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Box
Septal nuclei
complex
14.4
14
DEMENTIA
The cholinergic system in the forebrain
Acetylcholine (ACh) is a neurotransmitter present in several
large clusters of projection neurons in the central nervous
system (Fig. 14.8), as well as in numerous interneurons. The
human cholinergic systems in the basal forebrain include
neurons in the septal and diagonal complex and in the basal
nucleus (nucleus basalis) of Meynert.
Several subgroups can be distinguished:
• GroupCh1ofthemedialseptumcomprises10%ofthe
cells in this area.
• ThediagonalbandofBrocacomprisesgroupsCh2andCh3.
• Thelargestgroupofcholinergiccellsinthebasalforebrain
(~90 %)—Ch4—is represented by the basal nucleus
of Meynert. The number of cholinergic cells in Ch4 is
approximately 210,000 per hemisphere.
Groups Ch1 and Ch2 provide cholinergic input to the hippocampus, the Ch3 cells provide innervation to olfactory
areas and the Ch4 cells innervate the cortex and amygdala.
All cholinergic cells in the basal forebrain express high- and
low- affinity receptors for the neurotrophin nerve growth factor (NGF). This suggests that this neurotrophin is critical for
their survival. However, attempts to use NGF therapeutically
to protect cholinergic cells in Alzheimer’s disease (AD) have
not had much success.
ACh is synthesized from acetyl coenzyme A (acetyl- CoA)
and choline. Choline is present in extracellular fluid and is
taken up into the terminal through an active uptake system.
Dietary supplements of choline have been used in an attempt
to boost the falling levels of ACh in the brain in AD, but this
strategy has had very limited success.
ACh can bind and activate both nicotinic and muscarinic
receptors. The former are ligand- gated ion channels, whereas
the latter are metabotropic receptors, coupled to G proteins. Positron emission tomography (PET) studies suggest
that nicotinic receptor deficits are an early phenomenon in
AD. Interestingly, it has been shown that Aβ peptides can
block the interaction of nicotinic agonists with their receptors, suggesting a direct link between amyloid pathology and
impaired neurotransmission.
The muscarinic receptors M1 to M5 have a widespread distribution in the body. M1 and M2, and to a lesser extent M3,
M4 and M5, are present in the CNS. M1 receptors mediate
excitatory effects, whereas M2 receptors have mainly inhibitory effects and a predominantly presynaptic location. Using
non-selective muscarinic ligands, PET studies have shown
that age and AD lead to decreased muscarinic receptor binding in the cortex. It has been reported that M1 agonists may
decrease the levels of Aβ amyloid by shifting processing of
APP towards the non-amyloidogenic pathway. Thus, a therapeutic strategy based on muscarinic agonists might not only
improve cognition but might also have a disease- modifying
effect by interfering with plaque formation.
Basal nucleus
of Meynert
Hippocampus
Fig. 14.8 The cholinergic system in the forebrain.
Cortex
Pontomesencephalotegmental
The role of acetylcholine (ACh) in cognition is well established in experimental models. For example, cholinergic
receptor antagonists, such as the muscarinic antagonist
scopolamine, impair learning and memory. Therefore
the cognitive deficit seen in AD is at least partly due to
the deficit in ACh. A deficit in cholinergic transmission
is also supported by a significant decrease in choline
acetyltransferase (ChAT) activity in the cortex and hippocampus of patients with AD. It has been shown that
there is a correlation between the loss of cortical cholinergic receptors and synapses and cognitive decline.
Inhibiting the cholinesterase activity that inactivates
ACh would lead to potentiation of the failing cholinergic
signal. There are two types of cholinesterase: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).
The two types are related structurally but their distribution in the body, substrate specificity and functional roles
differ. AChE is present in the brain and its main function
is to hydrolyse the released acetylcholine. BuChE is present in the brain but also in the skin, gastrointestinal tract,
liver and plasma, and has a broader substrate specificity
than AChE. Tacrine was the first cholinesterase inhibitor
to be approved for the treatment of AD, at the beginning
of the 1990s. This drug inhibits both AChE and BuChE
and was shown to improve the MMSE score. However,
it is associated with a high incidence of gastrointestinal
309THE NERVOUS SYSTEM
14
side effects, such as diarrhoea, nausea and vomiting, and
can induce hepatotoxicity. It was withdrawn in 2013, and
replaced by second- generation inhibitors such as donepezil, rivastigmine and galantamine.
