Chronic Progressive Course Of Disease Research Articles

German Parkinson’s network as a scalable approach for integrated care in daily medical routine

Due to the sectoral boundaries of the German healthcare system, a lack of interdisciplinary cooperation is evident. As a result, patients are either under-supplied or incorrectly treated. Mainly initiated by regional players, health care networks help to overcome local deficits in care. The core element of health care networks is the inclusion of all health care providers in the patient-centered treatment as well as a strengthened exchange of experiences and knowledge.
 Parkinson's disease (PD) is a neurodegenerative disorder, with a chronic progressive disease course divided into different stages. It is the second most common neurodegenerative disease with the fastest increase in the number of people affected of all neurological disorders worldwide. PD is considered as a model condition for the implementation of innovative healthcare concepts in chronic neurological diseases. For adequate healthcare and an optimized support, a multidisciplinary approach is necessary, considering the individual needs as well as the complexity of PD with its various motor and non-motor symptoms.
 Based on the findings of recent research projects, especially from the Dutch ParkinsonNET, several regional network structures for PD have been established in Germany in the past five years. Meanwhile, the German care landscape includes more than ten regional PD health care networks. In 2022, the “German PD network” has been founded as an umbrella organization.
 The overall goal of the umbrella organization is to provide PD patients in Germany with nationwide access to the networked structures described above. To ensure such universal access, data from international experiences as well as from Germany demonstrate that a coordinating institution is indispensable. The coordinating institution (networking centre) is responsible for the daily and practical integration of the PD patients into the network as well as for the maintenance and further development of the networks. Scientific evidence for the effects of PD networks is widely available , therefore the goal of the German PD network is to reach the financial support of network structures by statutory health insurance, while evaluation the structures on an ongoing basis. Therefore, the German PD network designs structures, such as a digital care path, to create an integrated and coordinated care concept for PD patients which then can be transmitted to further neurological diseases.
 Challenges in PD healthcare routines are targeted using multidisciplinary care networks. Scientific evidence shows clear effects of PD network structures evolving in a strengthened intra- and interdisciplinary communication as well as greater and improved treatment coordination. Simultaneously, increased coordination leads to a reduction in the use of resources and mortality, a higher health-related quality of life as well as self-management for PD patients. Support and active participation in the development process of PD networks by the statutory health insurance is sought as a next step.

Aberrant peak lactate response in MS.

The peak blood lactate response to an exhaustive exercise test in a number of chronic conditions has been shown to differ from that seen in healthy, untrained individuals. However, this has not been investigated for patients with multiple sclerosis (MS). The main objective was to determine and compare the peak blood lactate response to exercise and the maximal workload between two groups of MS patients with different illness severity. Twenty-five patients with a relapsing-remitting disease course (Group RR) and 41 patients with a secondary- or primary chronic progressive disease course (group CP) performed an exhaustive incremental bicycle ergometry. Peak blood lactate, maximal workload, peak oxygen consumption and maximal heart rate were measured. The peak blood lactate levels and maximal workload differed significantly between the groups (group CP < group RR; p < 0.001). Furthermore spiroergometric peak performance markers in both groups were significantly lower than predicted for healthy age and sex matched untrained groups. A reduced peak blood lactate response to exercise is a novel finding for MS patients. This calls into doubt if the lactate performance tests and lactate thresholds used for healthy individuals can be transferred to MS patients.

CatWalk gait analysis in a rat model of multiple sclerosis.

Background Myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for multiple sclerosis. The characteristic feature of the MOG-EAE model in Brown Norway rats is consistent involvement of the spinal cord resulting in limb paresis. The aim of the study was to investigate whether early subclinical gait abnormalities are present in this animal model and can be detected by CatWalk XT, a fully automated gait analysis system. Furthermore, we investigated the usability of CatWalk system for treatment studies.ResultsOur gait analysis showed no preclinical abnormalities in MOG-EAE animals. Nevertheless, we characterized a combination of gait parameters that display a high predictive capacity in regard to disease onset. Our detailed histopathological analysis of the spinal cord revealed that lesion formation starts in the lumbar region and propagates toward the cervical part of the spinal cord during the disease course. In the treatment study, the stabilization of gait parameters under the treatment with methylprednisolone was detected in CatWalk as well as in traditional EAE-scoring system.ConclusionsThe results from CatWalk test indicate no benefit of lab-intensive automated gait system in EAE-model with chronic-progressive disease course as well as in therapeutic studies with pronounced effect on the severity of clinical symptoms. However, due to its quantitative and objective nature this system may display a refined test to detect small but functional relevant changes in regeneration-orientated studies.

