Dementia

Published on 13/06/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 1481 times

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.

Key Points

The most important risk factor for Alzheimer’s disease (apart from advancing age) is possession of one or more copies of the APOE4 allele, which is present in more than 50% of patients.

Alzheimer’s disease is also more common in people with ischaemic heart disease, in those with limited educational attainments, lower socioeconomic status or a history of head injury.

It is more common in females and hormone-replacement may be beneficial in post-menopausal women. The positive effect of anti-inflammatory drugs is unproven.

Moderate consumption of alcohol may also be beneficial, together with regular mental, physical and social activities.

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).

Neurofibrillary tangles (Fig. 12.6)

The second major pathological finding in Alzheimer’s disease is the neurofibrillary tangle (NFT). This is a filamentous inclusion composed of the microtubule-associated protein tau, which is normally present in axons (see Ch.5).

Fig. 12.6 Neurofibrillary tangles in Alzheimer’s disease.
Micrograph showing two cortical neurons containing neurofibrillary tangles. The small, rounded inclusion (right) is a ‘globose’ tangle whilst the larger, more pyramidal-shaped inclusion (left) is a ‘flame’ tangle. The different appearances of the pathological inclusions reflect the shape of the neuronal cell body, which is filled with abnormal tau protein. A few fine ‘neuropil threads’ can also be seen, representing neuronal processes filled with tau [immunohistochemistry for hyperphosphorylated tau protein].

Tangles are best demonstrated by immunohistochemistry for tau. They are found in the cytoplasm of surviving neurons and may persist after a neuron has died to form a ghost tangle in the extracellular space. Tau-positive inclusions are also found in dystrophic neurites (in ‘neuritic’ plaques) and in other abnormal neuronal processes, as neuropil threads.

Tau is a phosphoprotein with 79 serine and threonine phosphorylation sites, less than half of which are normally phosphorylated. Neurofibrillary tangles contain hyperphosphorylated tau in the form of paired helical filaments (PHFs) that resemble twisted ribbons (Fig. 12.7).

Fig. 12.7 Paired helical filament (PHF) tau forms neuronal inclusions in Alzheimer’s disease and other neurodegenerative conditions.
**(A)** Illustration showing the twisted structure of PHF-tau, which has a diameter of 22 nm and a periodicity of 80 nm; **(B)** An electron micrograph showing paired helical filament tau. From Ellison and Love: Neuropathology 2e (Mosby 2003) with permission.

Neuronal and synaptic loss

Quantitative post-mortem studies in patients with Alzheimer’s disease have shown significant neuronal loss in the hippocampus and medial temporal lobe. The entorhinal cortex is particularly affected, with more than 90% neuronal loss in advanced Alzheimer’s disease. This area gives rise to the perforant path (a major afferent projection to the hippocampus, see Ch. 3), meaning that the hippocampus is effectively ‘disconnected’ from the neocortex in Alzheimer’s disease.

More widespread loss of nerve cells and synaptic connections is found throughout the cerebral cortex and there is a reduction in the number of dendritic spines (see Ch. 5). Cell death also occurs in the brain stem, including the noradrenergic loci coerulei (singular: locus coeruleus) in the pons, which are normally pigmented but appear pale in Alzheimer’s disease.

Profound neuronal loss occurs in Meynert’s nucleus, a large cholinergic nucleus in the base of each cerebral hemisphere which contributes to the diffuse neurochemical system for acetylcholine (see Ch. 1). Degeneration of this projection (which diffusely innervates the neocortex and hippocampus) has a negative impact on memory, attention and cognition. For this reason, agents that potentiate cholinergic neurotransmission may improve symptoms in Alzheimer’s disease (see below).

Key Points

Pathological changes in Alzheimer’s disease include brain atrophy, ventricular enlargement and cortical thinning. Microscopic examination shows plaques and tangles in the cortex.

Diffuse and neuritic plaques are composed of Aβ, which is deposited in the extracellular compartment (between nerve cells) as insoluble aggregates.

Neurofibrillary tangles occupy the neuronal cytoplasm and are composed of insoluble filamentous aggregates of hyperphosphorylated tau protein, arranged as paired helical filaments.

