Abstract
Background
The pathology of Corticobasal syndrome (CBS) is characterized by 4‐repeat (4R)‐tau aggregation in Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) in ∼50%, ...or by (3/4R)‐tau aggregation in Alzheimer’s disease (AD) in ∼25% of patients. The second generation tau‐PET ligand
18
F‐PI2620 showed high affinity to 3/4R‐tau in AD and also revealed affinity to 4R‐tau pathology. The aim of this study was to investigate
18
F‐PI2620 in patients with CBS that are part of the interdisciplinary AD study “Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer‘s Disease (ActiGliA)”.
Method
ActiGliA comprises a comprehensive clinical assessment, multimodal prospective imaging
in vivo
and fluid biomarker analyses. Thirty‐five patients (70±8y) with probable or possible CBS according to MDS‐PSP or Armstrong‐criteria underwent
18
F‐PI2620 PET together with ten age‐matched healthy‐controls. Distribution volume ratios (DVR, 0‐60 min) of subcortical and cortical brain‐regions were generated using cerebellar reference tissue. DVR‐data were quantitatively and visually compared between CBS and healthy‐controls. Regional
18
F‐PI2620 binding was compared with clinical severity (PSP rating scale, PSPRS), and disease duration. Amyloid‐PET served for assessment of β‐amyloid status.
Result
26% (9/35) of CBS patients (PSPRS: 25±13) were amyloid‐positive. Overall, a visually discernible
18
F‐PI2620 was observed in 26 subjects (74%) and in 89% of amyloid‐positive CBS patients. Significantly elevated
18
F‐PI2620 DVR was observed in the whole group of CBS patients versus healthy controls in the putamen, globus pallidus and subthalamic nucleus (Cohen’s d: 1.19/ 1.44/ 1.11, all p<0.01). The cortical signal was higher in amyloid‐positive when compared to amyloid‐negative CBS patients (DVR: 1.05±0.15 vs. 0.95±0.05, p=0.005, Figure 1). Cortical binding in CBS was heterogeneous (positive in 49%; 17/35, Figure 2). Asymmetry of PET tracer uptake matched the contralateral clinical dominance in 94% of CBS cases.
18
F‐PI2620 binding showed a correlation with disease severity in the globus pallidus after controlling for age, sex and β‐amyloid‐status (R=0.426, p=0.021).
Conclusion
The application of
18
F‐PI2620 in the ActiGliA study shows that
18
F‐PI2620 is a potential biomarker for evaluation of CBS, facilitating detection of heterogeneous neuropathology and variable cortical and subcortical deposition sites, which could serve for monitoring disease status, progression, and target engagement.
Progressive supranuclear palsy is a sporadic and progressive neurodegenerative disease, most often presenting as a symmetric, akinetic-rigid syndrome with postural instability, vertical supranuclear ...gaze palsy and frontal lobe deficits. It belongs to the family of tauopathies and involves both cortical and subcortical structures. Although the exact pathophysiology is not yet fully understood, several lines of evidence point to a crucial contribution from both genetic predisposition and mitochondrial dysfunction. Recently gained insights into the pathophysiology of this disease have led to several hypothesis-driven therapeutic approaches aiming at disease-modification rather than mere symptomatic neurotransmitter-replacement therapy. Agents targeting mitochondrial dysfunction have already shown a positive effect in a phase II study and further studies to verify and expand these results are ongoing. Clinical studies with agents targeting tau dysfunction such as tau-kinase inhibitors, tau-aggregation inhibitors and microtubule stabilizers are in preparation or ongoing. This review presents the current pathophysiological concepts driving these exciting therapeutic developments.
Abstract Gaucher disease is an autosomal recessive disease, caused by a lack or functional deficiency of the lysosomal enzyme, glucocerebrosidase (GCase). Recently, mutations in the ...glucocerebrosidase gene (GBA) have been associated with Parkinson's disease (PD) and GBA mutations are now considered the most important genetic vulnerability factor for PD. In this study, we have investigated (i) in vivo whether inhibition of the enzyme glucosylceramide synthase by miglustat may protect C57Bl/6 mice against subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication and (ii) in vitro whether a decrease of GCase activity may render dopaminergic neurons susceptible to MPP+ (1-methyl-4-phenylpyridinium) or alpha-synuclein (α-Syn) toxicity and amenable to miglustat treatment. We could demonstrate that reduction of glucocerebroside by inhibition of glucosylceramide synthase partially protects mice against MPTP-induced toxicity. Conversely, we could show that inhibition of GCase activity with conduritol-B-epoxide (CBE) enhances both α-Syn and MPP+ induced toxicity in vitro . However, only CBE-induced enhancement of MPP+ toxicity could be reversed by miglustat. Moreover, we were unable to reveal any alterations of complex I activity or cell respiration upon treatment with either CBE or miglustat. Our findings suggest that the reduction of GCase activity rather than an accumulation of glucocerebroside increases aSyn toxicity.
