and symptoms of cognitive, memory, mood and motor function disorders, it is important to understand normal ageing effects and those of specific disease entities, and also the effects of normal ovarian ageing and the menopause. The scope of this chapter does not allow comprehensive coverage of these treatments, but it is important to understand that these are complex issues and it may be difficult and time-consuming to discern between normal brain functional changes and pathology in the clinical practice .

Quality of life is a major concern for ageing individuals, and concerns are often brought to clinic. As mean life expectancy increases, this concern goes beyond frank disease; it is integral to the life of every ageing person, and the basis of increased interest in stress-reducing measures, exercise, dietary improvements, hormone treatment, and the use of over-the-counter nutraceuticals designed to improve health.

Imaging techniques and functional testing are new developments in our understanding of the effects of ageing on the brain, and build on our current understanding of the effects of ageing on the brain based on clinical testing. Reporting the state of the art in the area of imaging and functional testing has been purposely conservative, as it is necessary and useful to chronicle the translational aspects of the field at this time. Normal brain ageing continues until death, and the ability to separate the unintended consequences of hormones, medications and other agents, and reassure the ageing person of their normalcy, is a great service to them .

Brain cells

The brain is composed of many cell types. Neurones are the main functional units. They are networked and act in concert like computer chips to run programmes by synaptic neurotransmission ( Fig. 1 ).

The cortex: a computer regulated by oestrogen.

The brain has bilateral hippocampi located in the temporal lobes, They are so-named because when cut on-end the coiled white and grey matter resembles a sea horse. Trauma to the hippocampus (e.g. in contra-coup injuries), and degenerative diseases (e.g. Alzheimer dementia), results in loss of short-term memory. Each hippocampus is targeted by inflow tracts that carry messages about external sensory conditions and internal messages from the other areas of the brain. This input is analogous to the computer keyboard and its connections to the computer’s chip(s). In order to be received, the signals must leap across the synaptic cleft to the hippocampus’ post-synaptic elements’ protuberances (spines) on hippocampal dendrites. The spines, according to their length, preprocess the signals before they are fed into the circuitry of the hippocampus. The spine length and number of synapses are under the control of internal secretions (e.g. oestrogen, growth factors, cytokines and neurotransmitters). This transmission furnishes the short-term memory. Then the information is fed-forward for incorporation in long-term memory. Other information follows the same path and fed to the appropriate areas of the brain. In Fig. 1 , the limbic brain connections (white) are analogous to circuits, computer programmes, and folders or files of the brain, including the cortical neurones of the limbic, sensory and motor brain. Failure to make the leap onto the hippocampal circuitry can result in disturbances in short- and long-term memory and autonomic function. The ageing brain also may develop lesions that interrupt the input tracts, transmission onto the hippocampal circuitry and processing and distribution by the hippocampus. Such lesions may be found in Alzheimer disease.

Astroglia is a sort of fibroblast of the brain that also forms networks for decontaminating the brain of the by-products of neurotransmission, and carries out non-synaptic communication. Microglia are the macrophages of the brain, and oligodendroglia spin out the myelin that insulates the axons, outgoing processes of neurones, vascular cells, and form a barrier to the passage of cells and substances into the brain parenchyma. Fibroblasts are the main components of the membranes that envelope the central nervous system and hold the cerebral spinal fluid that is the ‘shock-absorber’ of the brain .

In the brain, only one in 19 cells is a neurone, and the rest are largely the service apparatus for the neurones. Neurones were once thought to be a syncytium (Golgi), but that was disproven , and the doctrine of synaptic connections has been expanded to include all the functions of the brain. In order to function, synapses must pass neurotransmitter-active substances back and forth between the pre- (axonal, incoming) and post-synaptic (dendritic, receiving) elements. These agents and their metabolites must be contained from nearby neurones, or false neurotransmission and toxic damage to the nearby neurones and fibres could occur. Each synapse is a complete containment area that surrounds the pre- and post-synaptic elements, and seals them off from the adjacent neurones, glia, and other elements. The synapses are constructed from interlocking astrocyte cell membranes, and are vulnerable to dissolution and re-formation (synaptic plasticity) Synaptic plasticity has been shown to occur during normal brain function as well as pathological states . The two examples referred to caused by the effects of oestrogen, a classic inducer of synaptic plasticity . We have shown that, in extreme amounts and over long periods of time and repetitive synaptic plasticity, pre-ovulatory levels of oestrogen may be accompanied by significant damage in the rodent brain . In apparent contrast, oestrogen has been shown to be neuroprotective; it is an anti-oxidant , antagonises the hyperphosphorylation of the neural microtubule protein tau that is integral to the development of Alzheimer’s dementia lesions , and induces anti-inflammatory proteins .

