Scientists these days have a good opportunity to improve their knowledge about the function of the aging brain, because people live longer than ever before. In the United States, 13% of the citizens are 65 years and older. The life expectancy at birth there is 81years for women and 76 years for men. Researchers estimate that one in five citizens by the year 2030 will be seniors and they also think that the oldest old (85 years and older) will be the fastest growing segment of the population. Given these numbers, it is important for research to focus on normal and pathological ageing.

We now know and accept that that some degree of cognitive decline associated with ageing is inevitable and these declines are different for every person. There is a variation in cognitive performance in areas as fluid intelligence and memory when people age. When people age, there is an increase in the proportion of old people who show normative age-associated cognitive decline. However, there will also be an increase in the pathological cognitive decline. There are some aspects of cognition that remain relatively stable with normal ageing. Some of these are vocabulary, storage of knowledge and implicit memory. The decline that often goes together with normal cognitive ageing is a decreased efficiency in information processing in multiple areas. These areas are speed of processing, short-term memory, reaction time, verbal fluency and executive control. Visual-perception also declines with age.

Slowed processing speed is an important cognitive change in the ageing brain. Research has found that visual-motor tracking and sequencing slow with age. Older people have a slower processing speed in general and this mediates cognitive efficiency by restricting the speed at which cognitive processes can be executed. The quality of performance can also be affected by reduced processing. This is because there is a decreased quantity of information processed that is necessary for completion of the task. Also, the products of earlier processing can be lost by the time later processing happens and this makes the integration of relevant information difficult or even impossible. Reduced processing can lead to a decrease in working memory capacity, because less information can be processed in a certain amount of time.

Also, higher-order cognitive functions, like elaboration and abstraction, can be impaired. This is because the relevant information is not available anymore in the working memory or storage. Older people have a reduced inhibition of selective attention and because of this, the changes in their working memory occur. Older people show a decreased ability to suppress the processing of irrelevant stimuli. Their attention will be dis-regulated because of this and this will also have an effect on different aspects of executive performance, like suppressing responses. Cognitive ageing is also related to poorer effortful processing, but automatic processing remains relatively intact. Normal age-related changes in language function are an inefficiency in word retrieval. This means that older people have more trouble in finding words and this is also called the ‘tip of the tongue’ phenomenon.

Structural brain changes

Normal ageing goes together with a couple of changes in brain structure, like volumetric shrinkage, loss of dopaminergic receptors, more neurofibrillary tangles and plaques and a decreased white matter density. The most thinning and shrinking of the brain occurs in the hippocampus, cerebellum, caudate and prefrontal areas. Ventrical volumes increase in old age. Decreases in white matter density are most common in frontal or occipital regions of the brain. White matter changes result in cognitive slowing. This is because the function of white matter is to transport signals between different areas of the brain via myelinated axons. Myelin integrity degrades with age and the speed of cognitive processing will therefore also degrade. The loss of dopaminergic receptors contributes to attentional dis-regulation, difficulty with contextual processing and executive dysfunction. Researchers have proposed that contextual representations are housed in the dorsolateral prefrontal cortex and they are regulated by dopamine projections to this spot. Context processing plays a big role in attention, working memory and inhibition. Studies have found that old people have more neurofibrillary tangles than younger people. The most affected regions are the amygdala, entorhinal cortex, subiculum and inferior temporal regions. The orbitofrontal, midfrontal and parietal regions are less affected and occipital regions are minimally affected. Senile plaques (SP) are also found in older people these affect all brain regions equally, but the occipital cortex is the most spared region. People who were not demented at death, showed less plaques and tangles than people with mild cognitive impairment and dementia. Functional imaging techniques show that older people show more bilateral activation in older adults. This means that the older brain activates the contralateral hemisphere more to achieve greater cognitive benefits.

Theories of ageing

Researchers proposed that abilities that are relatively independent in early life (cognition, sensory ability), are more interrelated with old age. This can be seen as a decrease in neural specificity. Regions that respond selectively in younger adults change and respond to a wider array of inputs in older adults. In older adults, prefrontal activation is associated with decreased parahippocampal activation and hippocampal volume shrinkage. In younger people, activation in the parahippocampal regions is associated with learning new material, but in older adults there is more prefrontal activation and this suggests that greater frontal activity may be a compensatory mechanism for decreased activation of other regions.

Salthouse’s processing-speed theory of cognitive ageing proposes that a wide range of cognitive task performances are limited by the imposed constraints on the speed of processing. Slow processing speed can have an effect on cognition in two ways. The first is that cognitive operations are executed too slowly to be fulfilled successfully in the available time and the second is that the amount of available information that is necessary for higher-level processing is reduced. This is because early processing is not available anymore when new processing occurs. Complex operations depend on the products of simple operations and that’s why they are most affected by slow processing speed. The accuracy of performance is dependent on the number of operations that can be carried out in a given time period. Due to disruptions in the synchronization of signals, the amount of simultaneously available information may also be reduced.

