Journal of Geriatric Psychiatry and Neurology

Frontotemporal dementia (FTD) is the most common syndrome in which the focus of neurodegeneration is the frontal lobes. FTD is frequently familial. It is also often due to a susceptibility locus on chromosome 17q21-22. Some 17q21-22-linked families have mutations in the tau gene and most have microscopically visible aggregates of hyperphosphorylated tau. Demonstrating that mutations in tau can produce neurodegeneration will necessitate a reassessment of the role of tau in the pathogenesis of the many diseases in which tau biology is disrupted.

Huntington disease (HD) is a fascinating neurodegenerative disorder whose features straddle the boundaries of psychiatry, neurology, and genetics. The clinical symptoms of HD consist of a triad of motor, cognitive, and psychiatric/behavioral disturbances. In 1993, the HD Collaborative Research Group identified the gene and the mutation responsible for HD. HD was one of the first neurodegenerative disorders discovered to be caused by a novel mutational mechanism known as trinucleotide repeat expansion. Since then, HD has been the model for autosomal dominant neurogenetic disorders. The clinical, pathological, and genetic aspects of the disease are reviewed and some of the questions that remain to be answered by researchers of the 21st century are outlined.

Mental disorders due to cerebral microvascular disease have been known for over 100 years. Recently, an autosomal dominant form of cerebral arteriopathy (CADASIL) has been described in association with a Notch3 family gene on the short arm of chromosome 19. CADASIL causes subcortical lacunar infarction and dementia in over 80% of cases and depression in a large proportion of patients. Clinically, CADASIL may appear to be very similar to hypertensive microvascular disease (Binswanger's disease), a condition that is seen in the elderly. This article reviews the clinical, pathologic, and genetic features of CADASIL. CADASIL is of interest to neurologists and psychiatrists because it is the first syndrome of vascular dementia and depression with an identified gene. How the gene causes the widespread arteriopathy is not yet known. Insights gained from the study of CADASIL should help us better understand its etiology, as well as the options for treatment of the more common forms of microvascular disease seen in the elderly.

The prion diseases are an interesting group of neurodegenerative disorders for a variety of reasons. The most obvious is their property of transmissibility, but beyond that they constitute a fascinating example of the diversity of disease expression possible from a common etiologic factor. Thought of as “strains” in animals and phenotypes in humans, these varied expressions of prion disease are most likely due to subtle conformational changes in the pathogenic form of the prion protein. These strain-like characteristics are best exemplified in the genetic varieties of human prion disease in which specific mutations are associated with specific phenotypic profiles. This review attempts to highlight the clinical and pathologic features of the prion diseases with a particular focus on the genetic determinants that define the various familial forms and that modify sporadic and iatrogenic forms of the disease.

The cause of Parkinson's disease (PD) is unknown. The major risk factors identified to date are family history, age, and elements of rural living. Nearly one-third of all PD cases are familial, a small subset of which appears autosomal dominant; however, the majority exhibit no clear inheritance pattern. Autosomal dominant PD is genetically heterogeneous: two PD genes have been mapped to chromosomes 2 and 4 and there may be additional as yet unidentified genes. The common forms of PD—both familial and sporadic cases—appear to involve a complex interplay of genetic susceptibility and environmental exposure. The observations that rural residence and pesticide exposure increase the risk of developing PD, and that a synthetic drug, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, can cause parkinsonism, suggest that at least a subset of PD may be caused by a toxin. Furthermore, modest but significant associations have been reported between PD susceptibility and genes that regulate metabolism of drugs and neurotoxins. There is also evidence for mitochondrial dysfunction in PD, a finding that was recently traced to anomalies in mitochondrial DNA. At the present time, the genetics of PD appear to be complex, involving multiple nuclear genes and possibly mitochondrial genes as well.

Progressive supranuclear palsy (PSP) is, after Parkinson's disease, the most common form of degenerative parkinsonism. Several clinical features are used in the recognition of this disorder as well as in the differentiation from related disorders. Clinical criteria that could increase diagnostic accuracy in research studies are also emphasized. Due to a better understanding of the genetic aspects of PSP, recent studies have suggested that it is a recessive disorder in linkage disequilibrium with the tau (τ) gene, rather than a sporadic disorder. In addition, the recent identification of mutations in the τ gene associated with a similar neurodegenerative condition (frontotemporal dementia and parkinsonism linked to chromosome 17) has further strengthened the argument that τ dysfunction is somehow involved in the pathogenesis of PSP. Nongenetic factors that could trigger or perpetuate the cascade of events leading to neuronal degeneration in PSP are also reviewed.