ALZHEIMER'S MAD COW LINK?

In this update I was looking for new information on any Alzheimers/mad cow connections and I found old information on the connection instead. Unfortunately, it appears that the possible connection is both known and documented, with individuals presenting with both CJD and Alzheimers. CJD can cause Alzheimer's symptoms and Alzheimer's injected into monkeys can cause CJD. The blood of family members of Alzheimer's patients generated CJD in hamsters. Genetic susceptibility obviously plays a role, but the transmission by blood of the prions makes the acquiring of Alzheimer's more of an issue. While Alzheimers has some variation from the admitted prion diseases, the amyloid plaques of Alzheimers are "indistinguishable" from scrapie or mad cow.

Vet Rec. 2001 Apr 28;148(17):531-6. Links

Evidence for the transmission of scrapie to sheep and goats from a vaccine against Mycoplasma agalactiae.

* Caramelli M,

* Ru G,

* Casalone C,

* Bozzetta E,

* Acutis PL,

* Calella A,

* Forloni G.

Centro per le Encefalopatie Animali, Istituto Zooprofilattico Sperimentale del Piemonte, Torino, Italy.

An accidental infection from a vaccine was suggested as the explanation for the sudden increase in outbreaks of scrapie in Italy in 1997 and 1998. This paper describes a recent outbreak of scrapie in sheep and goats which were exposed to the same vaccine. No ewes or goats had been imported into the herd since 1992, but a vaccine against Mycoplasma agalactiae had been administered twice, in 1995 and 1997. High rates of crude mortality and scrapie incidence were experienced by both species, all birth cohorts were involved and a large proportion of aged animals was affected. A pattern of brain lesions was observed, with slight differences between the sheep and goats, which was very similar to the pattern observed in animals previously exposed to the same vaccine but clearly different from that observed in the brains of sheep with scrapie in a flock not exposed to the vaccine. Regardless of their exposure status, genotype analysis of the sheep showed the presence of polymorphism only at codon 171. The patterns of both incidence and brain lesions provide evidence that the epidemic of scrapie was due to the use of the vaccine.

PMID: 11354646 [PubMed - indexed for MEDLINE]

J Gen Virol. 2006 Feb;87(Pt 2):471-7.Click here to read Links

Atypical prion protein in sheep brain collected during the British scrapie-surveillance programme.

* Everest SJ,

* Thorne L,

* Barnicle DA,

* Edwards JC,

* Elliott H,

* Jackman R,

* Hope J.

Department of TSE Molecular Biology, Veterinary Laboratories Agency, New Haw, Addlestone, Surrey KT15 3NB, UK.

Scrapie of sheep and goats is the most common prion disease (or transmissible spongiform encephalopathy, TSE) of mammals and aggregates of abnormal, proteinase-resistant prion protein (PrP(Sc)) are found in all naturally occurring prion diseases. During active surveillance of British sheep for TSEs, 29 201 sheep brain stem samples were collected from abattoirs and analysed for the presence of PrP(Sc). Of these samples, 54 were found to be positive by using an ELISA screening test, but 28 of these could not be confirmed initially by immunohistochemistry. These unconfirmed or atypical cases were generally found in PrP genotypes normally associated with relative resistance to clinical scrapie and further biochemical analysis revealed that they contained forms of PrP(Sc) with a relatively protease-sensitive amyloid core, some resembling those of Nor98 scrapie. The presence of these atypical forms of protease-resistant PrP raises concerns that some TSE disorders of PrP metabolism previously may have escaped identification in the British sheep population.

PMID: 16432036 [PubMed - indexed for MEDLINE]

Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16031-6. Epub 2005 Oct 20.Click here to read Click here to read Links

A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes.

* Le Dur A,

* Beringue V,

* Andreoletti O,

* Reine F,

* Lai TL,

* Baron T,

* Bratberg B,

* Vilotte JL,

* Sarradin P,

* Benestad SL,

* Laude H.

Virologie Immunologie Moleculaires and Genetique Biochimique et Cytogenetique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France.

Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrP(c)), into a misfolded form, abnormal PrP (PrP(Sc)), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrP(Sc) detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrP(Sc) molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrP(ARR) allele (A(136)R(154)R(171)), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.

PMID: 16239348 [PubMed - indexed for MEDLINE]

Nat Clin Pract Neurol. 2006 Jun;2(6):321-9.Click here to read Links

Comment in:

Nat Clin Pract Neurol. 2006 Jun;2(6):287.

Prion infections, blood and transfusions.

* Aguzzi A,

* Glatzel M.

