A Breakdown of Immune Tolerance in the Cerebellum.

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood-brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum-or any structure in the CNS-is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood-brain barrier, blood-CSF barrier, and blood-leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often-particularly in infectious diseases-the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum.

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.

Autoimmunity plays a role in the onset of diabetes after 40 years of age.

AIMS/HYPOTHESIS: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. METHODS: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. RESULTS: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. CONCLUSIONS/INTERPRETATION: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges.

Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), antiglutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen( s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the "cerebellar reserve" is necessary for the improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of "Time is Cerebellum" in IMCAs.

Endocrine disorders and the cerebellum: from neurodevelopmental injury to late-onset ataxia.

Hormonal disorders are a source of cerebellar ataxia in both children and adults. Normal development of the cerebellum is critically dependent on thyroid hormone, which crosses both the blood-brain barrier and the blood-cerebrospinal fluid barrier thanks to specific transporters, including monocarboxylate transporter 8 and the organic anion-transporting polypeptide 1C1. In particular, growth and dendritic arborization of Purkinje neurons, synaptogenesis, and myelination are dependent on thyroid hormone. Disturbances of thyroid hormone may also impact on cerebellar ataxias of other origin, decompensating or aggravating the pre-existing ataxia manifesting with motor ataxia, oculomotor ataxia, and/or Schmahmann syndrome. Parathyroid disorders are associated with a genuine cerebellar syndrome, but symptoms may be subtle. The main conditions combining diabetes and cerebellar ataxia are Friedreich ataxia, ataxia associated with anti-GAD antibodies, autoimmune polyglandular syndromes, aceruloplasminemia, and cerebellar ataxia associated with hypogonadism (especially Holmes ataxia/Boucher-Neuhäuser syndrome). The general workup of cerebellar disorders should include the evaluation of hormonal status, including thyroid-stimulating hormone and free thyroxine levels, and hormonal replacement should be considered depending on the laboratory results. Cerebellar deficits may be reversible in some cases.

GAD65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies.

BACKGROUND: Autoantibodies against the smaller isoform of glutamate decarboxylase (GAD65Ab) reflect autoimmune etiologies in Type 1 diabetes (T1D) and several neurological disorders, including Stiff Person Syndrome (SPS). GAD65Ab are also reported in cases of epilepsy, indicating an autoimmune component. GAD65Ab in patients with co-occurring T1D, epilepsy or SPS may be part of either autoimmune pathogenesis. To dissect the etiologies associated with GAD65Ab, we analyzed GAD65Ab titer, epitope specificity and enzyme inhibition in GAD65Ab-positive patients diagnosed with epilepsy (n = 28), patients with epilepsy and T1D (n = 10), patients with SPS (n = 20), and patients with T1D (n = 42). RESULTS: GAD65Ab epitope pattern in epilepsy differed from T1D and SPS patients. Four of 10 patients with co-occurring T1D and epilepsy showed GAD65Ab profiles similar to T1D patients, while lacking GAD65Ab characteristics found in GAD65Ab-positive epilepsy patients. One of these patients responded well to anti-epileptic drugs (AEDs), while another patient did not require medication for seizure control. The third patient was refractory due to a diagnosis of meningioma. The response of the remaining patient to AEDs was unknown. GAD65Ab in the remaining six patients with T1D and epilepsy showed profiles similar to those in epilepsy patients. CONCLUSIONS: Different autoimmune responses associated with T1D, epilepsy and SPS are reflected by disease-specific GAD65Ab patterns. Moreover, the epileptic etiology in patients diagnosed with both T1D and epilepsy may present two different etiologies regarding their epileptic condition. In one group T1D co-occurs with non-autoimmune epilepsy. In the other group GAD65Ab are part of an autoimmune epileptic condition.

Time Is Cerebellum.