The cortex shows widespread loss of neurons, synapses and dendritic spines and a global reduction in cholinergic neurotransmission (due to severe degeneration of Meynert’s nucleus).

More than 90% of patients with Alzheimer’s disease also have deposition of amyloid beta in cortical blood vessels, leading to cerebral amyloid angiopathy (CAA).

Pathogenesis of Alzheimer’s disease

Accumulation of amyloid beta is widely believed to be a key initiating event in the development of Alzheimer’s disease. This appears to trigger a cascade of pathological events in the neuron, leading to tau hyperphosphorylation and tangle formation: the amyloid cascade hypothesis. Neuronal injury is thought to be mediated by a combination of cytopathic mechanisms including oxidative stress, excitotoxicity and inflammation, culminating in programmed cell death (see Ch. 8).

Formation of amyloid beta

Amyloid beta is a soluble peptide of 40 or 42 amino acids (Aβ40, Aβ42). It is produced by proteolytic cleavage of amyloid precursor protein (APP) (Fig. 12.8A). This is a large transmembrane protein that appears to be involved in synaptic plasticity and learning. There are six isoforms of APP in the human brain, composed of 695–770 amino acids (depending on alternative splicing). It has a single intramembranous portion, a large extracellular domain and a short cytoplasmic tail. The Aβ sequence is partly contained in the intramembranous portion.

Fig. 12.8 Amyloid precursor protein (APP).
**(A)** The sequence corresponding to the amyloid beta peptide (Aβ) is shown in red, partially embedded in the neuronal plasma membrane; **(B)** A closer view, showing the sites of action of the main APP processing enzymes. Gamma-secretase is a multi-subunit integral membrane protein that includes the enzymes presenilin-1 and presenilin-2 (PS1/PS2).

Amyloid processing

There are two APP processing pathways (Fig. 12.9) mediated by a family of proteolytic enzymes called secretases (see also Fig. 12.8B). The pathogenic Aβ fragment is released from APP by sequential beta and gamma secretase cleavage. The C-terminal fragment is released into the cytoplasm and is involved in nuclear signalling. APP is encoded on chromosome 21, which accounts for the high incidence of Alzheimer-type changes in people with Down’s syndrome (trisomy 21) who have an extra copy of the chromosome. This leads to increased production of Aβ, associated with a greater than 50% chance that the brain will contain plaques and tangles by early middle age.

Primary (alpha) pathway

The primary pathway for APP processing involves sequential activity of alpha and gamma secretase (Fig. 12.9A). Alpha secretase releases a large soluble APP fragment into the extracellular fluid. This is followed by gamma secretase cleavage, which acts on the intramembranous portion of APP. The cleavage point of alpha secretase falls in the middle of the Aβ sequence, thereby destroying the pathogenic peptide. The primary pathway is therefore non-amyloidogenic and since it is dominant, very little Aβ is normally produced in the brain.

Alternative (beta) pathway

This pathway involves the sequential action of beta and gamma secretases. It liberates amyloid beta from APP and is therefore potentially amyloidogenic (Fig. 12.9B). Beta-secretase cleaves APP at the distal end of the Aβ sequence and gamma secretase acts at the proximal end (within the plasma membrane). The alternative pathway releases either a 40 or 42 amino acid species of amyloid beta.

Ratio of Aβ40 to Aβ42

This is determined by the multi-protein gamma-secretase complex that includes the enzymes presenilin-1 and presenilin-2 (PS-1 and PS-2) and affects the pattern and distribution of the pathological changes. Aβ42 tends to form plaques in the cerebral cortex and is more associated with dementia. The more soluble Aβ40 fragment is frequently deposited in blood vessels, causing cerebral amyloid angiopathy. Several inherited forms of Alzheimer’s disease involve mutations in genes concerned with APP processing that increase the amount of Aβ (or Aβ42) (Clinical Box 12.6).

Clinical Box 12.6: Familial Alzheimer’s disease

Familial Alzheimer’s disease (FAD) accounts for only 5% of cases, but has provided invaluable insights into the pathogenesis of sporadic disease. All forms show autosomal dominant inheritance with a high degree of penetrance. Presentation is usually below the age of 65 and the term early-onset Alzheimer’s disease is therefore used. Most cases of familial Alzheimer’s disease are due to mutations in one of the three main genes involved in amyloid processing:

APP, on chromosome 21, which encodes amyloid precursor protein.