Department of Pathology, Zurich University, Switzerland. adriano.aguzzi@usz.ch

Prion infections lead to invariably fatal diseases of the CNS, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), and scrapie in sheep. There have been hundreds of instances in which prions have been transmitted iatrogenically among humans, usually through neurosurgical procedures or administration of pituitary tissue extracts. Prions have not generally been regarded as blood-borne infectious agents, and case-control studies have failed to identify CJD in transfusion recipients. Previous understanding was, however, questioned by reports of prion infections in three recipients of blood donated by individuals who subsequently developed variant CJD. On reflection, hematogenic prion transmission does not come as a surprise, as involvement of extracerebral compartments such as lymphoid organs and skeletal muscle is common in most prion infections, and prions have been recovered from the blood of rodents and sheep. Novel diagnostic strategies, which might include the use of surrogate markers of prion infection, along with prion removal strategies, might help to control the risk of iatrogenic prion spread through blood transfusions.

PMID: 16932576 [PubMed - indexed for MEDLINE]

Microbiol Immunol. 2006;50(8):565-78.Click here to read Links

Bovine spongiform encephalopathy in Japan: history and recent studies on oxidative stress in prion diseases.

* Onodera T,

* Sakudo A,

* Wu G,

* Saeki K.

Department of Molecular Immunology, School of Agricultural and Life Sciences, University of Tokyo.

With the respect to BSE and vCJD, compliance with the following three rules should strictly be observed: (i) Identification and destruction of all clinically affected cattle; (ii) destruction of all mammalian proteins used in feeding ruminant livestock; and (iii) destruction of all high-risk tissues for use in human consumption. Scrapie in sheep has been documented in the 18th century in the United Kingdom. Through studies of brain-to-brain transmission in the same species in 1935, Cuille et al. successfully isolated the culprit protein from the sheep brain. To transmit said protein from an animal to another, intracerebral inoculation was much more efficient than intraperitoneal or oral route in certain species; i.e. the hamster and mouse. Since discovery of the more efficacious infection route, studies and development of prion research have undergone 4 developmental phases. Phase I depicted discoveries of the pathological features of Creutzfeldt-Jakob disease (CJD) and scrapie with typical lesions of spongiform encephalopathy, while Phase II revealed individual-to-individual (or cross-species) transmissions of CJD, kuru and scrapie in animals. Phases I and II suggested the possible participation of a slow virus in the infection process. In Phase III, Prusiner et al. proposed the 'prion' theory in 1982, followed by the milestone development of the transgenic or gene-targeted mouse in prion research in Phase IV. By strain-typing of prions, CJD has been classified as type 2 or 4 by Parchi et al. and Wadsworth as type-2 or -4 and type-1 or -2, respectively. Wadsworth type 1 is detected in the cerebellum, while Wadsworth type 2 was detected in the prefrontal cortex of 10% of sporadic CJD patients. In 1999, Puoti et al. have reported the co-existence of two types of PrP(res) in a same patient. These reports indicated that PrP(res)-typing is a quantitative rather than a qualitative process, and the relationship between the molecular type and the prion strain is rather complex. In fact, previous findings of Truchot have correlated type-1 distribution with synaptic deposits, and type-2 with arrangement of diffuse deposits in neurons. Although the normal function of PrP(C) has not been fully understood, recent studies have shown that PrP(C) plays a role in copper metabolism, signal transduction, neuroprotection and cell maturation. Further search of PrP(C)-interacting molecules and detailed studies using Prnp(-/-) mice and various type of Prnp(-/-) cell lines under various conditions are the prerequisites in elucidating PrP functions. In the pathogenesis of prion diseases, present results support the hypothesis that 'loss-of-function' of PrP(C) decreases resistance to oxidative stress, and 'gain-of-function' of PrP(Sc) increases oxidative stress. The mechanisms of (i) the 'loss-of-function' of PrP(C) in enhanced susceptibility to oxidative stress and (ii) the 'gain-of-function' of PrP(Sc) in generation of oxidative stress remain to be elucidated, although their mechanisms of action, at least in part, involve the decrease and increase in SOD activity, respectively.

PMID: 16924141 [PubMed - in process]

Folia Neuropathol. 2004;42 Suppl B:109-19. Links

Amyloid plaques in transmissible spongiform encephalopathies (prion diseases).

* Liberski PP.

Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Poland. ppliber@csk.am.lodz.pl

Amyloid plaques are encountered in all cases of kuru and Gerstmann-Straussler-Scheinker disease (GSS) and in some 10-15% of sporadic Creutzfeldt-Jakob disease (sCJD) cases. In variant Creutzfeldt-Jakob (vCJD) the particular type of plaque known as "florid" or "daisy" plaque exists in 100% of cases. By electron microscopy several types of amyloid plaque were delineated, corresponding to those seen by PrP immunohistochemistry. Unicentric "kuru" plaques consisted of stellate arrangements (stars or cores) of amyloid bundles emanating from a dense interwoven centre. A proportion of kuru plaques formed very dense stars, reminiscent of sea urchins in shape. Others presented a looser pattern. Amyloid stars were enveloped by astrocytic processes. High-power electron micrographs revealed that amyloid bundles were concealed within grooves of obscure cellular origin. Interestingly, basement membranes lined with electron-dense material were observed at the periphery of many amyloid plaques of GSS. Dystrophic neurites were seen only rarely. Microglial cells formed a significant part of the amyloid plaques. Occasionally clusters composed of several kuru plaques were found. These were intermediate forms to multi-centric plaques, which consisted of several merging stellate cores. Smaller amyloid deposits surrounded larger cores. In contrast to the kuru plaques, associated with a limited number of dystrophic neurites (DN), numerous such structures were seen at the periphery. The DN were filled with abnormal organelles such as electron-dense bodies, multi-vesicular bodies and multilamellar bodies and thus were indistinguishable from those seen in scrapie and CJD or Alzheimer's disease, except that they did not contain paired helical filaments (PHF). Instead, piled neurofilaments were often detected in the centres of DN. Similar DN were observed but these were not associated with any plaques. The last and, by the same token, the rarest type of plaque was the purely neuritic plaque. These consisted of large areas filled with DN of different sizes and shapes (sometimes bizarre) but not amyloid bundles. Analogously to the kuru and multi-centric plaques, astrocytic processes were observed at the periphery. By means of light microscopy and semi-thin (1 microm) sections discrete PrP-immunopositive plaques were observed (data not shown), in the subependymal region but not in the deep brain neuroparenchyma, in both 263K and 22C-H scrapie-infected hamster brains. These plaques were not discernible by routine haematoxylin and eosin staining. Ultrastructurally, plaques were recognised as areas of low electron density containing haphazardly-oriented fibrils which, when immunogold techniques were applied, were heavily decorated with PrP-conjugated gold particles.

PMID: 16903146 [PubMed - indexed for MEDLINE]

J Neuropathol Exp Neurol. 2006 Apr;65(4):348-57.Click here to read Links

Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo.

* Unterberger U,

* Hoftberger R,

* Gelpi E,

* Flicker H,

* Budka H,

* Voigtlander T.

Institute of Neurology, Medical University of Vienna, Austria.

Prion diseases and Alzheimer disease (AD) share a variety of clinical and neuropathologic features (e.g. progressive dementia, accumulation of abnormally folded proteins in diseased tissue, and pronounced neuronal loss) as well as pathogenic mechanisms like generation of oxidative stress molecules and complement activation. Recently, it was suggested that neuronal death in AD may have its origin in the endoplasmic reticulum (ER). Cellular stress conditions can interfere with protein folding and subsequently cause accumulation of unfolded or misfolded proteins in the ER lumen. The ER responds to this by the activation of adaptive pathways, which are termed unfolded protein response (UPR). The UPR transducer PERK, which launches the most immediate response to ER stress (i.e. the transient attenuation of mRNA translation), and the downstream effector of PERK, eIF2alpha, were shown to be activated in AD. We demonstrate that neither in sporadic nor in infectiously acquired or inherited human prion diseases can the activated forms of PERK and eIF2alpha be detected, except when concomitant neurofibrillary pathology is present; whereas the distribution of phosphorylated PERK correlates with abnormally phosphorylated tau in AD. In brains of scrapie-affected mice and mice infected with sporadic or variant Creutzfeldt-Jakob disease, activated PERK is only very faintly expressed. The lack of prominent activation of the PERK-eIF2alpha pathway in prion diseases suggests that, in contrast to AD, ER stress does not play a crucial role in neuronal death in prion disorders.

PMID: 16691116 [PubMed - indexed for MEDLINE]

Curr Opin Neurol. 1993 Dec;6(6):872-81. Links

Alzheimer's disease and Creutzfeldt-Jakob disease: overlap of pathogenic mechanisms.

* DeArmond SJ.

Department of Pathology, University of California, San Francisco 94143-0506.

