Hearing Loss, Epilepsy May Be Early Signs of Parkinson's

 Hearing loss and epilepsy were associated with a future diagnosis of Parkinson's disease, an observational study of primary care records in East London showed.

Among ethnically diverse primary care patients, epilepsy (OR 2.5, 95% CI 1.63-3.83) and hearing loss (OR 1.66, 95% CI 1.06-2.58) were linked with a subsequent Parkinson's diagnosis, reported Alastair Noyce, PhD, of Queen Mary University of London, and co-authors in JAMA Neurology.

Known symptoms associated with Parkinson's disease, such as tremor and memory problems, were spotted in primary care records years before diagnosis. Tremor was seen up to a decade before (OR 11.66, 95% 6.59-20.64) and memory symptoms emerged 2 to 5 years (OR 3.08, 95% CI 1.81-5.24) before Parkinson's was diagnosed.

"People see their GPs with symptoms but often don't get a diagnosis until 5 to 10 years after this," Noyce said in a statement.

"Tremor, for example, is one of the most recognizable symptoms of Parkinson's, but was seen 10 years before eventual diagnosis in our study," he pointed out. "This is too long for patients to wait."

The primary care setting often is where symptoms that herald the onset of Parkinson's are first discussed, observed Bhavana Patel, DO, of the University of Florida in Gainesville, and co-authors in an accompanying editorial. "However, little is known regarding the prediagnostic manifestations of Parkinson's disease that are seen in primary care clinics, particularly in underserved populations," they wrote.

"As neuroprotective and disease-modifying treatments become available for Parkinson's disease, early identification and specialist referrals will depend on primary care clinicians," Patel and colleagues added.

The researchers conducted a nested case-control study using electronic health records from 1990 to February 2018 in primary care practices in East London. In total, 1,055 people with a Parkinson's diagnosis were matched with 10,550 controls.

In East London, 45% of residents are Black, South Asian, or members of other ethnic groups. Overall, 80% of study participants were from low-income households.

Noyce and co-authors selected 24 exposures based on previous studies of prediagnostic signs and risk factors. "Epilepsy and hearing loss were included given preliminary evidence that these might be prediagnostic features of Parkinson's disease," they noted. Three time periods -- less than 2 years, 2 to less than 5 years, and 5 to 10 years before diagnosis -- were analyzed.

As expected, the researchers identified constipation, fatigue, insomnia, dizziness, cognitive impairment, shoulder pain, and tremor as prediagnostic concerns in the Parkinson's disease group.

They also found many markers included in prodromal Parkinson's research criteria: never smoking, type 2 diabetes, parkinsonism, constipation, hypotension or dizziness, erectile dysfunction, depression, anxiety, and global cognitive deficits.

The researchers saw no relationship between ethnicity or economic deprivation and Parkinson's diagnoses, in contrast to what has been recently reported for dementia.

Epilepsy was associated with subsequent Parkinson's across all assessed time frames. Hearing loss was associated when identified less than 2 years, or 2 to less than 5 years, before Parkinson's diagnosis.

"Novel temporal associations were observed for epilepsy and hearing loss with subsequent development of Parkinson's disease," Noyce and co-authors noted.

The researchers performed a replication analysis using case-control data from the U.K. Biobank cohort and found that epilepsy and hearing loss again were associated with subsequent Parkinson's diagnoses over the three time periods. ORs for epilepsy were about 3 and ORs for hearing loss were approximately 1.2, except for hearing loss in the period closer to Parkinson's diagnosis (OR 1.03, 95% CI 0.69-1.52).

"There is an emerging literature on auditory processing difficulties in Parkinson's disease and impaired recognition of musical and nonverbal vocal emotions," Noyce and colleagues wrote. "Although the role of early hearing loss requires further research, it is possible that this factor represents another deficit in sensory processing that occurs as part of Parkinson's disease pathogenesis, similar to visual impairment."

