Immunotherapy in neurodegenerative diseases

Immunotherapy in neurodegenerative diseases
Theme: Ageing and dementia
Sunday 23rd April, 10:20 – 12:00

There has been an enormous effort over the last 20 years towards immunisation strategies against proteins that aggregate in the brain in Alzheimer's disease, Parkinson's disease and other neurodegenerative conditions. In 2021 Aducanumab was approved by the FDA and this has raised both hope and controversy. Alzheimer's disease and Lewy body diseases are the most common causes of neurodegeneration and dementia. Amyloid-beta (Aβ), tau and alpha-synuclein (α-syn) are  key proteins involved in the pathogenesis of these neurodegenerative diseases. Immunotherapy aims to reduce the harmful effects of protein accumulation by neutralising toxic species and facilitating their removal. The results of the first immunisation trial against Aβ led to a small percentage of meningoencephalitis cases which revolutionised vaccine design, causing a shift in the field of immunotherapy from active to passive immunisation. While the vast majority of immunotherapies have been developed for Aβ and tested in Alzheimer's disease, the field has progressed to targeting other proteins including α-syn. Despite showing some remarkable results in animal models, immunotherapies have largely failed final stages of clinical trials to date, with the exception of Aducanumab recently licenced in the US by the FDA. Neuropathological findings translate quite effectively from animal models to human trials, however cognitive and functional outcome measures do not. The apparent lack of translation of experimental studies to clinical trials suggests that we are not obtaining a full representation of the effects of immunotherapies from animal studies. This symposium will cover the pathology, imaging signs observed after immunotherapy, as well as experimental studies and a look to the future for the success of immunotherapy.

 James Nicoll, Southampton General Hospital, UK (co-chair): Pathology of immunotherapy in dementias

 Biography: James Nicoll was appointed to the Chair of Neuropathology at the University of Southampton in 2001. Having graduated in Medicine from the University of Bristol, he trained in Pathology in Oxford and Cardiff and returned to Bristol to undertake specialist training in Neuropathology. He completed his MD in Bristol investigating the role of herpes simplex virus in neurological disease using molecular tools. He then held a clinical academic post in Neuropathology at the Institute of Neurological Sciences/University of Glasgow. While in Glasgow he developed interests in the parallels between the response of the brain to acute injury, for example due to trauma or stroke, and Alzheimer's disease; specifically that they share common cellular reactions, upregulation of similar proteins and possibly share genetic influences.

In Southampton, Prof Nicoll has continued his research interests in neuroinflammation, neurodegeneration and cerebrovascular disease. His work closely links diagnostic neuropathology and neuroscience research. He and his colleagues were the first to describe and characterise the effects on the human brain of immunisation against Aβ, being used as potential therapy in Alzheimer's disease.

Talk Abstract: A unifying feature of neurodegenerative diseases is abnormal protein aggregation in the CNS.  For Alzheimer’s disease (AD), the amyloid cascade hypothesis puts accumulation of amyloid-β (Aβ) as a key initiating factor in the pathogenesis.  We have performed a long term neuropathology follow up of patients in the first trial of Aβ immunotherapy for AD.  The main findings include removal of plaques with an active vaccine, an effect that can last for as long as 14 years.  There were additional alterations in vascular pathology, inflammation and tau pathology, providing information related to disease pathogenesis.  These studies have helped to guide subsequent clinical trials of Aβ immunotherapy providing information on: (i) side effects encountered (“amyloid-related imaging abnormalities”); (ii) providing a possible explanation why most of these trials have shown only limited slowing of cognitive decline, potentially due to persisting spread of tau pathology through the brain, despite plaque removal; (iii) nearly a quarter of the subjects did not have AD as the cause of their dementia, highlighting the importance of biomarkers and imaging for more accurate diagnosis during life; and (iv) encouraging intervention earlier in the disease process.  In terms of pathogenesis, a sequence of Aβ accumulation followed by an inflammatory reaction which promotes tau accumulation and neurodegeneration explains much of the evidence.  It is proposed that different therapeutic targets are required for different stages of the disease process: Aβ for primary prevention, inflammation for secondary prevention and tau for established disease.  Recently, Aβ immunotherapy has been approved for clinical use in the United States.  Despite recent advances in imaging technology, these studies highlight the value of post mortem neuropathology in trials of therapy for neurodegenerative conditions.  Trials of immunotherapy targeting proteins of importance in other neurodegenerative conditions are in progress.

Chenxi Qiu, Harvard Medical School, USA (co-chair): Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice

Jean-Cosme Dodart, Vaxxinity, USA (co-chair): The UBITh platform in neurodegenerative diseases

Nivedita Agarwal, IRCCS Eugenio Medea, Italy: Amyloid Related Imaging Abnormalities after immunotherapy

​Session convened by the British Neuropathological Society.

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