Die Pathogenese der HIV-Demenz

Trotz hoch aktiver antiretroviraler Therapie ist die Prävalenz von HIV-assoziierten neurokognitiven Störungen hoch. Die "Bystander Hypothese" postuliert mikroglial vermittelte Neurotoxizität unabhängig von viraler Replikation und Viruslast im Zentralnervensystem. Um dies zu untersuchen wurde ein Zellkulturmodell basierend auf primärer humaner Mikroglia und HIV-Partikel infizierten monozytären Zellen entwickelt. Als virale Determinanten mikroglialer Aktivierung wurden die frühen Schritte der Infektion und die Anwesenheit von viraler RNA im monozytären Zytosol identifiziert. Die Expression weiterer HIV-kodierter Gene hatte keinen verstärkenden Einfluss auf mikrogliale Aktivierung. Die funktionelle Relevanz entsprechender Zytokine wurde durch eine positive Korrelation mit Neurofilament H in Liquor cerebrospinalis von neurokognitiv asymptomatischen HIV-positiven Patienten bestätigt. Dies trägt zu einem tieferen Verständnis der inflammatorischen Vorgänge von Mikroglia in diesem Kontext bei

Longitudinal evaluation of the effect of tricyclic antidepressants and neuroleptics on the course of Huntington's disease

$\textbf {Background:}$ Reducing the progress of neurodegeneration is a key goal in Huntington's disease (HD). A previously performed systematic screening for medications with neuroprotective features identified tricyclic antidepressants and neuroleptics as neuroprotective and mitochondrioprotective agents. Here, we analyzed the characteristics of disease manifestation, progression and potential beneficial effects in HD patients treated with afore-mentioned medications compared to un- and otherwise treated motor-manifest patients in a large real-world cohort over two years. $\textbf {Methods:}$ We analyzed cross-sectional data of the largest cohort worldwide of motor-manifest HD patients using the ENROLL-HD database, including demographic, moleculargenetic, clinical-motoric, cognitive and functional data. Longitudinal data of up to two years were obtained to analyze potential effects on disease progression between groups with different medications used. Data were analyzed using repeated ANOVA-analyses while controlling for the co-variates age and CAG-repeat length. $\textbf {Results:}$ We identified $\it n$ = 7397 motor-manifest HD patients using no or different medication (HD-ctrl) and subgroups treated with clomipramine ($\it n$ = 56), clozapine ($\it n$ = 66), chlorpromazine ($\it n$ = 17), doxepine ($\it n$ = 34) and desi-, imi- or trimipramine ($\it n$ = 19). Demographic parameters, disease onset and CAP-score did not differ. Total motor scores (TMS) at baseline were higher in patients treated with clozapine ($\it p$ < 0.001), chlorpromazine and clomipramine ($\it p$ < 0.05) compared to HD-ctrl with higher sub scores for bradykinesia (all $\it p$ < 0.01) and dystonia in clozapine treated patients ($\it p$ < 0.001). Functional and cognitive capacities were worse in medication groups in comparison to HD-ctrl at baseline ($\it p$ < 0.001). Repeated measures analysis of variance documented no differences regarding motoric, functional and cognitive disease progressions between groups. $\bf Conclusions:$ We identified group differences, potentially caused by side effects or potential selection bias in terms of bradykinetic motoric symptoms, more dystonia and lower functional and cognitive performance in some treatment groups at baseline, which were not entirely explained because of underlying fundamental characteristics. Disease progression regarding clinical, functional and cognitive outcomes over two years was not affected by any of the treatment groups compared to HD-ctrl. Our data do not support our hypothesis of a potential neuroprotective effect of these drugs on disease progression

