Pan European Networks provides coverage of the AD/PD 2017 event in Vienna, which was designed to uniquely combine distinct neurodegenerative diseases in one setting
In April 2017, Pan European Networks attended the 13th International Conference on Alzheimer’s and Parkinson’s diseases and related neurological disorders in Vienna, Austria. The event, which attracted a multidisciplinary mix of participants representing both clinical investigators and basic scientists, as well as both established investigators and young researchers, was designed to uniquely combine distinct neurodegenerative diseases in one setting and examine their similarities and differences; a strong focus was placed on the mechanisms of disease, prevention, and therapy.
The event has an impressive history of attendance by Nobel laureates. Julius Axelrod, who was awarded the 1970 Nobel Prize in Physiology or Medicine presented in 1993, while Paul Greengard and Arvid Carlsson who received the 2000 Nobel Prize in Physiology or Medicine presented in 2001. Aaron Chiekanover who was awarded the 2004 Nobel Prize in Chemistry presented in 2011, and Ada Yonath who received the 2009 Nobel Prize in Chemistry presented in 2013. Thomas C. Südhof, who was awarded the 2013 Nobel Prize in Physiology or Medicine (shared with James Rothman and Randy Schekman) is an AD/PD veteran, having delivered speeches at the events in 2013 and 2015, returned again in 2017 to deliver a plenary address on ApoE, synapses, and Alzheimer’s disease.
Südhof, who is the Avram Goldstein Professor at Stanford University’s School of Medicine’s Department of Molecular & Cellular Physiology, USA, used his presentation to explain that humans express “three genetic isoforms of the gene encoding the apolipoprotein ApoE, ApoE2, ApoE3, and ApoE4, that differ by two residues. Of these genetic variants, ApoE4 represents the most important risk factor for Alzheimer’s disease, whereas ApoE2 protects against Alzheimer’s disease. In addition to serving as an apolipoprotein for LDL and VLDL particles in blood, ApoE is abundantly produced in brain by astrocytes, but its function in brain and the relation of that function to the role of ApoE in Alzheimer’s disease has remained unclear.” His speech went on to discuss his studies on human neurons that investigate a possible signalling function of ApoE, while relating this function to Alzheimer’s disease.
bold Gene silencing therapy
Another plenary address was delivered by Professor Don Cleveland from the Laboratory for Cell Biology at the Ludwig Institute for Cancer Research at the University of California in the USA. Discussing gene silencing therapy for human neurodegenerative disease, Cleveland explained that “the genes whose mutations causes human neurodegenerative disease are widely expressed within neurons and non-neurons of the nervous system, producing damage not only within the most vulnerable neurons but also within their partner neurons, glia, and endothelia. Sustained gene silencing or altered pre-mRNA splicing broadly within neurons and non-neurons throughout the nervous system has been achieved using a clinically feasible antisense oligonucleotide (ASO) injection into the nervous system.
“Beginning with the founding example for inherited ALS caused by mutation in superoxide dismutase, single doses of this ‘designer DNA-based’ drug approach have been shown to produce sustained, catalytic (RNase H-dependent) RNA degradation of a target gene, thereby producing slowing of disease progression (for ALS-like disease in rodents) or sustained partial disease reversal for Huntington’s-like disease from single dose injection.
“Therapy with ASO injection is now in trial for ALS, Huntington’s disease, and myotonic dystrophy. An additional trial using an ASO that corrects the splicing of the SMN2 gene has demonstrated efficacy in spinal muscular atrophy (SMA). A trial is anticipated to initiate in 2017 for the most frequent cause (hexanucleotide expansion in the C9orf72 gene) of both ALS and frontal temporal dementia. An extension of this approach is development of synthetic CRISPR RNAs to induce transient activation of Cas9 nuclease to cleave and permanently inactivate a selected target gene,” he concluded.
The plenary lecture delivered by Professor Virginia Lee, from the Perelman School of Medicine at the University of Pennsylvania, USA, was entitled ‘Transmission of α-synuclein strains in synucleinopathies’. Here, the professor informed her audience that the accumulation of pathological α-synuclein (α-syn) as Lewy bodies (LBs) in neurons is found in a number of neurodegenerative diseases including Parkinson’s disease without and with dementia, and dementia with Lewy bodies (DLB). “However,” she explained, “in multi-system atrophy (MSA) misfolded α-synuclein accumulates as glial cytoplasmic inclusions (GCIs) in oligodendrocytes suggesting that they could represent a different unique strain of synucleinopathies.”
