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Adult polyglucosan body disease (APBD) is a rare glycogenosis manifesting progressive spastic paraparesis, sensorimotor polyneuropathy and neurogenic bladder. Misdiagnosis of APBD may lead to unnecessary investigations and to potentially harmful therapeutic interventions. To examine the frequency of misdiagnosis of APBD, we retrospectively reviewed the clinical data of 30 patients diagnosed between 1991 and 2013. Diagnosis was based on the combination of typical clinical and imaging findings, reduced glycogen branching enzyme activity, and the presence of p.Y326S GBE1 mutation. Initial symptoms started in the 5th-6th decade with bladder dysfunction (47 %), gait problems (33 %) or both. Diagnosis of APBD was delayed by 6.8 (±4.8) years. Consistent signs at diagnosis were spasticity in the legs (93 %), decreased or absent ankle reflexes (100 %), bilateral extensor plantar response (100 %) and distal sensory deficit (80 %). Nerve conduction study showed invariable sensorimotor polyneuropathy, and MRI demonstrated cervical spinal cord atrophy (100 %) and leukoencephalopathy (97 %). All 30 patients were initially misdiagnosed. Common misdiagnoses included cerebral small vessel disease (27 %), multiple sclerosis (17 %), amyotrophic lateral sclerosis (17 %) and peripheral neuropathies (20 %). Consequently, 27 % received inappropriate therapy. In addition, lower urinary tract symptoms in 60 % of men were attributed solely to prostatic disorders but did not respond to medical treatment or prostatectomy. These findings suggest that despite limited clinical variability, APBD is invariably misdiagnosed and patients are often mistreated. Physicians' unfamiliarity with the typical clinical and imaging features of APBD appears as the main reason for misdiagnosis.

When studying a rare or orphan disease, we hope to shed light on more prevalent syndromes. Neuromyelitis optica (NMO), also known as Devic's disease, is a rare disease with a prevalence of about 4 in 100,000. Since 2005 when the anti-Aquaporin 4 (AQP4) NMO autoantibody was discovered by Lennon's group at the Mayo clinic, an enormous amount of data have been acquired on the pathogenesis of the disease. A review of the literature showed 47 relevant publications in 2004, compared with 353 in 2013. The auto-antigen AQP4 is expressed on the astrocytic foot processes suggesting a role for astrocytes in the pathogenesis of the disease. However, the astrocytes might play a more active role than has previously been suggested in the immune cascade of NMO pathology. Here we will review epidemiological, clinical diagnostic and therapeutic aspects of NMO and highlight the possible role of astrocytes as major direct and indirect players in the pathogenesis of NMO and related CNS inflammatory diseases.

Tumefactive demyelination (TD) is a solitary cerebral demyelinating lesion clinically and radiologically mimicking brain tumors. It can occur in isolation or may be rarely associated with other demyelinating diseases. The underlying pathogenic mechanisms are unknown. We present the first report of TD following in-vitro fertilization (IVF) in a 36-year-old healthy woman who developed subacute right hemiparesis shortly after a scheduled IVF cycle. Evaluation revealed left hemispheric space-occupying lesion pathologically diagnosed as TD. Treatment with intravenous methylprednisolone promptly resulted in a clinical and radiological improvement maintained thereafter. This report confirms and expands the spectrum of inflammatory demyelinating conditions associated with IVF and suggests possible hormonal influence in the development of TD.

Epidemiological studies show that stimulating activities reduce the risk of dementia. In animal models of Alzheimer disease, there have been conflicting results of the effects of environmental enrichment (EE) on disease-related amyloid pathology. Here, we tested the direct effect of EE, independently of amyloid pathology, on brain neurofibrillary tangles (NFTs), which best correlate with dementia. We exposed transgenic mice (E257K/P301S-Tau-Tg driven by the natural tau promoter) to moderate nonstrained EE or regular environment. Concomitant with neurogenesis, we detected a decrease in NFT burden and a decrease in the activation of microglia in EE versus regular-environment mice. There was also a trend toward improvement in cognitive tasks in the EE mice. Increased immunoreactivity of brain-derived neurotrophic factor, which is involved in the regulation of tau phosphorylation, was detected in the EE mice, suggesting its possible involvement in the beneficial effects on NFTs and other parameters in the EE mice. These results suggest that NFTs may be directly responsive to environmental stimulating activities and that even nonstrained activities may mitigate tauopathies independent of the involvement of amyloid.