DEMENTIA
Donepezil is a non-competitive, non-selective, reversible inhibitor of AChE, whose long half- life makes oncedaily dosing possible. In clinical trials it has been shown
that the administration of donepezil to patients with
moderate- to- severe AD leads to improved cognition and
daily functioning compared with patients who receive a
placebo. However, when treatment is stopped there is an
immediate and accelerated deterioration in all measures
and, by the time drug washout is complete, the scores of
patients receiving the drug and those receiving the placebo
become the same. Therefore it is unlikely that cholinesterase inhibitors modify, even in a minor way, the disease
process. Rivastigmine is another example of a cholinesterase inhibitor. It is a pseudo- irreversible inhibitor of AChE
and is not metabolized by liver microsomes. Galantamine
is a cholinesterase inhibitor and a positive allosteric modulator of nicotinic cholinergic receptors. The latter property
may offer an advantage compared to the other inhibitors,
as the drug could enhance the signal mediated by nicotinic
receptors, which is relevant for cognition. It appears to
have fewer and milder side effects than the other inhibitors and there is less tolerance to its effects.
Overall, the tolerability of cholinesterase inhibitors is
reasonable. Most inhibitors have unwanted gastrointestinal effects that are more prominent in the first year of
treatment. The inhibitors induce a global improvement
in cognitive performance, although the response is variable between patients. It is still unclear how beneficial
these compounds are in the severe forms of the disease.
Starting therapy early, at the mild AD stage, increases
the likelihood of a better outcome and may significantly
delay admission to nursing homes. There is not enough
evidence to prove superiority of one agent over another.
Based on the same rationale of decreased cholinergic
signalling in AD, muscarinic receptor agonists and nicotinic receptor agonists or allosteric modulators are also
being actively researched, and they may offer distinct
advantages, such as reduced toxicity compared with the
cholinesterase inhibitors named above.
Glutamatergic agents
Glutamate is a key excitatory transmitter both in corticosubcortical projections and in corticocortical fibres. It is
likely that the physiopathology of AD involves an excitotoxic component, which may be due to dysregulated
glutamatergic transmission. Furthermore, the toxicity of
glutamate is enhanced by amyloid peptides. In addition,
the increased activation of glutamatergic transmission
through NMDA receptors could enhance the production
of phosphorylated tau.
Memantine is an uncompetitive NMDA receptor
antagonist that has relatively strong voltage dependence
and rapid unblocking kinetics. The interaction of memantine with the NMDA receptor channel is reminiscent of
the action of Mg2+, which blocks the channel under resting conditions. Because of its voltage dependence and
fast kinetics, it has been suggested that memantine does
not interfere with normal glutamatergic transmission,
but blocks increased transmission under chronic conditions of hyperactivity. It has been shown that memantine
significantly slows down the rate of cognitive and functional decline and has a positive synergistic effect with
cholinesterase inhibitors such as donepezil, without adding to the burden of unwanted effects. It is used in the
moderate- to- severe stages of AD.
Antioxidants
Like other neurodegenerative diseases, AD has been
associated with increased levels of oxidative stress and
free radical- induced damage. Both the monoamine oxidase type B (MAOB) inhibitor selegiline and vitamin E
have been shown to have mild beneficial effects in AD.
Similarly, the herbal extract of Ginkgo biloba may provide
some neuroprotection; this would be a consequence of a
postulated improvement in blood flow and reduced oxidation and neuroinflammation. This extract is approved
in some countries for use in dementia, but its effectiveness remains controversial.
Nonsteroidal anti-inflammatory drugs
Epidemiological evidence shows that the use of certain
NSAIDs, such as ibuprofen, reduces the risk of developing AD. However, preventive or interventional clinical
trials designed to confirm and further investigate such
observations have failed to show an overall significant
neuroprotective effect of NSAIDs. However, it is not
contested that AD physiopathology involves an inflammatory component; thus, a better understanding of this
component may help in the elucidation of the exact role
of anti-inflammatory therapies in the management or
prophylactic treatment of AD.
Reduction of risk factors
There is a possible link between cholesterol and AD,
and several epidemiological studies have shown that
the use of statins, which decrease the production of
cholesterol, leads to a decreased risk of developing AD.
Cholesterol reduction leads to a reduction in the activity
of β- secretase and possibly γ- secretase, and an increase
in α- secretase activity. Large- scale prospective studies
are required to confirm these observations and clarify
the role of cholesterol in the middle or late stage of the
disease.
Similarly, a strong link between hypertension and
cognitive impairment is well recognized, and hypertension has been linked to AD. Thus, although midlife
hypertension is a risk factor for late- life dementia, hypertension may also promote the neurodegenerative pathology underlying AD by producing microinfarcts/bleeds
310 SYSTEMS OF THE BODY
14
and white matter lesions, resulting in CNS ischaemia.
