Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to α-synuclein localisation and expression of modifications associated with LBD. To determine whether α-synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of α-synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

[18F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in lewy body diseases

While [18F]-AV-1451 was developed as a positron emission tomography (PET) radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of “off-target” [18F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [18F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson’s disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n = 14). Associations with motor symptoms, cognition, and disease duration were evaluated using linear regression models. The dementia with Lewy bodies group had significantly reduced substantia nigra [18F]-AV-1451 binding compared to controls after adjusting for age (p < 0.05). However, there were no significant differences in substantia nigra [18F]-AV-1451 binding between Parkinson’s disease and controls. Substantia nigra [18F]-AV-1451 binding was not associated with age, disease duration, Movement Disorders Society—Unified Parkinson’s Disease Rating Scale and cognitive scores in dementia with Lewy bodies and Parkinson’s disease groups. Despite the reduction of substantia nigra [18F]-AV-1451 binding in dementia with Lewy bodies, these findings suggest that substantia nigra [18F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson’s disease. Further investigations in longitudinal cohorts are warranted.

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer’s and 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.

Insights into Lewy body disease from rare neurometabolic disorders

Professor 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.

Canadian Association of Neuropathologists L’Association Canadienne des Neuropathologistes

The Canadian Association of Neuropathologist – L’ Association Canadienne de Neuropathologistes (CANP-ACNP) held their 59th annual meeting at the Delta Kingston Waterfront from October 23rd to 26th, 2019, under the leadership of Dr. Peter Gould, President of the CANP-ACNP, Dr. Julia Keith, Secretary Treasurer of the CANP-ACNP, and Dr. John Rossiter, local organizer. The annual banquet was held at River Mill Restaurant in Kingston.The academic program comprised 14 Abstracts, 14 unknown cases, a Symposium on Neurodegenerative Neuropathology, and a Neuropathology Practice lecture by Dr. Gerard Jansen entitled CJD, CJD Surveillance, and Occupational Risk. Can worms ever be re-canned? The interactive forum on Neuropathology Practice was moderated by Dr. Gould and Dr. Keith and focused on safety around autopsy diagnosis of CJD, the Neuropathology workforce analysis in Canada 2019 presented by Dr. Patrick Shannon, and accreditation of neuropathology laboratories in Canada. Digital pathology images from the 14 unknown cases are available for viewing online (www.canp.ca) thanks to the CANP webmaster Dr. Jason Karamchandani.The Presidential Symposium 2019 on Neurodegenerative Neuropathology featured the Jerry Olszewski Lecture given by Dr. Douglas Munoz on Using eye tracking to identify behavioural biomarkers of neurodegeneration, the David Robertson lecture given by Dr. Tom Beach on Staging systems for Lewy body diseases, and the Gordon Mathieson lecture given by Dr. Ian Mackenzie on C9orf72: FTD, ALS and beyond. The program was completed Dr. Gabor Kovacs’ presentation on Tau pathologies in the aging brain and Dr. Carmela Tartaglia’s presentation on Dementia; the times they are a changing.The award for best clinical science presentation by a trainee (Dr. Mary Tom Award) in 2019 went to Dr. Suzy Kosteniuk (Supervisor Dr. Lothar Resch), and the award for best basic science presentation by a trainee (Dr. Morrison H. Finlayson Award) was won by Hoang D. Nguyen (Supervisor Dr. Maxime Richer).The following abstracts were presented at the 59th annual meeting of the Canadian Association of Neuropathologists – Association Candienne des Neuropathologistes (CANP-ACNP) in October 2019.