Background: Anti-aquaporin-4 antibodies are believed to have a central pathogenetic role in neuromyelitis optica (NMO). B-cell activating factor (BAFF) is one of the crucial factors that determines the fate and survival of B cells and may play a role in induction of antibody-mediated autoimmunity. Objectives: To evaluate the blood and cerebrospinal fluid (CSF) levels of BAFF in NMO and multiple sclerosis (MS) patients. Methods: Peripheral blood samples were collected from 21 definite NMO patients, 22 healthy controls and 45 MS patients and CSF from 8 NMO and 11 MS patients. BAFF levels were measured using an ELISA technique. Results: We found significantly higher levels of BAFF in the CSF of NMO patients compared with that in MS (215.6 ± 41 pg/ml in NMO and 77.4 ± 11 pg/ml in MS, p < 0.001). There were no differences in serum BAFF levels between NMO, MS and healthy donors. MS patients treated with interferon-beta (IFNβ) or glatiramer acetate (GA) had significantly higher serum BAFF levels, as compared with untreated patients (1227 ± 203 pg/ml in untreated MS, 2253 ± 83.4 pg/ml in GA-treated, p < 0.01, and 2106 ± 277.9 pg/ml in interferon-treated, p < 0.05) Conclusion: The presence of increased BAFF, a soluble factor associated with B-cell activation in the proximity of the disease target organ (CSF) in NMO, and its increase in association with immunomodulating treatments, may help our understanding of the immunopathogenetic mechanisms involved in this disease and contribute to more successful and targeted therapeutic intervention.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration.

Alpha-fetoprotein (AFP) is an immunomodulatory glycoprotein associated with the normal growth of the mammalian fetus. Ws have shown that treatment with recombinant human AFP (rhAFP) reduced lymphocyte reactivity and the extent of neuroinflammation in mice with experimental autoimmune encephalomyelitis (EAE). In the present study we found involvement of AFP in immune cell apoptosis, attesting to its possible mechanism of action. AFP increased the expression of the Bax, Bid, Bad and ApaF genes in peripheral lymphocytes, together with an enhanced expression of Caspase-3, Fas, FasL and TRAIL among infiltrating immune cells. The induction of apoptosis markers was accompanied with an increased expression of Foxp3 in lymph node cells, as well as accumulation of CD4+Foxp3+ regulatory T cells in the CNS. Overall, these immunological alterations gave rise to a milder disease and accelerated remission rate. Our results suggest a new role for AFP in controlling the autoimmune inflammation associated with EAE.

The neurofibrillary-tangles (NTFs), characteristic of tauopathies including Alzheimer's-disease (AD), are the pathological features which correlate best with dementia. The objective of our study was to generate an authentic transgenic (tg) animal model for NFT pathology in tauopathy/AD. Previous NFT-tg mice were driven by non-related/non-homologous promoters. Our strategy was to use the natural tau promoter for expressing the human-tau (htau) gene with two mutations K257T/P301S (double mutant, DM) associated with severe phenotypes of frontotemporal-dementia in humans. Cellular, biochemical, behavioral and electrophysiological studies were subsequently conducted. The tg mice showed a tolerated physiological level of the DM-htau protein, mostly in cortex and hippocampus. The mice demonstrated tauopathy-like characteristics, which increased with age, that included NFT-related pathology, astrogliosis, argyrophilic plaque-like (amyloid-free) structures in brain, with memory deficits and signs of anxiety. Moreover, the tg mice showed a robust synaptic plasticity deficit selectively expressed in a severe impairment in their ability to maintain hippocampal long-term-potentiation (LTP) in response to stimulation of the perforant path, providing evidence that "tau-pathology only" is sufficient to cause this memory and learning-associated deficit. This is a unique mutant-htau-tg model which presents a wide spectrum of features characteristic of tauopathy/AD, which does not show unrelated motor deficits described in other models of tauopathy. In addition, expressing the DM-htau in a neuronal cell model resulted in tau-aggregation, as well as impaired microtubule arrangement. Both animal and cell models, which were regulated under the natural tau promoter (of rat origin), provide authentic and reliable models for tauopathy, and offer valuable tools for understanding the molecular events underlying tauopathies including AD.

Standard CD44 (CD44s) and its alternatively spliced variants (CD44v) were found to be associated with the metastatic potential of tumor cells, and with cell migration of autoimmune inflammatory cells, including cells involved in experimental autoimmune encephalomyelitis (EAE). The aim of the present study was to evaluate whether induction of anti-CD44 immune reactivity, through cDNA vaccination could down-regulate EAE. Our vaccination technique involved the insertion of CD44s or CD44v cDNA into a silicone tube filled with 2.5 cm long segment of hydroxylated-polyvinyl acetate wound dressing sponge (forming a virtual lymph node) which was implanted under the skin of SJL/J mice immunized with myelin antigens for EAE induction. Animals vaccinated with CD44v cDNA developed significantly less severe EAE when compared with sham vaccinated animals or animals vaccinated with CD44s cDNA. The in vitro proliferation of lymphocytes was preserved regarding myelin antigens and mitogens. Histopathological examinations revealed a significant reduction of EAE lesions and enhanced apoptosis in central nervous system (CNS)-infiltrating cells of the successfully vaccinated animals. Such methods of cDNA vaccination with CD44 could be applicable in inflammatory CNS diseases, like multiple sclerosis.

While the presence of naturally occurring antibodies (Abs) against amyloid-beta in AD patients and healthy subjects have been repeatedly reported, no data on the presence of naturally occurring Abs against tau protein, in its unphosphorylated as well as its pathologically phosphorylated state, has been reported so far. We describe here the detection of circulating Abs against unphosphorylated and pathologically phosphorylated tau protein in sera of 17 aged subjects: nine Alzheimer's disease (AD) patients and eight healthy individuals. An ongoing autoimmune process may take place, as is suggested by the presence of both IgM class anti-tau Abs, as well as IgG. A preliminary evidence for higher anti-phosphorylated-tau Abs of IgM class in AD patients relative to controls is indicated, but demands further confirmation in a larger sample. Detection of naturally occurring anti-tau antibodies may point to the possibility that some autoimmune process may take place against the tau neuronal protein, including its pathologically phosphorylated state which compose the neurofibrillary tangles. Whether these Abs are neuroprotective or neurotoxic - is unknown, as it is with anti-amyloid-beta Abs.

