Int. J. Exp. Path (1992) 73, 535-550

Current Status Review: Cerebral amyloid L.W. Duchen Department of Neuropathology, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

The brain is the site of deposition of amyloid in a diverse range of clinical conditions which are included in the group of f3-fibrilloses, as defined by Glenner (1980). Although the fibrillar proteins deposited have some features in common such as their tinctorial, crystallographic and ultrastructural properties, it has become increasingly clear that there are major differences in their biochemical composition, immunological reactivity and genetic determinants. Cerebral amyloidosis is not a significant feature of the pathology of any of the seven varieties of familial amyloidotic polyneuropathy (FAP). An occasional report (Ushiyama et al. 1991) describes amyloid infiltration of meningeal arteries and arterioles in type 1 (transthyretin) FAP. The clinical features, pathology, biochemistry and molecular genetics of the FAPs were reviewed by Glenner and Murphy (1989) and by Thomas et al. (1992). There is also no significant deposition of amyloid in the brain in the various other

systemic amyloidoses or in those forms characterized by deposits localized to individual viscera or associated with tumours. Since there is a circulating amyloidogenic serum protein in some of these systemic amyloidoses it may be assumed that barrier mechanisms prevent cerebral or cerebrovascular deposition in these conditions. The cerebral amyloidoses are best considered as falling into several categories, as shown in Table 1. These are usually well defined entities, but on some occasions the differences may not be clear-cut.

Age-related cerebral amyloid angiopathy

(CAA) (1) Deposition of amyloid in vessel walls is the form of cerebral amyloid that is most commonly related to increasing age. Older terminology such as 'dyshoric' or 'drusige Entartung' (see Vinters 1987) seem no longer to serve a useful purpose, but indicate that the recognition of the association between age-

Table 1.

(1) Age-related amyloid angiopathy with or without intracerebral deposits t2) Hereditary amyloid angiopathy of meningeal and cortical vessels associated with cerebral haemorrhage: (a) Icelandic type; (b) Dutch type (3) Hereditary amyloid angiopathy affecting the entire CNS (4) Alzheimer's disease: sporadic, familial or associated with Down's syndrome (5) Cerebral amyloid associated with prion disease sporadic spongiform encephalopathy: Creutzfeldt-Jakob disease (CJD) familial prion disease: familial CJD, Gerstmann-Striiussler-Scheinker (GSS) disease and atypical familial prion disease prion disease in animals (6) Familial oculoleptomeningeal amyloidosis

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ing and CAA goes back to the early years of the century. Mountjoy et al. (1982) noted, in a study of brains of 30 non-demented old people and 15 with senile dementia (Alzheimer's disease) that vascular amyloid increased with each decade but that there was no significant correlation between the total amount of vascular amyloid and the clinical severity of dementia. Intracerebral plaques occurred in the absence of CAA and in two cases CAA was not accompanied by plaques. In their study of the ageing brain, Vinters and Gilbert (1983), examined 84 subjects aged 60-97 years and found some degree of CAA in 36%, also noting that a higher proportion of cases were affected in each decade. Esiri and Wilcock (1986) studied 159 brains with a mean age of 81 years from patients who had previously been assessed clinically. Of those considered nondemented, 33% were affected by CAA of mild to moderate degree of severity. Hauw et al. (1986) examined the brains of 12 centenarians noting CAA in nine. These cases however presented the frequently encountered problems of assessment of higher cerebral function in the very old because of a high incidence of severe deafness, blindness, or effects of prolonged institutionalization. Esiri and Wilcock (1986) emphasized that CAA may occur in intellectually normal old people and, unlike Mountjoy et al. (1982) and Vinters and Gilbert (1983), did not observe a clear increase in CAA with increasing age between 61 and 102. In the ageing brain the amyloid infiltrates the media of small arteries and arterioles in meninges and cerebral cortex, the occipital and parietal lobes being most commonly involved. The hippocampus and white matter are usually spared as are cerebellum, brain-stem and spinal cord. Among the complications of CAA are cerebral haemorrhage, infarction, loss of myelin in central white matter and, perhaps, a form of granulomatous angiitis. Okazaki et al. (1979) in a study of 23 patients with CAA, observed major cerebral haemorrhages in

nine, petechial haemorrhages in 19, and small cortical infarcts in 21 cases. Mandybur (1986) reviewed 25 patients with CAA (limited to the occipital lobe in 10) and noted seven with haemorrhage. Vinters (1987) reviewed the literature on the association of CAA with haemorrhage and noted that there was no preponderance of either sex, that most haemorrhages occurred in the sixth or seventh decade, and that about 30% of cases had clinically documented hypertension. Haemorrhages usually involved cortex and subcortical white matter (Gilberta & Vinters 1983). These and other individual case reports indicate that amyloid vascular change could be a significant aetiological factor in otherwise unexplained cerebral haemorrhage in the elderly; the hereditary diseases discussed below emphasize this association. The report by Gray et al. (1985) describes the changes found in 12 brains of patients aged 5 5-83 which showed widespread CAA ('diffuse haemorrhagic CAA'). These all showed cortical petechial haemorrhages with or without small cortical infarcts but Gray et al. drew special attention to the myelin loss in the deep cerebral white matter, in the absence of amyloid infiltration of the vessels of the white matter. They ascribed the myelinic rarefaction to stenosis of long perforating meningeal and cortical vessels by the amyloid infiltrations leading to chronic hypoperfusion of the deep white matter. The importance of recognizing the association between CAA and white matter loss is emphasized by the identification of the latter change with neuro-imaging techniques. Cerebral granulomatous angiitis associated with amyloid has been described in many single case reports (Probst & Ulrich