Brain Viscoelasticity Alteration in Chronic-Progressive Multiple Sclerosis

IntroductionViscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS.MethodsWe determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity μ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS.ResultsIn chronic-progressive MS patients, μ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001).ConclusionsChronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.

The relevance of animal models in multiple sclerosis research

Multiple Sclerosis (MS) is a complex disease with an unknown etiology and no effective cure, despite decades of extensive research that led to the development of several partially effective treatments. Researchers have only limited access to early and immunologically active MS tissue samples, and the modification of experimental circumstances is much more restricted in human studies compared to studies in animal models. For these reasons, animal models are needed to clarify the underlying immune-pathological mechanisms and test novel therapeutic and reparative approaches. It is not possible for a single mouse model to capture and adequately incorporate all clinical, radiological, pathological and genetic features of MS. The three most commonly studied major categories of animal models of MS include: (1) the purely autoimmune experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally induced chronic demyelinating disease models, with the main model of Theiler's Murine Encephalomyelitis Virus (TMEV) infection and (3) toxin-induced models of demyelination, including the cuprizone model and focal demyelination induced by lyso-phosphatidyl choline (lyso-lecithine). EAE has been enormously helpful over the past several decades in our overall understanding of CNS inflammation, immune surveillance and immune-mediated tissue injury. Furthermore, EAE has directly led to the development of three approved medications for treatment in multiple sclerosis, glatiramer acetate, mitoxantrone and natalizumab. On the other hand, numerous therapeutical approaches that showed promising results in EAE turned out to be either ineffective or in some cases harmful in MS. The TMEV model features a chronic-progressive disease course that lasts for the entire lifespan in susceptible mice. Several features of MS, including the role and significance of axonal injury and repair, the partial independence of disability from demyelination, epitope spread from viral to myelin epitopes, the significance of remyelination has all been demonstrated in this model. TMEV based MS models also feature several MRI findings of the human disease. Toxin-induced demyelination models has been mainly used to study focal demyelination and remyelination. None of the three main animal models described in this review can be considered superior; rather, they are best viewed as complementary to one another. Despite their limitations, the rational utilization and application of these models to address specific research questions will remain one of the most useful tools in studies of human demyelinating diseases.

Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases

Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.

CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mouse model of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease, peaking 21 days after alpha-myosin H chain peptide (MyHC-alpha)/CFA immunization and largely resolving thereafter. In IFN-gammaR(-/-) mice, however, EAM is exacerbated and shows a chronic progressive disease course. We found that this progressive disease course paralleled persistently elevated IL-17 release from T cells infiltrating the hearts of IFN-gammaR(-/-) mice 30 days after immunization. In fact, IL-17 promoted the recruitment of CD11b(+) monocytes, the major heart-infiltrating cells in EAM. In turn, CD11b(+) monocytes suppressed MyHC-alpha-specific Th17 T cell responses IFN-gamma-dependently in vitro. In vivo, injection of IFN-gammaR(+/+)CD11b(+), but not IFN-gammaR(-/-)CD11b(+), monocytes, suppressed MyHC-alpha-specific T cells, and abrogated the progressive disease course in IFN-gammaR(-/-) mice. Finally, coinjection of MyHC-alpha-specific, but not OVA-transgenic, IFN-gamma-releasing CD4(+) Th1 T cell lines, together with MyHC-alpha-specific Th17 T cells protected RAG2(-/-) mice from EAM. In conclusion, CD11b(+) monocytes play a dual role in EAM: as a major cellular substrate of IL-17-induced inflammation and as mediators of an IFN-gamma-dependent negative feedback loop confining disease progression.

Hyperhomocysteinemia is associated with cognitive impairment in multiple sclerosis