Introduction Myasthenia gravis (MG) is considered a paraneoplastic phenomenon of thymomas in 15% of patients. Co-existence of MG with extrathymic malignancies, and an increased risk of second malignancy in patients with thymoma have been reported. Data on clinical characteristics of MG patients with extrathymic malignancies and the role of concomitant diseases and their treatment are lacking. Methods The clinical records of 188 consecutive MG patients were studied retrospectively. We examined whether gender, age, generalized disease, seropositivity for acetyl-choline receptor antibodies, occurrence of thymoma, immunosuppressive therapy and occurrence of other autoimmune diseases determined an increased risk for development of extrathymic malignancy. Results This group followed the typical epidemiological characteristics of MG. Thirty-three patients (17.6%) had a thymoma. Twenty-nine patients (15.4%) had 30 extrathymic malignant tumors of various origins. Only four patients with extrathymic tumors had an associated thymoma. Tumors were diagnosed between 20 years prior to and 35 years after the appearance of MG. Older age of MG onset was the only risk factor identified for development of malignancy in MG. Discussion Extrathymic malignancies are common in MG patients, especially in the older age group. There are no specific clinical features of the subgroup of MG patients with cancer. Although MG is not a paraneoplastic phenomenon of extrathymic malignancy, the association between MG and malignancy may be due to a common background of immune dysregulation.

The transthyretin Tyr77 variant of familial amyloid polyneuropathy (FAP) has been identified in a few North American and European patients, but the full spectrum of its clinical manifestations is still not known. We report a 3-generation family of Jewish-Yemenite origin with Tyr77 FAP presenting with atypical features. The affected individuals had sensorimotor and autonomic neuropathy and cardiomyopathy accompanied by prominent dysphagia, hearing loss and asymptomatic carpal tunnel syndrome. Brain MRI in the proband showed multifocal white matter lesions. These features extend the reported Tyr77 phenotype and support the modifying effect of additional factors on the disease expression.

G latiramer acetate (GA) previously known as C opolymer 1 (Cop 1), a synthetic amino acid copolymer, suppresses experimental autoimmune encephalomyelitis (EAE) and shows a beneficial effect in relapsing-remitting type of multiple sclerosis (MS). G A acts as a specific immunomodulator by binding to MHC C lass II molecules, inducing specific T suppressor (Ts) cells and interfering with T cell responses to myelin antigens. MS patients treated with GA developed GA reactive antibodies, which peaked at three months and decreased at six months. In order to find out whether anti-G A antibodies may neutralize the therapeutic effect of GA, we tested both polyclonal (mouse and human) and monoclonal G A specific antibodies for their ability to interfere with the biological activity of GA in several assay systems. None of the antibodies interfered with GA activities either in vitro (binding to MHC molecules and T cell stimulation) or in vivo (blocking of EAE). Furthermore, 53 samples of sera obtained from 34 MS patients that participated in the open label trial in Israel, and all developed G A specific antibodies, were tested for their ability to inhibit the proliferation response of GA specific Ts cell clone and to interfere with G A competitive inhibition of the response to peptide 84-102 of myelin basic protein (MBP). None of the sera inhibited and some even enhanced the in vitro activities of G A. Furthermore, representative MS sera with high titer of G A reactive antibodies did not neutralize the biological activities of G A and did not inhibit Th2 cytokine secretion by human G A specific clone. These results are consistent with the findings that the therapeutic effect of GA is not affected by GA reactive antibodies and is sustained upon long term treatment.

Background: Frontotemporal dementia with parkinsonism linked to chromosome 17q21–22 (FTDP-17) is an autosomal dominant tauopathy manifested by a variable combination of personality changes, cognitive decline and hypokinetic-rigid movement disorder. Significant clinical and pathological heterogeneity of FTDP-17 is related in part to more than 20 different pathogenic mutations identified in the tau gene. Among others, the P301S mutation has been previously reported in three families of European and one of Japanese origin presenting with different clinical phenotypes. Objectives To report a three-generation family of Jewish-Algerian origin with FTDP-17 due to the P301S tau mutation. Methods: Clinical, neuropsychological and neuroimaging evaluation of 3 patients, tau genotyping, and pathological study of the proband. Results: The 3 affected family members had a fairly stereotyped clinical course with early personality changes from their late 30s followed within a period of 1–2 years by a progressive cognitive and motor deterioration eventually leading to a state of akinetic mutism or death 3–5 years after the initial symptoms. The main clinical manifestations included severe dementia and hypokinetic-rigid movement disorder associated with supranuclear gaze impairment, pyramidal signs and frontal release signs. Brain imaging disclosed a variable degree of frontotemporal atrophy, ventriculomegaly and regional cerebral hypoperfusion or glucose hypometabolism. Frontal lobe biopsy in the proband revealed weak tau immunoreactivity in a few cortical neurons, in rare neurites and in some glial cells with no neurofibrillary tangles. Molecular DNA analysis identified a P301S mutation in exon 10 of the tau gene. Conclusions: The observed clinical features further expand the reported P301S phenotype and confirm a more aggressive course of the disease than in the other known tau mutations.

