The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis.

Glycogen storage disease type III (GSDIII) is a hereditary glycogenosis caused by deficiency of the glycogen debranching enzyme (GDE), an enzyme, encoded by Agl, enabling glycogen degradation by catalyzing alpha-1,4-oligosaccharide side chain transfer and alpha-1,6-glucose cleavage. GDE deficiency causes accumulation of phosphorylase-limited dextrin, leading to liver disorder followed by fatal myopathy. Here, we tested the capacity of the new autophagosomal activator GHF-201 to alleviate disease burden by clearing pathogenic glycogen surcharge in the GSDIII mouse model Agl-/-. We used open field, grip strength, and rotarod tests for evaluating GHF-201's effects on locomotion, a biochemistry panel to quantify hematological biomarkers, indirect calorimetry to quantify in vivo metabolism, transmission electron microscopy to quantify glycogen in muscle, and fibroblast image analysis to determine cellular features affected by GHF-201. GHF-201 was able to improve all locomotion parameters and partially reversed hypoglycemia, hyperlipidemia and liver and muscle malfunction in Agl-/- mice. Treated mice burnt carbohydrates more efficiently and showed significant improvement of aberrant ultrastructural muscle features. In GSDIII patient fibroblasts, GHF-201 restored mitochondrial membrane polarization and corrected lysosomal swelling. In conclusion, GHF-201 is a viable candidate for treating GSDIII as it recovered a wide range of its pathologies in vivo, in vitro, and ex vivo.

Ovariectomy and High Fat-Sugar-Salt Diet Induced Alzheimer's Disease/Vascular Dementia Features in Mice.

While the vast majority of Alzheimer's disease (AD) is non-familial, the animal models of AD that are commonly used for studying disease pathogenesis and development of therapy are mostly of a familial form. We aimed to generate a model reminiscent of the etiologies related to the common late-onset Alzheimer's disease (LOAD) sporadic disease that will recapitulate AD/dementia features. Naïve female mice underwent ovariectomy (OVX) to accelerate aging/menopause and were fed a high fat-sugar-salt diet to expose them to factors associated with increased risk of development of dementia/AD. The OVX mice fed a high fat-sugar-salt diet responded by dysregulation of glucose/insulin, lipid, and liver function homeostasis and increased body weight with slightly increased blood pressure. These mice developed AD-brain pathology (amyloid and tangle pathologies), gliosis (increased burden of astrocytes and activated microglia), impaied blood vessel density and neoangiogenesis, with cognitive impairment. Thus, OVX mice fed on a high fat-sugar-salt diet imitate a non-familial sporadic/environmental form of AD/dementia with vascular damage. This model is reminiscent of the etiologies related to the LOAD sporadic disease that represents a high portion of AD patients, with an added value of presenting concomitantly AD and vascular pathology, which is a common condition in dementia. Our model can, thereby, provide a valuable tool for studying disease pathogenesis and for the development of therapeutic approaches.

Sensory disturbances in Creutzfeldt-Jakob disease.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease characterized by rapidly progressive dementia, motor impairments, and psychiatric symptoms. Sensory disturbances were occasionally reported as well. The study aims to describe the sensory symptoms of the disease. METHODS: The CJD Israeli National Database was screened for patients who presented sensory symptoms throughout the disease course. Symptoms, characteristics, and distribution were reviewed and the demographic and clinical data (sex, etiologies of the disease, age of onset, disease duration, neurological exam finding, tau protein level, EEG and MRI findings) were compared with the demographics and clinical data of CJD without sensory symptoms. Then, the patients with sensory symptoms were divided into patients with symptom distribution consistent with peripheral nervous system (PNS) involvement and central nervous system (CNS) involvement. The demographics and clinical data of the 2 groups were compared. RESULTS: Eighty-four CJD patients with sensory symptoms and 645 CJD patients without sensory symptoms were included in the study. Sensory symptoms were more common in genetic E200K CJD patients (14.6% vs. 5.6% respectively, p = 0.0005) (chi-squared test). Numbness and neuropathic pain were the most common symptoms and distribution of symptoms of "stocking gloves" with decreased deep tendon reflexes suggesting peripheral neuropathy in 44% of the patients. In these patients, the classical EEG findings of Periodic Sharp Wave Complexes were less often found (58% vs. 22%, p = 0.02) (chi-squared test). CONCLUSIONS: Sensory symptoms are more common in E200K patients and often follow peripheral neuropathy distribution that suggests PNS involvement.