According to the scaffolding theory of ageing, structural brain changes are accompanied by efforts of the neural networks to maintain homeostatic cognitive functioning in the face of these changes. So, the brain function will change through the strengthening of existing connections, non-use of faulty connections and the formation of new connections. Scaffolding is often seen as the brain’s normal response to challenge. The neural networks shift from broad and dispersed to a specific circuit of neural regions. The regions will have dominant control over functions and the initial broad networks will be minimally active and they remain available for compensatory processing. Scientists think that scaffolding maintains healthy cognitive functions, when neural degradation occurs. The circuits of scaffolding can give us complementary, new or supplementary ways to complete cognitive tasks and these circuits reside largely in the prefrontal cortex. However, scaffolding networks are less efficient and more prone to error than honed circuits, because honed circuits are highly functionally interconnected. According to the theory, this will result in the observable cognitive decline seen in older adults.

Individual factors

There is variation in cognitive performance in older people, especially in the older old. Because of this, it is important to examine the individual difference factors related to the cognitive ageing process. Research has found that factors that contribute to cognitive reserve or cognitive decline are education, physical health, occupational complexity and diet. Cognitive reserve is ‘caused’ by a couple of processes: richer connections and organization between neural circuits, changes in intracellular signalling pathways and alterations in synaptic efficiency. Physical health is an important factor when it comes to the prediction of cognitive function. Medical disorders are better predictors of neuropsychological performance than chronological age. These disorders are obesity, white matter lesions, hypertension and high cholesterol. Some other measures of biological age have also been associated with poorer cognitive functioning. Higher education has been associated with preserved cognitive performance over time, but not all studies support this claim. Occupational complexity is also associated with better cognitive functioning. This is especially the case when one works with people. Once somebody retires, the cognitive benefits received from high occupational complexity cease. Once these skills are not being practised, they have no longer an effectiveness in bolstering cognitive ability.

Mild cognitive impairment

Usually a patient or his/her family refers him/her to a doctor when they perceive a decline in cognitive ability. A neuropsychologist determines whether the patient’s/family’s complaints of cognitive decline are due to normal cognitive ageing or due to an objective impairment in cognitive functioning. Mild cognitive impairment represents a decline in cognitive performance greater than would be expected for the person’s age but not sufficient enough to meet criteria for a diagnosis of dementia. Some scientists describe mild cognitive impairment as interposed between normal cognitive ageing changes and the early changes of dementing processes. It is seen as a pathological condition. The incidence and prevalence of mild cognitive impairment vary across studies, because different samples, diagnostic criteria and assessment procedures are used. The prevalence of mild cognitive impairment within the general population ranges from 1 to 19%. The original criteria for mild cognitive impairment are:

1. Normal activities of daily living

2. Presence of a memory complaint

3. Normal general cognitive function

4. Abnormal memory for age

5. Not demented

This is useful for patients who have intact cognitive performance in every domain, except for the memory domain. Those patients with an impairment in the memory domain are labelled as having amnesic mild cognitive impairment. Other criteria were also proposed by a multidisciplinary group of experts, because mild cognitive impairment is represented heterogeneous in clinics. Some patients have only impairments in the memory area, but others have memory impairment and also another domain impairment. Some have impairments in non-memory cognitive domains. The most updates diagnostic criteria for mild cognitive impairment are:

1. Concerns regarding change in cognition: the patient’s cognitive status has changed compared to his previous level.

2. Impairment in one or more cognitive domains: there is evidence of lower performance in one or more cognitive domains. This performance is lower than would be expected for the patient’s age and educational background.

3. Preservation of independence in functional abilities: these patients usually maintain their independence in daily living without help. However, some patients have mild problems with complex functional tasks.

4. Not demented

Subtypes

Research has found several subtypes of mild cognitive impairment. One that has already been mentioned, is amnesic mild cognitive impairment (a-MCI). Some patients show an impairment in a single non-memory cognitive domain, but they perform normally in other domains. These patients will get the label of single-domain non-amnesic mild cognitive impairment (na-MCI). There are also patients with impairments in multiple domains, but who show intact activities of daily living. These patients are classified as having multiple-domain mild cognitive impairment. When a deficit in memory is present in these patients, they are given the diagnosis of multiple-domain mild cognitive impairment with amnesia (md-MCI + a). If memory impairment is not present, then the patient will receive the diagnosis of multiple-domain mild cognitive impairment without amnesia (md-MCI-a).