Poor vascular health reduces Aβ and tau clearance and
increases levels of γ- secretase. Randomized control trials
of anti-hypertensive drugs, especially if started during
midlife, show reduction in the risk of dementia.
A link has been suggested between increased circulating homocysteine levels and AD. Present trials
are investigating the possible neuroprotective role of a
combination of vitamin B6, vitamin B12 and folic acid to
decrease homocysteine levels.
In terms of potential modifiable factors, attention
is also being given to the monitoring of good quality
sleep in elderly individuals, as there is some evidence
that sleep impairment can influence the development
of AD, possibly by affecting amyloid peptide clearance
through the glymphatic system. Interestingly, sleep
deprivation in healthy humans leads to an increase in
CSF tau levels.
A critical issue is how the genetic and lifestyle factors interact, that is, whether the genetic risk for
dementia can be modified by a healthy lifestyle.
Recent epidemiological studies showed that modifiable lifestyle risk factors were able to decrease dementia risk only in people who did not have an APOE4
allele (i.e. have a low genetic risk), suggesting genetic
susceptibility trumps lifestyle factors in terms of cognitive decline.
Anti-amyloid strategies
Inhibition of secretases
The amyloid cascade starts with production of amyloid
peptides, in particular the Aβ
form, through proteol-
1–42
ysis of APP by secretases. Inhibition of β- or γ- secretase
could lead to decreased production of amyloid peptides
and a reduced risk of aggregation and subsequent formation of plaques. There have been substantial efforts to
develop inhibitors of β- secretase (especially the BACE1
isoform of the enzyme) and also inhibitors of modulators
of γ- secretase activity, although nothing has moved successfully to the clinic so far.
Vaccines against amyloid peptides
The principle of targeting neurotoxic protein aggregates by developing vaccines is, in principle, applicable
not only in AD but also other types of neurodegenerative diseases (Box 14.5). Much hope was generated
when it was shown that transgenic mice made to overproduce amyloid peptides showed a reduced plaque
burden when vaccinated with Aβ
. This beneficial
1–42
effect could also be obtained by direct administration
of anti-amyloid antibodies. It was thought that this
effect may be linked to mechanisms such as: (1) antibodies bind to the plaque and activate the surrounding
microglia to phagocytose the plaque and (2) antibodies
act as a peripheral ‘sink’ and pull out the peptides from
the brain into the circulation. Although the first trials
Box
14.5
Immunization against
neurodegeneration—new
therapeutic hope
The use of vaccinations is historically associated with the
treatment of infectious diseases. Therefore, its possible relevance in neurodegenerative disease was ignored for a long
time. Another reason for this was that the central nervous
system (CNS) was considered to be a place where primary
immune responses do not occur. Any involvement of the CNS
in immune reactions was rather considered to be harmful.
In 1999 Schenk and collaborators showed that experimental immunization with β-amyloid (Aβ) peptide can reduce
amyloid load, and this turned public and scientific attention
to vaccination as a treatment approach in neurodegeneration. This report was followed by the observation in preclinical models that the administration of antibodies, that is,
passive immunization, could reduce the amyloid burden. It
was shown that antibodies ‘coated’ amyloid plaques in the
brain and could trigger a classic immune response, culminating with the removal of the labelled plaques by activated
microglia. Immunization also reversed the cognitive impairment, which was confirmed in two different transgenic
mouse models.
These studies also noted that the cognitive improvement was likely to be due to a reduction in a pool of nondeposited Aβ, likely the oligomeric form, as the reduction
was seen in diffuse deposits but not in fibrillar deposits.
Subsequent work also led to the suggestion that the beneficial effect of immunization is not necessarily associated with
penetration of the antibody into the CNS. What was seen
after passive immunization was a large increase in plasma
Aβ concentration. Hence, the antibodies could trigger a
‘sink effect’ that promotes the clearance of amyloid from
the brain parenchyma into the peripheral compartment.
A third possibility was that the antibodies prevent
the formation of oligomers and protofibrils, thus ultimately protecting against the formation of large insoluble plaques. Whatever the mechanisms involved in the
effects of vaccination, when the experimental studies were
transferred to the clinic for the first time, several patients
developed brain inflammation, which led to the cessation
of the clinical trial. This reaction was likely to be due to a
stimulation of T- cell- mediated immunity. It was hoped that
slight modifications of the immunization strategy would
avoid the activation of T- cells and its potentially fatal consequences. Recent progress in the production of a variety
of vaccines against amyloid pathology has shown that it
is possible to develop agents which are safe, although the
various vaccines tested in the last two decades have disappointed in terms of efficacy. However, with a better understanding of the mechanisms involved in antibody- mediated
clearance of abnormal proteins, this strategy could be
extended to other types of neurodegenerative disease
characterized by abnormal peptide aggregates which are
neurotoxic.