PSEN1, on chromosome 14, which encodes presenilin-1 (PS-1).

PSEN2, on chromosome 1, which encodes presenilin-2 (PS-2).

Mutations in the genes for PS-1 or PS-2 account for nearly half of familial Alzheimer’s disease cases. There is usually increased Aβ production, with alteration of the Aβ40:Aβ42 ratio, so that more of the plaque-forming Aβ42 species is produced. In many FAD families with known mutations in the APP gene, the region of the protein flanking the amyloid beta sequence is affected, which is also associated with increased Aβ42 production. This is in contrast to mutations affecting the central portion of the amyloid sequence, which are more likely to cause cerebral amyloid angiopathy.

Key Points

Deposition of Aβ in the cerebral cortex is believed to be a key initiating event in the development of Alzheimer’s disease, leading to tau hyperphosphorylation and tangle formation within neurons (the ‘amyloid cascade hypothesis’).

Aβ is produced by proteolytic cleavage of the precursor molecule APP. Processing via the primary (alpha secretase) pathway is dominant and does not lead to Aβ release.

Processing via the alternative (beta secretase) pathway releases soluble Aβ peptide. The ratio of Aβ40:Aβ42 is determined by the gamma secretase complex.

The less soluble Aβ42 tends to form cortical plaques and is more associated with dementia, whereas Aβ40 deposition in blood vessels leads to cerebral amyloid angiopathy.

Formation of neurofibrillary tangles

The next step in the ‘amyloid cascade’ is abnormal phosphorylation of the microtubule-associated protein tau. This normally binds to (and stabilizes) axonal microtubules, but in its hyperphosphorylated form, tau dissociates from microtubules and tends to self-aggregate (Fig. 12.10). This may reflect excessive activity in tau kinases (which add phosphate groups to proteins) such as glycogen synthase kinase 3-beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5) but the mechanism is not certain.

Fig. 12.10 Tau is a microtubule-associated protein (MAP) that is normally found predominantly in axons.
**(A)** In its unphosphorylated state, tau binds to microtubules and helps to stabilize them. Phosphorylation is regulated by the activity of kinases (which add phosphate groups) and phosphatases (which remove them); **(B)** Hyperphosphorylated tau monomers dissociate from microtubules and, at sufficient concentrations, tend to self-aggregate to form paired helical filament tau (the main constituent of neurofibrillary tangles).

Once dissociated from microtubules, monomers of phosphorylated tau aggregate into protofilaments (oligomers) and then filaments, eventually forming mature neurofibrillary tangles. The spread of tangle pathology through the brain follows six Braak stages, which can be divided into early, intermediate and late phases (Fig. 12.11).

Fig. 12.11 Progression of tangle pathology in Alzheimer’s disease.
**(A)** Coronal section through the temporal lobe showing the distribution of tangle pathology in early (Braak I–II) Alzheimer’s disease. The earliest and most severely affected area (between the dashed lines) is the transentorhinal cortex; **(B)** Progression of tangle pathology in the intermediate (Braak III–IV) and late (Braak V–VI) stages.

Tangles first appear in the entorhinal cortex and hippocampus (Braak stages I–II) during the presymptomatic phase of the disease. Pathology gradually spreads to involve more of the limbic lobe, amygdala and neighbouring fusiform gyrus in the intermediate phase (Braak stages III–IV). This is likely to correspond to incipient dementia or mild cognitive impairment. Clinical dementia appears as tangle pathology extends to the association areas of the neocortex (Braak stage V) and finally to the primary sensory and motor areas (Braak stage VI).

Key Points

Mutations in the presenilin or APP genes are responsible for most inherited (autosomal dominant) early-onset forms of Alzheimer’s disease. In all cases there is excessive Aβ production.

Deposition of Aβ in the cerebral cortex (particularly Aβ42) appears to trigger a cascade of events within neurons, leading to the accumulation of hyperphosphorylated tau.