1985; Gray et al. 1990; Le Coz et al. 1991). The lesion may present as a space-occupying mass and foreign-body type giant cells characteristicaily contain particles of congophilic debris suggesting that this is a foreign-body reaction rather than giant cell arteritis (Powers et al. 1990) although the exact sequence of events is not clear.

Cerebral amyloid 537 traumatic cerebral haemorrhages (Vinters CAA in ageing animals 1987). In two apparently distinctly different In the search for an animal counterpart of hereditary forms of CAA, (a) the Icelandic age-related pathology in the human brain a and (b) the Dutch, the characteristic clinical number of papers have described studies of presentation is that of cerebral haemorthe brains of old animals, i.e. old for the rhage. Both have autosomal dominant species. Dayan (1971) studied aged examinheritance. ples of many species, and the only pathology found with any frequency was CAA, in four of eight parrots, two of 40 mice and occasio- Hereditary cerebral haemorrhage with nal examples in other species. Walker et al. amyloid: Icelandic type (HCHWA-I) (a) (1990) examined the brains of three squirrel This Icelandic familial disease was described monkeys aged 8 years, six aged 22-27 and in detail by Gudmundsson et al. (1972) but two rhesus monkeys aged 31 and 34 respecthad been known for at least 200 years. A ively. The young squirrel monkeys showed subsequent review (Jensson et al. 1987) no detectable amyloid but in all the old ones identified 127 affected members of eight there was CAA involving meningeal or corti- families with neuropathological study of the cal arterioles and capillaries, sometimes brain in 19 cases. The characteristic presenassociated with perivascular extensions of tation is cerebral haemorrhage, most comamyloid into the parenchyma. The cerebel- monly in the third decade. All 19 had CAA, lum was in most animals free of amyloid but none were hypertensive, and none had intrathere were occasional meningeal vessels parenchymal amyloid deposits. Meningeal involved. White matter, hippocampus, basal arteries and arterioles as well as intracerebral ganglia, brain-stem and spinal cord were vessels are affected as are vessels in the spinal also virtually free of amyloid. Rhesus mon- cord. In one case with severe generalized keys had less vascular amyloid and more CAA amyloid was found in a submandibular parenchymal deposits. It seems that age- lymph node but with this exception none related cerebral amyloid in animals follows was observed in any other viscera. Cerebral the same pattern of distribution as in man, haemorrhage occurred most commonly in affecting predominantly meningeal and cor- the basal ganglia. In this form of CAA those tical vessels and sparing those in the white structures usually spared in the age-related matter, hippocampus and cerebellum. In CAA, such as brain-stem and cerebellum, both human and animal age-related amyloi- were affected (Vinters 1987). dosis, f-protein has been identified as the The amyloid in HCHWA-I has been shown protein deposited in the brain. This protein to be related to a protein cystatin C (gammaand the association between CAA and the trace) which is an inhibitor of cystein propresence of changes characteristic of Alzteinases (Cohen et al. 1983; Ghiso et al. heimer's disease are discussed below. 1986). It is normally present in high concentration in cerebrospinal fluid but in affected HCHWA-I cases it is only one-third of the Hereditary amyloid angiopathy of mean normal value (Grubb et al. 1984; meningeal and cortical vessels associated et al. 1987; Shimode et al. 1991). A Lofberg with haemorrhage (2) point mutation has been demonstrated in the Any cerebral vessel affected by amyloid may cystatin C of affected cases with the substiturupture and bleed, either because of tion of glutamine for leucine at position 68 of increased fragility, particularly in the presthe molecule, which lacks the first 10 aminoence of hypertension, or because of the terminal amino acid residues when comformation of microaneurysms. The presence pared with the normal cystatin C molecule of CAA may account for 5-10% of non(Ghiso et al. 1986). The immunohistochemi-