Synaptolytic and brain-toxic effects can be caused by leaking neurotransmitters and metabolites, free radicals, physical trauma, cytokines and growth factors produced during homeostatic regulation, or the response to microbial agents, stress, or environmental toxins . Recently, the ill-effects of over-exuberant immune responses have been highlighted for their possible role in the development of degenerative brain disease . In addition, the effects of defective brain capillary blood flow may result in both ischaemic damage and accumulation of toxic metabolites .

Ageing may be accompanied by acceleration of all of the above process. In addition to cellular morphological changes, ageing neurones display evidence of increasing DNA damage, accumulation of reactive oxygen species, calcium dysregulation, mitochondrial dysfunction, and inflammatory processes .

Brain cells

The brain is composed of many cell types. Neurones are the main functional units. They are networked and act in concert like computer chips to run programmes by synaptic neurotransmission ( Fig. 1 ).

The cortex: a computer regulated by oestrogen.

The brain has bilateral hippocampi located in the temporal lobes, They are so-named because when cut on-end the coiled white and grey matter resembles a sea horse. Trauma to the hippocampus (e.g. in contra-coup injuries), and degenerative diseases (e.g. Alzheimer dementia), results in loss of short-term memory. Each hippocampus is targeted by inflow tracts that carry messages about external sensory conditions and internal messages from the other areas of the brain. This input is analogous to the computer keyboard and its connections to the computer’s chip(s). In order to be received, the signals must leap across the synaptic cleft to the hippocampus’ post-synaptic elements’ protuberances (spines) on hippocampal dendrites. The spines, according to their length, preprocess the signals before they are fed into the circuitry of the hippocampus. The spine length and number of synapses are under the control of internal secretions (e.g. oestrogen, growth factors, cytokines and neurotransmitters). This transmission furnishes the short-term memory. Then the information is fed-forward for incorporation in long-term memory. Other information follows the same path and fed to the appropriate areas of the brain. In Fig. 1 , the limbic brain connections (white) are analogous to circuits, computer programmes, and folders or files of the brain, including the cortical neurones of the limbic, sensory and motor brain. Failure to make the leap onto the hippocampal circuitry can result in disturbances in short- and long-term memory and autonomic function. The ageing brain also may develop lesions that interrupt the input tracts, transmission onto the hippocampal circuitry and processing and distribution by the hippocampus. Such lesions may be found in Alzheimer disease.

Astroglia is a sort of fibroblast of the brain that also forms networks for decontaminating the brain of the by-products of neurotransmission, and carries out non-synaptic communication. Microglia are the macrophages of the brain, and oligodendroglia spin out the myelin that insulates the axons, outgoing processes of neurones, vascular cells, and form a barrier to the passage of cells and substances into the brain parenchyma. Fibroblasts are the main components of the membranes that envelope the central nervous system and hold the cerebral spinal fluid that is the ‘shock-absorber’ of the brain .

In the brain, only one in 19 cells is a neurone, and the rest are largely the service apparatus for the neurones. Neurones were once thought to be a syncytium (Golgi), but that was disproven , and the doctrine of synaptic connections has been expanded to include all the functions of the brain. In order to function, synapses must pass neurotransmitter-active substances back and forth between the pre- (axonal, incoming) and post-synaptic (dendritic, receiving) elements. These agents and their metabolites must be contained from nearby neurones, or false neurotransmission and toxic damage to the nearby neurones and fibres could occur. Each synapse is a complete containment area that surrounds the pre- and post-synaptic elements, and seals them off from the adjacent neurones, glia, and other elements. The synapses are constructed from interlocking astrocyte cell membranes, and are vulnerable to dissolution and re-formation (synaptic plasticity) Synaptic plasticity has been shown to occur during normal brain function as well as pathological states . The two examples referred to caused by the effects of oestrogen, a classic inducer of synaptic plasticity . We have shown that, in extreme amounts and over long periods of time and repetitive synaptic plasticity, pre-ovulatory levels of oestrogen may be accompanied by significant damage in the rodent brain . In apparent contrast, oestrogen has been shown to be neuroprotective; it is an anti-oxidant , antagonises the hyperphosphorylation of the neural microtubule protein tau that is integral to the development of Alzheimer’s dementia lesions , and induces anti-inflammatory proteins .

