Defining neurodegenerative diseases

Defining neurodegenerative diseases is like defining the continent of Europe: part history, part science, part politics, and to cap it, both could have an effect on health and prosperity.

A big advantage of the term is that it is a concept that patients can relate to from parallels in everyday life. Wearing out in time of certain components—sometimes replaceable, sometimes not—encompasses principles of selective neuronal death as a primary event with age as a major risk factor and good remedies patchy.

Paradoxes abound. Neurodegeneration is a major element and is often the cause of the disability in many diseases not usually classified as degenerative—for example, multiple sclerosis, epilepsy, some inborn errors of metabolism, schizophrenia, and even tumours. Conversely, inflammatory processes are activated and vascular compromise occurs in some degenerative diseases. A Napoleonic view could encompass most brain diseases under the rubric of neurodegenerative, but this would lack focus.

Few health authorities run services for neurodegenerative disease as a whole because they can cut across several subspecialties. Core members are the dementias, Parkinson's disease, motor neurone disease, cerebellar degenerations, Huntington's disease, and prion diseases. Subclassification is clearly of importance for research, management, and ultimately for more targeted treatment.

Problems exist with terminology. For example, patients whose diagnostic label changes midcourse may feel that they have been misled. Thus a patient initially labelled as having Parkinson's disease may have the diagnosis changed to a rarer label (Lewy body dementia, corticobasal degeneration, progressive supranuclear palsy, or multisystem atrophy) as additional features like dementia or a gaze palsy or autonomic failure become apparent. The case with Alzheimer's disease is similar—fronto-temporal, multi-infarct, and dysphasic versions of dementia.

When carving out bewildering classifications neurology has been slow to allow patients a vote. Practitioners may also have preferred a common stem of Parkinsonism or dementia, for example, with a subvariety—which was underplayed until the diagnosis was definite or a change needed because the treatment or prognosis altered significantly. Time could then be concentrated on more important errors—for example, missing Wilson's disease, mistaking essential tremor for Parkinson's disease, overlooking drug induced dementia or Parkinsonism, or mistaking conditions which respond to drug treatment, such as myasthenia or motor neuropathy, for motor neurone disease. In all these conditions, missing depression is easy enough unless it is specifically sought.

Contributions from basic science

Genes and proteins involved with these conditions are being rapidly elucidated, and naming the condition after the protein is an option.^1–5 This already happens for Creutzfeld Jakob disease—CJD/prion disease. However, until we are able to make a molecular diagnosis in life and offer specific treatment it is probably premature to use this strategy in clinical settings, even for those conditions where the molecular defect has been identified. Classifications that need postmortem data have caused enough problems in the past. Asking the diagnostician to predict the presence of a Lewy inclusion body or neuropathological changes of Alzheimer's disease when no test is available is to ask for a lot. Nevertheless we need to be aware of evolving terminology: alpha synuclein, parkin, and Parkinson's disease; amyloid and Alzheimer's; tau and fronto-temporal dementia and progressive supranuclear palsy; SODI (superoxide dismutase 1) and motor neurone disease; glutamine repeats and Huntington's disease; and the new neuroserpinopathies.⁶

Though causative mutations have been described in some families, both genetic and environmental risk factors play a part in the aetiology of these conditions. The ratio varies—the genetic contribution is higher in Huntington's disease, Alzheimer's disease, and cerebellar degenerations and lower in Parkinson's disease, motor neurone disease, and prion diseases. The expectation is that we will find the genes that interact with environmental factors, which may be dietary, chemical, or biological agents. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a good though rare example of an environmental agent that caused an epidemic of Parkinsonism among drug misusers.⁷ MPTP is a simple chemical, and a viable hypothesis is that autointoxication by similar molecules may cause sporadic diseases.⁸ Another example is the epidemic of a variety of degenerative diseases on Guam, where the environmental agent has not been discovered.⁹

A common feature of these conditions is a long run-in period until sufficient protein accumulates, followed by a cascade of symptoms over 2-20 years, with increasing disability leading to death. This provides a wide therapeutic window, especially as groups at risk are identified earlier and preclinical diagnosis becomes feasible. The increasing incidence with age can be seen as a threat (given population projections) or as an opportunity—a delay in the onset of these conditions by, say, 5-10 years would dramatically reduce their incidence and therefore costs. Individuals have realised that if they are lucky enough to side step or survive cancer and vascular disease the next threat is neurodegeneration in its various guises. But have governments realised this? Secondary postponement of disability is possible¹⁰ and it is impressive and fast moving in Parkinson's disease and modest in Alzheimer's and motor neurone disease.¹¹

The key characteristics of these conditions are that progressive degeneration occurs as a primary event long before symptoms develop and that it is selective, at least initially, for a particular neuronal pool. Other groups of neurones could join—for example, sensory end organ failure—and there is overlap with what we arbitrarily accept as ageing. In the future these diseases will be increasingly defined by the proteins involved. Improved diagnostics will hopefully change terminology and reduce the need to second guess pathology, thus increasing the accuracy of classification from the start. Eventually the mechanisms through which particular proteins cause toxicity would be elucidated, as will genetic and environmental risk factors. Primary preventive strategies could then emerge and ultimately (as in the case of polio and vaccination) these diseases will be defined by their solutions.