Dementia

Dementia (from the Latin, meaning loss of mind) is characterized by a marked decline in memory, intellect or personality that is severe enough to interfere with daily life or work. It is a clinical syndrome with many underlying causes rather than a specific diagnosis, but almost two-thirds of cases are due to Alzheimer’s disease. Reversible confusional states such as delirium are specifically excluded and most cases are chronic, progressive and incurable.

General aspects

Dementia is predominantly a sporadic disease of old age. The prevalence is about 1% in people over 60, rising exponentially to affect more than 20% of those aged 85 and above. Although the risk increases with advancing years, dementia is not a normal part of the ageing process and there are a number of early-onset forms that are more likely to be inherited.

Clinical Box 12.1: Mild cognitive impairment

Some patients present with mild cognitive impairment (MCI) that is confirmed on objective testing, but is not severe enough to interfere with daily life or work (and therefore does not meet the criteria for dementia). MCI is not a specific diagnosis and it may not be progressive, although a proportion of patients will eventually develop Alzheimer’s disease or another form of dementia. The prevalence of mild cognitive impairment may be up to 25% in people over 75.

Reversible causes

Some forms of cognitive impairment are potentially treatable and should be excluded in the investigation of a patient with suspected dementia. These include nutritional deficiencies (e.g. vitamin B₁₂, folate), endocrine disturbances (such as hypothyroidism), alcohol-related dementia (reversible with abstinence), syphilis (now rare in the developed world), depressive pseudodementia (treatable with antidepressant drugs) and normal pressure hydrocephalus (see Clinical Box 12.2). A ‘routine dementia screen’ therefore includes a range of blood tests and urinalysis, together with an MRI scan of the brain.

Clinical Box 12.2: Normal pressure hydrocephalus

Normal pressure hydrocephalus affects 1 in 200 people over the age of 65 and presents with a triad of dementia, gait disturbance and urinary incontinence. The cerebral ventricles are enlarged, but the CSF pressure is usually normal, although longer-term recording has revealed periodic pressure elevations in some people (hence the alternative term, intermittently raised pressure hydrocephalus). Up to 50% of patients show dramatic improvement after surgical implantation of a shunt to divert excess CSF to the abdomen (see Ch. 2, Clinical Box 2.2).

Key Points

Dementia is characterized by a marked decline in mental faculties (such as memory, intellect or personality) that is severe enough to interfere with daily life or work.

It is a syndrome rather than a specific diagnosis with many underlying causes, but by far the most common is Alzheimer’s disease, accounting for 65% of cases.

Dementia is not part of the normal ageing process, but risk increases exponentially beyond the sixth decade, with a prevalence of at least 20% in people over the age of 85.

Memory loss is a core feature in most types of dementia, together with deterioration in higher cognitive functions including reasoning, visuospatial ability and language.

Mild cognitive impairment (MCI) is present in up to 25% of people over the age of 75. It is not a specific diagnosis and does not always progress to dementia.

Alzheimer’s disease

Alzheimer’s disease is the leading cause of dementia in all age groups. The vast majority of cases appear to be sporadic, but 5% are clearly inherited in an autosomal dominant manner.

Clinical aspects

The diagnosis of Alzheimer’s disease is predominantly clinical and post-mortem studies suggest that it is correct in at least 80% of cases. Two variants of Alzheimer’s disease that might cause diagnostic confusion are discussed in Clinical Box 12.3.

Clinical Box 12.3: Alzheimer’s disease variants

In the frontal variant of Alzheimer’s disease there are prominent changes in personality and behaviour, with disturbance of frontal executive function (organizing, planning, decision-making) and expressive language. This presentation of Alzheimer’s disease (which is rare) is usually misdiagnosed as frontotemporal dementia. In posterior cortical atrophy the parietal lobes are particularly affected, leading to severe visuospatial and perceptual problems, with relative preservation of expressive language and memory. There may also be difficulty recognizing people and objects (particularly from unusual angles) or judging distance and speed (e.g. of approaching cars). Other common features in posterior cortical atrophy are dyslexia (difficulty reading and spelling) and dyscalculia (problems with simple arithmetic).

Memory loss

Loss of short-term memory is a prominent, early feature. Patients may ask the same question repeatedly or forget recent conversations and events. The ability to take in new information is affected first, with relative preservation of long-term memories and knowledge. Recollection of personal experiences (episodic memory) is particularly affected. Since the onset is insidious, this may initially be mistaken for normal age-related forgetfulness. As the disease progresses, earlier memories are gradually eroded and ultimately patients are unable to recall key details of their own lives.

Visuospatial problems

Patients with Alzheimer’s disease often get lost in familiar places and may forget where they have left things. These features, together with impaired recall of daily events, reflect severe pathology in the medial temporal lobe. This involves structures such as the entorhinal cortex and hippocampus that are involved in spatial navigation and formation of episodic memories (see Ch. 3).