DEMENTIA
311THE NERVOUS SYSTEM
14
DEMENTIA
in patients using an amyloid vaccination strategy were
stopped due to development of brain inflammation in
a number of patients, much research has been focused
over the last two decades on various types of vaccines, targeting various amyloid epitopes, amyloid species and aggregation stages, and with improved brain
penetrability. There have been some very encouraging
results using antibodies such as aducanumab, and this
approach still holds promise.
Anti-tau strategies
In parallel with efforts to develop an improved and efficacious vaccine against amyloid pathology, there are
parallel efforts to develop a vaccination approach (passive or active) against tau. There is also much interest in
targeting tau kinases. Inhibition of the activity of kinases
that hyperphosphorylate tau can be achieved with various existing compounds, including drugs such as lithium
and sodium valproate, whose strong inhibitory effect on
kinases such as GSK- 3β is rather unexpected. Lithium
can reduce amyloid peptide levels in an experimental
mouse transgenic model, so this therapeutic principle
has considerable potential and is currently under study.
Other types of dementia
Vascular dementia
After AD, vascular dementia is the second most common
type of dementia in the elderly. AD and vascular dementia may often coexist, as confirmed at postmortem. It is
caused by reoccurring thromboemboli from either extracranial sources or, more commonly, small vessels in the
brain. Patients often have vascular disease such as coronary heart disease or peripheral vascular disease. The
pathological presentation is heterogeneous and complex. It
includes infarcts, microhaemorrhages and global hypoxic
ischaemic injury. White matter injury, with or without
axonal loss, is common. Unlike with AD, onset is rapid
and progression of the disease is stepwise, with focal neurological defects, which is consistent with multiple, small
infarcts (Fig. 14.9). These infarcts may be accompanied
by brief periods of impaired consciousness and visual or
sensory loss. As the disease evolves there is significant
impairment of cognition, for example, in executive function (planning, decision making, flexibility) and processing
speed. At present there is no disease- modifying treatment;
the symptomatic treatment of the cognitive dysfunction
includes cholinesterase inhibitors (galantamine, donepezil, rivastigmine) and memantine. The progression of
the disease could be halted if further strokes can be prevented, so management of this condition needs to focus on
the reduction of cardiovascular risk factors. Observational
studies suggest that targeting risk factors may decrease
the risk of vascular dementia. As a prevention strategy,
for example, the American Heart Association/American
Fig. 14.9 Vascular (multiinfarct) dementia. Infarcts of variable size
and location are indicated (arrowheads) in four pathological specimen
examples. (From Klatt EC. (2021) In: Robbins and Cotran, Atlas of
Pathology, 4th edition, Elsevier Ltd., Oxford.)
Stroke Association recommend monitoring health status
using a score based on assessing the components of the
‘Life’s Simple 7 Rule’: smoking status, level of physical
activity, healthy diet score, body mass index (ideally <25
kg/m2), blood pressure (<120/<80 mm Hg, untreated),
total cholesterol level (<200 mg/dL, untreated) and fasting blood glucose level (<100 mg/dL, untreated). Increases
in life expectancy, a worldwide trend, are associated with
an increased risk of ischaemic events and stroke, so an
increase in this type of neuropathology is likely in the
future. There is a significant need for biomarkers of early
diagnosis and the monitoring of disease progression.
Dementia with Lewy bodies
In western populations dementia with Lewy bodies comprises 5%–6% of cases of dementia diagnosed in primary
and secondary care settings. This type of dementia is
pathologically characterized by Lewy bodies, which are
intraneuronal, proteinaceous structures with radiating
filaments, which can also be detected in neurites (Lewy
neurites). The major protein detected in Lewy bodies is
312 SYSTEMS OF THE BODY
14
α- synuclein, present in an aggregated form. These protein aggregates can also be found in the brain of parkinsonian patients, in nigrostriatal neurons and in neurites
(see Chapter 10). However, in dementia with Lewy bod-
ies the aggregates are more widely distributed in the
CNS, as well as the peripheral autonomic nervous system.