This article compares beta-amyloid precursor protein (beta-APP) disorders exemplified by Alzheimer's disease (AD), with prion protein (PrP) disorders, exemplified by Creutzfeldt-Jakob disease (CJD) in humans and scrapie in animals. Although there are obvious differences in the etiology and pathogenesis of both sets of disorders, a remarkable number of similarities exist. Both sets of disorders are characterized clinically by age-related sporadic and familial diseases. In both, an abnormal form of a neuronal membrane protein appears to play a key role in the pathogenesis: beta-A4 peptide in AD and PrPCJD in CJD. Both beta-A4 and PrPCJD are amyloidogenic. Neuritic plaques characteristic of AD were once thought to be exclusively associated with beta-A4 amyloid; however, some pedigrees with familial prion disease produced neuritic plaques with PrP amyloid cores. Finally, beta-APP accumulation in skeletal muscle has been implicated in the age-related muscle disorder, inclusion body myositis. A similar myopathy has recently been discovered in transgenic mice expressing high levels of normal PrP. These similarities suggest that what is learned about one set of disorders may be applicable to the other.

PMID: 7904883 [PubMed - indexed for MEDLINE]

Neurology. 1990 Feb;40(2):226-8. Links

Coexistence of Creutzfeldt-Jakob disease and Alzheimer's disease in the same patient.

* Brown P,

* Jannotta F,

* Gibbs CJ Jr,

* Baron H,

* Guiroy DC,

* Gajdusek DC.

Laboratory of CNS Studies, NINDS, National Institutes of Health, Bethesda, MD 20892.

We report the case of a 73-year-old patient in whom a diagnosis of Creutzfeldt-Jakob disease, suggested by the clinical course, was verified by the neuropathologic finding of widespread spongiform change and astrogliosis, the presence of proteinase-resistant protein in brain extracts, and the experimental transmission of spongiform encephalopathy to primates inoculated with brain tissue. However, neuropathologic examination also revealed a profusion of senile and neuritic plaques and neurofibrillary tangles that reacted with antibody to the amyloid beta-protein characteristic of Alzheimer's disease, but not with antibody to the scrapie amyloid protein characteristic of Creutzfeldt-Jakob disease.

PMID: 2405293 [PubMed - indexed for MEDLINE]

Histopathology. 1995 May;26(5):445-50. Links

Creutzfeldt-Jakob disease with Alzheimer-type A beta-reactive amyloid plaques.

* Barcikowska M,

* Kwiecinski H,

* Liberski PP,

* Kowalski J,

* Brown P,

* Gajdusek DC.

Department of Neuropathology, Medical Research Center, Polish Academy of Sciences, Warsaw.

Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome are classified as transmissible cerebral amyloidoses, in contrast to the non-transmissible amyloidoses of Alzheimer's disease type. While the aetiologies of Creutzfeldt-Jakob disease and Alzheimer's disease and the molecular composition of their amyloids are different, similar basic pathogenetic mechanisms operate in both diseases through synthesis and processing of amyloid precursor proteins, to produce an accumulation of amyloid deposits. We report here a case of Creutzfeldt-Jakob disease exhibiting numerous diffuse A beta immunoreactive plaques, thus presenting features of both Creutzfeldt-Jakob disease and Alzheimer's disease. The existence of such cases underlines the existence of a 'grey' area between the two types of amyloidoses.

PMID: 7657313 [PubMed - indexed for MEDLINE]

J Alzheimers Dis. 2006 Aug;9(3 Suppl):29-33.Click here to read Links

The essential lesion of Alzheimer disease: A surprise in retrospect.

* Ball MJ.

Department of Pathology L-113, Oregon Health & Science University, 3181 SW Sam Jackson Pk. Rd., Portland, OR 97239-3098, USA. Tel.: +1 503 709 3946; Fax: +1 503 452 1229; E-mail: ballm@ohsu.edu or emball@teleport.com.

In the absence of any naturally occurring animal model of Alzheimer's disease (AD), the British conviction in the 1970's that clinicopathological investigations of human cases offered the best approach to unraveling the pathogenesis of AD rapidly influenced clinical neuroscientists, neuropathologists and funding agencies in Canada and the USA. But as with my confreres, years of our quantifying AD lesions in autopsy brains have yet to yield definitive conclusions about what is the most important neuronal abnormality. However, during my elusive search, evidence has been slowly gathered that reactivation of latent Herpes simplex virus, traveling from trigeminal ganglia into neighbouring mesial temporal cortex, might best explain the limbic predilection for and earliest site of neurofibrillary tangle formation. This maturing hypothesis may serendipitously prove to have been a more essential byproduct of generating the voluminous data than all the publications from our laboratory that reflected endless hours of quantitative morphometry.

PMID: 16914842 [PubMed - in process]

J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):413-6.Click here to read Links

Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting.

* Preusser M,

* Strobel T,

* Gelpi E,

* Eiler M,

* Broessner G,

* Schmutzhard E,

* Budka H.