Contemplating dichotomous nature of gamma delta T cells for immunotherapy

$\gamma$$\delta$ T cells are unconventional T cells, distinguished from $\alpha$$\beta$ T cells in a number of functional properties. Being small in number compared to $\alpha$$\beta$ T cells, $\gamma$$\delta$ T cells have surprised us with their pleiotropic roles in various diseases. $\gamma$$\delta$ T cells are ambiguous in nature as they can produce a number of cytokines depending on the (micro) environmental cues and engage different immune response mechanisms, mainly due to their epigenetic plasticity. Depending on the disease condition, $\gamma$$\delta$ T cells contribute to beneficial or detrimental response. In this review, we thus discuss the dichotomous nature of $\gamma$$\delta$ T cells in cancer, neuroimmunology and infectious diseases. We shed light on the importance of equal consideration for systems immunology and personalized approaches, as exemplified by changes in metabolic requirements. While providing the status of immunotherapy, we will assess the metabolic (and other) considerations for better outcome of $\gamma$$\delta$ T cell-based treatments

Antineuroinflammatory drugs in HIV-associated neurocognitive disorders as potential therapy

Today, HIV-infected (HIV+) patients can be treated efficiently with combined antiretroviral therapy (cART), leading to long-term suppression of viral load, in turn increasing life expectancy. While cART reduced the occurrence of HIV-associated dementia, the prevalence of subtle forms of HIV-associated neurocognitive disorders (HAND) is unchanged. This is related to persistent immune activation within the CNS, which is not addressed by cART. Pathologic processes leading to HAND consist of the release of proinflammatory cytokines, chemokines, reactive oxygen metabolites and glutamate, and the release of HIV proteins. Some of those processes can be targeted using medications with immunomodulatory and neuroprotective properties such as dimethyl fumarate, teriflunomide, or minocycline. In this review, we will summarize the knowledge about key pathogenic processes involved in HAND and potential therapeutic avenues to target HAND

Positive effect of immunomodulatory therapies on disease progression in Huntington’s disease?

$\bf Background:$ The role of neuroinflammation and autoimmune processes in neurodegenerative diseases is not fully understood. Activation of microglia with expression of proinflammatory cytokines supports the hypothesis that immune processes may play an important role in the pathophysiology of Huntington’s disease (HD) and thus, immunomodulating therapies might have potential neuroprotective properties. Until now, no disease-modifying therapy (DMT) is available for HD. $\bf Objective:$ The aim of this research was to characterize a cohort of patients suffering from both HD and autoimmune demyelinating diseases of the central nervous system (classified as G35-37 in ICD-10; ADD-CNS) in comparison to HD cases without ADD-CNS. In particular, we were interested to investigate potential modulating effects on disease manifestation and progression of HD over time of prescribed immunomodulating medications (DMT). $\bf Methods:$ We analyzed the course of HD regarding motoric, functional, and cognitive aspects, using longitudinal data of up to 2 years from the worldwide registry study ENROLL-HD. Additional cross-sectional data in the largest cohort worldwide of HD patients was analyzed using demographic and molecular genetic parameters. Data were analyzed using analysis of variance (ANOVA) for cross-sectional and repeated-measures ANOVA for longitudinal parameters in IBM SPSS Statistics V.27. $\bf Results:$ Within the ENROLL-HD database, we investigated $\it N$ = 21,116 participants and identified $\it n$ = 60 participants suffering from ADD-CNS. Molecular, genetic, and demographic data did not differ between groups. The subgroup of $\it n$ = 32 participants with motor-manifest HD revealed better cognitive performance in five out of eight cognitive tests at baseline with less progression over time in two tests (all $\it p$ < 0.05). Differentiation between DMT-treated and untreated patients revealed better cognitive and motor performance in the DMT group; those patients, however, tended to be younger. Pre-manifest HD patients simultaneously diagnosed with ADD-CNS ($\it n$ = 12) showed lower functional scores and more decline over time when compared with other pre-manifest HD ($\it p$ < 0.05). $\bf Conclusion:$ Patients suffering from motor-manifest HD and simultaneously from ADD-CNS have better cognitive capacities compared with other motor-manifest HD patients. Moreover, DMTs might have beneficial effects on progression of neurodegeneration including the motor phenotype. However, this effect might have been biased by younger age in DMT-treated patients. Pre-manifest HD patients showed more functional impairment as expected due to their additional ADD-CNS disease