Tau hyperphosphorylation is thought to be mediated by an imbalance between phosphatases and kinases, with excessive activity of tau kinases such as CDK5 and GSK-3β.

Neurofibrillary tangles first appear in the medial temporal lobe (hippocampus, entorhinal cortex) and spread progressively throughout the limbic lobe and neocortex in six Braak stages.

Amyloid beta clearance

In normal individuals, small amounts of Aβ are continuously produced and eliminated. Abnormal build-up of Aβ may therefore reflect increased production, decreased elimination or some alteration in the balance between these two processes. Excessive production of Aβ is implicated in a small minority of cases (e.g. in Down’s syndrome and in familial Alzheimer’s disease associated with mutations of PSEN1, PSEN2 or APP) but in the vast majority of sporadic disease, failure of Aβ clearance appears to be the most important factor.

Mechanisms for Aβ removal

Several enzymes have been identified in the brain and within the walls of arteries that contribute to the elimination of amyloid beta, including neprilysin and insulin-degrading enzyme (IDE). Many other enzymes are capable of degrading Aβ and may contribute to its clearance, including some that are typically associated with other roles (e.g. angiotensin converting enzyme). Export of Aβ from the brain, across the blood–brain barrier, is mediated by a low-density lipoprotein-receptor-related protein (LRP-1) in the endothelium of cerebral blood vessels.

The efficacy of enzyme degradation and export to the bloodstream declines in the elderly, in whom the much slower process of perivascular drainage may be more important. This is less effective in stiff, arteriosclerotic blood vessels (since there is reduced transmission of arterial pulsations that encourage bulk flow of perivascular fluid) which helps to explain the association between dementia and ischaemic heart disease.

Pathological effects of amyloid beta

The degree of cognitive decline correlates poorly with the amount of insoluble (plaque-associated) Aβ deposited in the cerebral cortex, but is strongly associated with (i) the extent of tangle pathology and (ii) the soluble Aβ fraction. This raises the possibility that a prefibrillar species of amyloid (contained in the soluble fraction) may be primarily responsible for neurotoxicity in Alzheimer’s disease, leading to the formation of neurofibrillary tangles. This raises the possibility that amyloid plaques may therefore be protective rather than harmful, representing an attempt by the cell to ‘trap’ potentially neurotoxic components as insoluble aggregates.

Toxic oligomeric species

Soluble Aβ monomers self-aggregate to form oligomers which associate with the cell membrane and form ring-like arrangements with an aqueous pore. This is similar to the membrane attack complex of the complement cascade. Pore formation compromises the neuronal plasma membrane, admitting sodium, water and free calcium ions, which damage the cell. Excessive influx of calcium, in particular, is known to be a final common pathway in many forms of neuronal cell death. There is also evidence that Aβ oligomers: (i) are toxic to mitochondria, increasing oxidative stress and lowering the threshold for apoptosis; (ii) may contribute to the formation of neurofibrillary tangles within nerve cells, by promoting hyperphosphorylation of tau; and (iii) appear to cause synaptic dysfunction and loss.

Pathological ageing and cognitive reserve

Post-mortem studies have shown that the typical pathological changes of Alzheimer’s disease are present to a greater or lesser extent in many elderly people with no history of dementia. This is referred to as pathological ageing. In some cases the pathology is advanced, despite no evidence of cognitive decline during life. This is thought to reflect greater cognitive reserve capacity in some people, due to higher levels of premorbid intelligence or education (Fig. 12.12).

Fig. 12.12 The concept of cognitive reserve.
Individuals of average intelligence (red line) may show clinical signs of dementia much earlier after disease onset than people with a higher degree of premorbid intelligence or education (purple line), assuming that the rate of progression is similar.

Key Points

In normal individuals a small amount of Aβ is continuously produced and eliminated.

Mechanisms for removal include enzymatic degradation and active transport into the bloodstream (which decline with age) and perivascular drainage (which also declines with age and is less effective in people with cerebrovascular disease).

The mechanism by which Aβ damages neurons is not entirely certain, but Aβ oligomers are known to be associated with neuronal membranes and form pore-like structures (similar to those of the membrane attack complex) which admit sodium, water and calcium into the cell.

