Neurodegenerative Disorders
Neurodegenerative
disorders are
those conditions in which the primary pathological event is a progressive
loss of populations of CNS neurones over time. However, it is increasingly
being recognized that most neurodegenerative disorders have an inflammatory
component to them, and that inflammatory diseases of the central nervous system
(CNS) (such as multiple sclerosis, see Chapter 62) will cause
neuronal loss and degeneration.
Aetiology
There are a number of
theories on the aetiology of neurodegenerative disorders, which may not be
mutually exclusive. Of late there has been much work looking at the genetic
risk factors for developing these disorders (see Chapter 63), and some common
sets of genes are being found for them, e.g. genes involved with inflammation
and immunity.
An infective disorder
Neuronal death with a
glial reaction (gliosis) is commonly seen in infective disorders (typically
viral) with inflammation in the CNS. However, in neurodegenerative disorders
such a reaction is not seen, although the observation that human
immunodeficiency virus (HIV) infection can
cause a dementia has raised the possibility that some neurodegenerative
disorders may be caused by a retroviral infection. Furthermore, the development
of dementia with spongiform changes throughout the brain in response to the
proliferation of abnormal prion proteins as occurs in Creutzfeldt–Jakob
disease has further fuelled the debate on an infective aetiology in
some neurodegenerative disorders (eg α-synuclein in PD).
An autoimmune process
Autoantibodies have been
described in some neurodegenerative conditions, e.g. antibodies to calcium
channels in motor neurone disease (MND). However,
the absence of an inflammatory response would argue against this hypothesis,
although neuronal degeneration with a minimal inflammatory infiltrate can be
seen in the paraneoplastic syndromes (see Chapter 62) as well as
the more recently described autoimmune disorders targeting ion channels and
receptors.
The result of excitotoxic
cell death and free radical production
Excitatory amino acids
are found throughout the CNS (see Chapter 19) and act on a range of receptors
that serve to depolarize the neurone and allow Ca2+ to influx into
the cell. On entering the neurone, calcium is normally quickly buffered; if the
level of excitation is great then there may be an excessive influx of Ca2+,
which can lead to the production of toxic free radicals and cell death.
Indeed it may even be
that the problem lies within the glia and their failure to buffer glutamate.
This has been postulated to occur in MND. Furthermore in some cases of familial
MND there is a loss of one of the free radical scavenger molecules superoxide dismutase and in Parkinson’s disease, deficiency in
complex I activity of the mitochondrial respiratory chain in the substantia
nigra, both of which may lead to the overproduction of free radicals.
The ingestion or
production of a neurotoxin
Many toxins can induce
degenerative conditions (e.g. parkinsonism with manganese poisoning) but no
such exogenous compound has consistently been found to cause any of the major
neurodegenerative disorders.
Dementia of the
Alzheimer type (DAT),
is associated with the development of neurofibrillary tangles (NFTs) and senile
neuritic plaques (SNPs) in the parahippocampal and parietotemporal cortical
areas. The density of NFTs correlates well with the cognitive state of the
patient. NFTs contain paired helical filaments made up of an abnormal form of
the microtubule associated protein tau a protein that normally serves to maintain
the neuronal cytoskeleton and maintain normal axonal transport (see Chapter
12). Thus, abnormalities in axonal transport may underlie some neurodegenerative
conditions, either as a direct consequence of abnormalities in tau or proteins
associated with it. In contrast, SNPs contain abnormal forms of the protein
β-amyloid, derived from the ubiquitously expressed membrane bound
glycoprotein amyloid precursor protein (APP).
The reason as to why
these abnormal proteins are produced and in what order is not clear – certainly
some of the rare familial forms of DAT have genetic defects that
influence the production of the amyloid protein (although there are rare forms
of frontotemporal dementia with parkinsonism that also result from tau
mutations). Whatever the reason for the development of these abnormal proteins,
the result is cortical cell death. This leads to a secondary loss in the
cholinergic innervation of the cortex with an associated atrophy of the
cholinergic neurones in the basal forebrain, which has prompted clinical
studies in the use of drugs that potentiate CNS cholinergic transmission (donepezil,
rivastigmine and galantamine). These drugs are inhibitors of
acetylcholinesterase in the brain. They have been shown in clinical trials to
be of some limited benefit.
Most neurodegenerative
conditions have now been found to contain intracellular inclusions of abnormal
protein (e.g. hunting tin in Huntington’s disease, tau in some complex
parkinsonian con- ditions, α-synuclein in Parkinson’s disease and
multiple system atrophy), and may all induce disruption of the
ubiquitin–proteosome system (UPS) or the autophagic lysosomal degradation
pathway. These systems normally serve to package up and get rid of proteins,
and as such their dysfunction will affect the processing and removal of
intracellular proteins and the formation of inclusion bodies.
The loss of a
specific neurotrophic factor
(Or abnormal axonal
transport of substances – see above.)
Neurones are maintained
by the production of a specific growth or neurotrophic factor (see Chapters 48
and 49), and the loss of one or some of these factors may underlie the
development of the various neurodegenerative disorders. Clinical trials using
neuro- trophic factors in patients with neurodegenerative disorders have been
undertaken with some disputed success with glial cell line- derived
neurotrophic factor (GDNF) in Parkinson’s disease.
The activation of
programmed cell death (apoptosis) The loss of cells in most conditions (e.g. inflammation) is by a process
of necrotic cell death but all cells contain the necessary machinery to
initiate their own death: programmed cell death or apoptosis. It is therefore
possible that neurodegenerative disorders are caused by an inappropriate activation
of this programme, possibly secondary to the loss of a neurotrophic factor.
The role of
inflammation
There is increasing
interest in the possibility that neurodegenerative processes in the CNS may be
enhanced by local inflammatory responses, especially the microglia.
