ABSTRACT
INTRODUCTION This chapter provides a description of a major group of neurodegenerative diseases, which include i) akinetic-rigid and hyperkinetic movement disorders principally due to diseases affecting the basal ganglia (Table 12.1), ii) miscellaneous disorders affecting the basal ganglia and iii) disorders of central autonomic systems. Some of the diseases discussed in this chapter are of significant epidemiological importance and relatively common in the general neuropathological practice and these are best exemplified by Parkinson’s disease (PD), which is the second most common neurodegenerative disease after Alzheimer’s disease. An up-to-date summary of the genetic basis and pathogenesis of these diseases will be provided and, in addition to single gene mutations causing inherited neurodegenerative diseases, information about genetic risk factors is presented. Much of the knowledge about the genetic basis of diseases has been translated into clinical practice, as through genetic testing, ante-mortem diagnosis has become available in several of the inherited movement disorders. This is exemplified by diseases such as Huntington’s disease, the ever-increasing number of familial forms of parkinsonism and dystonia, as well as several other disorders that are discussed in this chapter (see Tables 12.3, 12.15 and 12.19). Although several of the mutations may only occur in a relatively small number of families, for example, with an inherited form of parkinsonism, the knowledge deriving from these discoveries can help to map out important molecular pathways such as those relevant for the survival of the substantia nigra (SN) dopaminergic neurons or Lewy body formation. Since the last edition, the Braak hypothesis describing a stereotypic spread of α-synuclein pathology, together with data from experimental work and
pathological observations of a host-to-graft spread of Lewy body pathology in PD patients treated with striatal transplants of embryonal mesencephalic neurons, provided a practical conceptual framework for a better understanding of disease progression in PD.16,46,51,297,332
In the absence of reliable biomarkers, pathological diagnosis, utilizing the knowledge that many of the degenerative movement disorders are characterized by accumulation of an abnormal protein, has remained the ‘gold standard’ for definite diagnosis. Therefore, we have continued to follow a clinicopathological classification in this chapter, which is further justified by the fact that distinct clinical phenotypes can have several underlying pathological causes. For example, in addition to a number of rather rare conditions, parkinsonism may be caused by at least three common or relatively common disorders; PD, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Similarly, several different pathologies can underlie the clinical presentation of corticobasal syndrome. Equally important is the knowledge that the same neurodegenerative processes can have a number of clinicopathological variants that are well exemplified by the different subtypes of PSP or the Lewy body disorders, whose clinical phenotypes range from a movement disorder to dementia. However, widely used terms, such as ‘synucleinopathy’ for diseases characterized by accumulation of α-synuclein,162,517 ‘tauopathy’ for diseases with accumulation of the tau protein164 and ‘polyglutamine diseases’ with expanded polyglutamine tracts, indicate a common molecular basis for clinically and pathologically diverse conditions and point to a likely future molecular classification of diseases. With advances in molecular understanding of the pathogenesis, preservation of tissues for future studies of molecular and pathophysiological aspects of neurodegenerative diseases remains part of routine practice in brain banks.
