The 3 and 4R Tauopathies

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We turn now to a set of disorders in which tau protein that makes up the inclusions is a various mix of 3R and 4R isoforms. Alzheimer's disease belongs to that category and because of its frequency is the first disorder to be considered in this chapter.

Alzheimer's Disease

Alzheimer's-type pathology is the only detectable lesion in a significant proportion of cases in which the diagnosis of IPD has been made premortem (20,164,165). This observation raises the possibility that Alzheimer's disease, in the absence of dementia, causes the parkinsonian symptoms by a direct involvement of the nigrostriatal pathway (165). It is not the place to review here the pathology of Alzheimer's disease: suffice it to say that extracellular deposition of Ap peptide and intracellular accumulation of both 3R and 4R tau isoforms are the principal lesions. Tau accumulates in three compartments: the neuronal cell body (NFT), the dendrites (neuropil threads), and the axonal component of the corona of the senile plaques (their "neuritic" component). Ap deposition, without a neuritic component, does not correlate with symptoms or only weakly, whereas tau pathology usually strongly does. The abundance of Ap peptide deposits in the striatum has been known for a long time (166) but it is doubtful, in view of what has just been said, that they explain the clinical signs. It is more likely that the NFTs found in many large and in a few medium-size neurons of the same nucleus (166) play a role. There is also evidence that the NFTs present in the substantia nigra (167) are the main culprit; their abundance is indeed linked with the severity of the extrapyramidal signs (168). The existence and the severity of the neuronal loss in this nucleus is discussed (168-170).

The involvement of the substantia nigra could be more severe in the common type of DLB, in which Lewy bodies and NFTs combine their effects. Extrapyramidal symptoms belong to the cardinal signs, which should raise the possibility of DLB in cases of dementia. However, as already mentioned, it is difficult to differentiate on a clinical basis Alzheimer's disease with and without Lewy bodies (171) from DLB cases with and without Alzheimer's lesions (37).

Dementiapugilistica, the dementia that develops in boxers, is characterized by a severe extrapyramidal syndrome. Its pathology resembles Alzheimer's disease pathology (172). Quite intriguing is the finding of isolated neocortical NFTs in a young boxer who died early in his career (173). This suggests that head trauma could, by itself, induce the formation of NFTs, preceding amyloid deposition (174) (see Chapter 4 for further developments).

The two disorders that are considered next, PEP and PDC, are rare. The epidemic at the origin of PEP ended a long time ago. PDC is confined to one small geographic area. Data from these disorders may help answer two questions: Are the differences in the ratio of tau isoforms between tauopathy explained by the cell types in which tau accumulates? Are tauopathies explained by a specific etiology? (1) To explain that different tau isoforms accumulate in various diseases, the hypothesis has been put forward that their relative abundance depends on the cellular type, neuronal or glial, in which the inclusions are found. PEP and PDC show that this is probably not the case: tau accumulates only in neurones in Alzheimer's disease, a 3&4R tauopathy. PEP and PDC are also 3&4R tauopathies but the inclusions are not limited to the neurones. (2) PEP also indicates that NFTs cannot be considered as indicating a specific etiology. It is indeed observed in disorders caused by mutations, head traumas (dementia pugilistica), or, as shown by PEP, an infectious disease of the brain. NFTs could be a "process specific" marker, the evidence of a stereotyped reaction of the neurone to injury.

Postencephalitic Parkinsonism

Parkinsonism, and other movement disorders, followed acute episodes of encephalitis lethargica, initially described by von Economo during an outbreak of the disease in 1916-1917 in Vienna. Cases were reported in 1918 in France, England, and North America. The disease presented with a variety of symptoms such as somnolence, ophthalmoplegia, hyperkinesias, and akinesia. Parkinsonism, described as the chronic form of the episode, could appear years after the acute episode (175). Most salient clinical characteristics of PEP are onset below middle age, symptom duration lasting more than 10 yr, presence of oculogyric crisis, and obviously a history of encephalitis (176). The disease has been linked to the "Spanish" influenza pandemic that occurred at approximately the same time. The influenza virus responsible for the Spanish flu has been isolated from an archival 1918 autopsy lung sample; its RNA was not detected in archival brain tissues from acute encephalitis lethargica. These data make the connection between Spanish flu and encephalitis lethargica doubtful (177).

In the acute phase, the disease was characterized by a severe inflammation, with perivascular cuffing and neuronophagia, in the mesencephalon, particularly the substantia nigra, and in the dien-cephalon. Pathology is characterized by abundant neurofibrillary tangles present in a wide range of regions, the substantia nigra being usually massively involved and showing severe neuronal loss. Of more recent notice is the presence of glial fibrillary tangles or astrocytic tufts (178), characterized by the presence of tau protein in astrocytes, not necessarily found in the regions most affected by tangle formation (179).

