Neural cell engraftment therapy for sporadic Creutzfeldt-Jakob disease restores neuroelectrophysiological parameters in a cerebral organoid model.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is a fatal neurodegenerative disease with currently no treatment options. Stem cell therapy for neurodegenerative diseases is emerging as a possible treatment option. However, while there are a few clinical trials for other neurodegenerative disorders such as Parkinson's disease, prion disease cell therapy research has so far been confined to animal models. METHODS: Here, we use a novel approach to study cell therapies in sCJD using a human cerebral organoid model. Cerebral organoids can be infected with sCJD prions allowing us to assess how neural precursor cell (NPC) therapy impacts the progression of sCJD. After 90 days of sCJD or mock infection, organoids were either seeded with NPCs or left unseeded and monitored for cellular composition changes, prion infection parameters and neuroelectrophysiological function at 180 days post-infection. RESULTS: Our results showed NPCs integrated into organoids leading to an increase in neuronal markers and changes in cell signaling irrespective of sCJD infection. Although a small, but significant, decrease in protease-resistant PrP deposition was observed in the CJD-infected organoids that received the NPCs, other disease-associated parameters showed minimal changes. However, the NPCs had a beneficial impact on organoid function following infection. sCJD infection caused reduction in neuronal spike rate and mean burst spike rate, indicative of reduced action potentials. NPC seeding restored these electrophysiological parameters to the uninfected control level. CONCLUSIONS: Together with the previous animal studies, our results support that cell therapy may have some functional benefit for the treatment of human prion diseases.

Enfermedades por priones humanas. Una revisión general / Human prion diseases: An overview

Las enfermedades por priones constituyen un grupo de enfermedades neurodegenerativas, cuyo agente causal es una proteína normal del cerebro (PrP) que se agrega en una conformación anómala. La proteína anormal, conocida como prion (PrPSc), tiene la propiedad de autopropagarse, induciendo la plegadura anómala de la proteína normal PrP. Estas enfermedades se presentan de manera esporádica, por transmisión genética, o de forma adquirida por ingesta de carne contaminada con priones o por exposición iatrógena. Su diagnóstico resulta difícil. La utilización de exploraciones complementarias de alta sensibilidad y especificidad, como la resonancia magnética o la RT-QuIC, facilitan su diagnóstico. El diagnóstico definitivo se establece por el estudio histopatológico de muestras de tejidos. Actualmente, no se dispone de ningún tratamiento que modifique el curso de la enfermedad, pero su diagnóstico precoz es fundamental para planificar los cuidados del enfermo, adoptar las medidas de prevención necesarias y el consejo genético (AU)

Prion diseases are a group of neurodegenerative diseases. The disease-causing agent is a protein (PrP), that is normally produced in the nervous system, aggregated in an abnormal form. The abnormal protein, known as prion (PrPSc), is capable of self-propagation promoting the misfolding of the normal protein (PrP). These conditions can be acquired sporadically, genetically, or infectiously either by eating meat contaminated with prions or from iatrogenic exposure. The diagnosis of these diseases is often challenging. The use of highly sensitive and specific diagnostic tools, such as MRI and RT-QuIC, may aid in the diagnosis. Neuropathological examination of brain tissue ensures a definite diagnosis. At present, no treatment significantly improves the course of prion diseases; however, an early diagnosis is of paramount importance for patient care decision planning, infection control purposes, and genetic counseling (AU)

Developing neuropalliative care for sporadic Creutzfeldt-Jakob Disease.

We aimed to identify targets for neuropalliative care interventions in sporadic Creutzfeldt-Jakob disease by examining characteristics of patients and sources of distress and support among former caregivers. We identified caregivers of decedents with sporadic Creutzfeldt-Jakob disease from the University of California San Francisco Rapidly Progressive Dementia research database. We purposively recruited 12 caregivers for in-depth interviews and extracted associated patient data. We analysed interviews using the constant comparison method and chart data using descriptive statistics. Patients had a median age of 70 (range: 60-86) years and disease duration of 14.5 months (range 4-41 months). Caregivers were interviewed a median of 22  (range 11-39) months after patient death and had a median age of 59 (range 45-73) years. Three major sources of distress included (1) the unique nature of sporadic Creutzfeldt-Jakob disease; (2) clinical care issues such as difficult diagnostic process, lack of expertise in sporadic Creutzfeldt-Jakob disease, gaps in clinical systems, and difficulties with end-of-life care; and (3) caregiving issues, including escalating responsibilities, intensifying stress, declining caregiver well-being, and care needs surpassing resources. Two sources of support were (1) clinical care, including guidance from providers about what to expect and supportive relationships; and (2) caregiving supports, including connection to persons with experience managing Creutzfeldt-Jakob disease, instrumental support, and social/emotional support. The challenges and supports described by caregivers align with neuropalliative approaches and can be used to develop interventions to address needs of persons with sporadic Creutzfeldt-Jakob disease and their caregivers.