A comparison of the incidence rate (IR) and the prevalence rate (PR) of multiple sclerosis (MS) in subgroups of the same ethnic origin, but born and living in different geographical areas, may delineate the relationship between environmental and genetic risk factors for MS. Previous epidemiological studies of MS in Israel did not include the Arab population and used diagnostic criteria that did not include MRI findings. Therefore, we studied the age-adjusted IR and PR of MS in a more recent sample in different population groups, including Arabs, of Greater Jerusalem. We found that the PR of MS in Israeli Jews is higher than previously described. Furthermore, the PR was significantly lower among immigrant Jews from Asia/Africa (A/A) than among native-born Jews of Asian/African origin (I-A/A). Since these groups have similar genetic susceptibilities to MS, the higher PR in the latter is probably due to environmental factors. Our study does not support the effect of latitude on the risk of developing MS since no difference in the PR was found between immigrant Jews from Europe/America (E/A) and native-born Jews of European/American origin (I-E/A). Among Arabs, the PR was similar to that among A/A. Therefore, we hypothesized similarity in environmental etiologic factors for MS between the countries of origin of A/A immigrants and of Arabs communities in Greater Jerusalem. The IR of I-E/A was higher than that of I-A/A and Arabs, although this difference did not reach statistical significance.

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. We have previously shown that treatment of EAE-mice with high doses of cyclophosphamide (CY) (350 mg kg), followed by syngeneic bone marrow transplantation (SBMT), completely abrogates the clinical paralytic signs and even prevents the appearance of new relapses in the chronic-relapsing model of the disease. In the present study we examined whether this treatment protocol induces long term tolerance and whether this tolerance is antigen-specific. EAE was induced by immunization with spinal cord homogenate (MSCH) in complete Freund's adjuvant (CFA). The treatment with CY and SBMT was performed on day 6 post immunization. Treated and untreated mice were rechallenged with MSCH, or a non-relevant antigen (OVA) in CFA at various stages after the first paralytic attack. In contrast to previous data showing that animals recovering from acute EAE are usually refractory to re-induction of the disease, repeated injections of MSCH at different sites from the initial immunization, followed by i.v. injection of inactivated Bordetella bacteria, 2, 4 and 6 months after the initial EAE-induction, caused a severe and usually lethal relapse in all the untreated, control animals. Mice treated with CY and SBMT were resistant to all rechallenges with the same encephalitogenic inoculum. Following the second rechallenge, peripheral lymph node cells were examined in vitro for their proliferative responses to myelin antigens or to OVA. Lymphocytes obtained from CY+SBMT treated mice did not proliferate in vitro in response to myelin basic protein (MBP), but proliferated against OVA, when immunized with this antigen, after SBMT. Adoptive transfer of lymphocytes from tolerant mice to naive recipients did not transfer resistance to EAE-induction. Our results indicate that high doses of CY, followed by SBMT, induce long term antigen-specific tolerance presumably by a mechanism of clonal deletion or anergy.

The presence of antibodies to cardiolipin (ACL Abs) has been reported in some patients suffering from multiple sclerosis (MS), especially of the "neuromyelitic" type. In addition, bright T2-imaging foci (unidentified bright objects) are occasionally detected on brain magnetic resonance imaging (MRI) scans, in patients with antiphospholipid syndrome. From a cohort of 100 patients with a probable or definite diagnosis of MS according to Poser's criteria, we isolated a subgroup of 20 patients (8 males and 12 females) consistently positive for ACL Abs. These patients were followed up neurologically for 1 to 3 years and brain MRI scanning and a complete autoimmune screening were performed. Nineteen (19 of 20) of our patients had the classic neuroimaging features of MS (multiple white-matter T2 bright foci on the MRI scan). The most common neurological syndrome was chronic, slowly progressing myelopathy (presenting as myelopathy, neuromyelitis optica, or spinocerebellar syndrome; 15 of 20), and optic neuropathy (6 of 20). Headache was a dominant symptom in 8 of 20 patients. Less common symptoms included cognitive and psychiatric disorders and chronic fatigue. The mean levels of ACL Abs were 38.8+/-28.2 GPL (normal values up to 7.5). Oligoclonal bands in the cerebrospinal fluid were detected in only 3 of 20 patients. Patients were treated with acetylsalycilic acid and occasionally with short courses of steroids. The progression of the chronic myelopathic/spinocerebellar syndrome was slower than expected in MS (only 2 patients deteriorated whereas 4 improved during a mean follow-up period of 20.8+/-7.1 months). We conclude that patients with probable or definite diagnosis of MS, and consistently elevated levels of ACL Abs show a slower progression and some atypical (for MS) features, such as persistent headaches and absence of oligoclonal bands in the cerebrospinal fluid. In these patients, other, presumably vascular, mechanisms may be involved in the pathogenesis of the neurological symptoms. Therefore, management should include antiplatelet or even anticoagulant agents.