Autonomic dysfunction is reflected by symptoms such
as orthostatic hypotension, sexual dysfunction, delayed
gastric emptying and constipation. There is significant
dopaminergic and cholinergic dysfunction. Patients with
Lewy body dementia have major sleep impairment (in
particular, REM sleep behavioural disorder during which
patients act out their dreams or produce vocalizations and
other abnormal movements), visual hallucinations, fluctuations in cognitive function and some evidence of parkinsonism. Diagnosis is difficult and definitive diagnosis
is only obtained at autopsy. Pure AD, by definition, has
no Lewy bodies, but modern sensitive techniques have
shown that Lewy bodies do occur in AD. The presence
of α- synuclein in Lewy bodies has led to the suggestion
that dementia with Lewy bodies and PD both be considered synucleinopathies. Thus, new treatments addressing
this common pathogenesis, for example, vaccines targeting the aggregation of α- synuclein, may be effective in
the two diseases. There are no specific treatments for this
type of dementia, and management of this dementia is
difficult because of the need to control a variety of symptoms—medication for one type of symptoms may worsen
another. A worsening of the condition can be caused by
even small amounts of antipsychotic drugs, which will
exacerbate the parkinsonism, whereas dopamine agonists will exacerbate the neuropsychiatric problems.
Cholinesterase inhibitors such as rivastigmine and donepezil can improve attention and processing speed and
alleviate apathy. When these inhibitors are not tolerated,
the NMDA receptor antagonist memantine can be used
with some benefit. The individual disease evolution may
differ but all patients will gradually develop increased disability and death will ensue. Average survival after onset
of the disease is approximately 8 years, although some
patients may live longer.
Frontotemporal dementia
Frontotemporal dementia is an umbrella term for a range
of complex and heterogeneous forms of dementia that
affect the frontal and temporal lobes. The onset of this
condition occurs at an earlier age than AD, commonly
between 40 and 65 years of age, affecting both sexes
approximately equally. Patients with this type of dementia have dramatic changes in their personality and behave
in a socially inappropriate manner. They can be impulsive
or emotionally indifferent and lose the ability to use language in both receptive and expressive aspects. They show
apathy and decreased personal hygiene. Frontotemporal
dementia is classified into two main types: the behavioural subtype (previously known as Pick’s disease) and
the language subtype, the latter being subclassified into
non-fluent and semantic variants of primary progressive
aphasia. There is also a form of frontotemporal dementia
with amyotrophic lateral sclerosis. The behavioural variant is characterized by symptoms such as loss of behavioural inhibition, decreased social cognition, inertia, loss
of empathy and perseverative or compulsive behaviours.
The semantic variant patients have difficulty in naming or
recognizing objects or drawings, limited speech production and inability to recognize words. The non-fluent variant leads to impaired speech production and difficulty in
the comprehension of complex sentences.
Frontotemporal dementia is a highly inheritable disorder, and variants have been linked to a range of specific
genetic mutations, some of which are shared with amyotrophic lateral sclerosis. Examples are mutations in the
following genes: MAPT (on chromosome 17, encoding
the tau protein), GRN (also on chromosome 17, encoding the protein granulin), C9orf72 (chromosome 9 open
reading frame 72, expansion mutation) and TARDBP
(on chromosome 1, encoding transactive response DNA
binding protein 43 (TDP- 43)). Frontotemporal dementia
is difficult to diagnose; structural MRI can reveal atrophy
of the frontal and/or temporal lobes but not at an early
stage of the disease. Neurofilament light (neurofilament
L)—a structural component of axons—is a promising
biomarker; it is increased in CSF and plasma and its levels are associated with severity of disease, brain atrophy
and survival duration. There are no specific treatments at
present. Pharmacological management can be attempted:
selective serotonin reuptake inhibitors have been used to
control impulsivity and disinhibition, and antipsychotic
drugs have been used to control agitation. Other supportive management includes physiotherapy, occupational therapy and speech and language therapy.
HIV- associated dementia
More than three decades ago, after the onset of the human
immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, it became apparent that
there was a very clear neurovirulence associated with HIV.
Infection with HIV can lead to neurological symptoms in
both the early phase and the later stages. The infection
causes cognitive and motor dysfunction, and prior to the
introduction of effective antiretroviral therapies, large
numbers of infected adults (one- third) and even more
children (one- half) ultimately developed HIV- 1- associated
dementia (HAD). Worldwide, although advances in
the treatment of HIV have dramatically improved survival rates, the infection continues to be a cause of neurological impairment, ranging from a mild cognitive
dysfunction to severe dementia, collectively designated
as ‘HIV- associated neurocognitive disorder’. Two- thirds
of the cases affected by this disorder occur in sub-Saharan
Africa. The symptoms of HAD include apathy, depression,
poor concentration and memory, tremor, hyperreflexia,
seizures and myoclonus. HIV enters the CNS through
infected monocytes and leads to the activation of resident microglia. Pathological changes are detected in the
basal ganglia, neocortical grey matter, cerebellum and brainstem.