Physiological expression of mutated TAU impaired astrocyte activity and exacerbates ß-amyloid pathology in 5xFAD mice.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia in the world. The pathology of AD is affiliated with the elevation of both tau (τ) and ß-amyloid (Aß) pathologies. Yet, the direct link between natural τ expression on glia cell activity and Aß remains unclear. While experiments in mouse models suggest that an increase in Aß exacerbates τ pathology when expressed under a neuronal promoter, brain pathology from AD patients suggests an appearance of τ pathology in regions without Aß. METHODS: Here, we aimed to assess the link between τ and Aß using a new mouse model that was generated by crossing a mouse model that expresses two human mutations of the human MAPT under a mouse Tau natural promoter with 5xFAD mice that express human mutated APP and PS1 in neurons. RESULTS: The new mouse model, called 5xFAD TAU, shows accelerated cognitive impairment at 2 months of age, increased number of Aß depositions at 4 months and neuritic plaques at 6 months of age. An expression of human mutated TAU in astrocytes leads to a dystrophic appearance and reduces their ability to engulf Aß, which leads to an increased brain Aß load. Astrocytes expressing mutated human TAU showed an impairment in the expression of vascular endothelial growth factor (VEGF) that has previously been suggested to play an important role in supporting neurons. CONCLUSIONS: Our results suggest the role of τ in exacerbating Aß pathology in addition to pointing out the potential role of astrocytes in disease progression. Further research of the crosstalk between τ and Aß in astrocytes may increase our understanding of the role glia cells have in the pathology of AD with the aim of identifying novel therapeutic interventions to an otherwise currently incurable disease.

The epidemiological and clinical characteristics of patients with young-onset genetic Creutzfeldt-Jakob disease.

OBJECTIVES: The onset of Creutzfeldt-Jakob disease (CJD) is usually around the age of 60, but younger patients have been described as well. Our study characterizes the demographic and clinical features of young-onset CJD patients. METHODS: The CJD Israeli National Database was reviewed, and the patients were divided into groups of young (<40-year-old) (Y|) and older disease onset (>40-year-old) (O). Each group was further divided into sporadic (sCJD) and genetic (gCJD) patients. Clinical and demographic parameters were compared between the groups. RESULTS: The study included 731 patients (Y- 18 patients, O- 713 patients). MRI showed classical features more often in the older population (O-76.9%, Y-36%, p = 0.006). Rapidly progressive dementia as a presenting feature was more common in the older group (O = 58%, Y = 27.7%, p = 0.019) whereas cerebellar onset (gait instability, dysarthria) was more common in the younger group (O = 6.7%, Y = 27.7%, p = 0.036)). Among gCJD patients, rapidly progressive dementia was commonly seen in older patients (O = 54%, Y = 21% p = 0.008) whereas cerebellar symptoms were seen in young patients (O = 7%, Y = 30% p = 0.01) Typical MRI findings were seen in 37% of young people compared to 87% of older patients (p = 0.002). No significant differences were between young and older patients in the sCJD group. CONCLUSION: Young-onset gCJD patients have unique disease features including less typical brain MRI changes, a lower prevalence of dementia, and a higher prevalence of cerebellar signs at disease onset.

Is There Horizontal Transmission of Creutzfeldt-Jakob Disease?