Objective. Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model.Methods. ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose.Results. mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters.Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.

Antigen-driven tolerance is an effective method for suppression of autoimmune diseases. Adult animals can be tolerized against the induction of experimental autoimmune encephalomyelitis (EAE) by both oral and parenteral administration of myelin basic protein (MBP). We have found that in contrast to previous studies of neonatal tolerance in which parenterally administered autoantigens induced tolerance, the oral administration of MBP in neonatal rats did not result in tolerization to MBP, but instead, primed for immunologic responses. Proliferative responses to MBP and its encephalitogenic epitope were present in animals fed with MBP as neonates and co-culture of encephalitogenic T cells with cells from neonatal rats fed with MBP were associated with enhanced MBP responses rather than the suppression observed with cells from adult rats fed with MBP. Furthermore, neonates fed with MBP and immunized 6-8 weeks later with MBP in adjuvant to induce EAE revealed enhancement of disease severity, and were not protected from a second attack upon active reinduction of EAE. Subcutaneous injection of soluble MBP into neonates had no effect on EAE induction as adults, whereas intraperitoneal injection of MBP in neonates was associated with marked suppression of disease in adults. Suppression of EAE began to appear in animals fed with MBP at 4 weeks of age, and was similar to oral tolerance in adult animals when animals were fed at 6 weeks of age. These results suggest that immaturity of the immunoregulatory network associated with oral tolerance and sensitization to autoantigens via the gut in the neonatal period may contribute to the pathogenesis of autoimmune diseases.

Linomide (LS-2616, quinoline-3-carboxamide) is a synthetic immunomodulator that stimulates natural killer cell activity and activates several lymphocytic subpopulations in experimental animals and humans. In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outbred strain of rats (Sabra) by subcutaneous injection of spinal cord homogenate in adjuvant followed by inoculation with Bordetella pertussis. Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide-treated mice (0/41) and Sabra rats (0/15) developed any clinical or pathological signs of experimental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% died from the disease. Lymphocytes obtained from linomide-treated animals had reduced in vitro proliferative responses to guinea pig myelin basic protein, proteolipid protein of the myelin, and tuberculin-purified protein derivative, unlike antigen-independent proliferation which was rather unaffected. Natural killer cell activity (tested by a cytotoxic assay on radiolabeled YAC-1 target cells) was significantly enhanced in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of experimental autoimmune encephalomyelitis in the absence of systemic immunosuppression. Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders.

Creutzfeldt-Jakob disease is a transmissible neurodegenerative disorder that occurs more than 100 times more frequently among Libyan Jews than in the worldwide population. We examined 11 patients with the disease--10 Libyan Jews from Israel and 1 Libyan Jew from Italy--to determine whether abnormalities of the prion protein could be detected in them. Abnormal forms of this host-encoded protein are the predominant if not sole components of the transmissible agent that causes the disease.The prion-protein open-reading frame in peripheral-leukocyte DNA from the Italian patient was amplified with the polymerase chain reaction and sequenced. Allele-specific oligonucleotide hybridization was used to assess a prion-protein codon 200 lysine mutation in the 10 Israeli patients and 37 control subjects.The prion-protein sequence in DNA from the Italian patient revealed a single nucleotide change (G----A) at the first position of codon 200 that resulted in a substitution of lysine for glutamate. This substitution was detected in all 10 Israeli patients, 8 of whom had a positive family history of Creutzfeldt-Jakob disease. One patient was homozygous for the lysine mutation, and her clinical course did not differ from that of the patients heterozygous for the mutation. The lysine mutation was not found in one Moroccan Jew from Israel with Creutzfeldt-Jakob disease.The codon 200 lysine mutation of the prion-protein gene is consistently present among Libyan Jews with Creutzfeldt-Jakob disease, strongly supporting a genetic pathogenesis of their illness. The similarity of the clinical courses of the patient homozygous for this mutation and the patients heterozygous for it argues that familial Creutzfeldt-Jakob disease is a true dominant disorder.

In chronic inflammatory diseases like multiple sclerosis (MS), neuroprotection refers to strategies aimed at prevention of the irreversible damage of various neuronal and glial cell populations, and promoting regeneration. It is increasingly recognized that MS progression, in addition to demyelination, leads to substantial irreversible damage to, and loss of neurons, resulting in brain atrophy and cumulative disability. One of the most promising neuroprotective strategies involves the use of bone marrow derived stem cells. Both hematopoietic and non-hematopoietic (stromal) cells can, under certain circumstances, differentiate into cells of various neuronal and glial lineages. Neuronal stem cells have also been reported to suppress EAE by exerting direct in situ immunomodulating effects, in addition to their ability to provide a potential source for remyelination and neuroregeneration. Preliminary results from our laboratory indicate that intravenous or intracerebral/intraventricular injection of bone marrow derived stromal cells could differentiate in neuronal/glial cells and suppress the clinical signs of chronic EAE. Both bone marrow and neuronal stem cells may therefore have a therapeutic potential in MS. It seems that future treatment strategies for MS should combine immunomodulation with neuroprotective modalities to achieve maximal clinical benefit.