Synaptolytic and brain-toxic effects can be caused by leaking neurotransmitters and metabolites, free radicals, physical trauma, cytokines and growth factors produced during homeostatic regulation, or the response to microbial agents, stress, or environmental toxins . Recently, the ill-effects of over-exuberant immune responses have been highlighted for their possible role in the development of degenerative brain disease . In addition, the effects of defective brain capillary blood flow may result in both ischaemic damage and accumulation of toxic metabolites .

Ageing may be accompanied by acceleration of all of the above process. In addition to cellular morphological changes, ageing neurones display evidence of increasing DNA damage, accumulation of reactive oxygen species, calcium dysregulation, mitochondrial dysfunction, and inflammatory processes .

Cognition

Cognition is a complex function that originates in several areas of the brain, including the prefrontal cortex and hippocampus. The hippocampus acts as a ‘feed-forward neuronal circuitry’ ( Fig. 1 ), and is the entry site for short-term memory that feeds long-term memory. It is also the site of Alzheimer’s disease. The function and malfunctions described in this chapter are mainly documented in the hippocampus. The hippocampus has many connections (tracts) to and from other brain areas involved in cognition. Hippocampal-limbic connections, for example, explain the common correlation between memory loss and the development of affective disorders in ageing. We will touch on some of these functions, mood and fear, which are regulated by the amygdala (limbic system) and play important roles in dysphorias and dementia, which are common in ageing .

Individual exceptions occur, of course, but clinical anecdotes and studies of cognitive changes in ageing people support an age-related decline in cognition and neurological functioning in other parts of body. Meta-analyses of cross-sectional and longitudinal data sets have shown a decline in two major cognitive domains: memory and executive function, and processing speed and driving test scores; both show extended reaction times . Results of testing indicate that ageing differentially affects brain functioning . Nevertheless, the Study of Women’s Health across the Nation (SWAN) reported a positive cross-sectional association between self-reported forgetfulness and being perimenopausal.

The hippocampus is essential for short-term memory that feeds the long-term memory formation ( Fig. 1 ). As memory storage is apparently located in non-feed-forward areas of the hippocampus and in other areas of the brain, ageing may differentiate between these functions. Commonly, long-term memories remain intact, whereas the feed-forward areas of the hippocampus fail. The result is the loss of short-term memory without loss of long-term memory . By default, when the development of new short-term memory has been ongoing for a long period, long-term memory may be the only functional part of the system and will become the dominant expression.

During the ageing process, some brain areas, such as the hippocampus, may decrease their volume; however, this may not be associated with demonstrable cognitive impairment. This may reflect the predominance of non-neuronal cells in the brain . Functional imaging has also supported age-related changes in brain areas that are associated with different facets of what is collectively termed ‘cognition’ or ‘memory ; the possible role of oestrogen in cognition is discussed below.

Dementia

Dementia may have two origins. Organic dementia (dementia) is characterised as an irreversible impairment of the intellect, memory, and personality, whereas functional dementia may be caused by medications, metabolic disturbances, or other reversible conditions. Dementia can occur abruptly or be progressive and episodically progressive. Dementia has two main causes in otherwise-normal ageing people: Alzheimer’s disease and vascular dementia. As vascular disease is increasingly common among older people, and often a mixture of the two occurs . Other causes of dementia include syphilis, alcoholism and environmental toxicity, but these are not specific to ageing populations. Alzheimer’s disease, with its typical history and lesions on imaging, accounts for 60–80% of all dementia diagnoses in the USA. Vascular disease, including repeated small strokes and Alzheimer’s disease will both increase their prevalence with the extension of longevity .

Non-organic dementia is more common than initially thought. The cerebral effects of any number of medications may await a psychiatrist’s care long before being diagnosed . Various forms of toxic coma, including liver and renal failure, may also be misdiagnosed. Perhaps the most common and potentially lethal non-organic dementias are associated with electrolyte imbalance . These causes must be ruled out before a final diagnosis is made and treatment given.

Alzheimer’s disease is a neurodegenerative disease associated with neuronal cell loss and development of degenerative lesions called amyloid plaques and neurofibrillary (tau) tangles that are late signs of the disease. In fact, by the time that these lesions are found by imaging, the involved neurones and glia are well along toward destruction and involved in inflammatory reactions that destroy nearby normal cells and fibres of passage . With the exception of the hereditary form of early onset Alzheimer’s disease, which is an outcome of abnormal lipoproteins, the cause of the above changes in normal brain constituents, the basis of, or inciting factor for, Alzheimer’s disease is not yet known . Soluble amyloid is a normal component of blood and tissues; in fact it is a strong anti-oxidant. Amyloid is precipitated to immunogenic plaque during Alzheimer’s disease genesis. Tau is a normal constituent of the cytoskeleton that is hyperphosphorylated to form tangles during the development of Alzheimer’s disease. It is not surprising, therefore, that tau-related tangles and amyloid plaque would be present in Alzheimer’s disease in relatively larger numbers than seen in normal ageing .