"We believe our findings raise potentially important practical considerations for primary care physicians and the opportunity to address patient concerns at an earlier stage of the disease," they added. "It is not a case of screening for asymptomatic disease but correctly identifying the underlying cause in patients who are presenting with symptoms and may seek timely onward referral."

The study had several limitations, the researchers acknowledged. Data were collected from routine primary care records and some signs of Parkinson's might not have been recorded. Parkinson's disease may have been misdiagnosed, and information about patient medications, including those that could lead to drug-induced parkinsonism, were not known.

Disclosures

Support for this study came from Barts Charity, Health Data Research U.K., and the National Institute for Health Research UCLH Biomedical Research Center.

Noyce disclosed relationships with Parkinson's U.K., Aligning Science Across Parkinson's, Cure Parkinson's, Alchemab, Michael J. Fox Foundation, National Institute for Health Research, Barts Charity, uMed, AbbVie, Charco Neurotech, AstraZeneca, Britannia, Biogen, Roche, UCB, and Bial. Co-authors reported relationships with Barts Charity, Biogen, GE Healthcare, MS Society of Great Britain and Northern Ireland, National Multiple Sclerosis Society, BMA Foundation, Horne Family Charitable Trust, Medical Research Council, Roche, Merck, Teva, Novartis, Wolfson Institute of Population Health, and Britannia Pharmaceuticals.

Editorialists reported relationships with the National Institute on Aging, Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia, American Brain Foundation, Mary E. Groff Charitable Trust, Smallwood Foundation, Florida Department of Health, Lewy Body Dementia Association, Alzheimer's Therapeutic Research Institute, Alzheimer's Disease Cooperative Study, Parkinson's Foundation Grant, and the American Academy of Neurology.

Primary Source

JAMA Neurology

Source Reference: Simonet C, et al "Assessment of risk factors and early presentations of Parkinson disease in primary care in a diverse UK population" JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.0003.

Secondary Source

JAMA Neurology

Source Reference: Patel B, et al "Identifying Parkinson risk markers in primary care -- old associations and new insights" JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2021.5542.

https://www.medpagetoday.com/neurology/parkinsonsdisease/97533

Brain Changes Seen After Mild COVID Infection

 Tissue damage and shrinkage in brain areas related to smell were seen months after people had mild SARS-CoV-2 infection, longitudinal data from the U.K. Biobank showed.

Compared with controls, people who had mild COVID demonstrated a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus, and greater changes in markers of tissue damage in regions functionally connected to the primary olfactory cortex, reported Gwenaëlle Douaud, PhD, of the University of Oxford in England, and co-authors in Nature.

COVID patients also had a greater reduction in global brain size. On average, infected participants showed larger cognitive decline.

"Using the U.K. Biobank resource, we were in a unique position to look at changes that took place in the brain following mild -- as opposed to more moderate or severe -- SARS-CoV-2 infection," Douaud said in a statement.

"Despite the infection being mild for 96% of our participants, we saw a greater loss of grey matter volume, and greater tissue damage in the infected participants, on average 4.5 months after infection," she noted. "They also showed greater decline in their mental abilities to perform complex tasks, and this mental worsening was partly related to these brain abnormalities. All these negative effects were more marked at older ages."

"This is an outstanding study," observed Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, who wasn't involved with the research.

"A novel aspect of this study is the access to MRI scans prior to COVID-19 and then on average 140 days after COVID-19," Nath told MedPage Today. "They show that the olfactory pathways in the brain are atrophic in these patients as a group. This also includes areas involved in cognition although, interestingly, it was an area in the cerebellum."

"These findings might have major implications since it is unlikely they will reverse on their own after so many months," he added. "The critical question is whether this can result in an acceleration of the neurodegenerative process, since the researchers also noted global atrophy."

Douaud and colleagues looked at brain changes in 785 U.K. Biobank participants 51 to 81 years old who had two MRI scans an average of 3.2 years apart.