DEMENTIA
313THE NERVOUS SYSTEM
14
The intensity of the HAD symptoms correlates with the
degree of monocyte infiltration and microglial activation. The neurological dysfunction is a consequence of
the damage sustained before initiation of antiretroviral
DEMENTIA
therapy and also the persistent immune activation associated with the residual presence of the virus. Many of the
drugs used to treat HIV infection do not penetrate well
into the brain; therefore, CNS infection of macrophages
and microglia creates a reservoir that is not affected by
peripheral treatments. Patients with advanced HAD show
cerebral atrophy, with losses of up to 30% of neocortical
neurons. Neurons may be either damaged directly by HIV
proteins or killed by compounds released from infected
cells. Neurons themselves are not infected with HIV, but
it is thought that infected macrophages and microglia
release neurotoxic compounds, such as glutamate, which
can trigger excitotoxicity (see Chapter 11) and inflammatory cytokines. Large neurons seem to be more susceptible
than small neurons and the infection leads to free radical
production, metabolic compromise and oxidative stress,
which lead to neuronal death. Antiretroviral therapy can
improve cognitive impairment but the effect is both limited and variable. Impairment can persist even in those
with an undetectable plasma viral load.
Creutzfeldt–Jakob disease
Creutzfeldt-Jakob disease (CJD) is a rare disease that
affects approximately 1/1,000,000 of the population annually and is characterized by rapidly progressing dementia,
personality changes, psychosis, involuntary movements,
speech impairment, myoclonus and ataxia. Most patients
die within a year after disease onset. CJD belongs to
the larger family of transmissible spongiform encephalopathies. The name of these conditions arises from the
appearance of vacuoles within the brain, as observed
postmortem. The disease is associated with widespread
neuronal loss, astrocytic gliosis and spongiform changes.
Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF levels of protein
14- 3- 3 (a protein involved in phosphorylation processes),
MRI using fluid- attenuated inversion recovery (FLAIR)
and diffusion- weighted (DW) analysis to detect changes
in tissue intensities, and EEG (patients may present a
characteristic pattern of periodic sharp waves). There are
three types of CJD: sporadic (the most common), inherited
(linked to specific mutations) and acquired (e.g. transmitted by exposure to specific medical procedures). Medical
procedures that are associated with the spread of this form
of CJD include transfusion of blood from an infected individual, use of human- derived pituitary growth hormones
for gonadotropin hormone therapy, and some transplants
(e.g. corneal transplants or dura mater grafts). Variant CJD
is a form of acquired CJD believed to be due to ingestion
of beef from cattle affected by bovine spongiform encephalopathy (‘mad cow disease’). The transmissible agent
responsible for CJD is a prion protein (see Chapter 12).
Stanley Prusiner, who was awarded the 1997 Nobel Prize
for his work on prions, coined the term ‘prion’, which
was derived from ‘proteinaceous infectious particle’, a
unique type of infectious agent. Prions are misfolded proteins that can multiply in the host latently for many years
and ultimately lead to large- scale neurodegeneration. The
PrP is encoded by a gene that is present and expressed to
the same extent in the cells of normal and affected individuals. The functions of the normal variant of PrP (named
PrPc) are not fully understood; the protein may have roles
in intercellular signalling and innate immunity. Prions are
composed of an abnormal, protease- resistant form of PrP,
designated PrPSc, which differs from PrPc by its β- sheet
structure (in contrast to the α- helices that characterize the
structure of PrPc). The increased presence of β- sheets leads
to the formation of fibrils, which ultimately deposit in the
brain. It is unknown how PrPc converts into PrPSc (possibly a spontaneous conversion or triggered by a mutation
in the prion gene PRNP) or how the fibrillary deposits
are responsible for generalized neurodegeneration. PRNP
mutations account for 10%–15% of sporadic forms of CJD.
A CSF- based sensitive test has recently been developed for the detection of pathogenic prions. It is important to note that infectious prions may not be inactivated
by routine surgical instrument sterilization procedures;
therefore the WHO has recommended the destruction
of instrumentation as required. There is at present no
treatment for this disease and there is evidence that the
incidence of sporadic CJD is increasing, with potential
incubation times longer than four decades. Symptomatic
treatment includes opioids for pain management, benzodiazepines for myoclonus, and antidepressant drugs.
General considerations in the management
of Alzheimer’s disease and other types of
dementia
A review of the AD drug development pipeline in 2020
shows 121 agents being explored in clinical trials for
use in AD, most of them disease- modifying agents and
targeting a variety of pathological mechanisms such as
amyloid, tau, neuroinflammation, neurogenesis, energy
metabolism and synaptic and vascular protection. There
is much hope that progress will be made in the following decades, possibly using combinatorial approaches.