L. W. Duchen cal characteristics have been studied by age-related angiopathy and Alzheimer's disLofberg et al. ( 198 7) who used immunofluor- ease (Van Duinen et al. 1987; Van Broeckhoescent and peroxidase localization of a poly- ven et al. 1990; Levy et al. 1990). The molecular genetics and biochemistry of clonal antibody to cystatin C. fl-protein are discussed below. Hereditary cerebral haemorrhage with Hereditary amyloid angiopathy affecting amyloid: Dutch type (HCHWA-D) (b) the entire CNS (3) Cerebral haemorrhage, known to be associated with CAA, has been described in A number of cases with remarkably similar several families in the Netherlands. To date pathology have been described by Worsterapproximately 300 cases have been Drought et al. (1940, 1944), Griffiths et al reported. Wattendorff et al. (1982) reported (1982), Love and Duchen (1982) and Plant that in 11 patients in one family cerebral et al. (1990). To these should be added case 6 haemorrhage occurred in the 5th or 6th of Hollander and Strich (1970). The case decade. In some cases there were recurrent described by Shaw (1979) possibly belongs haemorrhages. Four brains of this series to the same group. These cases are characwere examined. All showed the presence of terized by autosomal dominant inheritance amyloid angiopathy affecting cortical and and most had dementia, cerebellar ataxia leptomeningeal vessels. In two of these the and slowly progressive spasticity beginning vessels in the meninges over the brain-stem in the 5th or 6th decade and a duration of and cerebellum were also affected. None had illness for 5-10 years or more. Plant et al. amyloid parenchymal deposits or neurofi- (1990) gathered information from various brillary tangles. In the same family another sources about the family of their case and not five cases developed progressive dementia, only did they show that the individuals preceded by strokes in three. No pathology described by themselves, Worster-Drought et was described in this group. al. (1940, 1944) and Griffiths et al. (1982) all Haan et al. (1990) described the clinical belong to the same kindred, they were also features in seven patients who had cerebral able to identify 26 affected members in five haemorrhage in their forties and noted amy- generations. loid infiltration of meningeal and cortical In all cases of this group the pathology is vessels and also confirmed previous reports remarkably uniform, varying only in the that there were no neurofibrillary tangles or degree of intensity of the pathological amyloid plaques within the cerebral paren- changes found in different regions of the chyma. They paid special attention to cere- nervous system. The amyloid infiltration bral white matter pathology in view of affected small arteries and arterioles of menneuro-imaging findings. Rarefaction of inges and cortex of all regions of cerebrum, hemispheric myelin, due to hypoperfusion or cerebellum, brain-stem and spinal cord. Parrelated to areas of cortical destruction, was ticularly noteworthy is involvement of the described but this was not due to direct vessels of the white matter resulting in involvement of vessels in white matter by widespread ischaemic damage of varying amyloid. The rarefaction is very like that severity ranging from myelin rarefaction to described by Gray et al. (1985) discussed frank infarction. Microangiopathy, i.e. infilabove and is very different from the patho- tration of capillary walls by amyloid, in logy in the cases discussed in the following hippocampus and cerebellar cortex is sections. another feature. This last-named abnorThe amyloid in HCHWA-D has been iden- mality is not found in any other form of tified by immunochemistry and biochemical cerebral amyloidosis. analysis as fl-protein, similar to that found in In addition to CAA and microangiopathy,

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Cerebral amyloid amyloid plaques, varying in size and in the amount of degenerative material surrounding an amyloid core, are present in the hippocampus in large numbers and in lesser numbers throughout the neocortex. Neurofibrillary tangles are present, predominantly in the hippocampus. The family described by Love and Duchen (1982) had less severe intellectual deterioration and less severe plaque and tangle formation in the hippocampus.

The place of this group in relation to other forms of cerebral amyloidosis is not clear and the biochemical and immunoreactive characteristics of this amyloid have not yet been determined. There are clearly points of resemblance to CAA in the aged, to the hereditary forms of CAA discussed above and to the pathology of Alzheimer's disease, particularly in cases such as those described by Corsellis and Brierley (19 54). Some of the amyloid deposits resemble 'kuru-type' plaques usually associated with prion diseases. The absence of cerebral haemorrhage is unlike the hereditary Icelandic or Dutch forms of CAA whilst spasticity due to degeneration of myelinated fibres in the centrum semiovale and in the spinal cord, and cerebellar ataxia are rarely encountered with other forms of CAA except as a result of haemorrhage or infarction.

Alzheimer's disease (4) The association between clinical dementia in the aged (senile dementia) or in middle age (presenile dementia) on the one hand and the pathology of Alzheimer's disease (AD) on the other, has been recognized for many years (see Tomlinson 1992). The association between the pathology of AD and amyloid is also well known and in recent years has become better defined than ever before. The studies of cerebral amyloid angiopathy (CAA) all emphasize that a very high proportion of cases with clinical dementia due to AD also had evidence of CAA. Esiri and Wilcock (1986) noted CAA in 82% of cases of AD compared with 27% of brains of old people

