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.
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.