A growing body of evidence suggests that Alzheimer's disease (AD) is associated with local inflammation processes, including the activation of inflammatory cytokines. We performed a case-control association study between sporadic AD patients and the exon 5 position +3953 polymorphism in the potent pro-inflammatory cytokine, interleukin-1beta (IL-1B). Recent association studies of this locus with AD revealed conflicting results, suggesting that the association – if it exists – is not universal but rather population specific. In our study no association was detected with AD: neither as a risk factor nor as a modifier gene affecting the age at onset and disease progression. These findings show no evidence for an association between the IL-1B +3953 polymorphism and AD in the Jewish population.

Experimental autoimmune encephalomyelitis (EAE) was found to have a chronic and significantly worse course in apolipoprotein-E (apoE) deficient female mice when compared with matched controls. Disease measures compared included incidence of EAE (64% versus 31%, P 2 test), maximal clinical score (average ±SD 2.81±2.5 versus 0.75±1.1, P 2 test). A poE deficient mice had significantly increased lymphocyte proliferation responses to both myelin antigens and mitogens and significantly more infiltrating lesions in the central nervous system (CNS) in histopatho logy. Defective neuronal repair mechanisms and enhanced immune reactivity in apoE deficient mice may explain our findings. C linical implications for MS are discussed.

Cytokeratin expression in normal postnatal human thymus was studied immunohistochemically by using monoclonal antibodies against various cytokeratin polypeptides. An attempt was made to characterize cell populations giving rise to the cornified structures of Hassal's corpuscles. Monoclonal antibody KB-37, a marker of squamous epithelium basal cells, was applied to distinguish the earliest cells capable of undergoing squamous differentiation. Parts of the subcapsular epithelium were extensively stained with this reagent. This epithelium, like the basal layer of certain squamous epithelia, exhibited a high incidence of cytokeratins 13 and 14, and pronounced expression of cytokeratin 19. Simple epithelium cytokeratins 8, 18, and 19 were present in the cortex. Scattered cells reacted with KB-37 antibody. All stellate epithelial cells in the medulla were positive for cytokeratin 19. Most of the medullar epithelial cells were positive for cytokeratins 13, 14 and 17 of complex epithelium, in contrast to the cortex, where only a few cells were positive for these cytokeratins. A significant proportion of the medullar cells was positive for KB-37 antigen. Cytokeratins 8 and 18 were expressed in single cells and in groups of cells surrounding Hassal's corpuscles. The outermost cells of these corpuscles were positive for cytokeratin 19 and KB-37. In the peripheral parts of Hassal's corpuscles, simple epithelium cytokeratins 7, 8, 18, and cytokeratins 4, 13, 14, and 17, characteristic of stratified nonkeratinizing epithelia, were coexpressed with keratinization-specific cytokeratins 10/11. The inner parts of the swirls were uniformly positive for cytokeratins 10/11. However, the expression of other cytokeratins was reduced.

The incidence and prevalence of multiple sclerosis (MS) were compared, controlling for age, in native-born Israelis of different origins and in immigrants to Israel. This comparison was carried out in two populations, countrywide and in Jerusalem. In the countrywide population, ascertainment was based mainly on hospitalizations; it included 252 patients who were native-born and 150 who had immigrated from Africa-Asia (AA immigrants). The 89 MS patients of Jerusalem also included patients diagnosed in outpatient clinics. In native-born Israelis whose father was born in Europe-America (I-EA), the incidence and prevalence of MS were found to be as high as or even higher than that found previously in immigrants from Europe-America. Among native-born Israelis whose father was born in Africa or Asia (I-AA), the yearly age-adjusted incidence and prevalence rates were found to be 1.4- to 1.8-fold higher than among AA immigrants, pointing to environmental factors. The incidence and prevalence rates in the I-EA were 1.2- to 1.6-fold higher than in the I-AA, pointing to genetic factors. These results seem to point to both environmental and genetic factors in the aetiology of MS. Further research is needed, however, to disentangle the genetic factors from possible environmental differences in the two ethnic groups.

We report five patients who had multiple sclerosis (MS) associated with type I diabetes mellitus (TODM). Examination of the Israeli National Neurological Disease Register revealed the prevalence of TODM among 334 MS patients under the age of 30 years to be 8.98 per 1,000. This is significantly higher than the prevalence of TODM in the general population of Israel for the same age group, which is 0.095 per 1,000. MS and TODM share clinical, epidemiological and immunological features, and both diseases have a target site that is neuroectodermal in origin. The association between these two putative autoimmune diseases may suggest a similar pathogenetic mechanism.