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (s-CJD) is a rare, fatal neurodegenerative disorder. Familial cases of Creutzfeldt-Jakob disease (f-CJD) due to mutations in the PRNP gene are even rarer around the world; however, in Israel there is a focus of f-CJD patients carrying the E200K mutation. As the number of CJD E200K carriers in Israel is high and increasing, transmission of CJD to normal people was suspected. If such transmission occurs, the incidence of s-CJD would be expected to increase as well, resulting in changes of the ratio of familial/sporadic cases. METHODS: Using data from the National CJD Registry and official statistics on the Israeli population, we studied incidence rates of f-CJD and s-CJD for the period from 1985 to 2018 applying the Surveillance Epidemiology and End Results (SEER) statistical packet developed in the US National Cancer Institute. RESULTS: In total, 621 CJD patients (405 f-CJD and 216 s-CJD) cases are included in the registry. In the cohort of f-CJD patients, the mean age-adjusted annual incidence rate over the abovementioned period was 1.88 ± 0.09 (95% CI: 1.7-2.08) per 1,000,000. In the cohort of s-CJD patients, the mean age-adjusted incidence rate over the same period was 0.93 ± 0.06 (95% CI: 0.81-1.06) per 1,000,000 people. No significant time trends were found over the observation period in either s-CJD or f-CJD. The ratio f-CJD/s-CJD decreases over the observation period from 2.2 to 1.80. CONCLUSION: Israel has a high predominance of f-CJD compared to s-CJD. The mean incidence rate of s-CJD in Israel is similar to most countries. Between 1985 and 2018, the annual age-adjusted incidence rates for both forms of CJD remained stable. Thus, there is no evidence that CJD is transmitted from affected individuals to others.

The Beneficial Effect of Mitochondrial Transfer Therapy in 5XFAD Mice via Liver-Serum-Brain Response.

We recently reported the benefit of the IV transferring of active exogenous mitochondria in a short-term pharmacological AD (Alzheimer's disease) model. We have now explored the efficacy of mitochondrial transfer in 5XFAD transgenic mice, aiming to explore the underlying mechanism by which the IV-injected mitochondria affect the diseased brain. Mitochondrial transfer in 5XFAD ameliorated cognitive impairment, amyloid burden, and mitochondrial dysfunction. Exogenously injected mitochondria were detected in the liver but not in the brain. We detected alterations in brain proteome, implicating synapse-related processes, ubiquitination/proteasome-related processes, phagocytosis, and mitochondria-related factors, which may lead to the amelioration of disease. These changes were accompanied by proteome/metabolome alterations in the liver, including pathways of glucose, glutathione, amino acids, biogenic amines, and sphingolipids. Altered liver metabolites were also detected in the serum of the treated mice, particularly metabolites that are known to affect neurodegenerative processes, such as carnosine, putrescine, C24:1-OH sphingomyelin, and amino acids, which serve as neurotransmitters or their precursors. Our results suggest that the beneficial effect of mitochondrial transfer in the 5XFAD mice is mediated by metabolic signaling from the liver via the serum to the brain, where it induces protective effects. The high efficacy of the mitochondrial transfer may offer a novel AD therapy.

Genetic Creutzfeldt-Jakob disease in Turkish Jews-demographic and clinical features.

BACKGROUND: The largest cluster of genetic Creutzfeldt- Jakob Disease (CJD) exists in Libyan Jews carrying the E200K mutation in the PRNP gene. However, there is another cluster of genetic CJD with E200K mutation in families of Turkish-Jewish origin. AIMS: In this retrospective study, we aim to describe the demographic and clinical features of this population of patients. MATERIAL AND METHODS: The Israeli National CJD database was searched for demographic, clinical, imaging, and laboratory data of genetic CJD patients of Libyan and Turkish ancestry with the E200K mutation. The data of Libyan and Turkish patients were compared with notice similar or different demographic or clinical courses. RESULTS: Four hundred and twenty-three patients with CJD of Libyan (L) ancestry and 27 patients with CJD of Turkish (T) ancestry were identified. There were no significant differences in demographic and clinical data between the two populations (age of onset: T = 62 ± 8.8, L = 60 ± 9.7; age of death: T = 63 ± 8.6, L = 61 ± 9.7; and disease duration: T = 7.8 ± 8.4 months, L = 9.6 ± 13.6 months). Rapidly progressive dementia was the most common presentation in both groups, followed by pure cerebellar onset. The levels of tau protein in CSF did not differ between groups (T = 1290 ± 397.6 pg/ml, L = 1276 ± 594.2 pg/ml). MRI and EEG showed classical CJD features in most patients in both groups. DISCUSSION: The E200K mutation is the most common mutation among gCJD patients and was reported in different ethnical populations, suggesting several independent haplotypes of the mutation. The Turkish-Jew cluster, first described in this study, shares similar demographic and clinical features with the bigger cluster of Libyan-Jews CJD patients. CONCLUSION: E200K gCJD patients of Turkish ancestry share similar demographic and clinical features to patients of Libyan descent, suggesting a common origin of both populations.