It was here that the professor’s research has led, she said, to the discovery that pathological α-syn in GCIs and LBs (GCI-α-syn and LB-α-syn, respectively) are “conformationally and biologically distinct”. “GCI-α-syn forms more compact structures and is ~1,000-fold more potent than LB-α-syn in seeding α-syn aggregation, consistent with the highly aggressive nature of MSA,” she said.
Going on to discuss her results, Lee added: “Surprisingly, the seeding properties of GCI-α-syn and LB-α-syn show no cell type preference, raising the question of why they demonstrate different cell type distribution in diseased brains. Strikingly, we found that oligodendrocytes but not neurons could transform misfolded α-syn into GCI-like strain, highlighting that distinct α-syn strains could be generated by different intracellular milieus. Finally, GCI-α-syn maintains its high activity when propagated in neurons,” before concluding that “the properties of pathological α-syn are determined by both misfolded seeds and intracellular environments.”
Advances in Parkinson’s
Speaking about current developments in the treatment of Parkinson’s disease ‘from disease modification to prevention’, Professor Werner Poewe, director of the Department of Neurology at Innsbruck Medical University in Austria, used the opening of his plenary speech to describe how, over the past 50 years, the treatment of Parkinson’s disease has seen dramatic advances: “Ever since the discovery of striatal dopamine deficiency in the late 1950s substituting striatal dopamine has remained the gold standard approach. Levodopa has remained the gold standard of efficacy to reduce the cardinal motor symptoms of PD, but long-term efficacy is limited by the evolution of motor complications.
“Ever since the 1980s until today, drug delivery efforts concentrate on optimising levodopa pharmacokinetics and delivery and progress continues to evolve with current development programs of novel oral extended-release formulations, novel COMT-inhibitors, as well as formulations for novel delivery routes including intrapulmonary and subcutaneous levodopa delivery,” he said.
Alternative approaches at restoring striatal dopamine via cell-based therapies were pioneered in the 1980s, he went on, but these have remained challenging with important concerns raised by observations of Lewy-body formation in grafted neurons. “Delivery of dopamine synthesising enzymes via gene therapy is under current investigation with recent encouraging findings with a tri-cistronic vector encoding for TH, CH1 and AADC,” Poewe added.
He continued: “Drug therapy beyond the dopaminergic system has received much attention and effort in the past ten years, but so far with limited success. In contrast, multiple randomised controlled trials have established superiority of DBS versus best medical management in patients with levodopa-related motor complications and efforts continue to improve stimulation protocols, hardware and targets.”
For Poewe, the ‘Holy Grail’ of Parkinson’s disease (PD) therapy remains elusive, however. “While neuroprotection moved into the focus with the DATATOP trial in the late 1990s, the history of disease modification trials has remained largely disappointing. There is new hope with the identification of pathological synuclein processing and trafficking as a novel target and the first alpha-synuclein-devoted immunotherapy trials in PD are underway. The urgency of this development is also driven by important progress in identifying prodromal stages of PD opening up perspectives for preventive therapies for subjects at risk to develop PD,” he said.
On Saturday 1 April, Professor Keith Johnson, from Massachusetts General Hospital, USA, delivered a plenary lecture on staging pathology with PET, where he argued that “Amyloid-beta and tau protein fibril depositions, the defining pathologies of Alzheimer’s disease, can now be detected during life with molecular imaging using positron emission tomography. Quantitative, anatomically localised measures of amyloid-beta and tau deposits can disclose the presence and evolution of Alzheimer’s pathology in preclinical as well as clinical populations.
“Recent studies suggest that molecular measures relate to clinical diagnosis, cognitive performance, and likelihood of progression. Amyloid-beta measures are widely employed to determine eligibility for anti-amyloid therapeutic trials, but of perhaps greatest interest is recently available evidence indicating that the increase in tau pathologic burden occurs more rapidly than disease changes reflected in more established Alzheimer’s biomarkers. If these early indications from natural history studies are confirmed, efforts to develop therapies aimed at modifying Alzheimer’s pathology could be substantially more efficient.”