► Most dopaminergic neurons express neuregulin-1 receptor ErbB4 in the human substantia nigra. ► Rate of ErbB4 expression in remaining nigral dopaminergic neurons increases in Parkinson disease. ► ...Mean ErbB4 expression per nigral dopaminergic neuron is increased in Parkinson disease. ► Cultured human midbrain dopaminergic neurons upregulate ErbB4 when exposed to MPP+ or 6-OHDA. ► Diseased dopaminergic neurons might be susceptible to neuregulin-1 treatment in Parkinson disease.
Previously we demonstrated that systemically administered neuregulin-1-β1, a nerve growth and differentiation factor, passed the blood–brain barrier and accumulated in brain areas with expression of its receptor ErbB4. In substantia nigra (SN), neuregulin-1-β1 phosphorylated ErbB4 and protected dopaminergic neurons in a toxin-based mouse model of Parkinson disease (PD). We studied ErbB4 in the context of human midbrain dopaminergic degeneration in vivo and in vitro. Post-mortem ventral midbrain tissue sections of neuropsychiatric healthy individuals and PD patients (matched for age, gender and post-mortem delay) were immunostained for ErbB4. Cultured Lund human mesencephalic (LUHMES) post-mitotic dopaminergic neurons were treated with dopaminergic toxins and analyzed for ErbB4 expression. In control individuals, 85.0±5.0% of dopaminergic neurons, containing cytoplasmic neuromelanin, expressed ErbB4 in the SN. In PD cases, the percentage of ErbB4-positive nigral dopaminergic neurons was increased to 94.9±2.5%. The mean ErbB4 immunoreactivity of melanized neurons was higher in PD than controls. LUHMES neurons upregulated ErbB4 when exposed to toxins 1-methyl-4-phenylpyridinium and 6-hydroxydopamine. Increased rate of ErbB4-positive dopaminergic neurons in PD may either reflect a better survival of ErbB4-positive neurons or an increased expression of ErbB4 by remaining neurons to seek trophic support. Enhanced ErbB4 expression in human in vitro toxin-based PD models supports the latter interpretation. Thus, dopaminergic neurons in SN might be susceptible to neuregulin-1 treatment in PD.
Abstract Introduction The aim of this German national guideline is to optimize the clinical care of patients with Parkinson's disease (PD) in terms of diagnostics, drug and surgical treatment and ...care. Summary or definition of the topic This guidance was prepared for the German Society of Neurology (DGN) in collaboration with the Austrian Society of Neurology (ÖGN) and the Swiss Neurological Society (SNG) for German-speaking countries. The guidelines for the diagnosis and treatment of PD have been revised by a national expert group and the guideline commission of the DGN at S2k level. The main objective of these guidelines is to optimize the clinical care of PD patients regarding diagnosis, including early detection, technical diagnostic examinations, and pharmacological as well as invasive treatment options. Recommendations The updated PD diagnosis and treatment guidelines are emphasizing optimized clinical care. Key revisions include preferring the name "Parkinson's disease" over previous terms and adopting International Parkinson and Movement Disorder Society (MDS) diagnostic criteria. Recommendations cover genetic and imaging diagnostics, initial pharmacotherapy considering efficacy and patient factors, and tailored pharmacological combinations for complications. Guidelines extend to managing cognitive, affective, psychotic, and autonomic symptoms, along with non-oral therapies like pump therapy and deep brain stimulation. Special situations like akinetic crisis, driving ability, and care concepts are addressed, ensuring comprehensive management for PD patients at various stages and conditions. Conclusions This guidance reflects the state of the art at the beginning of 2024.