Sleeve Gastrectomy Reduces Glycemia but Does Not Affect Cognitive Impairment in Lean 5xFAD Mice.

Obesity and hyperglycemia are risk factors for cognitive decline and for the development of Alzheimer's Disease (AD). Bariatric surgery is an effective treatment for obesity that was shown to improve cognitive decline in obese patients. Bariatric surgery was shown to exert weight loss independent effects on metabolic diseases such as type 2 diabetes. We tested whether sleeve gastrectomy (SG), a common bariatric surgery, can affect the cognitive impairment in lean, normoglycemic female 5xFAD mice, a genetic model for AD. 5xFAD mice and wild-type (WT) littermates underwent SG or sham surgery at the age of 5 months and were tested for metabolic, behavioral, and molecular phenotypes 90 days later. SG led to a reduction in blood glucose levels and total plasma cholesterol levels in 5xFAD mice without inducing weight loss. However, the surgery did not affect the outcomes of long-term spatial memory tests in these mice. Analysis of ß-Amyloid plaques corroborated the behavioral studies in showing no effect of surgery on the molecular phenotype of 5xFAD mice. In conclusion, SG leads to an improved metabolic profile in lean female 5xFAD mice without inducing weight loss but does not affect the brain pathology or behavioral phenotype. Our results suggest that the positive effects of bariatric surgery on cognitive decline in obese patients are likely attributed to weight loss and improvement in obesity sequelae, and not to weight loss independent effects of surgery.

Epidemiological and clinical characteristics of patients with late-onset Creutzfeldt-Jakob disease.

BACKGROUND: Creutzfeldt-Jacob disease (CJD) is a fatal neuro-degenerative disease, characterized by rapid and intense deterioration, mainly cognitive, leading to death. The typical onset of the disease is around the age of 67. PURPOSE: To characterize the demographic and clinical features of the population of CJD patients with late-onset disease. METHODS: In this retrospective study, the Israeli national database of prion diseases was screened for CJD patients with disease age of onset > 80 years between 1960 and 2016. Patient's demographic and clinical data were collected including sex, type of disease (sporadic/ genetic), clinical presentation, lab results including tau protein level, imaging, and EEG characteristics. Then, the clinical and demographic data of patients with late onset (> 80 years) (L) and patients with usual age of onset (< 80 years) (U) were compared. RESULTS: The study included 728 patients, 23 patients (3.3%) with late-onset disease (82.2.4±4 years, range 80-88) and 705 with usual disease onset (61.31 ± 9.47 years, range 34-80). Sporadic CJD was more common in the late-onset group (18/23 patients (78.2%) (L) vs. 256/705 patients (36.3%) (U)) (p = 0.0001, chi-square test). Classical EEG finding of periodic sharp wave activity were seen more often in the late-onset patients (55% (L) vs. 32.5% (U)) (p = 0.05, chi-square test). The rest of the demographic and clinical features were similar in both groups. CONCLUSION: Late- and usual-onset diseases are similar in most of demographic and clinical features suggesting a common disease type with normal distribution of age of onset.

Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism.