Delay of gCJD aggravation in sick TgMHu2ME199K mice by combining NPC transplantation and Nano-PSO administration.

gCJD is a fatal late-onset neurodegenerative disease linked to mutations in the PRNP gene. We have previously shown that transplantation of neural precursor cells (NPCs), or administration of a nanoformulation of pomegranate seed oil (Nano-PSO, GranaGard), into newborn asymptomatic TgMHu2ME199K mice modeling for E200K gCJD significantly delayed the advance of clinical disease. In the present study, we tested the individual and combined effects of both treatments in older and sick TgMHu2ME199K mice. We show that while transplantation of NPCs at both initial (140 days) and advance clinical states (230 days) arrested disease progression for about 30 days, after which scores rapidly climbed to those of untreated Tgs, administration of Nano-PSO to transplanted TgMHu2ME199K mice resulted in detention of disease advance for 60-80 days, followed by a slower disease progression thereafter. Pathological examinations demonstrated the combined treatment extended the survival of the transplanted NPCs, and also increased the generation of endogenous stem cells. Our results suggest that administration of Nano-PSO may increase the beneficial effects of NPCs transplantation.

Understanding Creutzfeldt-Jackob disease from a viewpoint of amyloidogenic evolvability.

Creutzfeldt-Jackob disease (CJD), the most common human prion disorder, is frequently accompanied by ageing-associated neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. Although cross-seeding of amyloidogenic proteins (APs), including amyloid ß and α-synuclein, may be critical in the co-morbidity of neurodegenerative disorders, the direct interaction of APs with prion protein (PrP), the central molecule involved in the pathogenesis of CJD, is unlikely. Currently, the nature of this biological interaction and its significance remain obscure. In this context, the objective of the present study is to discuss such interactions from the perspective of amyloidogenic evolvability, a putative function of APs. Hypothetically, both hereditary- and sporadic CJD might be attributed to the role of PrP in evolvability against multiple stressors, such as physical stresses relevant to concussions, which might be manifest through the antagonistic pleiotropy mechanism in ageing. Furthermore, accumulating evidence suggests that PrP- and other APs evolvability may negatively regulate each other. Provided that increased APs evolvability might be beneficial for acquired CJD in young adults, a dose-reduction of α-synuclein, a natural inhibitor of αS aggregation, might be therapeutically effective in upregulating APs evolvability. Collectively, a better understanding of amyloidogenic evolvability may lead to the development of novel therapies for CJD.

Prion Diseases: actual clinical and diagnostic aspects

Recently, the problem of neurodegenerative diseases in the medical community has become increasingly relevant. This is due to many factors: from insufficiently studied mechanisms of development of some nosological units to low awareness of medical workers. Among neurodegenerative diseases in humans, prions constitute a very specific group, which are infectious protein particles with a unique morphological structure and capable of causing a number of incurable diseases. Despite years of research, no optimal remedy has yet been found to treat them. This review examines the already studied aspects of prion diseases as a class, including small historical background, features of ethiology, pathogenesis, course and outcome of the most common of them, as well as existing research on experimental methods of diagnostics, treatment and prevention of prion infections.

Young-onset sporadic Creutzfeldt-Jakob disease with atypical phenotypic features: a case report.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease, with a mean survival of 6 months, is duly considered among the most fatal neurological disorders. Rapidly progressive dementia with multi-axial involvement of the nervous system is the known presentation. Although, the peak age at onset is between sixth and eighth decades, cases of young-onset sporadic Creutzfeldt-Jakob disease have also been reported in the literature. Interestingly, these young-onset cases were reported to have some features distinct from their older age group counterparts, such as slower progression as well as longer duration of illness, dominance of psychiatric manifestations at the onset, and relatively less prevalence of radiological and electroencephalographic abnormalities. CASE PRESENTATION: We describe here the case of a 42-year-old Asian woman from India who presented with cerebellar ataxia, pyramidal and extrapyramidal involvement, followed by rapidly progressive dementia along with myoclonus, all within a span of 1 month. Probable infective, metabolic, autoimmune, and paraneoplastic etiologies were ruled out. Magnetic resonance imaging of her brain revealed bilateral caudate nucleus hyperintensity in T2/fluid-attenuated inversion recovery sequence. Diffusion-weighted imaging revealed bilateral caudate and putaminal diffusion restriction plus ribbon pattern in bilateral parieto-occipital and insular cortex. Serial electroencephalography revealed diffuse slowing of background activity along with triphasic waves in short periodic interval. Cerebrospinal fluid was tested positive for 14-3-3 protein. Based on these findings, a diagnosis of sporadic Creutzfeldt-Jakob disease was made. CONCLUSION: Our patient represents an atypical clinical situation as she is much younger than the usual presentation of Creutzfeldt-Jakob disease and it progressed far too rapidly. Cognitive decline came late in the temporal sequence of clinical events; rather, the onset was dominated by features consistent with cerebellar ataxia and basal ganglia involvement. The presence of magnetic resonance imaging abnormality and electroencephalography changes are other rare findings in young-onset sporadic Creutzfeldt-Jakob disease.