Other potential mechanisms of Aβ toxicity include mitochondrial dysfunction, oxidative stress, promotion of tau hyperphosphorylation and disruption of synapses.

Alzheimer-type changes are present to a variable extent in many cognitively normal older people, which is thought to reflect greater cognitive reserve capacity.

Treatment of Alzheimer’s disease

No agents are currently available that can reverse or halt the progression of Alzheimer’s disease. Treatment is therefore limited to symptomatic and supportive measures.

Pharmacological agents

The cholinergic deficit in Alzheimer’s disease contributes to memory impairment and can be improved to some degree by cholinesterase inhibitors (e.g. donepezil, rivastigmine, galantamine). These drugs potentiate cholinergic transmission by inhibiting acetylcholine degradation in the synaptic cleft. Modest benefit is seen in at least 50% of patients with mild to moderate dementia, but the improvement usually lasts less than 12 months. Side effects include diarrhoea, nausea and vomiting.

A second agent used in patients with Alzheimer’s disease is memantine, an NMDA receptor antagonist that inhibits glutamatergic neurotransmission (see Ch. 7). The mechanism is uncertain, but may include protection against neuronal calcium overload. Clinical trials have shown some benefit in patients with moderate dementia, but not in those with mild cognitive decline.

Disease-modifying agents

A number of potential disease-modifying agents are currently in clinical trials, most of which aim to interfere with amyloid processing or tangle formation; strategies include:

Immunotherapy (Aβ vaccination) to trigger an active immune response that will remove deposits of amyloid beta peptide from the brain (see below).

Passive immunization with anti-Aβ antibodies, which also aims to remove amyloid deposits from the brain, but does not generate a lasting immunological response.

Inhibition of beta-secretase, to block processing of APP in the alternative (amyloidogenic) pathway and therefore reduce Aβ production.

Inhibition of amyloid fibril formation, preventing the molecular progression of the disease or blocking formation of a toxic prefibrillary species.

Inhibition of tau aggregation, e.g. by the experimental agent methylthioninium chloride (methylene blue) which has shown encouraging results in clinical trials.

Inhibition/modulation of gamma-secretase (e.g. PS-1/PS-2 inhibitors) altering the ratio of Aβ40 to Aβ42 so that less pathogenic (plaque-forming) Aβ42 is produced.

One of the most promising approaches to date has been Aβ vaccination, which has achieved almost complete plaque clearance in mouse models. Follow-up post-mortem studies in patients with Alzheimer’s disease have confirmed some degree of plaque clearance, but: (i) only 20% of patients generate anti-Aβ antibodies; (ii) the improvement in cognitive state is minimal; and (iii) severe meningoencephalitis (inflammation of the brain and its coverings) occurs in 1 in 20 people. Theoretical concerns have also been raised that disrupting plaques may release harmful oligomeric species.

Key Points

No disease-modifying treatments are currently available for Alzheimer’s disease, but some symptomatic improvement can be gained using cholinesterase inhibitors or memantine.

Potential disease-modifying strategies include: (i) inhibition of beta secretase to reduce Aβ production; (ii) interference with amyloid fibril formation/maturation; and (iii) inhibition/modulation of gamma secretase to alter the ratio of Aβ40 to Aβ42.

Active immunotherapy (Aβ vaccination) has been very successful in animal models (achieving almost complete amyloid plaque clearance) but clinical trials have been disappointing.

Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common type of dementia after Alzheimer’s disease, accounting for 20% of cases. It is predominantly sporadic, but rare familial forms with autosomal dominant inheritance have been described.

Clinical features

The three core elements of dementia with Lewy bodies (in addition to cognitive decline) are: (i) visual hallucinations; (ii) fluctuation in cognitive performance; and (iii) features of parkinsonism, such as tremor, rigidity and bradykinesia (see Ch. 13). Additional findings in support of the diagnosis include reduced dopamine levels in the basal ganglia or a sleep disorder (Clinical Box 12.7).

Clinical Box 12.7: Sleep disorders in DLB

Dementia with Lewy bodies may be associated with a number of sleep disorders including vivid dreams and nightmares. A characteristic feature occurs during rapid eye movement (REM) sleep, the phase during which dreaming is most likely to take place. This is called REM sleep behaviour disorder and is characterized by ‘acting out’ dreams or sleepwalking. It is thought to be due to interference with the normal brain stem mechanisms that ensure paralysis during sleep.