Prognosis

There are not only subtypes, but also multiple etiologies for mild cognitive impairment. Petersen thought there were four main etiologies: degenerative (Alzheimer’s disease), psychiatric (depression), vascular (cerebrovascular disease) and traumatic (head injury). There are also other potential etiologies that can be considered, like medication side effects, infection or toxic factors. Some subtypes are more common associated with certain etiologies than other. Patients with a-MCI are more likely to get Alzheimer’s disease than patients with na-MCI. Patients with impairments in non-memory domains, like executive functions, are more likely to get dementia with Lewy bodies. One study showed that there is a rate of progression from mild cognitive impairment to dementia of 12% per year. After six years, approximately 80% of mild cognitive impairment patients have progressed to dementia (in one study). Other studies have found rates of 10-19% per year from mild cognitive impairment to Alzheimer’s disease. 1-2% of the general population develops Alzheimer’s disease per year and this means that mild cognitive impairment places a person at increased risk for future dementia. In one study, people with a-MCI were found in one study to have a fourfold greater risk than non-cognitively impaired individuals to develop Alzheimer’s disease. However, there are also many people with mild cognitive impairment that remain stable with their diagnosis or even revert to normal. In one clinical study, 41% remained stable over time and 17% returned to normal cognitive status. This means that for some people mild cognitive impairment is an intermediate point on a continuum from normal cognition to dementia and for others, mild cognitive impairment is a transient period of cognitive decline that resolves with time.

Pathophysiology

Neuroimaging data shows that mild cognitive impairment is a unique diagnosis, different from dementia and normal cognitive functioning states. With the help of neuro-imagining techniques it was found that the retention of Pittsburgh compound B, PIB (used to image beta-amyloid plaques), in patients with mild cognitive impairment is higher than that of normal controls but lower than in in Alzheimer’s Disease patients. The patients who converted to Alzheimer’s Disease within the 2-16 month follow-up period had higher PIB retention rates than patients with mild cognitive impairment who remained stable. Other studies have also shown that patients with mild cognitive impairment who progressed to Alzheimer’s Disease, had greater volume loss than stable mild cognitive impairment groups. Studies that looked at the increase of ventricular volume have shown that the greatest volume increase is found in Alzheimer’s Disease patients, followed by patients with mild cognitive impairment and the smallest change is seen in cognitive normal.

Assessment

The referrals for mild cognitive impairment as a diagnostic consideration may come from different sources. Referrals might come from the primary care physician, psychiatrist, neurologists and self-referral. Usually, the patients or relatives of the patient prompt the consultation for memory loss. Many patients are first seen by neurologists who then give a neuropsychological referral for a more comprehensive evaluation. Cognitive impairments often involves a question of Alzheimer’s disease pathology versus other causes, like vascular cognitive impairment or Parkinsons’s plus syndrome (for example, Parkinson’s disease with Lewy body dementia). There are common differential diagnosis for mild cognitive impairment. Some of these are normal cognitive ageing, many forms of dementia, like Alzheimer’s disease, vascular dementia and Parkinson with Lewy bodies dementia and depression. Another issue that may be relevant to referring physicians, is the beginning with a cognitive enhancing medication or with a drug that treats mood disorders. The evaluation is often called for in order to track the trajectory of cognitive decline.

Clinical interview

It is important to obtain an accurate picture of the emergence of cognitive symptoms and functional difficulties when assessing people with mild cognitive impairment. It is therefore important to have an informant present at the interview so he or she can provide his or her insight into the patient’s behaviour and functionality. The informant is usually a spouse, sibling, child or other close relative or friend who knows about the patient’s history and who can tell more about the changes in functional and cognitive status. An important diagnostic criteria of mild cognitive impairment is the presence of a cognitive complaint. This complaint is subjective. Sometimes the patient complains about the his/her memory and the informant agrees, other times the informant’s report is the only evidence for subjective cognitive change. It is important to receive a thorough history of the emergence of cognitive symptoms. The evaluation of functional abilities is also important when considering the diagnosis mild cognitive impairment. Functional independence is the most important factor in the differential diagnosis of mild cognitive impairment and early dementia. People with mild cognitive impairment have intact basic activities of daily living. So, when making an assessment, the patient should be asked about his/her ability to take care for his/her basic needs (hygiene, feeding oneself) and instrumental needs (financial management, driving).