The cerebellum characteristically has the capacity to compensate for and restore lost functions. These compensatory/restorative properties are explained by an abundant synaptic plasticity and the convergence of multimodal central and peripheral signals. In addition, extra-cerebellar structures contribute also to the recovery after a cerebellar injury. Clinically, some patients show remarkable improvement of severe ataxic symptoms associated with trauma, stroke, metabolism, or immune-mediated cerebellar ataxia (IMCA, e.g., multiple sclerosis, paraneoplastic cerebellar degeneration, gluten ataxia, anti-GAD65 antibody-associated cerebellar ataxia). However, extension of a cerebellar lesion can impact upon the fourth ventricle or the brainstem, either by direct or indirect mechanisms, leading to serious complications. Moreover, cerebellar reserve itself is affected by advanced cell loss and, at some point of disease progression, deficits become irreversible. Such phase transition from a treatable/restorable state (the reserve is still sufficient) to an untreatable state (the reserve is severely affected) is a loss of therapeutic opportunity, highlighting the need for early treatment during the restorable stage. Based on the motto of "Time is Brain," a warning that stresses the importance of early therapeutic intervention in ischemic diseases, we propose "Time is Cerebellum" as a principle in the management of patients with cerebellar diseases, especially immune ataxias whose complexity often delay the therapeutic intervention. Indeed, this concept should not be restricted to ischemic cerebellar diseases. We argue that every effort should be made to reduce the diagnostic delay and to initiate early therapy to avoid the risk of transition from a treatable state to an irreversible condition and an associated accumulation of disability. The myriad of disorders affecting the cerebellum is a challenging factor that may contribute to irreversible disability if the window of therapeutic opportunity is missed.

Effect of dietary palmitic and stearic acids on sucrose motivation and hypothalamic and striatal cell signals in the rat.

We have reported that motivation for sucrose is increased in rats fed a moderate (31%) mixed-fat diet for 4-6 wk. In this study, rats were fed diets containing 32% stearic (STEAR) or palmitic (PALM) acid, and behavior, metabolic profile, and cell signals were compared with those of rats fed a matched low-fat diet (LF; 11% fat) diet. Rats fed STEAR or PALM increased sucrose motivation relative to LF rats (one-way ANOVA for lever presses; P = 0.03). Diet did not change fasting glucose, insulin, total cholesterol, triglycerides, intravenous glucose tolerance test glucose profile, percent body fat, or total kilocalories, although kilocalories as fat were increased (ANOVA, P < 0.05). Cell signals were assessed in rats ranked from high to low sucrose motivation. Diet did not alter Thr and Ser phosphorylation of Akt in the medial hypothalamus (HYP) and striatum (STR). However, Ser phosphorylation of GSK3Β was decreased in HYP and STR from both high- and low-performer tertiles of STEAR and PALM rats (ANOVA within each brain region, P < 0.05). Two histone 3 (H3) modifications were also assessed. Although there was no effect of diet on the transcription-repressive H3 modification, H3K27me3, the transcription-permissive H3 modification, H3K4me3, was significantly decreased in the HYP of high performers fed PALM or STEAR (ANOVA, P = 0.013). There was no effect of diet on H3K4me3 levels in HYP of low performers, or in STR. Our findings suggest signal-specific and brain region-specific effects of PALM or STEAR diets and may link downstream signaling effects of GSK3Β activity and H3 modifications with enhanced motivational behavior.

Immune-mediated cerebellar ataxias: from bench to bedside.

The cerebellum is a vulnerable target of autoimmunity in the CNS. The category of immune-mediated cerebellar ataxias (IMCAs) was recently established, and includes in particular paraneoplastic cerebellar degenerations (PCDs), gluten ataxia (GA) and anti-GAD65 antibody (Ab) associated-CA, all characterized by the presence of autoantibodies. The significance of onconeuronal autoantibodies remains uncertain in some cases. The pathogenic role of anti-GAD65Ab has been established both in vitro and in vivo, but a consensus has not been reached yet. Recent studies of anti-GAD65 Ab-associated CA have clarified that (1) autoantibodies are generally polyclonal and elicit pathogenic effects related to epitope specificity, and (2) the clinical course can be divided into two phases: a phase of functional disorder followed by cell death. These features provide the rationale for prompt diagnosis and therapeutic strategies. The concept "Time is brain" has been completely underestimated in the field of immune ataxias. We now put forward the concept "Time is cerebellum" to underline the importance of very early therapeutic strategies in order to prevent or stop the loss of neurons and synapses. The diagnosis of IMCAs should depend not only on Ab testing, but rather on a rapid and comprehensive assessment of the clinical/immune profile. Treatment should be applied during the period of preserved cerebellar reserve, and should encompass early removal of the conditions (such as remote primary tumors) or diseases that trigger the autoimmunity, followed by the combinations of various immunotherapies.

Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.