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who were not demented and had no CNS disease. Gray et al. (1985) also noted the presence of parenchymal plaques and neurofibrillary tangles in all but one of their 12 cases with CAA and Mandybur ( 19 8 6) found that all 2 5 brains with CAA that he studied had plaques but only half of them had neurofibrillary tangles. Glenner and Wong ( 19 8 7) reported that 92% of cases of AD had associated CAA. Certainly the association is very strong though it must be remembered that AD may occur without concomitant CAA and that the converse is also true. In cases of HCHWA of either Dutch or Icelandic types no intracerebral plaques or intraneuronal tangles are found. The morphological characteristics of AD include cerebral atrophy, the formation of 'senile plaques' in grey matter, the presence of Alzheimer's neurofibrillary tangles in neurons, granulo-vacuolar degeneration of, mainly, hippocampal pyramidal cells and, often, CAA. Amyloid deposition is clearly associated with plaque formation. The exact sequence of events has been the subject of discussion and controversy for many years but evidence has accumulated that the earliest stage of plaque formation is the 'amorphous' or 'diffuse' plaque in which fibrillar material in rounded aggregates varying considerably in diameter can be identified by immunostaining using amyloid #-protein antibody. These plaques do not have a solid congophilic or birefringent core and do not contain argyrophilic neuritic elements (Yamaguchi et al. 1988; Ikeda et al. 1989; Behrouz et al. 1991) and are more readily immunostained by anti fl-protein after pretreatment of the section with formic acid (Kitamoto et al. 1987) or periodic acid (Behrouz et al. 1991). The 'classic' senile plaque has a prominent amyloid element, extracellular fibrils forming a solid core which is congophilic and birefringent and, on occasion, argyrophilic depending on the silver staining method used. Surrounding this core of amyloid are numerous processes of degenerative neurites containing dense bodies, mitochondria and

L. W. Duchen clusters of paired helical filaments which are brains, as shown by Corsellis and Brierley also the constituents of the neurofibrillary (1954) and seen also by the present writer, tangles. Electron microscopic studies (Kidd capillary, as well as the more commonly seen 1964; Terry & Wisniewski 1970; and see arteriolar, amyloid is invariably well Tomlinson, 1992) have not established the marked. In recent years the development of the precise site of the first amyloid fibril deposition. Microglial (macrophage) processes con- pathological changes of AD in cases of taining lipofuscin and astrocytic processes Down's syndrome has become recognized. are also found between the other compo- This is because of the longer survival of nents of plaques. In what were considered to Down's syndrome patients at the present be 'burnt-out' plaques only a solid dense time than hitherto and it is probably true to deposit of amyloid is seen, without neuritic or say that every Down's patient who survives macrophage processes around it although into middle age will develop Alzheimer's astrocytes and their processes may be pres- disease. This pathology is associated with increasing dementia, which may be difficult ent. The neurofibrillary tangles found in neur- to assess, and with cerebral atrophy making onal perikarya and their processes, mainly if such patients more susceptible than most to not solely dendritic, are another element the development of subdural haematomas. essential for the pathological diagnosis of The amyloid of plaques and blood vessels in AD. These tangles are composed of skeins or Down's patients is also immunostained by bundles of filaments arranged in pairs anti-fl-protein antibody (see Glenner & Murtwisted around each other in a helical phy 1989). fashion. These filaments are stained by silver impregnation methods such as those of The amyloid fl-protein and its precursor Bielschowsky, Glees or Von Braumiihl. They are also immunostained by antibodies to Immunodetection of f-protein in blood vespaired helical filaments, protein and neurofi- sels and intracerebral plaques is now generlament protein. The paired filaments of neur- ally accepted as characteristic of age-related ofibrillary tangles also have characteristics of CAA, HCHWA-D, AD, and the AD of Down's amyloid in that they are congophilic (par- syndrome (Masters et al. 1985b; Allsop ticularly in the pyramidal cells of the hippo- 1986; Ikeda et al. 1987; and see Frangione 1989). fl-Protein is a 4kDa protein of about campus) and birefringent and have been shown to have a fl-pleated conformation. 40 amino acids and the first 28 aminoThe plaques of AD and the congophilic terminal residues were sequenced by Glenangiopathy, but not the neurofibrillary tan- ner and Wong (1987). There are slight gles, are immunostained with antibody to differences in the characteristics of the fiamyloid ,B-protein (Ikeda et al, 1989; but see protein in the cores of amyloid plaques (42 Masters et al. 198 5a). residues) compared with the meningovascuThe relationship of senile amyloid plaques lar amyloid (39 residues, Prelli et al. 1988). to blood vessels has been the subject of The mRNA for f-protein has been localized discussion for a very long time, some in a widespread distribution of cerebral neurobservers asserting that every plaque has a ons including those preferentially affected in capillary or its remnant in the midst of the Alzheimer's disease (Bahmanyar et al. 1987; amyloid core. In the writer's view this does Higgins et al. 1988). It has been found that not hold true but the clearly strong associ- the f-protein is a fragment of a larger ation between vessels infiltrated by amyloid amyloid precursor protein (APP). The gene and radiating fibrils of amyloid projecting which encodes for APP is located on human chromosome 21 in the region 2 1q21. into the cerebral parenchyma is a real one, particularly in familial cases of AD. In these Clones have been isolated that encode

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Cerebral amyloid several alternate mRNAs for APP which have 695, 751 or 770 amino acids. APPs are membrane-associated glycoproteins and although their functions are not clearly understood APP751 and 770 have been found to form inhibitory complexes with serine proteases. In vessel walls infiltrated by amyloid in AD and in HCHWA-D, APP and fl-protein co-exist. APP reactivity is also found in senile plaques in AD (Tagliavini et al. 1990). Molecular genetic studies in familial Alzheimer's disease have shown linkage to chromosome 2 1q2 2.2 but there was no linkage to markers in 2 1q22 region in Down's cases, nor to ,B precursor protein gene (see Neve et al. 1990). The amyloid f-protein gene is not duplicated in brains of patients with AD (Tanzi et al. 1987). A transgenic mouse model incorporating the human APP-75 1 gene has been reported by Quon et al. (1991). In this mouse, extracellular deposits immunoreacting with antibody to fl-APP were observed.