This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys ) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

Spatial distribution of abnormal EEG activity in Creutzfeldt-Jakob disease.

OBJECTIVES: Electroencephalogram (EEG) pattern in Creutzfeldt-Jakob disease (CJD) is characterized by diffuse abnormal activity, although lateralization to one hemisphere has been described in the first stages of the disease. This study aimed to determine whether abnormal EEG activity predominantly occurs in anterior versus posterior brain regions. METHODS: As part of a prospective study, the demographics, clinical features and MRI findings of genetic E200K CJD patients were collected. EEG was performed and the recordings reviewed for the typical periodic sharp wave complex (PSWC) and non-specific slow activity. Data were analyzed using the qEEG tool, and the activity in anterior and posterior regions of the brain compared. RESULTS: Eleven genetic E200K CJD patients were included in the study (67% women). The average age was 59.1 ±â€¯8.4 SD years and the average disease duration was 2.4 ±â€¯2.1 months. EEG showed the classic PSWC pattern in 5/11 (45%) of the patients, and slow activity was seen in 9/11 (82%). EEG was normal in 2 patients. PSWC activity was diffuse in 2/5 patients and unilateral in 3/5 patients; slow activity was diffuse in 9 patients. Quantitative analysis of PSWC and slow activity showed no significant difference between anterior and posterior distribution. CONCLUSION: The abnormal EEG activity in CJD is diffuse with no clear spatial predominance in anterior or posterior brain regions.

Cerebrospinal Fluid (CSF) Exchange Therapy with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Cognitive Deficits and Brain Pathology in Alzheimer's Disease Mice.

BACKGROUND: The high complexity of neurodegenerative diseases, including Alzheimer's disease (AD), and the lack of effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. OBJECTIVE: To test the efficacy of 'cerebrospinal fluid (CSF) exchange therapy' in AD-mice. This novel therapeutic approach we recently proposed is based on the exchange of the endogenous pathogenic CSF with a new and healthy one by drainage of the endogenous CSF and its continuous replacement with artificial CSF (aCSF) enriched with secretions from human mesenchymal stem cells (MSCs). METHODS: We treated AD-mice (amyloid-beta injected) with MSC secretions-enriched-aCSF using an intracerebroventricular CSF exchange procedure. Cognitive and histological analysis were performed. RESULTS: We show that the MSC secretions enriched CSF exchange therapy improved cognitive performance, paralleled with increased neuronal counts (NeuN positive cells), reduced astrocytic burden (GFAP positive cells), and increased cell proliferation and neurogenesis (Ki67 positive cells and DCX positive cells) in the hippocampus. This beneficial effect was noted on days 5-10 following 3-consecutive daily exchange treatments (3 hours a day). A stronger effect was noted using a more prolonged CSF exchange protocol (3-consecutive daily exchange treatments with 3 additional treatments twice weekly), with cognitive follow-up performed as early as 2-3 days after treatment. Some increase in hippocampal cell proliferation, but no change in the other histological parameters, was noticed when performing CSF exchange therapy using unenriched aCSF relative to untreated AD-mice, yet smaller than with the enriched aCSF treatment. CONCLUSION: These findings point to the therapeutic potential of the CSF exchange therapy using MSC secretions-enriched aCSF in AD, and might be applied to other neurodegenerative and dementia diseases.

Familial Creutzfeldt-Jakob disease homozygous to the E200K mutation: clinical characteristics and disease course.