Hyperhomocysteinemia (HHcy) has been associated with cognitive impairment in various neurological diseases. Cognitive impairment occurs early in multiple sclerosis (MS). Conflicting data have been reported regarding plasma total homocysteine (tHcy) levels in MS patients, and the impact of HHcy on cognitive impairment in MS is not known. This study investigated whether plasma total homocysteine levels are increased in MS and if HHcy is associated with cognitive impairment in MS. We compared tHcy levels in 94 patients with MS and 53 healthy age-matched controls. We used a neuropsychological test battery that included the Raven's Coloured Progressive Matrices, the Visual Search Test, the Trail Making Test A and B, the Immediate and Delayed Recall of a Short Story, the 30 Paired Word Associates, the Rey-Osterrieth Complex Figure Test, and the Semantic and Verbal Fluency Tests. Clinical (sex, age, type of MS, relapse, disease duration, coexisting disease, smoking habit, and physical disability) and laboratory variables (HHcy, low serum levels of folate and vit.B12, MTHFR genotype) were evaluated for their ability to predict cognitive impairment. The mean tHcy was higher in patients (13.19 micromol/L, SD5.58) than in controls (9.81 micromol/L, SD2.53; p < 0.001). Univariate analysis determined the following factors to be associated with cognitive impairment: higher age at observation, chronic progressive course of disease, longer disease duration,moderate or severe physical disability, and frequency of HHcy. With multivariate regression analysis, there remained a significant association only between frequency of HHcy and cognitive impairment (beta 0.262, p = 0.01). We conclude that tHcy levels are increased in MS and that HHcy is associated with cognitive impairment in this disease.

Fright is a provoking factor in vanishing white matter disease

Leukoencephalopathy with vanishing white matter is an inherited disorder with a chronic progressive disease course and additional episodes of rapid neurological deterioration. These episodes typically are provoked by febrile infections or minor head trauma. We report on two patients who experienced an episode of rapid neurological deterioration after a fright.

Functional outcome and quality of life in adult patients with idiopathic inflammatory myositis.

To present the outcome of patients with idiopathic inflammatory myositis, focusing on functional ability and quality of life. Analysis was performed using data from 105 adult patients with definitive polymyositis, dermatomyositis or overlap myositis, who were followed up at a single centre. The diagnosis was made between 1979 and 2000 based on Bohan and Peter's criteria. Functional ability was assessed after a minimum follow-up of 3 yr with the Health Assessment Questionnaire Disability Index (HAQDI) and quality of life was measured with the Short Form 36-item questionnaire (SF-36). Fifteen patients in our cohort died and 87 participated in the evaluation of functional outcome. Functional ability after a median follow-up of 107.1 months (range 36.4-273.3) was heterogeneous. The median HAQDI score was 0.875 (range 0-2.875). Polyphasic or chronic-progressive disease course, osteoporosis and long-term follow-up were predictive of higher HAQDI scores. In terms of quality of life, significant differences from population norms were shown in all domains of the SF-36. There were no significant differences in the SF-36 scores among the patients according to clinicopathological subset or disease course. Although the mortality of our cohort was favourable, myositis continues to have a great impact on life in the medium and long term. The present work indicates that myositis patients have a significantly poorer quality of life than the normal population, but there was no difference among the patients according to clinicopathological subsets.

Interleukin‐12 is detectable in sera of patients with multiple sclerosis — association with chronic progressive disease course?

Multiple sclerosis (MS) is widely accepted as a systemic T- cell-mediated autoimmune disease with a T-helper type-1 (TH-1) profile of cytokine production. We addressed the question whether interleukin-12 (IL-12), as a central mediator of TH-1-cell activities, is detectable in sera of MS patients, and if there is any association with disease activity. We analysed 171 sera of patients with MS and meningitis, and healthy controls. IL-12 p40 protein was detectable at low levels in MS patients (median 43 pg/ml) and controls (median 49 pg/ml). Analysing different disease courses and activities, a significant elevation in stable primary progressive MS cases compared with controls (median 66 pg/ml) was found. IL-12 p40 protein was not detectable in cerebrospinal fluid probes of 10 patients. We conclude that the function of IL-12 in MS depends on expression and degradation of the different proteins. These could act proinflammatory as well as limiting the disease process.

Differential Expression of Inflammatory Cytokines Parallels Progression of Central Nervous System Pathology in Two Clinically Distinct Models of Multiple Sclerosis

Multiple sclerosis is an immune-mediated demyelinating disease of unknown etiology that presents with either a chronic-progressive or relapsing-remitting clinical course. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) and relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4+ T cell-mediated demyelinating models that recapitulate the multiple sclerosis disease phenotypes. To determine the cellular and molecular basis for these observed differences in clinical course, we quantitatively analyzed the temporal expression of pro- and antiinflammatory cytokine mRNA expression in the central nervous system (CNS) and the phenotype of the inflammatory mononuclear infiltrates. TMEV-infected SJL/J mice expressed IFN-gamma, TNF-alpha, IL-10, and IL-4 mRNA during the preclinical phase, and their levels continued to increase throughout the duration of the chronic-progressive disease course. These data correlated with the continued presence of both CD4+ T cells and F4/80+ macrophages within the CNS infiltrates. In contrast, SJL/J mice with PLP(139-151)-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory cytokines, IFN-gamma and TNF-alpha, with expression peaking at the height of the acute phase and relapse(s). This pattern correlated with dynamic changes in the CD4+ T cell and F4/80+ macrophage populations during relapsing-remitting disease progression. Interestingly, IL-4 message was undetectable until disease remission(s), demonstrating its potential role in the intrinsic regulation of ongoing disease, whereas IL-10 was continuously expressed, arguing against a regulatory role in either disease. These data suggest that the kinetics of cytokine expression together with the nature of the persistent inflammatory infiltrates are major contributors to the differences in clinical course between TMEV-IDD and R-EAE.