However, the pharmacological and non-pharmacological management of dementia sufferers at present poses
numerous challenges. Patients and their carers are
affected not only by the cognitive loss, but also by all the
other symptoms that may be comorbid with dementia
such as psychosis, aggression, depression and the generalized change in personality. Such neuropsychiatric disorders occur in up to 90% of dementia patients and are
one of the main causes of admission to residential homes.
Depression in dementia is widely studied because of
the difficulties of differential diagnosis between a depressive syndrome and the early stage (or prodromal stage) of
dementia. Often, depression is reactive at the beginning
314 SYSTEMS OF THE BODY
14
(as a consequence of the psychological impact of the diagnosis) but later on may increase in severity and result from
changes in the corticolimbic circuitry. Preference is given
to treatment with antidepressant drugs, such as selective
serotonin reuptake inhibitors, as these are generally better
tolerated than other antidepressant drugs and they have
no anticholinergic effects that may accelerate cognitive
decline.
Psychosis is treated with antipsychotic drugs. Newer
antipsychotics, such as risperidone and quetiapine, are
preferable because of the reduced anticholinergic component and also because they are better tolerated overall.
The use of antipsychotics should be limited because of
the increased risk of mortality in this population.
It is also important to make sure that pain and infection, or any other cause of distress, are kept under
control and that the patient is placed in a supportive
environment as the disease progresses.
Care strategies must also take into account what has
long been neglected: care- giving to a patient with dementia can itself lead to pathology in the carer. Therefore, preventive healthcare strategies must be developed for carers
and respite care must be made more available. The move
from care at home to institutional care must be better
planned and should not only be a reaction to a crisis or the
consequence of carer burnout.
Self- assessment case study
Sheila B. was a 74- year- old woman admitted to hospital
with a history of rapid decline in mental status. She had
started deteriorating 4–5 months before admission. She
had cared for her terminally ill husband for 2 years and
began showing signs of depression after his death. The
family assumed that this was a natural reaction to grief
and that it would subside. However, the antidepressants
prescribed by her general practitioner (GP) had no effect
and, 3 weeks before admission to hospital, her confusional
state became significant and she started having auditory
and visual hallucinations, for which the GP prescribed
haloperidol.
On admission, her pupils were reactive and equal. She
had very brisk symmetrical reflexes, myoclonus and limited verbal communication. The computed tomography
scan was normal and a magnetic resonance imaging scan
showed mild, chronic ischaemia of the white matter. The
electroencephalogram showed repetitive sharp waveforms
and a high level of protein 14- 3- 3 was detected when the
cerebrospinal fluid was analysed. The status of the patient
continued to deteriorate and a brain biopsy showed early
spongiform change, neuronal loss and reactive astrogliosis.
Her mental status continued to decline further, with akinetic mutism and onset of seizures. She was discharged to a
hospice, where she died after 2 months.
After studying this chapter, you should be able to
answer the following questions:
1. What is a ‘spongiform change’ and how can the
symptoms of this patient’s disease be explained?
The typical spongiform aspect at pathological examination suggests that this patient suffered from Creutzfeldt–
Jakob disease (CJD). The symptoms and other test results
are supportive of this diagnosis.
2. What caused the disease that affects this patient?
There are several types of CJD: sporadic (the most common), inherited (linked to specific genetic mutations) and
acquired (transmitted by exposure to specific medical
procedures or by ingestion of food infected with prions,
which are the pathological substrate of this disease). It is
unclear what the most likely cause was in this patient.
3. What are the treatment options available?
There are no disease- modifying treatments at present
for CJD. The only treatment is symptomatic, for example,
the use of benzodiazepines to control motor problems, or
antidepressant drugs.
DEMENTIA
315THE NERVOUS SYSTEM
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SCHIZOPHRENIA AND
NEURODEVELOPMENTAL
DISORDERS
Chapter summary
1. Schizophrenia is a complex chronic psychiatric disorder that is
accompanied by significant impairment in cognition, awareness,
affect and social behaviour. Evidence indicates that schizophrenia
is linked to abnormalities in neurodevelopment. Other conditions
that are strongly linked to altered neurodevelopment and are
characterised by disrupted communication and socialisation patterns
include autism- spectrum disorders (autism, Asperger’s syndrome).
2. Schizophrenia and autism- spectrum disorders have a significant
heritable component. The genetic alterations include mutations
and copy number variations that cover the whole genome.