Other visuospatial problems are due to abnormalities of the temporal and parietal association areas. Parietal lobe pathology may interfere with the ability to understand spatial relationships and manipulate objects, making it difficult to carry out ordinary daily tasks like getting dressed. Degeneration of the temporal neocortex may affect visual recognition of objects and people (including close friends and family members).

Reasoning and language

As with most forms of dementia, there is a general decline in problem-solving ability and abstract reasoning which impairs decision-making and judgement. This affects the capacity to manage personal affairs without supervision and interferes with ordinary daily activities such as shopping, cooking and paying bills. Language problems are very common, with word-finding difficulties and reduced verbal fluency in the initial stages, sometimes progressing to almost complete loss of verbal communication in advanced dementia.

Psychiatric features

Early in the course of the disease, patients tend to become withdrawn and may experience depression or anxiety. There may be disinhibition, with inappropriate or child-like behaviour. Awareness of declining intellectual ability and loss of independence may lead to frustration and irritability, with mood swings or angry outbursts. As time passes, apathy is more common, with reduced interest in activities that were previously enjoyable. Delusions, hallucinations and paranoia sometimes occur in the very late stages.

Functional brain imaging in early Alzheimer’s disease may show reduced blood flow and glucose metabolism in the posterior temporo-parietal regions and hippocampus (Fig. 12.3), before obvious structural changes are evident on MRI. Over time there is progressive brain atrophy, with ventricular dilatation, cortical thinning and hippocampal atrophy. Longitudinal studies show that people with Alzheimer’s disease lose brain tissue at a rate of 2% per year on average (up to 5% per year in the hippocampus), which is four times higher than in age-matched controls (Fig. 12.4).

Fig. 12.3 Reduced hippocampal blood flow in early Alzheimer’s disease.These images were obtained via single photon emission computer tomography (SPECT) scanning using a radioactive tracer and show regional cerebral blood flow. The upper image is a normal control subject and the lower image is from a patient with early Alzheimer’s disease. The sections are in the axial (horizontal) plane and pass through the temporal lobe. The black box shows the position of the hippocampus in the medial temporal lobe. From Rodriguez, G. et al.: Hippocampal perfusion in mild Alzheimer’s disease. Psychiatry Research: Neuroimaging (2000, pp. 65–74) with permission.

Fig. 12.4 Neuroimaging showing progressive brain atrophy in Alzheimer’s disease (AD) in comparison to an age-matched control.These are fluid-registered volumetric MRI scans from a 60-year-old patient with Alzheimer’s disease [right] and a normal age-matched control [left]. In each case, two MRI scans were acquired one year apart and have been registered together. Regions of brain loss are shown as blue-green; increases in CSF spaces are shown as red-yellow. In the patient with Alzheimer’s disease, there is marked volume loss in the hippocampi and temporal lobes, with widespread symmetrical atrophy in other parts of the cerebral hemispheres and dilation of the ventricles. The control shows normal age-related atrophy. Courtesy of Professor Nick Fox.

Progression and death

The rate of progression is highly variable, with typical disease duration ranging from 5 to 15 years. Patients may initially be able to remain at home, but will require assistance with day-to-day activities and become increasingly dependent on carers. Ultimately, supervision is required for all activities of daily living including bathing and toileting. At some point specialized institutional care is usually most appropriate, particularly if the primary carers are themselves elderly. In the advanced stages of dementia, most sufferers tend to be become bed-bound and mute. Death is often due to a complication of immobility such as pneumonia.

Key Points

Alzheimer’s disease is the leading cause of dementia in all age groups. Early features include (i) marked loss of episodic memory and (ii) spatial disorientation (both reflecting severe medial temporal lobe degeneration).

As the disease progresses there is a gradual decline in all aspects of cognitive ability over a variable period of around 5–15 years, together with changes in mood, personality and behaviour.

The frontal variant of Alzheimer’s disease is characterized by striking personality and behavioural changes. In posterior cortical atrophy the clinical picture is dominated by visuospatial problems, with relative preservation of memory and language.

Risk factors

The most important risk factor for Alzheimer’s disease, apart from advancing age, is possession of a particular variant of the Apolipoprotein E gene (APOE) on chromosome 19 (discussed below). It is also more common in people with ischaemic heart disease, in those with limited educational attainments or lower socioeconomic status – and in association with previous head injury (Clinical Box 12.4).

Clinical Box 12.4: Dementia pugilistica

Dementia pugilistica or ‘punch drunk’ syndrome is a form of acquired cognitive impairment that occurs in up to a fifth of professional boxers (Latin: pugilator, boxer). It also occurs in other sports in which there may be mild head trauma, such as football and horse racing. The microscopic features are similar to Alzheimer’s disease, but the anatomical distribution is different. Pathology is often found in the substantia nigra of the midbrain and cognitive decline may be combined with features of Parkinson’s disease (in which nigral degeneration is a key pathological feature; see Ch. 13).