Blood brain barrier
Following this presentation, on Sunday 2 April, Professor Berislav V Zlokovic, from the Keck School of Medicine at the University of California’s Zilkha Neurogenetic Institute, USA, delivered the event’s final plenary lecture. Entitled ‘Blood brain barrier dysfunction, neurodegeneration and Alzheimer’s disease’.
Zlokovic argued that the tight interrelationship between blood vessels in the brain – which are organised with “surprising precision” and are “patterned in parallel with the major brain circuits tasked with sensation, memory and motion” may reflect “key functional roles in neuronal normal function, brain aging and diseases such as Alzheimer’s disease.”
His work is therefore involved with examining the cellular and molecular composition of the blood brain barrier (BBB) and the role of neurovascular unit in neurodegeneration in rare human monogenic disorders and complex neurological diseases such as Alzheimer’s disease. In his presentation, he made comparisons with animal transgenic models and explained how “the use of multiparametric magnetic resonance imaging (MRI) in the living human brain and animal brain, CSF biomarkers and tissue analysis can be used to evaluate how changes in brain microcirculation relate to brain connectivity and cognition.”
Discussing his preclinical findings, he explained that he has found that cellular and molecular findings in blood vessels and signalling in pericytes, endothelium and astrocytes that can lead to neurodegeneration in humans and animal models; the effects of AD risk genes (e.g., APOE4, PICALM, CLU) on blood vessels and BBB; new BBB imaging and molecular biomarkers in the living human brain in relation to cognitive impairment; and targets and treatments directed at the BBB that have advanced to Phase 3 and Phase 2 clinical studies in AD and stroke patients, respectively.
“It is probably a good time for us to begin thinking how to update our model of the AD pathophysiological cascade by including vascular dysfunction as a major contributor and/or a possible driver of disease pathogenesis,” he concluded.
The conference also played host to numerous symposia which tackled a range of subject areas. These were:β-Amyloid diseases (AD, prodromal AD, cerebral amyloid angiopathy (CAA), Down’s syndrome (DS) and mild cognitive impairment (MCI)), tauopathies (AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease and chronic traumatic encephalopathy)), α-synucleinopathies (PD, PD dementia, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), olivopontocerebellar atrophy (OPCA)), TDP-43- and C9orf72-related diseases (amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), ALS-FTD spectrum diseases), vascular dementia (multi-infarct dementia (MID), white matter disease and stroke), prion diseases (Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI) and Gerstmann-Straussler-Scheinker disease (GSSS)), Huntington’s disease (HD) and other neurodegenerative disorders, demyelinating diseases (multiple sclerosis (MS), leucodystrophy), lysosomal and storage diseases (Gaucher, Niemann Pick etc.), psychiatric and epileptic symptoms in neurodegenerative diseases, and patient care and caregiver support.
Pre-conference workshops were also available. The ‘Basic Neuropathology of Age-Associated Neurodegenerative Diseases’ workshop was, according to the AD/PD website, intended to provide the participant with ‘an understanding of the basic neuropathological features of age associated neurodegenerative diseases. This will include neuropathological hallmark lesions (e.g., amyloid-β plaques, neuritic plaques, neurofibrillary tangles/ threads, Lewy bodies/ neurites etc.) and an explanation how these lesions are assessed to classify diseases (e.g. neuritic Braak stages, amyloid-β phases, CERAD score, NIA-AA criteria, McKeith Criteria etc.)’ As it was not intended to showcase most recent neuropathological developments that would be of interest to an audience already familiar with neuropathology, it was essentially geared towards students, PhDs and physicians.
A pre-conference full day satellite workshop on the ‘common features of neurodegenerative diseases: exploring the brain-eye connection and beyond’ held that interdisciplinary research to compare and contrast human diseases is a key component of many academic and industry research programmes.’ The workshop was thus intended to provide participants with ‘an understanding of the common and distinct features of neurodegenerative diseases, which include not only those affecting the brain, such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementia; but also the ocular diseases including age-related macular degeneration, glaucoma, and diabetic retinopathy.’
The working group sought to discuss and identify knowledge and barriers to bridging ocular neuroscience with the broader field of neurodegenerative diseases, and provide thoughtful guidance to investigators seeking to meaningfully incorporate the idea of interdisciplinary research in their own research programmes.
The scope of the conference was very wide, and while only some of the areas have been discussed above, it is clear that the event was both ambitious and a success.
This article will feature in issue one of Pan European Networks: Health, due for publication in May.