Cerebral amyloid associated with prion diseases (5) A group of progressive, invariably fatal spongiform encephalopathies in man and animals has characteristics in common. They are transmissible and at least some are inherited. Cerebral amyloid is found in many of them and is characteristic of some. The term 'prion disease' was coined by Prusiner following the isolation of a protease resistant protein of molecular weight 2 7-30kDa which was designated prion protein (PrP), first detected in the brains of sheep with scrapie and subsequently in the other entities which comprise the prion diseases (see Prusiner 1991). The human diseases in this group include sporadic or familial subacute spongiform encephalopathy (CreutzfeldtJakob disease); the familial GerstmannStraussler-Scheinker disease; and kuru. Prion diseases in animals include scrapie in sheep and goats, transmissible encephalopathy in mink, captive mule deer and elk,

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and bovine spongiform encephalopathy (BSE). Spongiform encephalopathy has also been described in cats and other animals held in zoos. The human gene for PrP has been localized in the short arm of chromosome 20. The function of the normal PrP gene product is not known. PrP, whose mRNA is widely distributed in neurons throughout the brain, has a molecular weight of 33-35kDa. Its normal form has been designated PrPC. An abnormal form, PrPsc of similar molecular weight is found in the diseased brain. The difference between PrPc and PrPSc is not known but is thought to involve post-translational modifications. Prion protein is the proteinase-K resistant 2 7-3OkDa core of the larger PrPsc. The main neuropathological characteristics of all the prion disease are a spongiform change in grey matter, astrocytic hyperplasia and neuronal vacuolation although there is considerable variation between diseases and between individual cases. Amyloid deposition is a characteristic feature of some forms of prion disease but is not well defined in others. Creutzfeld-Jakob disease (CJD) occurs most often as a sporadic diseases (Beck & Daniel 198 7) of middle age or later life and is characterized by progressive dementia, ataxia, myoclonus and amyotrophy, all varying in degrees of severity and in the order of presentation. The appearance of typical periodic complexes on EEG is also a common finding even though it may be late in the course of the disease. The duration of the clinical course may be as short as 6 weeks, most often is less than 1 year, but may rarely last 2-3 years. There are many papers in the literature on the clinical and epidemiological features of CJD, and this topic has been reviewed recently by Gajdusek (1990) and Prusiner et al. (1989). CJD occurs in a familial form in about 15% of cases (Gajdusek 1990) when it is inherited in an autosomal dominant fashion. Amyloid deposition in the brain is said to occur in about 10% of CJD cases (Masters et al. 1981). Abundant amyloid deposits have

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been described in some cases by Chou and Martin (1971), Kriicke et al. (1973) and Adams et al. (1974). Keohane et al. (1985) described a patient with CJD with cerebral amyloid angiopathy as well as intracerebral amyloid plaques. Amyloid angiopathy (including capillary angiopathy) in association with CJD has also been found in a case studied by the present author (unpublished). This elderly patient had a short history, 6 months, of progressive dementia and in addition to the CAA, intracerebral deposits resembling neuritic plaques were present but there were no neurofibrillary tangles. Extensive deposition of amyloid was also found by the writer in a patient who developed CJD after treatment with human growth hormone (see Markus et al. 1992). The amyloid deposits varied widely in size and appearance in this case, ranging from typical 'kuru' type, through 'diffuse' plaques to those with an appearance exactly like the neuritic plaques of Alzheimer's disease. This case is discussed again below. The difficulties which beset the identification of amyloid in the brain suggest to the writer that the incidence of cerebral amyloid of various morphological types, in association with CJD, is likely to be considerably higher than the 9-10% proposed by Masters et al. (1981) and by Glenner and Murphy (1989). The familial Gerstmann-StraiusslerScheinker (GSS) (1936) syndrome has autosomal dominant inheritance, tends to begin at a younger age (4th or 5th decade) than CJD and has a longer clinical course. In the family described by Adam et al. (1982) the disorder most commonly began with cerebellar ataxia and with dementia developing late in the disease which varied in its duration from less than one year to 10 years. The case report by Rosenthal et al. (1976), described a member of the same family who had emigrated to the USA, and who had a clinical presentation and pathology indistinguishable from that of CJD. Two members of the family had little spongiform change, two others had severe generalized spongiosis, all had cerebellar degeneration and all had