Around 50% of patients with DLB are highly sensitive to neuroleptics (antipsychotic agents) which act by antagonizing central dopamine receptors; this leads to severe muscular rigidity with immobility and confusion. Another common feature in patients with DLB is autonomic dysfunction including postural hypotension with fainting and falls. A proportion of patients exhibit frankly psychotic features, with hallucinations and delusions.

Psychological testing and neuroimaging

Neuropsychological testing typically shows deficits in attention and frontal lobe executive function (such as planning, organizing and decision-making) and difficulty with visuospatial tasks. It may also confirm fluctuation in cognitive performance and attention. In contrast to Alzheimer’s disease, there tends to be relative preservation of episodic memory.

Functional brain imaging often shows reduced metabolism and cerebral blood flow in the occipital and posterior temporoparietal regions (Fig. 12.13). This is in contrast to other forms of dementia in which the posterior hemisphere tends to be spared and may account for the prominent visual hallucinations in DLB.

Fig. 12.13 Functional neuroimaging in dementia with Lewy bodies (DLB).
Functional brain imaging in patients with DLB may show reduced glucose consumption (metabolism) in the occipital and posterior temporoparietal regions, as in this case. [The image was obtained by positron-emission tomography (PET) scanning, using ¹⁸F-FDG, a positron-emitting isotope of glucose]. From Silverman, D et al: Positron emission tomography scans obtained for the evaluation of cognitive dysfunction. Seminars in Nuclear Medicine. Neuronuclear Imaging (2008, pp. 251–261) with permission.

Key Points

DLB is the second most common type of dementia after Alzheimer’s disease, accounting for around 20% of cases.

The core features, in addition to cognitive decline, are: visual hallucinations, fluctuation in cognitive performance and parkinsonism.

Up to 50% of patients show neuroleptic sensitivity and there may be autonomic dysfunction or sleep disorders including REM sleep behaviour disorder.

Pathological features

Macroscopic examination of the brain is often unremarkable but there may be generalized atrophy and dilation of the ventricles, with pallor of the substantia nigra (see Ch. 13, Fig. 13.5) and locus coeruleus (see Ch. 1). The microscopic features are indistinguishable from Parkinson’s disease with dementia (PDD) and the distinction between PDD and DLB is purely clinical (see Ch. 13, Clinical Box 13.1).

Lewy bodies

Microscopic examination of the brain shows pathological inclusions (abnormal protein aggregates) in the cytoplasm of surviving neurons. These rounded intraneuronal structures, called Lewy bodies, appear bright pink on standard histological preparations (since they take up the red tissue dye eosin) and are often surrounded by a pale halo (Fig. 12.14A). Lewy bodies are best demonstrated by immunohistochemistry for alpha-synuclein protein, which is the major constituent (Fig. 12.14B). Cortical Lewy bodies are similar to those found in the brain stem, but lack a halo and are best seen on immunohistochemistry (Fig. 12.14C). Many patients also have some degree of Alzheimer’s disease pathology (Fig. 12.14D) and there may be a synergistic interaction between alpha-synuclein and Aβ.

Fig. 12.14 Lewy bodies and Lewy neurites.
**(A)** This is a routine haematoxylin and eosin (H&E)-stained section from the substantia nigra of a patient who had dementia with Lewy bodies (DLB). It shows a bright pink Lewy body in the neuronal cytoplasm, surrounded by brown neuromelanin pigment; **(B)** Lewy bodies can be demonstrated using immunohistochemistry (antibody labelling) for alpha-synuclein, which is the main protein constituent; **(C)** Cortical Lewy bodies are best detected by immunostaining for alpha-synuclein, in this case in the temporal lobe of a patient with DLB; **(D)** Immunohistochemistry for alpha-synuclein in a patient with Alzheimer’s disease showing co-existing Lewy bodies and Lewy neurites in the temporal lobe. From Popescu, A and Lippa, CF: Parkinsonian syndromes: Parkinson’s disease dementia, dementia with Lewy bodies and progressive supranuclear palsy. Clinical Neuroscience Research, Non-Alzheimer’s Disease Dementias (2004, pp. 461–468) with permission.