Vascular dementia seems to be the culmination of repeated ischaemic episodes . In typical vascular disease, these are often not recognised as strokes, and their chronology is not known. Moreover, unless the ischaemia is in areas or cell clusters necessary for cognitive function, the brain can withstand a great deal of shrinkage without signs of dementia (F. Naftolin, unpublished observations of magnetic resonance images of individuals with Parkinsons disease). Thus, with the exception of strategically placed strokes, it seems that no specific vascular trigger exists for dementia.

An analogy is arteriosclerosis, in which angina is a late, clinical sign. When Alzheimer’s disease becomes clinically evident, this is the culmination of a long period of subclinical disease and neurological dysfunction. The clinical accompaniment of this deterioration is termed minimal cognitive impairment. It has been recognised that people with Alzheimer’s disease have minimal cognitive impairment, a limited communication function otherwise known as ‘poverty of speech’ Minimal cognitive impairment is a risk factor for Alzheimer’s disease, and the evaluation of ageing people should include communication skills and history. In any case, early diagnosis is dependent on the clinician’s index of suspicion . As we now enter the period of discovery of agents that inhibit progress of Alzheimer’s disease and treat symptoms of Alzheimer’s disease, this early evaluation should become standard practice.

In contrast to the situation in Alzheimer’s disease, the returns from early diagnosis of brain vascular disease are great and attainable. It is, therefore, important to include screening for vascular disease in the work-up of ageing people. Suspicions should be followed up with appropriate imaging procedures, carotid artery intimal medial thickness, and brain scans . At present, the value of early imaging studies in confirming the presence of sub-clinical Alzheimer’s disease is not known, and such measures as magnetic resonance imaging for screening is not reported .

In a small number of people with a family history of early dementia, the presence of early dementia or clinical Alzheimer’s disease requires immediate genetic testing for abnormal lipoprotein constellations that are associated with membrane lipid oxidation and (familial) early Alzheimer’s disease .

As both Alzheimer’s disease and vascular disease result in irreversible neuronal death , there is every reason to screen for dementia and its precursors actively, and to refer any suspicious cases to specialised care .

In 2011, 35.6 million were reported to have dementia worldwide, and this figure is expected to increase to 115.4 million by 2050 . In contrast to isolated cognitive loss, dementia usually occurs in a constellation that precludes it from being managed in unsupervised surroundings, and the patient cannot be left alone. Dementia ultimately progresses to require constant supervision; it becomes a societal disease rather than an individual illness. This social fabric surrounding the patient is destructive and costly. In 2011, worldwide costs of dementia were US$ 604 billion, of which 84% were attributable to informal and formal costs. The prevalence of dementia is estimated to increase by 5% each year in women older than 65 years of age, reaching 50% in women older than 85 years . As our ageing population grows, so will the problems and costs of dementia. This is an area worthy of the most ardent research and clinical attention. It is a top priority of all involved, and progress is being made on all fronts .

Mood disorders

Depression is more common in women than men . Death wishes and suicidal ideation are common among older adults, and have been shown to be associated with mental and physical illness, functional disability, and social factors . In the Swan Study , depression was found to be common and of varied severity in ageing women.

It is now well-accepted that the cause of depression is neurotransmitter imbalance. This is a general term for a host of chemical and even cellular disruptions in neurotransmitter action in areas that control mood. The most common disruptions concern dopaminergic and serotoninergic connections .

No brain-based clinical tests, such as imaging, are available for depression screening. Diagnosis, on the other hand, may include imaging techniques . Screening and diagnosis mostly depend on history and clinical impression . Too often, the diagnosis is tentative and subject to a test of the response to psychotrophic drugs, such as various serotonin-reuptake inhibitors . As these drugs usually depend on rebalancing a wide gamut of neurotransmitter metabolism, their effects can be slow in reaching a new equilibrium; the therapeutic challenges with psychotrophic drugs, however, are not a substitute for proper evaluation, often with the collaboration of a specialist. In part, this is true because the drugs, especially selective serotonin reuptake inhibitors, have many and insidious side-effects that may confuse the case and delay proper attention to this potentially lethal complication of ageing. One of these effects is to improve vaso-motor episodes in some women . This is not surprising in light of the association of temperature regulation with dopamine physiology . Fortunately, although these side-effects may be clinically troublesome, there is no evidence that they induce pathological lesions in the brain . When they are properly used, these drugs are effective in treating depression in correctly diagnosed cases.