A total of 401 participants tested positive for SARS-CoV-2 infection between their scans, including 15 people who were hospitalized. People developed COVID between March 2020 and April 2021; they had a mean age of 58.9 at their first MRI and 62.1 at their second. The other 384 participants were age- and sex-matched controls.

Changes associated with SARS-CoV-2 infection varied in different brain regions but on average, infected participants showed an additional 0.2% to 2% loss compared with non-infected participants, with the largest differences seen in the volume of the parahippocampal gyrus (-1.3%) and entorhinal cortex (-1.8%).

To provide context, these percentages can be compared with the loss seen in normal aging -- "for instance, the longitudinal loss per year of ~0.2% (in middle age) to 0.3% (in older age) of hippocampal volume in community-dwelling individuals" -- the researchers noted.

"Our statistics also represent an average effect; not every infected participant will display brain longitudinal abnormalities," they emphasized.

Infected participants took significantly longer to complete complex tasks than non-infected participants, a difference that was more pronounced at older ages. These findings remained significant when excluding the 15 hospitalized cases. There were no signs of memory impairment.

No other brain imaging study has compared scans before and after infection from other viruses, Douaud and co-authors pointed out. A control analysis on 11 people in the U.K. Biobank who developed pneumonia not related to COVID-19 suggested the brain changes were specific to COVID-19 and not generic effects of respiratory illness.

The study had several limitations, the researchers acknowledged. There was no information about COVID symptoms, including smell or taste loss. There also was no formal way to determine which SARS-CoV-2 strain was involved, though the cohort was infected when the original strain and Alpha variant were dominant.

The brain imaging results may be hallmarks of a degenerative spread of SARS-CoV-2 through olfactory pathways, of neuroinflammation, or of a lack of sensory input due to loss of smell, Douaud and co-authors suggested. "Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up," they wrote.

Disclosures

This work was primarily supported by a Wellcome Trust Collaborative Award.

Douaud had no disclosures. Co-authors reported relationships with U.K. Biobank, Novartis, Bristol Myers Squibb, Biogen, and the U.K. Research and Innovation Medical Research Council Neurosciences and Mental Health Board.

Primary Source

Nature

Source Reference: Douaud G, et al "SARS-CoV-2 is associated with changes in brain structure in UK Biobank" Nature 2022; DOI: 10.1038/s41586-022-04569-5.

https://www.medpagetoday.com/neurology/generalneurology/97532

Zymergen Advances Molecules for Prominent Malaria and COVID-19 Drug Targets

 Biotechnology company Zymergen (ZY) is pleased to announce early results from its work on infectious disease, discovering hundreds of potential novel hits against malaria, tuberculosis, and COVID-19 targets. Hits for PfAPP, a critical target in the treatment of malaria, are now being advanced for validation, with hits for an emerging COVID-19 target, PLpro, expected to follow.

This ambitious multi-target infectious disease program is supported through a grant from the Bill & Melinda Gates Foundation, enabling Zymergen to identify novel hits for all three target pathogens. The early progress has been enabled by Zymergen’s differentiated cheminformatics capabilities and ability to search their proprietary virtual compound database of Natural Products.

“Virtual screening has been a powerful approach for discovering small molecule drugs, but applying this approach to more complex molecules has not been done on a large scale until now,” said Zymergen Research Fellow John Kulp. “Complex molecules like Natural Products have better bioactivity and are more likely to be able to treat hard-to-drug targets. Our platform and data give us a unique approach to leveraging these novel molecules.”

The targets were selected for their high therapeutic potential, but historic lack of progress using standard drug discovery approaches. For PfAPP, Zymergen has already identified >200 molecules with better docking scores than the current best-in-class molecule, apstatin. Docking scores are well-accepted in the industry for virtual screening campaigns and the best hits are now being moved into validation testing with a set of global partners. Zymergen will oversee all validation with funding provided as part of the Gates Foundation grant.