cerebral and cerebellar amyloid which consisted of heavy deposition of round plaques of amyloid with radiating fibrils at their periphery ('kuru' type) scattered throughout the molecular and granular layers and white matter of the cerebellum. Throughout the rest of the brain, mainly in the neocortical molecular layer, there was abundant amyloid in the form of multicentric plaques which are collections of rounded amyloid droplets. These were described by Gerstmann et al. (1936), Boellard and Schlote (1980) and Adam et al. (1982) who also found amyloid angiopathy in one of the familial GSS cases. Since the report by Adam et al. (1982) on four members of the 'W' family, a further member of that family died after several years with progressive dementia and ataxia. In the brain of this patient, studied by the present author, there was no spongiform encephalopathy, no gliosis and no multicentric plaque deposition. There were, however, many tiny rounded amyloid deposits in the molecular and granular layers and white matter of the cerebellum. This family is referred to again below in the discussion on transmission.

Molecular genetics of GSS Abnormalities of the PrP gene have been found in several families with inherited prion disease (see Prusiner 1991). A point mutation at codon 102 has been found in families with GSS in several countries, including the UK (the W family), as well as in the family originally described with the disease in 1936 by Gerstmann et al. Other point mutations within the PrP gene have been found at codons 117, 178, 198 and 200 and have usually been associated with characteristic CJD rather than GSS. An insert of 144 base pairs between codons 51 and 91 giving six additional octa-repeats has also been associated with spongiform encephalopathy in several families, probably all one kindred, in the UK (Owen et al. 1989; Poulter et al. 1992). The neuropathology of four members of this family range from typical

Cerebral amyloid spongiform encephalopathy to little abnormality at all (see Baker and Ridley 1992). The relationship between abnormalities, inherited or newly arisen as a mutation, of the PrP gene, and the development of a transmissible encephalopathy is not entirely clear and is extensively discussed by Prusiner (1991). It should be emphasized that occasional members of families with PrP gene abnormalities may have no apparent detectable cerebral pathology (Collinge et al. 1990) even when there had been severe clinical neurological or psychiatric abnormality. Kuru is a progressive neurological disease found among (and limited to) the Fore people in the highlands of New Guinea. The clinical features are mainly those of progressive ataxia and trembling (see Gajdusek 1990) and pathologically it is characterized by severe cerebellar degeneration, generalized astrocytic proliferation, intraneuronal vacuolation and amyloid deposits (Klatzo et al. 1959). Spongiform change in kuru is not a prominent feature though localized cortical sponginess has been described (Kakulas et al, 1967). This is in striking contrast to the severe cortical spongiform changes which occur in the primate brain after transmission of kuru by intracerebral inoculation. Immunostaining of amyloid in prion diseases has become a diagnostic procedure to which much importance has been attached. Antibodies raised against scrapie PrP2 7-30 reacted with amyloid plaques in CJD and GSS brains (Bockman et al. 1985; DeArmond et al. 1985, electron microscopy) and it has been suggested that the amyloid fibrils may represent aggregations of infectious particles. Anti-PrP antibody does not react with neuritic plaques of Alzheimer's disease nor with vascular amyloid in CAA (see Allsop 1986). It was found however (Allsop et al. 1988) that cerebrovascular amyloid in the brains of scrapie sheep did react with PrP antibody but not with fl-protein antibody. Among the animal prion diseases scrapie and bovine spongiform encephalopathy (BSE) are the best-known and commonest. Scrapie, a disease of the CNS in sheep which has been known for over 200 years, is

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characterized clinically by progressive ataxia, tremor and, typically, rubbing of the skin against anything hard such as a wooden fence or post. The pathology includes neuronal vacuolation, cerebellar degeneration, and generalized astrocytic proliferation (Beck et al. 1964). There is little spongiform change in grey matter in naturally occurring scrapie and cerebral amyloid plaques have been observed in a minority (about 10%) of cases. Gilmour et al. (1985) noted that the brains of more than 50% of sheep from six breeds affected by natural scrapie had amyloid angiopathy in cerebral and cerebellar cortex. Amyloid has not been described in BSE, an encephalopathy described in cattle in the UK (Wells et al. 1987). In this disease animals develop a rapidly progressive ataxia and 'dementia' which is fatal within a few months. Neurons in the brain-stem are vacuolated and the neuropil shows spongiform changes and astrocytic gliosis. It has been considered likely (Wilesmith et al. 1988) that cattle became infected after being fed concentrates containing meat and bonemeal derived from scrapie-affected sheep. Transmissibility of prion diseases has already been mentioned as one of their characteristics and although it is established as an undoubted property of these conditions there are many instances where transmission has not resulted from inoculation of prion-diseased brain tissue into animals. The relationship between heredity and transmissibility of scrapie has been a topic of discussion and even of recrimination for many years. Parry (1983) carried out studies of many flocks of sheep throughout the UK and produced strong evidence of an hereditary factor. The transmission of scrapie by inoculation of brain tissue of affected sheep to other sheep, goats and other animals has been convincing evidence of transmissibility (Cuille & Chelle 1939; Chandler 1961, 1963). Studies of the influence of the genotype of recipient mice and of the strains of scrapie agent have resulted in greater understanding of the pathogenesis of this encephalopathy and of the deposition of amyloid