OBJECTIVE: To characterize the demographic, clinical features and disease course of familial Creutzfeldt-Jakob disease (fCJD) patients homozygous to the E200K mutation. METHODS: The Israeli National CJD Database was screened for patients homozygous to the E200K mutation. Patients' demographic data, clinical presentation and neurological findings, tau protein levels in the cerebrospinal fluid (CSF) and EEG, were assessed. RESULTS: Ten homozygous E200K patients were identified (80% males). Average age of onset was 47.5 ± 6.1 years (range 40-56) and the average age of death was 49.3 ± 7. 7 years (range 42-63) with average disease duration of 27.7 ± 9.7 months (range 2-97). Initial clinical presentation included behavioral change in 4/10 patients, cognitive decline in 3/10 patients and focal neurological deficits in 2/10 patients. Throughout the disease course, the clinical signs in descending order of prevalence included cerebellar (70%), brainstem (60%), extrapyramidal (50%), pyramidal (50%), frontal lobe signs (30%), and disturbances of ocular motility (30%) Compared to the 228 heterozygous E200K fCJD patients, the 10 homozygous patients were significantly younger at disease onset (47.5 vs 59.7 years, p < 0.001), had a longer disease duration (27.7 vs 8.5 months, p < 0.001) and presented more frequently with behavioral changes as initial manifestation (4/10 vs. 34/228, p = 0.05). CONCLUSIONS: Homozygous E200K fCJD patients are characterized by a relatively younger age of onset and longer disease duration. Behavioral changes as a presenting symptom were more common in homozygous patients and cerebellar dysfunction was the most common neurological manifestation throughout the disease course.

Author Correction: Brain targeting of 9c,11t-Conjugated Linoleic Acid, a natural calpain inhibitor, preserves memory and reduces Aß and P25 accumulation in 5XFAD mice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Brain targeting of 9c,11t-Conjugated Linoleic Acid, a natural calpain inhibitor, preserves memory and reduces Aß and P25 accumulation in 5XFAD mice.

Deregulation of Cyclin-dependent kinase 5 (CDK5) by binding to the activated calpain product p25, is associated with the onset of neurodegenerative diseases, such as Alzheimer's disease (AD). Conjugated Linoleic Acid (CLA), a calpain inhibitor, is a metabolite of Punicic Acid (PA), the main component of Pomegranate seed oil (PSO). We have shown recently that long-term administration of Nano-PSO, a nanodroplet formulation of PSO, delays mitochondrial damage and disease advance in a mouse model of genetic Creutzfeldt Jacob disease (CJD). In this project, we first demonstrated that treatment of mice with Nano-PSO, but not with natural PSO, results in the accumulation of CLA in their brains. Next, we tested the cognitive, biochemical and pathological effects of long-term administration of Nano-PSO to 5XFAD mice, modeling for Alzheimer's disease. We show that Nano-PSO treatment prevented age-related cognitive deterioration and mitochondrial oxidative damage in 5XFAD mice. Also, brains of the Nano-PSO treated mice presented reduced accumulation of Aß and of p25, a calpain product, and increased expression of COX IV-1, a key mitochondrial enzyme. We conclude that administration of Nano-PSO results in the brain targeting of CLA, and suggest that this treatment may prevent/delay the onset of neurodegenerative diseases, such as AD and CJD.

Mitochondrial Transfer Ameliorates Cognitive Deficits, Neuronal Loss, and Gliosis in Alzheimer's Disease Mice.

Pathogenesis of neurodegenerative diseases involves dysfunction of mitochondria, one of the most important cell organelles in the brain, with its most prominent roles in producing energy and regulating cellular metabolism. Here we investigated the effect of transferring active intact mitochondria as a potential therapy for Alzheimer's disease (AD), in order to correct as many mitochondrial functions as possible, rather than a mono-drug related therapy. For this purpose, AD-mice (amyloid-ß intracerebroventricularly injected) were treated intravenously (IV) with fresh human isolated mitochondria. One to two weeks later, a significantly better cognitive performance was noticed in the mitochondria treated AD-mice relative to vehicle treated AD-mice, approaching the performance of non-AD mice. We also detected a significant decrease in neuronal loss and reduced gliosis in the hippocampus of treated mice relative to untreated AD-mice. An amelioration of the mitochondrial dysfunction in brain was noticed by the increase of citrate-synthase and cytochrome c oxidase activities relative to untreated AD-mice, reaching activity levels of non-AD-mice. Increased mitochondrial activity was also detected in the liver of mitochondria treated mice. No treatment-related toxicity was noted. Thus, IV mitochondrial transfer may possibly offer a novel therapeutic approach for AD.