Familial clustering of APOE alleles, together with a large number of unknown susceptibility genes, may help to explain the observation that Alzheimer’s disease is more common in people with an affected parent or sibling and that concordance rates are significantly higher in identical twins.

Apolipoprotein E

There are three common APOE alleles: epsilon-2 (APOE2), epsilon-3 (APOE3) and epsilon-4 (APOE4). These encode a lipoprotein that is involved in plasma lipid transport, including the uptake and distribution of cholesterol. APOE4 is associated with a higher incidence of sporadic Alzheimer’s disease, such that two copies of the allele increase risk approximately 20-fold and more than 50% of patients with Alzheimer’s disease have at least one copy. In contrast, APOE2 appears to be protective. The role of Apolipoprotein E in the pathogenesis of Alzheimer’s disease is incompletely understood, but it has been shown to bind to and influence the removal of amyloid beta peptide from the brain, accumulation of which is a key event in the pathogenesis of Alzheimer’s disease (discussed below).

Other genetic factors

Possession of a rare variant of the TREM2 gene (triggering receptor expressed on myeloid cells 2) on chromosome 6 is associated with a three-fold increase in Alzheimer’s disease risk. The mechanism is uncertain at present, but the gene is involved in microglial activation and brain inflammation, providing an important clue to pathogenesis in sporadic disease.

Genome-wide analysis has revealed single nucleotide polymorphisms or SNPs (‘snips’) in three genes that may be associated with modestly increased risk of Alzheimer’s disease: CLU (clusterin or Apolipoprotein J); PICALM (phosphatidylinositol-binding clathrin assembly protein); and CR1 (complement component 3b/4b receptor 1).

The associations of these SNPs are much weaker than for APOE but are most significant for the related gene CLU. Both encode apolipoprotein molecules that bind amyloid beta and are involved in its clearance from the brain: ApoE protein promotes amyloid beta clearance, whereas ApoJ is involved in its uptake into the brain from the bloodstream.

Protective factors

Alzheimer’s disease is more common in females, even after accounting for greater longevity, and hormone-replacement therapy (HRT) may be protective in post-menopausal women. Moderate consumption of alcohol also appears to be beneficial, together with regular mental, physical and social activities. It has been claimed that use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk, but clinical trials have failed to show a protective effect.

Pathological features

Post-mortem examination of the brain in Alzheimer’s disease shows reduced brain weight, with cortical atrophy and enlarged ventricles. Loss of brain tissue is often particularly obvious in the medial temporal lobes and hippocampi and there may be marked thinning of the cerebral cortex with widening of the sulci. Microscopic examination shows characteristic ‘plaques’ and ‘tangles’.

Plaques (Fig. 12.5)

A pathological hallmark of Alzheimer’s disease is the presence of plaques in the cerebral cortex, consisting of insoluble protein aggregates. Plaques are found in the extracellular space (between neurons) and are predominantly composed of amyloid beta peptide (Aβ). Like all forms of amyloid, the deposits take up the tissue stain Congo red and show apple-green birefringence under polarized light (see Ch. 8). Plaques can be identified using silver staining, but are best demonstrated using immunohistochemistry (antibody labelling).

Fig. 12.5 Cortical plaques in Alzheimer’s disease.This micrograph demonstrates extensive amyloid beta deposits (amyloid plaques) in the cerebral cortex of a person who died of Alzheimer’s disease. *Inset*: a single ‘cored plaque’ with a dense central core of amyloid is shown at higher magnification [immunohistochemical preparation for Aβ peptide].

Although widespread, plaques are most common in the hippocampus, entorhinal cortex and amygdala. They are found in moderate numbers in frontal, parietal and temporal association cortices, but are uncommon in the primary sensory and motor areas. There are two main types:

Diffuse plaques are composed of amyloid beta peptide in a non-fibrillary (non-amyloid) form and may be numerous in older people who do not have dementia.

Neuritic plaques are surrounded by abnormal dystrophic neurites (thickened, tortuous neuronal processes) and sometimes have a dense, central core of amyloid (‘cored plaques’; see Fig. 12.5).

Unlike diffuse plaques, neuritic plaques are strongly associated with cognitive decline. Aβ is also deposited in the walls of blood vessels, leading to cerebral amyloid angiopathy (Clinical Box 12.5).

Clinical Box 12.5: Cerebral amyloid angiopathy

Aβ is deposited in cortical blood vessels in 90% of patients with Alzheimer’s disease, which is termed cerebral amyloid angiopathy (CAA) (see Ch. 8, Fig. 8.14). Amyloid deposition leads to degeneration of vascular smooth muscle, weakening the vessel wall and predisposing to microinfarctions and intracerebral haemorrhage (see Ch. 10, Fig. 10.2B). CAA can occur in the absence of dementia and accounts for a quarter of intracerebral haemorrhages in the elderly. The bleeding is superficial or ‘cortical’ rather than deep (in contrast to hypertension-related haemorrhages, which frequently occur in the region of the basal ganglia).