In the absence of clinical history, the distinction between PSP and PEP may be particularly difficult. Subtle differences in the distribution of the lesions have been described (180), but the ultrastructural aspect of the tangles (more often PHFs similar to Alzheimer's disease tangles than straight filaments common in PSP) as well as the biochemical signature of tau accumulation (both 3R and 4R tau [83] in PEP; 4R tau in PSP) are ways of differentiating both disorders, despite their morphologic resemblance.

Parkinsonism Dementia Complex of Guam

This disease appears so tightly related to a geographical area that the island of Guam, where it was initially described, is mentioned in its very name. However, a similar disorder is probably found in other foci of the world—the Kii peninsula, in Japan, being one (see refs. 181-183 for a review of the pathology).

The neuropathologist Harry Zimmerman, assigned by the U.S. Navy to Guam during World War II, was the first to notice there a high incidence of amyotrophic lateral sclerosis (ALS). ALS was said to affect 10% of the population and the number of deaths attributed to ALS was 100 times higher in Guam than in other countries (184). It was secondarily noted that another degenerative disease, combining parkinsonism and dementia, was also highly prevalent. The neuropathology of this Guam "parkinsonism dementia complex" (PDC) was described by Hirano et al. (184,185). Hirano et al. divided the cases into three groups: Parkinsonism and dementia; Parkinsonism, dementia, and involvement of the upper motor neuron; cases with symptoms of lower motor neuron disease. The opinion has recently been expressed that ALS in Guam is not different from ALS in other parts of the world (181). The presence of Bunina bodies, the marker of classical ALS, in the Guam cases is one of the data in favor of this view (186).

The neuropathology of PDC combines NFTs and neuronal loss. Most of the tangles are made of paired helical filaments, similar to those seen in Alzheimer's disease. They are tau- and, for some of them, ubiquitin-positive and have the same immunological profile as Alzheimer's tangles. According to one study (187), they could occupy the cell body of the neuron for 2.5 yr before causing its death. They are then freed in the neuropil (ghost tangle). The distribution of the NFTs is widespread: isocortex and hippocampus, striatum and pallidum, hypothalamus, amygdala, substantia nigra, periaqueductal gray, pontine nuclei, dorsal nucleus of the vagus nerve, reticular formation, anterior and posterior horns of the spinal cord are among the affected structures. Neuronal loss explains the cerebral atrophy and is usually marked in the substantia nigra and locus coeruleus. The cerebellum is usually spared. Ap pathology and tau-positive threads are not features of PDC. Glial pathology, shown by Gallyas stain and tau immunohistochemistry, has been observed more recently. It consists in "granular hazy inclusions" found in the cell body of the astrocytes and "crescent/coiled inclusions" in oligodendrocytes (188). Hirano bodies, i.e., eosinophilic rodlike inclusions adjacent to neuronal cell bodies

(and occasionally within them), in the Sommer sector of the hippocampus, were initially described in Guam patients but were also found later in other degenerative diseases.

Guam ALS/PDC has raised many still unanswered questions. Since the disease seemed to be confined to the Chamorro population, the native people of Guam, a hereditary disorder was initially suspected. However, several facts argue against an etiologic role of heredity. The incidence of Guam ALS has been dramatically decreasing in the last decades (although the incidence of PDC not so markedly), a change that heredity cannot explain. The risk of developing the disease is lower in Chamorros that have left Guam but with inertia (a latency of several decades). Finally, Filipinos and a few Caucasians have also developed the disease (see review in ref. 183).

Many attempts made to identify the cause of Guam ALS/PDC have failed. The principal etiologies that have been considered are infectious (by a process similar to PEP after encephalitis lethargica) and toxic. The possibility that cycad, the seed of the false sago palm traditionally used in Chamorro food, contained toxic species, was put forward by P. Spencer (189). However the amount of seed necessary to obtain a toxic effect in the monkey seems incompatible with the common use of cycad by Chamorros (190). More recently, Perl et al. have shown a high concentration of aluminum and iron in the NFTs of Guam ALS/PDC and have suggested that these metals could play a role in the pathogenesis (see review in ref. 183). Although the identification of the etiological factor should be easier for a rare disorder developing in a circumscribed environment than for common diseases that are geographically widespread, the etiology of Guam ALS/PDC remains elusive.

The Use of the Terms Pick's Disease and Pick's Complex

Although parkinsonism in Pick's disease (in the restricted sense) is a secondary symptom and raises little diagnostic difficulty, the extensive use of the term Pick's disease and the recently introduced Pick's complex (which may include conditions otherwise defined as CBD) requires some explanation.