Institute of Neurology, Medical University of Vienna, Vienna, Austria.

We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the dura at the age of 5 years. A clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of disease associated prion protein (PrP(sc)) in a synaptic pattern, and western blot analysis identified PrP(sc) of type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for diagnosis of definite Alzheimer's disease (AD) were met in the absence of neurofibrillar tangles or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, (c) the first description of Alzheimer-type changes in iCJD, and (d) the second case of iCJD in Austria. Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly related to the childhood trauma.

PMID: 16484658 [PubMed - indexed for MEDLINE]

Neuropathology. 2004 Mar;24(1):46-55.Click here to read Links

Coexistence of CJD and Alzheimer's disease: an autopsy case showing typical clinical features of CJD.

* Tsuchiya K,

* Yagishita S,

* Ikeda K,

* Sano M,

* Taki K,

* Hashimoto K,

* Watabiki S,

* Mizusawa H.

Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan. ktsuchi@jcom.home.ne.jp

The present report concerns an autopsy case of CJD showing typical clinical features of CJD. The patient was a Japanese woman without hereditary burden or dementing disorder anamnesis who was 70-years-old at the time of death. She developed gait disturbance at age 68, followed by memory impairment, visual disturbance, and myoclonus. A neurological examination approximately 2 months after the disease onset revealed akinetic mutism, in addition to periodic synchronous discharges on electroencephalogram. Serial neuroradiological examinations disclosed progressive atrophy of the brain. She died of bronchopneumonia 25 months after the disease onset. The brain weighed 560 g (cerebrum 490 g, brainstem with cerebellum 70 g). Macroscopically, neuropathological examination showed prominent atrophy of the cerebrum, caudate nucleus, and cerebellum, in addition to necrosis of the cerebral white matter, compatible with panencephalopathic CJD. Histologically, there was neuronal loss with or without spongiform change in the cerebral cortex, parahippocampal gyrus, amygdala, striatum, pallidum, thalamus, pontine nucleus, and cerebellar granule cells, in addition to diffuse synaptic-type prion staining in the cerebrum and cerebellum. Furthermore, senile plaques, compatible with definite Consortium to establish a registry for Alzheimer's disease rank Alzheimer's disease, and neurofibrillary changes of the limbic system, consistent with stage IV of Braak's classification, were found. Based on these clinicopathological findings and a review of the published literature, it is concluded that there were two forms of coexistence of CJD and Alzheimer's disease in the same patient.

PMID: 15068172 [PubMed - indexed for MEDLINE]

Brain. 1981 Sep;104(3):535-58. Links

The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease.

* Masters CL,

* Gajdusek DC,

* Gibbs CJ Jr.

We have analysed the familial occurrence of Creutzfeldt-Jakob disease (CJD) in 27 families selected from a total of 73 families. Fifteen per cent of all cases of CJD have a family history of disease consistent with autosomal dominant transmission. The onset of disease in familial cases is significantly earlier than in sporadic cases. A maternal effect was not found, nor was there evidence for prenatal vertical transmission of the virus. Temporal and spatial separations between affected members demonstrates that incubation periods ranging at least from one to four decades are to be expected. Affected siblings tend to die at the same age, and not at the same time, which is consistent with some form of vertical transmission (either prenatal or early postnatal), assuming rather uniform incubation periods. CJD occurred in four families in members related by marriage, evidence in favour of horizontal or common source transmission in occasional cases. The familial occurrence of CJD and Alzheimer's disease (AD) were compared using data on 52 families with AD. The age at death and duration of disease in familial AD is greater than in familial CJD. Familial AD also occurs in a pattern of autosomal dominant transmission, without maternal effect. There were four families with AD in which one or more members died from CJD. There were an additional 17 families with AD in which one or more members presented with clinical features resembling CJD. Although virus causing an experimental spongiform encephalopathy was isolated from the brain of two cases of familial AD, most cases of sporadic and familial AD tested failed to cause disease when brain tissue was inoculated into nonhuman primates. The precise mechanism of spread of the virus in familial CJD remains unknown. The results of the present study are consistent with the hypothesis of a genetically inherited susceptibility to infection which is acquired in early infancy or childhood. Other proposed mechanisms such as prenatal vertical transmission or a common environmental source of infection seem less likely.

PMID: 7023604 [PubMed - indexed for MEDLINE]

Neurology. 1980 Sep;30(9):945-50. Links

Evidence for and against the transmissibility of Alzheimer disease.