Enfermedad de Creutzfeldt-Jakob esporádica de evolución atípica en paciente anciano / An atypical outcome of sporadic Creutzfeldt-Jakob disease in an elderly patient

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Symptomatic treatment, care, and support of CJD patients.

Prion diseases (e.g., Creutzfeldt-Jakob disease) are rapidly progressive neurodegenerative diseases that are invariably fatal. Diagnosing prion disease can be difficult and can lead to frustration. There is no currently available disease-altering treatment for prion diseases and the care and management of affected patients are directed towards symptomatic relief and quality of life. In this chapter, we highlight the many unique challenges of prion disease and how they affect care and management strategies. Symptomatic treatment follows many of the same principles observed in geriatric and/or hospice care, with some important differences due to disease-specific characteristics. We provide an overview of pharmacologic and nonpharmacologic strategies for managing symptoms of prion disease. Education and psychosocial support are also very important in managing patients and families affected by the illness and are discussed in detail. Readers of this chapter will understand the context of caring for a patient with prion disease and will be supplied with practical tools for managing symptoms and educating other healthcare personnel and caregivers. Additional resources for assistance in the care of prion disease patients are also discussed.

Nonopportunistic infection leading to rapidly progressive dementia in a patient with HIV/AIDS: A case report.

RATIONALE: Cognitive dysfunction is a common presenting symptom in patients with HIV/AIDS. It is usually directly associated with HIV infection or due to opportunistic infection. Rapidly progressive dementia, however, is rarely observed in acute HIV infection or during immune reconstitution. Recently, a case of Creutzfeld-Jakob disease (CJD) has been reported in a patient with chronic HIV infection. The incidence of CJD is not known to be increased among immunocompromised patients. PATIENT CONCERNS: We here report the case of a 59-year-old male patient with a recent diagnosis of HIV/AIDS and Pneumocystis jiroveci pneumonia presenting with secondary behavioral changes and disorientation. Over the course of several weeks, progressive dementia developed characterized by apraxia, gait ataxia, and mutism. DIAGNOSES: After the exclusion of common HIV-associated neurologic conditions, the clinical course as well as findings on electroencephalogram (EEG), magnetic resonance imaging (MRI), and a positive 14-3-3 assay converged into a probable diagnosis of CJD. The diagnosis was later confirmed histopathologically. OUTCOMES: Palliative care was provided, and the patient passed away within 2 months of symptom onset. LESSONS: HIV/AIDS is an important stratifying condition during the work-up of many clinical syndromes including encephalopathy but may prematurely exclude important differential diagnoses. Non-opportunistic etiologies have to be considered as part of a secondary workup as this case of concomitant AIDS and CJD demonstrates. Rapidly progressive dementia should be distinguished from delirium as early as possible in order to be able to choose the correct diagnostic pathway. Despite the common occurrence of neurologic syndromes in the setting of immunodeficiency, an analytical diagnostic approach is advisable to minimize diagnostic bias.

Amyloid-ß accumulation in the CNS in human growth hormone recipients in the UK.

Human-to-human transmission of Creutzfeldt-Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Aß) protein associated with Alzheimer's disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Aß accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Aß, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Aß seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Aß and give insights into the possibility of iatrogenic transmission of AD and CAA.

CJD mimics and chameleons.

Rapidly progressive dementia mimicking Creutzfeldt-Jakob disease (CJD) is a relatively rare presentation but a rewarding one to become familiar with, as the potential diagnoses range from the universally fatal to the completely reversible. Patients require urgent decisions about assessment and investigation and have quickly evolving needs for treatments and support, through symptom management and end-of-life care in most cases. We have based this pragmatic review on the experiences of a specialist prion referral centre in the UK, which, unsurprisingly, is strongly biased towards seeing patients with CJD. Cases eventually proven not to have prion disease might be described as 'CJD-mimics'; being referred from UK neurologists, these are the most challenging cases. CJD in its classical presentation is very rarely mimicked; however, it is highly heterogeneous, and atypical forms can mimic virtually all common neurodegenerative syndromes. Warning features of a mimic include generalised seizures, hyponatraemia, fever, a facial movement disorder, a normal neurological examination and a modestly rapid presentation. Contrast-enhancing lesions or MRI signal hyperintensity outside the striatum, thalamus or cortex and a cerebrospinal fluid pleocytosis are key investigation pointers to a CJD mimic.