The association of quantitative EEG and MRI in Creutzfeldt-Jakob Disease.

INTRODUCTION: Previous studies showed concordance between the typical Periodic Sharp Wave Complex (PSWC) activity in EEG of Creutzfeldt-Jakob Disease (CJD) patients and the MRI findings, while the concordance with slow activity in EEG is less established. The aim of this study was to better characterize the association between MRI findings and EEG changes using quantitative EEG (qEEG) analysis. METHODS: The demographics, clinical features, and the MRI findings of 12 familial E200K patients with CJD were gathered. EEG test was done and reviewed for the typical PSWC and for the non-specific slow activity. A possible association between the MRI findings and the EEG activity was examined. Then, EEG was analyzed using qEEG tool, and the association between the qEEG finding and the MRI was examined. RESULTS: Twelve patients were included in the study (67% women). Cortical MRI lesions finding were seen in 6/12 (50%) of the patients, and deep gray mater lesions were seen in 8/12 patients (67%). EEG showed the classic PSWC in 6/12 (50%) of the patients where slow activity was seen in 10/12 (83%). Slow activity and cortical MRI findings were associated in only 2/6 (33%) where deep gray matter findings and the slow activity had concordance of 4/8 (50%). qEEG analysis improved this concordance between slow activity and cortical findings to 3/6 (50%) and with the deep gray matter findings to 5/8 (63%). CONCLUSIONS: Quantitative EEG analysis modesty but not significantly, improves the association of EEG slow activity in familial E200K CJD patients with MRI findings.

Cerebrospinal Fluid (CSF) Exchange with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Experimental Autoimmune Encephalomyelitis.

The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination of pathogenic agents from the CNS and, in parallel, its enrichment with an array of neuroprotective substances, using a "cerebrospinal fluid (CSF) exchange" procedure, in which endogenous (pathogenic) CSF is removed and replaced by artificial CSF (aCSF) enriched with secretions of human mesenchymal stem cells (MSCs). MSCs produce a variety of neuroprotective agents and have shown beneficial effects when cells are transplanted in animals and patients with CNS diseases. Our data show that MSCs grown in aCSF secrete neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant agents; moreover, MSC-secretions-enriched-aCSF exerts neuroprotective and immunomodulatory effects in neuronal cell lines and spleen lymphocytes. Treatment of experimental-autoimmune-encephalomyelitis (EAE) mice with this enriched-aCSF using an intracerebroventricular (ICV) CSF exchange procedure ("CSF exchange therapy") caused a significant delay in the onset of EAE and amelioration of the clinical symptoms, paralleled by a reduction in axonal damage and demyelination. These findings point to the therapeutic potential of the CSF exchange therapy using MSC-secretions-enriched-aCSF in inflammatory/degenerative diseases of the CNS.

Exposure to 3-Nitropropionic Acid Mitochondrial Toxin Induces Tau Pathology in Tangle-Mouse Model and in Wild Type-Mice.

Oxidative stress, particularly of mitochondrial origin, plays an important role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and other tauopathies. Controversies regarding the responses of tau phosphorylation state to various stimuli causing oxidative stress have been reported. Here we investigated the effect of 3-nitropropionic acid (3NP), a mitochondrial toxin which induces oxidative stress, on the tangle-pathology in our previously generated double mutant (E257T/P301S, DM) -Tau-tg mice and in WT-mice. We detected an increase in tangle pathology in the hippocampus and cortex of the DM-Tau-tg mice following exposure of the mice to the toxin, as well as generation of tangles in WT-mice. This increase was accompanied with alterations in the level of the glycogen synthase kinase 3ß (GSK3ß), the kinase which phosphorylates the tau protein, and in the phosphorylation state of this kinase. A response of microglial cells was noticed. These results point to the involvement of mitochondrial dysfunction in the development of the tangle-pathology and may suggest that interfering with mitochondrial dysfunction may have an anti-tangle therapeutic potential.