The clinical symptoms of frontal involvement, which are seen at the onset in some cases of dementia, contrast strongly with the initial memory problems typical of Alzheimer's disease. In the old literature (191-193), those cases were grouped under the heading of Pick's disease. The term was historically incorrect since Pick had initially described cases with focal cortical deficit owing to "circumscribed atrophy" (in the language of the time) (194-196). Cases of frontal syndrome are not included in his main articles, which described cases of progressive aphasia (197) and of progressive apraxia (196). Alzheimer performed the neuropathological examination of cases of circumscribed atrophy (probably of the frontal lobe but this is barely mentioned in his paper) and found a new inclusion (198) (English translation in ref. 199), which was later known as Pick's body. It is a spherical accumulation of tau-positive and argyrophilic material, approximately the size of the nucleus, located in the cell body of the neurons. Pick's body is generally considered as almost exclusively made of 3R tau (148,149,200), although some doubts have been recently expressed concerning the selectivity of the isoform (201). Pick's bodies are particularly abundant in the dentate gyrus, where they are considered to be constant. They are generally associated with ballooned, chromatolytic neurons, called Pick's cells. Ramified astrocytes and small Pick's body-like inclusions, discovered more recently, are evidence that the disease does not spare the glia (202). Pick's bodies are generally found in cases of dementia with a predominant frontal syndrome.

The meanings of Pick's disease have been shaped by the various historical contexts in which the term has been used (focal cortical syndrome or "circumscribed atrophy"; frontal syndrome owing to a degenerative disease with or without Pick's bodies; dementia, generally of the frontal-lobe type, with Pick's bodies). A Venn diagram may visualize the relationship between these different meanings, from the least to the most specific ones, and helps explain why Pick's disease has come to be such a confusing label (see Fig. 6). The recent attempt to introduce the term Pick's complex for a large set of disorders with various neuropathology (203-209) may, in our view, be discussed since it

Fig. 6. The different meanings of Pick's disease. The different meanings of the term Pick's disease cover overlapping subsets of disorders. The concept of Pick's complex, more recently proposed (205), would probably include most of the cases that were historically described under the heading of "Pick's circumscribed atrophy." From the point of view adopted in this chapter, it seems more adequate to restrict the use of the term to its most specific meaning of "Pick's bodies dementia." Pick's bodies are generally found in sporadic cases with a predominant frontal syndrome. Cases with progressive aphasia (139,209,230) or apraxia (139) have been described, explaining why the last circle ("Pick's bodies dementia") overlaps the set of "circumscribed atrophies" (focal cortical syndromes). The surface areas enclosed in the three circles are subjective evaluations of the prevalence of the various disorders: the figure does not rely on objective data.

Pick " circumscribcd alrophy " (historical sense)

Pick disease = degenerative frontal syndrome, familial or sporadic, with or without Pick bodies

Fig. 6. The different meanings of Pick's disease. The different meanings of the term Pick's disease cover overlapping subsets of disorders. The concept of Pick's complex, more recently proposed (205), would probably include most of the cases that were historically described under the heading of "Pick's circumscribed atrophy." From the point of view adopted in this chapter, it seems more adequate to restrict the use of the term to its most specific meaning of "Pick's bodies dementia." Pick's bodies are generally found in sporadic cases with a predominant frontal syndrome. Cases with progressive aphasia (139,209,230) or apraxia (139) have been described, explaining why the last circle ("Pick's bodies dementia") overlaps the set of "circumscribed atrophies" (focal cortical syndromes). The surface areas enclosed in the three circles are subjective evaluations of the prevalence of the various disorders: the figure does not rely on objective data.

lumps diseases that all the recent data tend to separate. We would rather recommend restricting the use of Pick's disease to the cases of dementia with Pick bodies (210,211), as most neurologists and neuropathologists would (212). In this use, Pick's disease is a rare sporadic disease.

The Familial Tauopathies: Frontotemporal Dementia With Parkinsonism

Besides the sporadic cases with Pick's bodies, a large number of patients present with a frontal syndrome of progressive course. A fair proportion of them are familial. Among them, several exhibit parkinsonian symptoms. A consensus meeting identified some of those families with linkage to chromosome 17 and grouped those cases under the heading of frontotemporal dementia with parkinsonism linked to chromosome 17 or FTDP-17 (213). Shortly after, a mutation of the tau gene was found in some of these families (214,215). Tau mutations are very diverse and so is the neuropathol-ogy. The isoforms of tau, which accumulate depend on the mutation. Both 3R and 4R tauopathy are met in this group of disorders. It is not the place here to review the complex picture of FTDP-17 neuropathology (analyzed in details in ref. 216). It is useful however to emphasize here the pheno-typic mimicry of some specific mutations. The neuropathology of the sporadic diseases that we have previously considered, more specifically PSP (217), CBD (218,219), and Pick's disease (220,221), can, indeed, be mimicked by tau mutations. This observation suggests that the cellular type in which tau accumulation occurs, and its subcellular topography, is highly dependent on the tau molecule itself. The presence of ballooned neurons, NFTs, Pick's bodies, and glial inclusions may, indeed, be determined by one single change in the molecular structure of tau. This is not to say that all the diseases that were considered here have a genetic origin: PSP, CBD, and Pick's disease are, in the great majority of cases, sporadic. But the similarity of the phenotypes suggests that the pathogenic mechanism involves directly tau protein in the sporadic as well as in the hereditary tauopathies.

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