Progression of pathology

The pathological changes spread through the brain in a predictable fashion, analogous to the orderly progression of tangles in Alzheimer’s disease (Fig. 12.15). Six Braak stages are described, which are the same as those in idiopathic Parkinson’s disease (see also Ch. 13, Fig. 13.7). Synuclein-positive inclusions appear first in the olfactory bulb and medulla (stage I), before progressing to the pons (stage II) and midbrain (stage III). The first three stages are thus largely confined to the brain stem. Inclusions are next encountered in the limbic lobe, including the entorhinal cortex and amygdala (stage IV). The last two stages are neocortical, with inclusions in the higher-order association cortices (stage V) and finally in the primary sensory and motor areas (stage VI). The pathology and pathogenesis of the synuclein-related disorders (or synucleinopathies) is discussed further in Chapter 13.

Fig. 12.15 Progression of Lewy body pathology. From Basbaum, A: The senses: a comprehensive reference (Academic Press 2008) with permission.

Key Points

The pathological features in dementia with Lewy bodies are indistinguishable from Parkinson’s disease dementia, including widespread Lewy bodies (composed of alpha-synuclein protein).

Lewy bodies first appear in the olfactory bulb and medulla before progressively spreading to involve the midbrain, pons, limbic lobe, amygdala and neocortex (in six Braak stages).

Many patients also have variable Alzheimer-type changes and there appears to be a synergistic interaction between Aβ and alpha-synuclein.

Vascular dementia

Vascular dementia is the third most common cause of acquired cognitive decline in older people, accounting for approximately 10% of cases. The risk factors are the same as those for ischaemic heart disease and stroke (Fig. 12.16). The term vascular cognitive impairment is used to describe a non-progressive decline in intellectual ability with a vascular aetiology.

Clinical features

People with vascular dementia may show a step-wise loss of cognitive ability consistent with a series of strokes, referred to as multi-infarct dementia (Fig. 12.17). In others, the decline is more gradual and is dominated by generalized slowing of cognition with disturbed frontal executive function (i.e. bradyphrenia or ‘subcortical-type’ dementia). This is often due to diffuse white matter disease, sometimes referred to as Binswanger’s encephalopathy (pronounced: BINSE-vangers).

Fig. 12.17 Multi-infarct dementia.
Progression is classically said to occur in a step-wise fashion consistent with a series of small strokes, in contrast to the gradual decline seen in Alzheimer’s disease.

Distinction from Alzheimer’s disease

Distinguishing between Alzheimer’s disease and vascular dementia may not be straightforward and the two often co-exist, but certain clinical features (discussed below) are more suggestive of vascular dementia.

In contrast to Alzheimer’s disease, the course is more likely to fluctuate, with ‘good and bad days’ and the profile of deficits on neuropsychological testing may be more patchy. Mood changes such as anxiety, depression or emotional incontinence (inappropriate laughter or tearfulness) are also more prominent and symptoms tend to be worse in the evenings, called sundowning. The degree of memory loss is variable, but can be less obvious than in Alzheimer’s disease.

Associated damage to the basal ganglia sometimes leads to a pseudo-parkinsonian gait with short, shuffling steps: the marche à petit pas (French: walking with small steps) and there may be focal neurological signs consistent with one or more previous strokes. The typical imaging appearances are shown in Figure 12.18.

Fig. 12.18 Axial MRI scan showing the typical imaging features of cerebral small vessel disease.
There is confluent hyperintensity in the periventricular white matter and patches of hyperintensity in the deep and subcortical white matter. Additionally, there are several small focal cavities (with the same signal intensity as CSF) which are typical of ‘old’ lacunar infarcts [T2-weighted MRI with CSF suppression: fluid-attenuation inversion recovery or ‘FLAIR’ sequence]. Courtesy of Dr Andrew MacKinnon.

Pathological features

Vascular dementia may be caused by: (i) small vessel disease; (ii) large vessel disease; or (iii) a combination of the two. The term mixed dementia is used if there are co-existent features of Alzheimer’s disease or another dementia. A rare inherited form of vascular dementia is discussed in Clinical Box 12.8.