Zymergen recently announced its drug discovery business at the 40th annual JP Morgan Healthcare conference, with a goal of unlocking previously inaccessible chemical diversity to develop next generation therapeutics. Natural Products have a history of success as therapeutics and Zymergen’s unique platform that combines synthetic biology, cheminformatics and metagenomics has the potential to transform how these molecules are discovered and developed.

“We are incredibly pleased with the progress we are making through this collaboration, and today’s announcement is a reflection of our momentum,” said Zymergen VP of Innovation Devin Scannell. “Zymergen has a mission to make better products, a better way for a better world, and we’re looking forward to further progress in the development of treatments for these diseases that are an enormous burden on people, globally.”

https://www.biospace.com/article/releases/zymergen-advances-molecules-for-prominent-malaria-and-covid-19-drug-targets-for-further-testing/

Alpine Immune Sciences Shares Slip on Partial Study Hold

 Shares of Alpine Immune Sciences Inc. fell more than 10% on Monday after the U.S. Food and Drug Administration placed a partial clinical hold on one of its studies following the death of a patient.

The Seattle clinical-stage immunotherapy company said the partial hold involves a Phase 1 study of its davoceticept drug candidate in combination with Merck & Co.'s cancer drug Keytruda in adults with advanced malignancies.

Alpine said the patient who died had choroidal melanoma, a cancer that affects part of the eye, and had received a single dose each of davoceticept and Keytruda. The company said the patient suffered cardiogenic shock, a condition in which the heart suddenly can't pump enough blood to meet the body's needs, which it said was likely related to immune-mediated myocarditis, or possibly infection.

The study, which began dosing participants last June after Alpine inked a collaboration and supply agreement with Merck, is aimed at providing insights across a range of cancers and lines of therapy.

Alpine said it can't enroll any more patients until the partial hold is resolved, but it said patients currently enrolled in study can continue to receive treatment.

https://www.marketscreener.com/quote/stock/ALPINE-IMMUNE-SCIENCES-I-37230832/news/Alpine-Immune-Sciences-Shares-Slip-on-Partial-Study-Hold-39688100/

China reports highest COVID-19 tally since initial outbreak

 China on Monday recorded the highest single day tally of infections since the outbreak in Wuhan at the beginning of the global pandemic. 

The country reported 526 cases, including 312 asymptomatic patients, according to Bloomberg. 

Shanghai, which has seen few significant outbreaks, reported almost 50 cases, while Qingdao saw 163, likely the result of a spike among students at a high school.

China has continued to deploy its zero-tolerance protocols, which include widespread testing and intensive lockdowns, strict policies that the country has used to keep infection rates low throughout the pandemic. 

China and Hong Kong are among the final countries still upholding strict COVID-19 policies after places like Australia have moved to treat the virus as an endemic.

Earlier this month, Hong Kong Chief Executive Carrie Lam told citizens not to panic as people flooded grocery stores in anticipation of a lockdown with rising infections. 

Lam has said there would not be a citywide lockdown, and her administration is seeking to maintain calm as it plans an expansive testing system. 

According to Reuters, Hong Kong is reporting an average of 43,093 new infections each day as of Sunday.

https://thehill.com/policy/healthcare/public-global-health/597102-china-reports-highest-covid-19-tally-since-pandemic

Former Biden COVID-19 advisers call for more action from White House

 A group of 53 authors — some of whom served on President Biden's COVID-19 task force before he entered the White House — have released a roadmap for the "next normal," arguing for further action as the country prepares to live with COVID-19.

In their report released Monday, the authors acknowledged the sense of fatigue that many people are now experiencing as the pandemic stretches into its third year.

“Americans are beyond tired of waking up to uncertainty about what the future holds thanks to a COVID pandemic that feels never-ending," said Ezekiel Emanuel, Vice Provost for Global Initiatives at the University of Pennsylvania, who coordinated the report.

"As the threat of Omicron fades and Americans are looking for direction, it’s time the country maps out a way forward so that people can start to live their lives in a next normal," he added. 