Background A possible role of autoimmunity in Alzheimer disease pathogenesis has recently attracted increasing attention. Vaccination with amyloid-β peptide was reported to cause marked reduction in amyloid deposition, but it also induced encephalitis. Not much is known regarding neurofibrillary tangle–related autoimmune effects. Objective To use the main component of tangles—microtubule-associated tau protein—to test the feasibility of active induction of a neuroautoimmune disorder in mice. Design Prospective, randomized controlled animal study. Setting University medical center research laboratory. Subjects Female C57BL/6 mice. Interventions Inoculation with recombinant human tau protein emulsified in complete Freund adjuvant and with pertussis toxin. Main Outcome Measures Clinical, immunologic, pathologic, and behavioral evaluations were performed. Results Vaccination with tau protein induced histopathologic features of Alzheimer disease and tauopathies, indicated by the presence of neurofibrillary tangle–like structures, axonal damage, and gliosis. Also, mononuclear infiltrates without demyelination in the central nervous system, accompanied by neurologic deficits (such as a limp tail and limb paralysis), were observed. Anti–tau antibodies were detected in the serum of tau-immunized mice. Conclusions These results provide a link between tau autoimmunity and tauopathy-like abnormalities and indicate potential dangers of using tau for immunotherapy. This experimental autoimmune tauopathy-like model is due to a pathogenic immune response against an intraneuronal antigen and is not related to myelin antigens.

Background Choreoacanthocytosis (CHAC) is a slowly progressive multisystem disorder with involuntary movements, cognitive decline, behavioral changes, seizures, and polyneuropathy caused by mutations in the VPS13A gene. Objective To describe the early clinical features and possible genotype-phenotype correlation in CHAC. Design and Setting Case series in a tertiary care center. Patients and Main Outcome Methods Choreoacanthocytosis was diagnosed in 3 patients of Jewish origin from 3 unrelated families. We reviewed their medical histories and performed molecular analysis by screening all 73 exons of VPS13A . Results Trichotillomania, hypertrophic cardiomyopathy, and idiopathic hyperCKemia, in 1 patient each, preceded the development of the full clinical spectrum of CHAC by 2 to 20 years. At diagnosis, 2 patients manifested signs of overt neuromuscular involvement and were homozygous for the 6059delC mutation, whereas 1 patient had only hyporeflexia and was homozygous for the EX23del mutation. Because only 1 of the 2 patients with 6059delC had cardiomyopathy, its relevance to CHAC is unclear. Conclusions These findings extend the knowledge of significant early clinical heterogeneity in CHAC and suggest a possible genotype-phenotype correlation. Awareness of the early manifestations may prevent misdiagnosis and enable appropriate genetic counseling.

Objective To evaluate the presence and specificity of anti–myelin oligodendrocyte glycoprotein (MOG) antibody in the cerebrospinal fluid and plasma of patients with multiple sclerosis (MS). Design Case-control study of patients with clinically definite MS compared with patients with other neurologic diseases (ONDs) of the central nervous system and control subjects. Setting Referral center in the Department of Neurology of Hadassah University Hospital, greater Jerusalem area, Israel. Participants Consecutive cerebrospinal fluid samples from 31 patients with MS, 31 patients with ONDs, and 28 healthy controls; and plasma samples from 33 patients with MS, 28 patients with ONDs, and 31 healthy controls were taken from the cerebrospinal fluid and plasma bank of the Department of Neurology, Hadassah University Hospital. Main Outcome Measures Levels and frequencies of anti-MOG antibody in patients with MS, as defined by enzyme-linked immunosorbent assay. Results Cerebrospinal fluid levels of antibodies to MOG and to myelin basic protein were significantly higher in patients with MS ( P P =.001, respectively) and patients with ONDs ( P =.005 and P =.03, respectively) compared with controls; frequency of antibodies to MOG, but not to myelin basic protein, was higher in patients with MS and patients with ONDs ( P =.01 and P =.003, respectively, for the frequency of anti-MOG antibody, and P =.65 and P =.41, respectively, for the frequency of anti-myelin basic protein antibody). Plasma levels of antibodies to MOG and to myelin basic protein were higher in patients with MS compared with patients with ONDs ( P =.003 for both comparisons) and with controls ( P =.03 and P =.04, respectively); however, the frequency of antibodies to MOG and myelin basic protein was similar in patients with MS, patients with ONDs ( P =.54 and P =.82, respectively), and controls ( P =.50 and P =.14, respectively). Conclusions The elevated presence of anti-MOG antibody is not specific for MS because a similar appearance was also demonstrated in patients with ONDs. Therefore, it is not clear whether this antibody is pathogenic in MS or, on the contrary, has a defensive role against further immune-mediated damage after myelin breakdown.

Three children with subacute sclerosing panencephalitis (SSPE) were treated with alpha-interferon. Medication was administered via an Ommaya reservoir into the cerebral ventricular system over a period of 13 to 24 months in increasing amounts up to 1.0 X 106 IU twice weekly. Mild clinical improvement in two children and a stable course in the third were associated with improvement of electroencephalographic recordings in all patients and a decrease in antimeasles antibodies in the cerebrospinal fluid of two. The small number of patients does not enable us to determine whether this course was the natural history of SSPE in our patients or whether it was induced by treatment, yet it seems that intraventricular interferon treatment can modify the course of SSPE. ( J Child Neurol 1989;4:20-23).