Clinical Box 12.8: CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a rare autosomal dominant disorder that classically presents in young females who have a history of migraine with aura. It is characterized by multiple strokes affecting the subcortical white matter (Greek: leukos, white) leading to progressive dementia with psychiatric features. It is caused by mutation of the NOTCH3 gene on chromosome 19, the same locus that is responsible for familial hemiplegic migraine. Electron microscopy shows deposits of granular material in the walls of small blood vessels which include part of the extracellular domain of the notch3 receptor.

Small vessel disease

This is the most common finding in patients with vascular dementia. It is frequently associated with arterial hypertension, diabetes and other vascular risk factors. High blood pressure damages the walls of small and medium-sized blood vessels, leading to replacement of smooth muscle by collagen. This gives an amorphous or ‘hyaline’ (Greek: glassy) appearance under the microscope, termed hyaline arteriosclerosis (Fig. 12.19A). Some vessels show more striking wall destruction with replacement of smooth muscle by lipid-laden foam cells, termed lipohyalinosis.

Fig. 12.19 Pathological features of small vessel disease.
**(A)** Micrograph of a deep hemispheric blood vessel showing replacement of vascular smooth muscle by (pink) hyaline material. There is also marked enlargement of the perivascular space. From Prayson, R: Neuropathology 1e (Churchill Livingstone 2005) with permission; **(B)** Photograph of a coronal brain section showing multiple lacunar infarcts in the basal ganglia as a result of small vessel disease (including prominent slit-like spaces, labelled “S”). From Stevens and Lowe: Pathology 2e (Mosby 2000) with permission.

Both types of small vessel pathology contribute to ‘hardening’ of the arteries and arterioles, referred to as arteriosclerosis and arteriolar sclerosis respectively (Greek: sklerōs, hard). Normally distensible blood vessels are thus converted into rigid pipes with limited ability to dilate in response to fluctuations in blood pressure. This leads to small strokes (less than 1 cm in diameter) called lacunar infarcts (Latin: lacūna, hole or gap) (Fig. 12.19B). There may also be a more general attenuation of the subcortical white matter with expansion of perivascular spaces, creating a ‘moth-eaten’ appearance.

Large vessel disease

Some patients develop dementia after a series of strokes, having lost a critical volume of brain tissue (usually at least 50–100 mL). In some cases a so-called strategic infarct may lead to ‘single-stroke dementia’. This more abrupt decline is caused by damage to an area that is critical for memory such as the hippocampus or anteromedial thalamus.

Key Points

Vascular dementia is the third most common type of acquired cognitive decline in later life (following Alzheimer’s disease and dementia with Lewy bodies). It accounts for 10% of cases.

It may present with a stepwise loss of cognitive ability (consistent with a series of small strokes) or a gradual decline (more in keeping with diffuse white matter or small vessel disease).

Clinical features suggestive of vascular dementia rather than Alzheimer’s disease include a fluctuating course and patchy cognitive profile, ‘emotional incontinence’ and sundowning. There may also be parkinsonian features or neurological signs consistent with one or more strokes.

The most common pathological finding is small vessel disease (hyaline arteriosclerosis and lipohyalinosis) often in association with arterial hypertension and other vascular risk factors.

Other pathological features include lacunar infarcts, generalized attenuation of the subcortical white matter and enlargement of the perivascular spaces.

Regional infarcts may also be present. In some patients a ‘strategic infarct’ in an area critical for memory (e.g. the hippocampus or anteromedial thalamus) leads to an abrupt decline in cognitive ability, referred to as ‘single-stroke dementia’.

Frontotemporal dementia

Frontotemporal dementia (FTD) is a clinical term for a group of conditions in which there is selective degeneration of the frontal and temporal lobes (Fig. 12.20). The lifetime prevalence is 1 in 6000 and it is equally common in males and females. FTD accounts for less than 5% of dementia overall, but is the second most common cause in people under 60 (after Alzheimer’s disease). Onset is typically in middle age, with an average survival of around 6–8 years. A family history is present in 40% of cases.