L. W. Duchen than 20 years. Collinge et al. (1991) ana(Bruce & Fraser 1975; Bruce et al, 1976; lysed the prion gene amino acid sequence of Bruce 1981). It was shown that the intracerthe growth-hormone induced cases and ebral inoculation of scrapie brain tissue into observed that four out of seven of the UK mice results in the development of spongiosis and sometimes the formation of numerous cases were homozygous for valine (VV) at plaques of amyloid which are immuno- position 129 and since this is somewhat stained with PrP antibody. The amount of uncommon for the general population, pos-

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amyloid plaque formation was studied in three inbred strains of mice inoculated with scrapie brain by Bruce and Dickinson (1985). These mouse strains (VM, IM and MB) carried the p7 allele of the sinc gene (scrapie incubation gene) and the scrapie agents tested were ME7 and 8 7V. Strain MB mice inoculated with 87V scrapie had most plaques. Mice with longer incubation times had more plaques which suggested that amyloid plaque function depends to some degree on the duration of replication of scrapie agent in the brain. Kitamoto et al. (1990) made a similar observation in mice inoculated with two different strains of CJD. Transmission of kuru to primates (also by intracerebral inoculation) results in marked spongiform change in the neocortex (unlike the cortex in kuru itself) but not in the appearance of amyloid. Similarly the transmission of CJD or GSS does not result in the appearance of amyloid in chimpanzees or marmosets (Beck et al. 1969, 1973; Rosenthal et al. 1976; Masters et al. 1981; Baker et al. 1990). CJD has been accidentally transmitted to human patients on a number of occasions: by corneal transplant, by the use of inadequately sterilized electrodes used for intracerebral recording in epilepsy, by the use of cadaveric human dura to repair defects after neurosurgery, and following the administration of human pituitary-derived growth hormone (Buchanan et al. 1991) or gonadotrophic hormone. In only one instance, to the best of the writer's knowledge, has amyloid been identified in a recipient of growth hormone (Markus et al. 1992). In patients given pituitary-derived hormones, the hormone usually being injected subcutaneously over several years, the incubation period for CJD to develop has ranged from 4 to more

tulated that VV-129 renders the individual more susceptible to the development of CJD. Cases of CJD following cadaveric dura transplantation have mostly had shorter incubation times (8 years in a personally studied case) presumably because the implant is in direct contact with the brain. Transmission for CJD and GSS brain tissue injected intracerebrally into marmosets was compared by Baker et al. (1990). There was little difference in incubation time or in the pathology. The recipient brains did not show any evidence of amyloid deposition even though the GSS case had abundant cerebellar and cerebral multicentric amyloid deposits. In one affected member of the W pedigree (Adam et al. 1982) the brain showed no spongiform changes and had only small spots of amyloid in the cerebellum. Intracerebral inoculation of brain tissue from this case into marmosets has not, after more that 6 years, resulted in encephalopathy. It seems likely that the presence of spongiform change is an important element in transmission, at least in so far as the incubation time is concerned. Inoculation of BSE brain tissue into mice produced encephalopathy and recently marmosets also showed typical spongiform encephalopathy about 4 years after inoculation (H.F. Baker and R.M. Ridley, personal communication). Transgenic experiments have recently thrown new light on prion disease (Hsiao et al. 1990). Mouse PrP genes containing a codon 101 leucine substitution (homologous to the codon 102 in the human PrP gene) were inoculated into fertilized mouse oocytes. Progeny that expressed the PrP gene with the leucine substitution developed spongiform encephalopathy at 5 7-2 72 days

Cerebral amyloid of age. No amyloid plaques were observed. Transmission using brain tissue of affected mice suggests that the titre of infectious prions is low. Transgenic mice derived from oocytes with hamster PrP gene were subsequently inoculated with mouse scrapie prions and developed spongiform encephalopathy but no amyloid after prolonged incubation. Transgenic mice inoculated with hamster scrapie prions had shorter incubation periods before developing spongiform encephalopathy with many amyloid plaques. It was therefore shown that the characteristics of the neurological disease depend on the genetic origin ofthe prions, which is of significance in any consideration of the problem of trans-species spread of spongiform encephalopathy (see Prusiner, 1991). It thus appears that the disease spongiform encephalopathy in man or animals, inherited or transmitted, is due to the accumulation of the abnormal form of prion protein PrPSc. Possibly an individual's normal prion protein PrPc may become converted spontaneously to PrPsc and may be the basis for sporadic CJD. Inoculation of a foreign PrPSc leads to the host animal (or person) producing its own abnormal prion protein by a mechanism of protein modification which is still not clearly understood.