Patients and their informants should be asked about changes in behaviour or personality. These are usually early indicators of a primarily behavioural dementing process. Some of the behaviours to consider are apathy, disinhibition and behaviours that are not ordinary for that person. Also, irritability often goes together with symptoms of cognitive decline. Also, patients should be questioned about emotional symptoms and psychiatric history in order to see whether there is an increase in symptoms of depression or anxiety. Many patients with mild cognitive impairment have at least one neuropsychiatric symptom. The most commonly endorsed symptoms include depression, apathy, agitation and anxiety. Symptoms of depression that are often reported in mild cognitive impairment patients are poor concentration, pessimistic thoughts, reduced sleep, inability to feel, inner tension and reduced appetite. It is therefore important that patients are screened for clinical and subclinical symptoms of anxiety, depression, irritability and apathy. The clinician should receive a medical history and assessment of the patient’s current health status. It is also important to obtain results from neurodiagnostic studies (MRI, EEG), in case a differential diagnosis should be made. It is also important to have an assessment of the patient’s sleep quality. Also, the current and recent medications and the chronology of the patients should be reviewed, so a clinician could see whether medication has induced cognitive changes. Least, family history of dementia should be assessed.

Functional impairment

When a clinician looks at the carrying out of activities of daily living by a patient, he or she needs to know the history from the patient in order to figure out if something has changed. History from the patient should be obtained and ideally, also some information from the informant. A detailed interview is best to pick up subtle changes in functioning. According to research, patients with mild cognitive impairment report some degree of decline in their ability to handle daily tasks. They feel that they are more forgetful, have more trouble with planning and that they are less able to multitask. The ability to learn, perform higher-order executive skills and retain new information is dampened in persons with mild cognitive impairment. This usually results in less efficient daily functioning. People with mild cognitive impairment make errors in performing tasks accurately, but they are still able to complete tasks. People with mild cognitive impairment also show subtle declines in driving abilities. Some decline in functioning is observed in mild cognitive impairment patients, but it is not so severe as the decline in patients with dementia.

Cognitive impairment

Not only are self-reports and family reports about cognitive decline used to diagnose mild cognitive impairment, but objective measures of deficits in cognitive functioning are also used. There is not an exact cut-off score for what constitutes mild impaired, but mild cognitive impairment groups perform on average, 1.5 SD below normal-ageing people. The consensus criteria for scores on cognitive tests for patients with mild cognitive impairment is typically 1 to 1.5 SD below the mean for age and education. However, these are guidelines and not cut-off scores. The clinician should evaluate whether he thinks if somebody has mild cognitive impairment. For the assessment a detailed neuropsychological assessment is needed to improve the reliability of the diagnosis. The neuro-cognitive domains should be sampled and multiple measures of memory are needed. Different areas have to be assessed to determine etiology. Mood-functioning assessments should also be included.

Neurocognitive deficits

There are certain neuropsychological impairments that can be seen in patients with mild cognitive impairment who ultimately convert to Alzheimer’s Disease. One of them is a decline in episodic learning and memory early on. Patients with mild cognitive impairment show clearly defined memory impairments and only mild impairments in other domains. Patients with a-MCI show some difficulty in planning and problem solving and md-MCI patients show the most severe impairments. It is unclear why that is the case. Research has shown that patients with MCI show poorer performance than controls on tasks of semantic memory. The patients with MCI who convert to Alzheimer’s Disease show poorer immediate serial recall and divided attention than patients with MCI who do not ultimately convert to Alzheimer’s Disease. Once the diagnosis of MCI is established, the subtype of MCI needs to be selected. This is based on the results of the neurocognitive profile.

Recommendations

When a clinician reports the diagnosis of MCI to a patient and family, he or she needs to clearly explain the nature of the diagnosis. The clinician needs to convey that the patient is at increased risk for converting to dementia in the future, especially patients given an amnestic MCI diagnosis. The patients need to be told what the implications of the deficit will be, but the cognitive strengths should be highlighted in order to develop compensatory strategies for dealing with deficits and difficulties. Recommendations with a follow-up with the neurologist can also be made, to discuss the beginning of anti-dementia medication. Management with risk factors associated with cognitive decline should be recommended. Patients should also be encouraged to participate in an approved exercise regimen and maintain a healthy diet. Actively monitoring of anxiety, depression and other psychological factors is necessary. Patients should also be encouraged to maintain socially and cognitively active. Patients and relatives should also be told to monitor the functional status constantly. It is also important to schedule a follow-up appointment. However, it is difficult to determine what the best time for this is. One must looks at the severity and number of domains impaired and one must also look at the patient’s functional status. Patients with more severe cognitive impairments are further in their disease progression and patients with multiple impaired domains may reach a dementia diagnosis sooner. Therefore, these patients should receive a follow-up more sooner than patients with just one small impairment. The safest follow-up retest is a 1-year-follow-up period. However, when the family and/or patient notices a significant decline in cognitive ability or functional status, he or she should return sooner.