* Goudsmit J,

* Morrow CH,

* Asher DM,

* Yanagihara RT,

* Masters CL,

* Gibbs CJ Jr,

* Gajdusek DC.

Nonhuman primates were inoculated intracerebrally with brain tissue from 52 patients with confirmed Alzheimer disease (AD) in order to investigate the possibility of an infectious etiology. Animals inoculated with brain tissue from two patients with familial AD developed a spongiform encephalopathy that was indistinguishable from Creutzfeldt-Jakob disease (CJD). Seventeen other cases of AD on test for more than 50 months failed to produce similar changes, and 33 cases have not been incubating for a sufficient period of time to ascertain the presence of a transmissible agent. The initial transmission of spongiform encephalopathy with brain tissue from the two familial cases of AD has not been reproduced and the association between AD and an infectious agent has not yet been demonstrated with any reasonable degree of certainty. The frequent overlap of clinical symptoms of AD and CJD, and the occurrence of cases of CJD and AD in the same families indicate the need for continuing research on the relationship between the two diseases.

PMID: 6775247 [PubMed - indexed for MEDLINE]

Proc Natl Acad Sci U S A. 1988 Jul;85(13):4898-901.Click here to read Click here to read Links

Transmission studies from blood of Alzheimer disease patients and healthy relatives.

* Manuelidis EE,

* de Figueiredo JM,

* Kim JH,

* Fritch WW,

* Manuelidis L.

Section of Neuropathology, Yale University, School of Medicine, New Haven, CT 06510.

The etiology of Alzheimer disease (AD) is unknown. To investigate the transmissibility of AD, the buffy coat of the blood from 11 relatives of AD patients, including 2 with suspicious or early signs of AD, was inoculated intracerebrally into hamsters. In these pilot experiments, 5 individuals produced histologically documented spongiform encephalopathy on primary passage in recipient hamsters. Material from 3 of these positives was serially transmitted in a second passage. The histological alterations observed in the brains of positive hamsters were similar to those seen in experimental Creutzfeldt-Jakob disease (CJD). These transmission results raise the intriguing possibility that CJD-like agents may be involved in at least some forms of AD.

PMID: 3387446 [PubMed - indexed for MEDLINE]

Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7724-8.Click here to read Click here to read Links

A transmissible Creutzfeldt-Jakob disease-like agent is prevalent in the human population.

* Manuelidis EE,

* Manuelidis L.

Yale Medical School, New Haven, CT 06510.

The etiology of most human dementias is unknown. Creutzfeldt-Jakob disease (CJD), a relatively uncommon human dementia, is caused by a transmissible virus-like agent. Molecular markers that are specific for the agent have not yet been defined. However, the infectious disease can be transmitted to rodents from both brain and infected buffy coat (blood) samples. To determine whether human CJD infections are more widespread than is apparent from the low incidence of neurological disease, we attempted to transmit CJD from buffy coat samples of 30 healthy volunteers who had no family history of dementing illness. Primary transmissions from 26 of 30 individuals produced CJD-like spongiform changes in the brains of recipient hamsters at 200-500 days postinoculation. This positive evidence of viremia was found for individuals in all age groups (20-30, 40-50, and 61-71 years old), whereas 12 negatively scored brain samples failed to produce similar changes in hamsters observed for > 900 days in the same setting. We suggest that a CJD agent endemically infects humans but only infrequently produces an infectious dementia. Disease expression is likely to be influenced by several host factors in combination with viral variants that have altered neurovirulence.

PMID: 8356076 [PubMed - indexed for MEDLINE]

Proc Natl Acad Sci U S A. 1987 Feb;84(3):871-5.Click here to read Click here to read Links

Immortality of cell cultures derived from brains of mice and hamsters infected with Creutzfeldt-Jakob disease agent.

* Manuelidis EE,

* Fritch WW,

* Kim JH,

* Manuelidis L.

Isolates from six patients with Creutzfeldt-Jakob disease (CJD) were injected into various strains of hamsters and mice, and the infective agent was propagated. Serially passaged cultures were established from these CJD agent-infected brains and from uninfected control brains. All healthy cultures (21 out of 21) from CJD agent-infected brains became immortal and/or transformed. In contrast only 3 out of 13 normal brain cultures became immortal, and the rest died out with serial propagation in vitro. The fact that permanent cell lines were readily derived from multiple rodent strains and all CJD isolates tested suggests that a transforming capability is an intrinsic property of CJD agents. This conclusion is supported by demonstrations of in vitro cell transformation by CJD infectious brain fractions. Although the molecular mechanism of transformation events associated with the CJD agent is not presently known, a provocative possibility is that the CJD agent has a direct effect on the host genome by mechanisms analogous to those known for slowly oncogenic retroviruses.

