Insights into Lewy body disease from rare neurometabolic disorders

Journal of Neural Transmission ◽

10.1007/s00702-021-02355-7 ◽

2021 ◽

Author(s):

Daniel Erskine ◽

Johannes Attems

Keyword(s):

Rare Diseases ◽

Neurodegenerative Disorders ◽

Early Life ◽

Lewy Body ◽

Lewy Body Disease ◽

Neuroaxonal Dystrophy ◽

Infantile Neuroaxonal Dystrophy ◽

Disease Mechanisms ◽

Neurometabolic Disorders ◽

Lewy Body Diseases

AbstractProfessor Kurt Jellinger is well known for his seminal work on the neuropathology of age-associated neurodegenerative disorders, particularly Lewy body diseases. However, it is less well known that he also contributed important insights into the neuropathological features of several paediatric neurometabolic diseases, including Alpers–Huttenlocher syndrome, a syndrome of mitochondrial disease caused by POLG mutations, and infantile neuroaxonal dystrophy, a phenotype resulting from PLA2G6 mutations. Despite these rare diseases occurring in early life, they share many important pathological overlaps with age-associated Lewy body disease, particularly dysregulation of α-synuclein. In this review, we describe several neurometabolic diseases linked to Lewy body disease mechanisms, and discuss the wider context to pathological overlaps between neurometabolic and Lewy body diseases. In particular, we will focus on how understanding disease mechanisms in neurometabolic disorders with dysregulated α-synuclein may generate insights into predisposing factors for α-synuclein aggregation in idiopathic Lewy body diseases.

Download Full-text

Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer’s and Lewy Body Diseases

Journal of Alzheimer s Disease ◽

10.3233/jad-210147 ◽

2021 ◽

pp. 1-8

Author(s):

Mychael V. Lourenco ◽

Felipe C. Ribeiro ◽

Luis E. Santos ◽

Danielle Beckman ◽

Helen M. Melo ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Neurodegenerative Disorders ◽

Lewy Body ◽

Lewy Body Disease ◽

Brain Inflammation ◽

Vascular Endothelial ◽

Future Studies ◽

Cytokines And Chemokines ◽

Endothelial Growth Factor ◽

Lewy Body Diseases

Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. Objective: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. Methods: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). Results: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. Conclusions: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Download Full-text

New Tracers and New Perspectives for Molecular Imaging in Lewy Body Diseases

Current Medicinal Chemistry ◽

10.2174/0929867324666170609080000 ◽

2018 ◽

Vol 25 (26) ◽

pp. 3105-3130 ◽

Cited By ~ 6

Author(s):

Matteo Bauckneht ◽

Dario Arnaldi ◽

Flavio Nobili ◽

Dag Aarsland ◽

Silvia Morbelli

Keyword(s):

Molecular Imaging ◽

Neurodegenerative Disorders ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Accurate Diagnosis ◽

Imaging Biomarkers ◽

Number Of Individuals ◽

New Evidence ◽

Lewy Body Diseases

The term Lewy body diseases (LBDs) refers to a subset of neurodegenerative disorders that share the accumulation of the so-called Lewy bodies (LB) including: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and PD later characterized by the occurrence of dementia (PDD). Moreover, multiple system atrophy (MSA) and idiopatic Rem Sleeping behaviour disorders (RBD) complete the group of synucleinopathies and have also common symptoms with respect to LBDs. The clinical diagnosis of LBDs can be challenging for physicians, particularly in the early stages of disease. Given the growing number of individuals affected by these neurodegenerative disorders, early and accurate diagnosis can lead to improved clinical management of patients. For this reason, information obtained from molecular imaging biomarkers is playing an increasingly important role in this framework. The present narrative review discusses both established milestones and new evidence on the use of molecular imaging tracers already part of the clinical practice as well as available evidence on new molecular imaging approaches in PD, PDD and DLB.

Download Full-text

Expression of Cellular Prion Protein in the Frontal and Occipital Lobe in Alzheimer's Disease, Diffuse Lewy Body Disease, and in Normal Brain: An Immunohistochemical Study

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.4a6551.2005 ◽

2005 ◽

Vol 53 (8) ◽

pp. 929-940 ◽

Cited By ~ 18

Author(s):

Payam Rezaie ◽

Charlie C. Pontikis ◽

Lance Hudson ◽

Nigel J. Cairns ◽

Peter L. Lanto

Keyword(s):

Image Analysis ◽

Human Brain ◽

Prion Protein ◽

Neurodegenerative Disorders ◽

Lewy Body ◽

Lewy Body Disease ◽

Occipital Cortex ◽

Cellular Prion Protein ◽

Diffuse Lewy Body Disease ◽

Normal Human

Cellular prion protein (PrPc) is a glycoprotein expressed at low to moderate levels within the nervous system. Recent studies suggest that PrPc may possess neuroprotective functions and that its expression is upregulated in certain neurodegenerative disorders. We investigated whether PrPc expression is altered in the frontal and occipital cortex in two well-characterized neurodegenerative disorders—Alzheimer's disease (AD) and diffuse Lewy body disease (DLBD)—compared with that in normal human brain using immunohistochemistry and computerized image analysis. The distribution of PrPc was further tested for correlation with glial reactivity. We found that PrPc was localized mainly in the gray matter (predominantly in neurons) and expressed at higher levels within the occipital cortex in the normal human brain. Image analysis revealed no significant variability in PrPc expression between DLBD and control cases. However, blood vessels within the white matter of DLBD cases showed immunoreactivity to PrPc. By contrast, this protein was differentially expressed in the frontal and occipital cortex of AD cases; it was markedly overexpressed in the former and significantly reduced in the latter. Epitope specificity of antibodies appeared important when detecting PrPc. The distribution of PrPc did not correlate with glial immunoreactivity. In conclusion, this study supports the proposal that regional changes in expression of PrPc may occur in certain neurodegenerative disorders such as AD, but not in other disorders such as DLBD.

Download Full-text