Familial oculoleptomeningeal amyloidosis (6) Seven members of a family described by Goren et al. (1980) were affected in their fifth or sixth decades by a dominantly inherited disease in which there were strokes, seizures, dementia and visual deterioration. Diffuse amyloidosis affected leptomeninges over brain and spinal cord as well as blood vessels in the subarachnoid space. Amyloid deposits occurred on the ependyma and in subependymal vessels, retina, optic nerve sheath and, occasionally, intraneural and intramuscular vessels. There was no intracerebral amyloid angiopathy and no plaques or neurofibrillary tangles. The nature of this amyloid has not been established.

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Problems in pathological diagnosis of cerebral amyloidosis There are many case reports which demonstrate a considerable amount of overlapping of neuropathological changes which makes it difficult to categorize them clearly. Some instances have been mentioned earlier in this review, such as the member of the family with GSS who presented with pathology typical of CJD (Adam et al. 1982) and the amyloid angiopathy found by the writer in at least three cases of spongiform encephalopathy, one of which also had typical neuritic plaques much like the cases described by Brown et al. (1990) and Powers et al. (1991). These authors interpreted their case as having concomitant Alzheimer's and CJD, but the writer's view is that only one disease was present producing amyloid plaques of variable morphology. The case of Koo et al. (1987) is an illustration of the problem, when abundant plaque-like structures without amyloid but variable in neuritic elements were present throughout the brain in a 39year-old man with 7 years of a dementing illness, the cerebellum containing multiple 'kuru-type' plaques which immunoreacted for fl-protein. It was considered that a diagnosis of prion disease rests on transmissibility but such a positive result in the writer's experience is not invariable even when abnormality of the PrP gene has been determined. Masters et al. (1981) observed that many brains showing typical CJD also had neuritic plaques, as was also observed by Adam et al. (1982) in cases of GSS. Of interest in this respect is the family previously considered to have Alzheimer's disease but subsequently reclassified as GSS on the basis of morphology and immunostaining of plaques (Nochlin et al. 1989). Pro et al. (1980) examined brains of 24 demented patients and reported that seven of them, including five with a family history, had cere-bellar amyloid deposits resembling 'kuru-type' plaques in the presence of all the diagnostic criteria for Alzheimer's disease. Also of relevance in this context is the case of

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L. W. Duchen the young man who developed CJD after protease inhibitors is currently receiving growth hormone treatment whose brain much attention, in this regard, particularly showed typical spongiform encephalopathy because of the association between cystatinand amyloid plaques that included diffuse, C and HCHWA-I and the co-localization by neuritic and kuru-type forms (Markus et al. immunostaining of f-protein and cystatin-C 1992). in vessel walls in CAA and Alzheimer's It seems that the morphology of amyloid disease. We can expect many of these probdeposits is of less significance or reliability in lems to be answered in the near future. This the establishing of a pathological diagnosis is a fast-moving area of research, spurred on than immunoreactivity which must provide by recognition of the importance of 'amyloid' final diagnostic criteria. Somewhat compli- in the pathogenesis of some of the most cating this view are observations by Vinters widespread and enigmatic disorders to affect et al. (1990) and Maruyama et al. (1990) the human and animal nervous system. that cerebrovascular amyloid in Alzheimer's disease and senile CAA reacted both with References fl-protein and cystatin-C antibodies. A further problem is the question of wnat ADAM J., CROW T.J., DUCHEN L.W., SCARAVILLI F. & SPOKES E. (1982) Familial cerebral amyloidosis constitutes a negative result in attempted and spongiform encephalopathy. J. Neurol. transmission. Incubation periods after Neurosurg. Psych. 45, 37-45. inoculation of prions can be very long, as in ADAMS J.H., BECK E. & SHENKIN A.M. (1974) the iatrogenic transmission with human Creutzfeldt-Jakob disease; further similarities growth hormone, and although intracerewith kuru. J. Neurol. Neurosurg. Psych. 37, 195-200. bral inoculation should provide a shorter incubation period than peripheral subcuta- ALLSOP D. (1986) Biochemistry of cerebral amyloid in Alzheimer's disease, the unconventional neous ingestion even that route of infection slow virus diseases and Icelandic cerebrovascumay lead to encephalopathy only after lar disease. In Amyloidosis. Eds J. Marrink and several years have elapsed. Clearly the reciM.H. Van Rijswijk. Dordrecht: Martinus Nijpient animal's life-span must be sufficient to hoff. pp. 243-253. allow for very long incubation times. ALLSOP D., IKEDA S., BRUCE M. & GLENNER G.G. Conclusions There are many unresolved and challenging problems relating to the pathogenesis and effects of amyloid deposition in the brain. The relationship between amyloid deposition in the parenchyma to that in the vessel wall, and the different distribution pattern in different disorders, remains a puzzle. The presence of an amyloid deposit in the parenchyma may cause degeneration of neural processes in its proximity suggesting that at least some forms of amyloid are toxic. The mechanism of amyloid fibril deposition is not yet clear but it seems to be an extracellular phenomenon. It is not known with any degree of certainty whether similar mechanisms for amyloid fibril formation operate in the various disease entities. The role of

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