Dietary supplements containing plant materials of Annonaceae species (Annona muricata L., A. squamosa L., A. mucosa JACQ., A. squamosa × cherimola Mabb.) were extracted by hot, pressurized ethyl ...acetate and analyzed for their effect in vitro on Lund human mesencephalic neurons. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell death was determined by lactate dehydrogenase levels. Three supplements strongly decreased the cell viability at extract concentrations of 1 µg/mL, of which 1 decreased cell viability at 0.1 µg/µL. Also, strong neuronal toxicities of these supplements were found. Cell death was observed at concentrations of 10 µg/mL. The degree of toxicity was comparable to the ones found in Annonaceous fruit extracts. Two fruit pulps of Annonaceae (A. muricata and A. squamosa) showed a reduction in cell viability at lower concentrations. The fruit pulp extract of A. muricata revealed the strongest neurotoxic effect, with 67% cell death at a concentration of 1 µg/mL. A high reduction in cell viability coupled with pronounced cell death was found at 0.1 µg/mL for an Annonaceous seed extract. These results demonstrate that the intake of dietary supplements containing plant material from Annonaceae may be hazardous to health in terms of neurotoxicity.
Abstract Purpose To further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8+ T ...lymphocytes in humans. Methods In 15 healthy subjects (9 female (60%), 35.7 ± 12.1 years), apoptosis and cytotoxic function of CD8+ T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10 mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2 h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8+ T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR). Results High concentration of LEV decreased perforin release of CD8+ T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5–35.9%) vs. 16.6% (IQR 12–24.9%), p = 0.002). LEV had no influence on apoptosis and proliferation ( p > 0.05). VPA (100 mg/L) slowed apoptosis of CD8+ T lymphocytes after 24 h (VPA 100 mg/L vs. control: 7.3% (IQR 5.4–9.5%) vs. 11.3% (IQR 8.2–15.1%), p < 0.001), but had no effects on perforin release ( p > 0.05). SV2A protein was detected in CD8+ T lymphocytes. Conclusion LEV decreased degranulation of CD8+ T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect.
Aim
P
301
S
MAPT
transgenic mice (
P
301
S
mice) are a widely used model of frontotemporal dementia and parkinsonism linked to chromosome 17 with tau pathology (
FTDP
‐17‐tau). However, a ...systematic correlation between cognitive deficits and cellular tau pathology at different ages is still missing. Therefore, our study investigated memory deficits of
P
301
S
mice in relation to pathological tau species and dendritic spine pathology throughout adulthood.
Methods
We analysed
P
301
S
mice behaviourally with the novel open field, rotarod, and Morris water maze tests to measure deficits in locomotion, balance and cognition, respectively; immunohistochemically with different tau antibodies for specific tau species; and with
G
olgi staining for dendritic spine pathology.
Results
We confirmed the occurrence of locomotor deficits at an age of 5 months and newly report memory deficits from 2.5 months of age onwards. At this early age,
MC
1 and
CP
13, but not
AT
180 immunoreactivity, was prominent in the hippocampus of
P
301
S
mice. Neuronal cell loss in the hippocampus of
P
301
S
mice was not observed to occur till 6 months of age. However, there was a significant reduction in the density of dendritic spines from young adulthood onwards in hippocampal pyramidal neurones.
Conclusion
In
P
301
S
mice, memory deficits precede the onset of locomotor dysfunction and coincide with the appearance of conformationally changed,
S
202‐phosphorylated tau and reduced spine density in the absence of neuronal cell loss in the hippocampus. Our finding provides insights into the toxic effects of different tau species
in vivo
and may facilitate the development of new therapies against neurodegenerative tauopathies.
J. Neurochem.
(2011)
117
, 1066–1074.
Abstract
Neuregulin‐1 (Nrg1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The Nrg1 receptor ...ErbB4 is abundantly expressed on midbrain dopaminergic neurons. Nrg1 has been shown to penetrate blood‐brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of Nrg1 in the context of Parkinson’s disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of Nrg1β
1
(Nrg1β
1
‐ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. Nrg1β
1
‐ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6‐hydroxydopamine‐induced toxicity
in vivo.
Moreover, Nrg1β
1
‐ECD also protected human dopaminergic neurons
in vitro
against 6‐hydroxydopamine. In conclusion, we have identified Nrg1β
1
‐ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for Parkinson’s disease patients.
Neuregulin-1 (Nrg1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The Nrg1 receptor ErbB4 is abundantly expressed on midbrain ...dopaminergic neurons. Nrg1 has been shown to penetrate blood-brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of Nrg1 in the context of Parkinson's disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of Nrg1β1 (Nrg1β1-ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. Nrg1β1-ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6-hydroxydopamine-induced toxicity in vivo. Moreover, Nrg1β1-ECD also protected human dopaminergic neurons in vitro against 6-hydroxydopamine. In conclusion, we have identified Nrg1β1-ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for Parkinson's disease patients. PUBLICATION ABSTRACT
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