Environmental factors also influence the risk of developing these
disorders. Such factors include prenatal and perinatal injury and
infections, the parents’ age, maternal metabolic disorders such
as gestational diabetes and obesity, adverse socio- economic
circumstances and misuse of drugs during the critical period of
central nervous system maturation.
15
3. The pathophysiology of schizophrenia and autism- spectrum disorders
is reflected in a wide range of structural abnormalities, which affect
regions such as the prefrontal cortex, hippocampus, thalamus and
cerebellum. There is an indication of impairment in the maturation
of cerebral circuits and the stabilisation of synapses, and this leads to
complex changes in brain connectivity.
4. The pharmacological management of schizophrenia is based on the
use of antipsychotic drugs. A common characteristic of all classes of
antipsychotics is the blockade of dopaminergic receptors. Treatmentresistant patients may respond to the drug clozapine. Antipsychotics
improve positive symptoms but have limited impact on negative
15
symptoms and cognitive dysfunction. They also induce a wide range
of adverse effects that decrease patient compliance.
5. Non-pharmacological management of schizophrenia and autismspectrum disorders involves multidisciplinary approaches and is
aimed at improving the integration of patients in the community
and thus increasing their socialisation.
Introduction
One of the most complex aspects of human brain function concerns the processes of cognitive control, development of appropriate patterns of behaviour within a social
context and congruent emotional reactions. Psychosis is a
term that defines a state of mind characterised by a loss
of contact with reality. Short episodes of psychosis can be
associated with a wide variety of conditions, for exam-
SCHIZOPHRENIA AND NEURODEVELOPMENTAL DISORDERS
ple, neurodegenerative diseases such as Alzheimer’s
disease or Parkinson’s disease, brain tumours, drug misuse or malaria. In patients who present with psychosis,
behaviour is profoundly altered and the symptoms that
emerge are diverse, bizarre and disturbing, often leading to a gradual and irreversible alienation. Psychoses
challenge our understanding of higher brain functions
and their pathophysiology is much more complex than
that associated with sensory or motor dysfunction.
Schizophrenia is a complex, chronic psychiatric disorder
that has psychosis at its core. Schizophrenia is illustrated
in the case history presented in Box 15.1. In order to
understand the pathology of major psychotic disorders,
such as schizophrenia, it is important to identify the cerebral circuits and neurotransmitters that play key roles in
consciousness, cognition, emotions and moral reasoning.
Schizophrenia: the clinical diagnosis
The patient described in Box 15.1 was previously diagnosed with schizophrenia and the analysis of this case
starts with a brief mental state examination in order to
assess the following: (1) appearance and behaviour, (2)
speech, (3) affect, (4) thoughts, (5) perceptions, (6) cognitive state and (7) insight.
The examination of the patient (Box 15.2) confirms
the abnormal behaviour, deficits and distorted mental
perceptions that are indicative of major psychosis, in
the absence of an organic cause. Furthermore, the mood
of the patient is depressed and there is a clear risk of
suicide.
Schizophrenia is characterised by three major symptom clusters: positive symptoms, negative symptoms
and cognitive symptoms. Patients present with abnormal
ideas, abnormal perceptions, motor, volitional and behavioural disorders, formal thought disorder and emotional
disorders. These are described below. The diagnosis
Box
15.1
Jane was a 22- year- old Physics undergraduate. She also used
to work in the evenings as a proofreader. Two years ago, in
her final year at university, she visited her doctor accompanied by her parents, who were very concerned about changes
in her behaviour and communication at home. She had
become withdrawn and rather obsessed with religion. Finally,
she confessed to her parents that she had a mission to save
the country from a nuclear disaster and said that her ‘internal
voices’ would guide her. Jane was diagnosed with schizophrenia and was prescribed an antipsychotic. However, although
the medication helped a little and ‘the voices’ became less
persistent, she complained that she felt rather dizzy and tired
for most of the time, and that she put on weight. The drugs
made her feel so strange that at times she did not take them.
She could not continue her studies, and she started drinking
immoderately. She claimed that she felt ‘mentally numb’.
attempt. Following this, an antidepressant drug was added
to her antipsychotic medication. Her family continue to
wonder what may have caused this disease and want
to know if their daughter will ever recover. They are distraught and ask if you can prescribe a better treatment.
1. What is the explanation for the symptoms presented by
2. What are the neurobiological mechanisms underlying
3. What has triggered this major disruption of normal
Case history
You see Jane as a specialist, after a recent suicide
This case gives rise to the following questions:
this patient?
this type of mental dysfunction?
behaviour?
318
SYSTEMS OF THE BODY