PMID: 3543937 [PubMed - indexed for MEDLINE]

PLoS Pathog. 2006 Mar;2(3):e26.Click here to read Click here to read Links

The expanding universe of prion diseases.

* Watts JC,

* Balachandran A,

* Westaway D.

Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases-including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep-have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

PMID: 16609731 [PubMed - in process]

Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3065-70. Epub 2004 Feb 17.Click here to read Click here to read Links

Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt-Jakob disease.

* Casalone C,

* Zanusso G,

* Acutis P,

* Ferrari S,

* Capucci L,

* Tagliavini F,

* Monaco S,

* Caramelli M.

Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna, 148, 10195 Turin, Italy.

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrP(Sc)) of the host-encoded cellular prion protein (PrP(C)). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrP(Sc) fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt-Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called "species barrier" between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrP(Sc) accumulation. In addition, Western blot analysis showed a PrP(Sc) type with predominance of the low molecular mass glycoform and a protease-resistant fragment of lower molecular mass than BSE-PrP(Sc). Strikingly, the molecular signature of this previously undescribed bovine PrP(Sc) was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease.

PMID: 14970340 [PubMed - indexed for MEDLINE]

J Virol. 2005 May;79(9):5259-71.Click here to read Click here to read Links

Transmission barriers for bovine, ovine, and human prions in transgenic mice.

* Scott MR,

* Peretz D,

* Nguyen HO,

* Dearmond SJ,

* Prusiner SB.

Institute for Neurodegenerative Diseases, University of California, San Francisco, 94143-0518, USA.

Transgenic (Tg) mice expressing full-length bovine prion protein (BoPrP) serially propagate bovine spongiform encephalopathy (BSE) prions without posing a transmission barrier. These mice also posed no transmission barrier for Suffolk sheep scrapie prions, suggesting that cattle may be highly susceptible to some sheep scrapie strains. Tg(BoPrP) mice were also found to be susceptible to prions from humans with variant Creutzfeldt-Jakob disease (CJD); on second passage in Tg(BoPrP) mice, the incubation times shortened by 30 to 40 days. In contrast, Tg(BoPrP) mice were not susceptible to sporadic, familial, or iatrogenic CJD prions. While the conformational stabilities of bovine-derived and Tg(BoPrP)-passaged BSE prions were similar, the stability of sheep scrapie prions was higher than that found for the BSE prions but lower if the scrapie prions were passaged in Tg(BoPrP) mice. Our findings suggest that BSE prions did not arise from a sheep scrapie strain like the one described here; rather, BSE prions may have arisen spontaneously in a cow or by passage of a scrapie strain that maintains its stability upon passage in cattle. It may be possible to distinguish BSE prions from scrapie strains in sheep by combining conformational stability studies with studies using novel Tg mice expressing a chimeric mouse-BoPrP gene. Single-amino-acid substitutions in chimeric PrP transgenes produced profound changes in incubation times that allowed us to distinguish prions causing BSE from those causing scrapie.

PMID: 15827140 [PubMed - indexed for MEDLINE]

Neurology. 2006 May 9;66(9):1418-24.Click here to read Links

Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease.

* Landolt HP,

* Glatzel M,

* Blattler T,

* Achermann P,

* Roth C,

* Mathis J,

* Weis J,

* Tobler I,

* Aguzzi A,

* Bassetti CL.

Institute of Pharmacology & Toxicology, University of Zurich, Zurich, Switzerland.

BACKGROUND: The prevalence and characteristics of sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease (sCJD) are poorly understood. METHODS: Seven consecutive patients with definite sCJD underwent a systematic assessment of sleep-wake disturbances, including clinical history, video-polysomnography, and actigraphy. Extent and distribution of neurodegeneration was estimated by brain autopsy in six patients. Western blot analyses enabling classification and quantification of the protease-resistant isoform of the prion protein, PrPSc, in thalamus and occipital cortex was available in four patients. RESULTS: Sleep-wake symptoms were observed in all patients, and were prominent in four of them. All patients had severe sleep EEG abnormalities with loss of sleep spindles, very low sleep efficiency, and virtual absence of REM sleep. The correlation between different methods to assess sleep-wake functions (history, polysomnography, actigraphy, videography) was generally poor. Brain autopsy revealed prominent changes in cortical areas, but only mild changes in the thalamus. No mutation of the PRNP gene was found. CONCLUSIONS: This study demonstrates in sporadic Creutzfeldt-Jakob disease, first, the existence of sleep-wake disturbances similar to those reported in fatal familial insomnia in the absence of prominent and isolated thalamic neuronal loss, and second, the need of a multimodal approach for the unambiguous assessment of sleep-wake functions in these patients.