Combined Creutzfeldt-Jakob/ Alzheimer's Disease Cases are Important in Search for Microbes in Alzheimer's Disease.

The question whether Alzheimer's disease is infectious as brought up in the recent editorial published in the Journal of Alzheimer's Disease is complicated by the controversy whether the causal agent is a microbe or a misfolded host protein (amyloid). The replicating amyloid (prion) theory, based upon data from studies of Creutzfeldt-Jakob disease (CJD) and other transmissible spongiform encephalopathies (TSEs), has been challenged since the prion can be separated from TSE infectivity, and spiroplasma, a wall-less bacterium, has been shown to be involved in the pathogenesis of CJD. Further support for a microbial cause for AD comes from occurrence of mixed CJD/AD cases involving up to 15% of AD brains submitted to brain banks. The association of CJD with AD suggests a common etiology rather than simply being a medical curiosity. A co-infection with the transmissible agent of CJD, which we propose to be a Spiroplasma sp., would explain the diversity of bacteria shown to be associated with cases of AD.

Enfermedad de Creutzfeldt-Jakob: a propósito de un caso / Creutzfeldt-Jakob disease: a clinical case

Presentamos un caso clínico diagnosticado de enfermedad de Creutzfeldt-Jakob. En su evolución, inicialmente el paciente presentó trastorno cognitivo y de conducta a lo que se añadió de forma progresiva trastornos de la coordinación motora del tipo de ataxia cerebelosa, dificultades en la elaboración del lenguaje y mioclonías en extremidad superior derecha, con empeoramiento progresivo. Estudiado durante el ingreso en el Hospital Universitario Marqués de Valdecilla (HUMV) las pruebas complementarias no presentaban alteraciones de interés. Con la impresión diagnóstica de prionopatía el paciente continuó estudios con fines diagnósticos y fue seguido en su domicilio por parte de la unidad de cuidados paliativos en coordinación con su equipo de atención primaria y servicio de neurología. En la evolución se añadió cuadro convulsivo en extremidad superior derecha y dolor. Tratados por vía subcutánea (sc) con midazolam y morfina, respectivamente a dosis bajas con buen control tanto del dolor como de las mioclonías y convulsiones. Ante el empeoramiento del cuadro y en la situación de agonía, en consenso con la familia y el equipo de cuidados paliativos el paciente fue sedado con midazolam, falleciendo a los 2 días. La necropsia confirmó el diagnóstico de enfermedad de Creutzfeldt-Jakob esporádica

The clinical case is presented of a patient diagnosed with Creutzfeldt-Jakob disease. During its course, the patient initially presented with cognitive and conduct disorders, to which were progressively added, cerebellar ataxia type motor coordination disorders, difficulties in the expression of language, and myoclonus in the upper right extremity with progressive worsening. The complementary tests performed during admission in the Marqués de Valdecilla University Hospital (HUMV) were normal. With the diagnostic impression of prionopathy, further studies are continuing for diagnostic purposes, and he was followed up at home by the Palliative Care Unit in coordination with his Primary Care Team and Neurology Service. A convulsive episode in right upper extremity and pain was also observed during the course of the disease, which was treated subcutaneously with midazolam and morphine, respectively at low doses with good control of both the pain and the myoclonus and convulsions. Due to the worsening of the clinical picture and in the situation of agony, and in consensus with the family and the palliative care team the patient was sedated with midazolam, and died two days after. The autopsy confirmed the diagnosis of sporadic Creutzfeldt-Jakob disease

Preserved regional cerebral blood flow in the occipital cortices, brainstem, and cerebellum of patients with V180I-129M genetic Creutzfeldt-Jakob disease in serial SPECT studies.

Creutzfeldt-Jakob disease (CJD) with a causative point mutation of valine to isoleucine at codon 180 (V180I) is one of the major types of genetic CJD (gCJD) in Japan. V180I gCJD is rarely accompanied by a family history, and its clinical characteristics include late-onset, long disease duration, and edematous cortical hyperintensity in diffusion, fluid attenuate inversion and T2-weighted MRI. We performed serial imaging with single-photon emission computed tomography (SPECT) and MRI in three V180I gCJD cases over long-term observation. All cases were characterized by progressive dementia, parkinsonism, and the absence of cerebellar signs or cortical visual dysfunction in their clinical courses. Moreover, during the end-stage, SPECT findings showed preserved regional cerebral blood flow (rCBF) in the occipital cortices, brainstem, and cerebellum. Similarly, no apparent atrophy or increased signal intensities were observed in MRI images of the occipital and cerebellar regions. In conclusion, we report a decrease in rCBF predominantly in the frontal and temporal cortices during the early-stage, which became more widespread as the disease progressed. Importantly, rCBF was preserved in the occipital cortices, brainstem, and cerebellar regions until the end-stage, which may be distinct to V180I gCJD cases.