Side effect profile of interferon beta-1b in MS: results of an open label trial.

To determine which patients are prone to side effects from interferon beta-1b and which side effects are most troublesome, we studied 72 patients with clinically definite MS who were started on interferon beta-1b after its release and found that the side effects significantly associated with treatment included skin reactions, flu-like symptoms, fatigue, leukopenia, new or worsened depression, and new or worsened headache. Of these, only fatigue and depression were significantly associated with discontinuance of therapy. Moreover, the course of disease before initiation of treatment also had a significant impact on the likelihood of discontinuing medication. Thus, despite an apparently similar therapeutic benefit (as judged by the similarly reduced attack rate in each group), patients with a secondary chronic progressive course were more likely to discontinue treatment (63%) than patients with either a relapsing/progressive course (18%) or a remitting/relapsing course (7%). Indeed, in the final regression equation, the only factors significantly related (r = 0.875) to the discontinuance of therapy were fatigue (p < 0.0001), a fatigue-depression interaction (p < 0.0001), and a chronic progressive course of disease (p<0.0001). Thus, if future clinical trials are to provide useful information on the value of interferon beta-1b in progressive MS, the side effects of fatigue and depression will need to be ameliorated to limit the drop-out rate from such trials.

Clustering of Residence of Multiple Sclerosis Patients at Age 13 to 20 Years in Hordaland, Norway

Geographic and temporal variation and migration studies point to an exogenous agent in the etiology of multiple sclerosis. If infectious etiology is involved, space-time clustering would also be expected. The authors analyzed 381 patients with a clinical onset of multiple sclerosis between 1953 and 1987 in the county of Hordaland, Norway. Patients within the same birth cohort had lived significantly closer to each other than would be expected during ages 13-20 years, with peak clustering at age 18 years (p = 0.002). Clustering was also shown between patients in pairs comprised of one individual with initial remittent disease and the other with chronic progressive course of disease, suggesting a similar etiology for both clinical patterns. Clustering between cases with widely divergent dates of clinical onset provides evidence of marked variation in latency. No similar clustering was observed in age-, sex-, and area-matched hospital controls without multiple sclerosis, and no clustering was found among the cases when using fixed number of years before onset. These results are compatible with a common infectious agent, such as the Epstein-Barr virus, acquired in adolescence in genetically vulnerable persons who are also not protected by an infection acquired before this age of susceptibility. Susceptibility could be related to the route of transmission or to other age-related covariates or it may be hormonally mediated.

Clinical parameters and intrathecal IgG synthesis as prognostic features in multiple sclerosis. Part I.

In a search for early prognostic features in multiple sclerosis, the progression rate was calculated in 200 consecutive multiple sclerosis patients who had had a lumbar puncture, and correlated with age at onset, type of disease course, the patient's sex, as well as with indices of blood-brain barrier breakdown and intrathecal IgG synthesis. The present study demonstrates that age at onset plays a role in determining whether the disease will be remitting-relapsing or chronic progressive. Age at onset is also a factor determining the rate of progression of the remitting-relapsing form, but is without influence on the progression of the chronic progressive form. A chronic progressive disease course per se (independent of age at onset) is also associated with a more rapid deterioration. The patient's sex does not appear to be a differentiating factor. Only inconsistent correlations were found between IgG index or number of oligoclonal bands in the CSF and disease progression.

Cellular immunity to encephalitogenic protein in multiple sclerosis. Correlations with other laboratory characteristics at different disease courses.

A very suggestive, although non-significant, correlation was found between cellular immunity to encephalitogenic protein in multiple sclerosis and the genetic marker HLA-B7 in patients with no disease activity during at least the past 5 years and in those with a chronic progressive disease course during recent years, but not in patients studied longitudinally after a relapse. Only the latter group showed a significant correlation with parameters indicating intrathecal synthesis of immunoglobulin. No correlation was demonstrable with a parameter indicating intrathecal synthesis of measles antibodies.