PMID: 16682677 [PubMed - indexed for MEDLINE]

J Neuropathol Exp Neurol. 2005 Aug;64(8):716-21.Click here to read Links

Accumulation of prion protein in the peripheral nervous system in human prion diseases.

* Lee CC,

* Kuo LT,

* Wang CH,

* Scaravilli F,

* An SF.

Department of Pathology and Laboratory Medicine, Shin-Kong, Wu Ho-Su Memorial Hospital, Taipei Medical University, Taipei, Taiwan.

After the finding that anti-prion antibodies stain sensory and sympathetic ganglia in variant Creutzfeldt-Jakob disease (vCJD), it was suggested that this localization supported the oral route of entry. However, prion accumulation subsequently also appeared in the peripheral nervous system (PNS) in sporadic cases. This study aims at evaluating the extent of prion protein accumulation in the PNS in all clinicopathologic subgroups of the disorder, with the exception of the familial and sporadic forms of fatal insomnia. Patients included 2 vCJD cases, 2 Gerstmann-Straussler-Scheinker (GSS), 2 iatrogenic (iCJD), and 16 sporadic CJD (sCJD) cases. Gasserian (17) and spinal (9), celiac (2) and thoracic sympathetic (one) ganglia, spinal cord and medulla of one vCJD, 2 GSS, one iCJD, and 5 sCJD cases were examined. Immunostained sensory ganglia were seen in both vCJD, both iCJD, one GSS, and 10 sCJD cases; the celiac ganglion was positive in one of two sCJD cases, and the spinal dorsal horn and the medullary sensory nuclei were positive in one patient with vCJD, one with iCJD, and 3 with sCJD. Western blot demonstrated presence of PrP in the gasserian ganglion of one patient with sCJD. Accumulation of prion in ganglia (including autonomic) of the PNS, shared by all subgroups of spongiform encephalopathy, and in the dorsal horns and medullary sensory nuclei, shows that the sensory route is involved in the trafficking of this protein.

PMID: 16106220 [PubMed - indexed for MEDLINE]

Vox Sang. 2006 Oct;91(3):221-30. Links

Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review study.

* Hewitt PE,

* Llewelyn CA,

* Mackenzie J,

* Will RG.

National Blood Service, Colindale Centre, London, UK.

Background and Objectives This paper reports the results to 1 March 2006 of an ongoing UK study, the Transfusion Medicine Epidemiological Review (TMER), by the National CJD Surveillance Unit (NCJDSU) and the UK Blood Services (UKBS) to determine whether there is any evidence that Creutzfeldt-Jakob disease (CJD), including sporadic CJD (sCJD), familial CJD (fCJD), and variant CJD (vCJD) is transmissible via blood transfusion. Materials and Methods Sporadic CJD and fCJD cases with a history of blood donation or transfusion are notified to UKBS. All vCJD cases aged > 17 years are notified to UKBS on diagnosis. A search for donation records is instigated and the fate of all donations is identified by lookback. For cases with a history of blood transfusion, hospital and UKBS records are searched to identify blood donors. Details of identified recipients and donors are checked against the NCJDSU register to establish if there are any matches. Results CJD cases with donation history: 18/31 vCJD, 3/93 sCJD, and 3/5 fCJD cases reported as blood donors were confirmed to have donated labile components transfused to 66, 20, and 11 recipients respectively. Two vCJD recipients have appeared on the NCJDSU register as confirmed and probable vCJD cases. The latter developed symptoms of vCJD 6.5 years and 7.8 years respectively after receiving non-leucodepleted red blood cells (RBCs) from two different donors who developed clinical symptoms approximately 40 and 21 months after donating. A third recipient, given RBC donated by a further vCJD case approximately 18 months before onset of clinical symptoms, had abnormal prion protein in lymphoid tissue at post-mortem (5-years post-transfusion) but had no clinical symptoms of vCJD. CJD cases with history of transfusion: Hospital records for 7/11 vCJD and 7/52 sCJD cases included a history of transfusion of labile blood components donated by 125 and 24 donors respectively. Two recipients who developed vCJD were linked to donors who had already appeared on the NCJDSU register as vCJD cases (see above). No further links were established. Conclusion This study has identified three instances of probable transfusion transmission of vCJD infection, including two confirmed clinical cases and one pre- or sub-clinical infection. This study has not provided evidence, to date, of transmission of sCJD or fCJD by blood transfusion, but data on these forms of diseases are limited.

PMID: 16958834 [PubMed - in process]