1. Five new sustained-release dosage forms of valproic acid (VPA) were developed. 2. The new sustained-release formulations were administered to six healthy subjects for comparison with a standard tablet and an i.v. preparation of the drug. 3. Three of the formulations exhibited a more prolonged and uniform absorption rate and yielded more sustained serum levels after ingestion. These three formulations maintained serum therapeutic levels of VPA for 24 h after a single oral administration of 1 g, and were bioequivalent to a marketed standard tablet of VPA. 4. The absorption profile of the various oral formulations was analysed pharmacokinetically, using the Loo-Riegelman procedure.

Polyclonal rabbit antiserum to galactocerebroside (anti-GalC) produces titer-dependent lysis of cultured Percoll-isolated bovine and rat oligodendrocytes. In this study anti-GalC produced complement-dependent lysis of 76% of the bovine cells and 65% of the rat cells maintained for 3 to 6 days in vitro. With the concomitant addition of human umbilical cord serum fractions containing fetal alpha-fetoprotein (AFP), lysis was decreased to 31% and 39%, respectively. Control antisera (anti-complete Freund's adjuvant/albumin) showed a cytotoxicity index of 15% for bovine cells and 23% for rat cells. Neither albumin, nor normal human serum, nor any of several pregnancy-associated hormones reduced the lysis produced by anti-GalC. AFP-rich fraction reduced oligodendrocyte lysis when mixed with anti-GalC or complement, but not when first incubated with the cells. Similar findings were obtained when AFP was assayed in specific oligodendrocyte radioimmunoassays utilizing anti-GalC antibody. Our experiments indicate that AFP activity may result from its binding to anti-GalC antibody; it is possible that the Fc portion of the antibody is involved. These data provide in vitro evidence of a possible immunosuppressive role of AFP in the central nervous system.

— Oligodendroglia prepared from calf cerebral white matter were incubated with [3-14C]aceto-acetate (AcAc), d-[3-14C](-)-beta-hydroxybutyrate (OHbut) or 3H2O. Addition to the medium of the ATP-rate oxaloacetate lyase inhibitor (-)-hydroxycitrate diminished sterol labelling from OHbut and 3H2O, but caused 4-fold stimulation of sterol labelling from AcAc. The discrepancy between results with the two ketone bodies indicates the existence in oligodendroglia of an extrarnitochondrial pathway for conversion of AcAc but not OHbut to acetyl CoA. Acetoacetyl CoA synthetase, the first enzyme in this pathway, was more than 20-fold enriched in oligodendroglia over whole brain.

Two basic proteins, P1 of molecular weight 14,2000 and P2 of molecular weight 12,300, purified from bovine peripheral nerve, were assayed for biological activity. The P1 protein is an exclusively neuritogenic agent, capable of producing clinical signs of experimental allergic neuritis (EAN) and histological abnormalities in the peripheral nervous system (PNS) of guinea pigs and rabbits, without any changes in their central nervous system (CNS). P2 protein, like the CNS basic encephalitogenic protein (BE), has combined neuritogenic and encephalitogenic activities, therefore it induces in these animals neurological signs and pathological evidence of EAN, as well as histological characteristics of experimental allergic encephalomyelitis (EAE).

Masking of and by mechanical tactile stimuli was investigated as a function of spatial relations between the stimuli. Masking was stronger when the stimuli were applied to the same side of the body than when they were placed contralaterally to each other. Increasing the distance between the two stimuli decreased masking, but this effect was significant only in the case of ipsilateral masking. The results confirm those of former studies and are explained in terms of peripheral interactions as well as by the connections between the left and right somatosensory systems.

Sixty nine patients with Parkinson's disease were treated with L-DOPA for more than a year. L-DOPA produced remarkable improvement in akinetic patients, moderate improvement in rigidity and slight improvement in tremor. The degree of improvement in akinesia, rigidity and tremor tended to be reversely related to the severity of the disease. Rigidity and akinesia improved better in young patients, but there was no correlation between age and the response of tremor to the treatment. Except for rigidity there was no correlation between the improvement and the duration of the disease.

Two patients had centrl nervous system involvement from plasma cell tumor, onr with leptomeningeal infiltraion and the other with solitary intracranial plasmacytoma. In both, cerebrospinal fluid (CSF) electrophoresis revealed IgG index consistent with local synthesi of the myeloma protein. the CSF findings were helpful in the diagnosis and evaluation of tumor recurrence.

The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79 +/- 0.24 and 0.77 +/- 0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, nonhygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.

A patient with idiopathic hypoparathyroidism presenting with spells of paroxysmal choreoathetosis is described. The possible mechanisms by which hypoparathyroidism induces choreoathetosis and other extrapyramidal motor dyfunctions are discussed. The need for screening patients with extrapyramidal disease for hypoparathyroidism is stressed.

The influence of pregnancy on multiple sclerosis was studied in 338 women by determining in each trimester of pregnancy and post partum the number of relapses and the corresponding relapse rate. Eighty-five relapses occurred in association with 199 pregnancies, most (65) in the postpartum period, and a low number of relapses (2) were recorded in the last trimester of pregnancy. Comparing the average exacerbation rate of the study group with that of patients with multiple sclerosis in Israel (0.28 relapses per person per year), we found a statistically significant decrease in the third trimester (0.04) and a high increase in the first three months post partum (0.82). This pattern of remissions at the end of pregnancy and exacerbations post partum is similar to that observed in other putative autoimmune diseases.