The group of epidemiologists, immunologists, virologists and policy experts who put together the report said they have been in contact with the White House as their recommended plan came together.

Authors on the report included Luciana Borio, an infectious disease physician who served on the Biden-Harris transition COVID-19 advisory board; Jill Jim, the executive director for the Navajo Department of Health; and R.P. Eddy, a former White House official and senior diplomat for the U.S. and the U.N. 

The roadmap offers 12 recommendations to "sustain the next normal" and confront future biosecurity threats.

They advised that going forward, focus should be shifted from COVID-19 to encompass all respiratory viral illnesses such as the flu. This shift in focus should be accompanied by a goal of keeping annual deaths from respiratory viral illnesses below the worst flu season seen in the past decade, the authors wrote.

The authors also called on the federal government to support the production of at-home tests, develop standards to improve indoor air quality and support the development of new therapeutics. They also voiced support for a test-to-treat approach to treatment, which President Biden announced during his State of the Union address last week.

According to the authors, the next phase of living with COVID-19 has the potential to be an "improvement over life before the virus emerged," with a better work-life balance developing due to the rising prevalence of teleworking; the reimagining of education systems; and the development of more effective vaccines and therapeutics.

"The next normal with Covid requires a basic reorientation. The national discussion needs to shift away from Covid alone to one that encompasses major viral respiratory illnesses like influenza and respiratory syncytial virus (RSV)," the report read. "The pandemic and its restrictive measures should end when Covid death rates decline to those of a bad influenza season."

https://thehill.com/policy/healthcare/597134-former-biden-covid-19-advisers-experts-call-for-more-action-from-white

Death in Alpine's Keytruda combo trial triggers clinical hold, raises specter of earlier tragedy

 A patient has died in a clinical trial that is testing Alpine Immune Sciences’ davoceticept in combination with Merck’s Keytruda. The death in the study of adults with advanced malignancies triggered a partial clinical hold—and raised the specter of an earlier tragedy.

Davoceticept is part of a wave of candidates that have renewed interest in CD28, a target previously best known in oncology in relation to TGN1412. The administration of CD28 superagonist TGN1412 to healthy volunteers caused critical illnesses linked to cytokine storms in a phase 1 trial, temporarily dampening interest in stimulating the T-cell-expressed protein to treat cancer.

ALPN-202 is designed to limit the risk of systemic immune activation and toxicity. Alpine’s molecule is a conditional costimulator of CD28 and a dual PD-L1/CTLA-4 inhibitor. CD28 costimulation should require T-cell receptor signaling and expression of PD-L1 on the antigen-presenting cell.

Details of what happened in the trial of ALPN-202 and Keytruda are limited. A choroidal melanoma patient previously treated with Bristol Myers Squibb’s Opdivo and Yervoy received a single dose each of davoceticept and Keytruda. The participant’s death was attributed to the inability of their heart to pump enough blood and oxygen to vital organs, a condition known as cardiogenic shock. 

The treating physicians think the cardiogenic shock was likely related to immune-mediated myocarditis, or possibly infection. Work is now underway to better understand what happened and what precautions Alpine can take to prevent it from happening again. In a statement, Alpine CEO Mitchell Gold, M.D., expressed hope that “the study will soon be resumed after appropriate safety review.”

In the meantime, Alpine can continue to dose patients who are already enrolled in its NEON-2 trial but cannot enroll new participants. A clinical trial testing davoceticept as a monotherapy is unaffected by the partial clinical hold. 

ALPN-202 is one of a clutch of candidates designed to target CD28 to treat cancer. Regeneron is testing a trio of bispecifics that target CD28, Sanofi is studying a trispecific against the target and Johnson & Johnson bought a spot in the race last year through a tie-up with Xencor.

https://www.fiercebiotech.com/biotech/death-alpines-keytruda-combo-trial-triggers-clinical-hold-raises-specter-earlier-tragedy