Endocarditis following ocrelizumab in relapsing-remitting MS

Ocrelizumab is a monoclonal anti-CD20 antibody targeting B cells, which is authorized for relapsing-remitting MS (RRMS) and active primary progressive MS. Here, we report, to the best of our knowledge, the first case of infective endocarditis in a patient treated with ocrelizumab

Cross-sectional analysis of clinical aspects in patients with long-COVID and post-COVID syndrome

$\bf Objective:$ Regarding pathogenesis, clinical manifestations, at-risk individuals, and diagnostic methods for stratifying patients for therapeutic approaches, our understanding of post-COVID syndrome is limited. Here, we set out to assess sociodemographic and clinical aspects in patients with the long-COVID and post-COVID syndrome. $\bf Methods:$ We performed a cross-sectional analysis of patients presenting at our specialized university hospital outpatient clinic. We assessed patients' clinical presentation, fatigue, symptoms of depression and anxiety, and impairment of smell. $\bf Results:$ A total of 101 patients were included (73.3% female), of whom 78.2% had a mild course of COVID-19. At presentation, 93.1% suffered from fatigue, 82.2% from impaired concentration, and 79.2% from impaired memory, 53.5% had impaired sleep. The most common secondary diagnosis found in our cohort was thyroid disease. Fatigue analysis showed that 81.3% of female and 58.8% of male patients had severe combined fatigue. Female gender was an independent risk factor for severe fatigue (severe cognitive fatigue OR = 8.045, $\it p$ = 0.010; severe motor fatigue OR = 7.698, $\it p$ = 0.013). Males suffered from more depressive symptoms, which correlated positively with the duration of symptom onset. 70.3% of patients with anamnestic smell impairment had hyposmia, and 18.9% were anosmic. $\bf Interpretation:$ Most long-COVID patients suffered from severe fatigue, with the female sex as an independent risk factor. Fatigue was not associated with symptoms of depression or anxiety. Patients with long-COVID symptoms should receive an interdisciplinary diagnostic and therapeutic approach depending on the clinical presentation

Clozapine regulates microglia and is effective in chronic experimental autoimmune encephalomyelitis

$\bf Objective:$ Progressive multiple sclerosis is characterized by chronic inflammation with microglial activation, oxidative stress, accumulation of iron and continuous neurodegeneration with inadequate effectiveness of medications used so far. We now investigated effects of iron on microglia and used the previously identified neuroprotective antipsychotic clozapine $\textit {in vitro}$ and in chronic experimental autoimmune encephalomyelitis (EAE). $\bf Methods:$ Microglia were treated with iron and clozapine followed by analysis of cell death and response to oxidative stress, cytokine release and neuronal phagocytosis. Clozapine was investigated in chronic EAE regarding optimal dosing and therapeutic effectiveness in different treatment paradigms. Animals were scored clinically by blinded raters. Spinal cords were analyzed histologically for inflammation, demyelination, microglial activation and iron accumulation and for transcription changes of regulators of iron metabolism and inflammation. Effects on immune cells were analyzed using flow cytometry. $\bf Results:$ Iron impaired microglial function $\textit {in vitro}$ regarding phagocytosis and markers of inflammation; this was regulated by clozapine, reflected in reduced release of IL-6 and normalization of neuronal phagocytosis. In chronic EAE, clozapine dose-dependently attenuated clinical signs and still had an effect if applied in a therapeutic setting. Early mild sedative effects habituated over time. Histologically, demyelination was reduced by clozapine and positive effects on inflammation strongly correlated with reduced iron deposition. This was accompanied by reduced expression of DMT-1, an iron transport protein. $\bf Conclusions:$ Clozapine regulates microglial function and attenuates chronic EAE, even in a therapeutic treatment paradigm. This well-defined generic medication might therefore be considered as promising add-on therapeutic for further development in progressive MS