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Potential Parkinson's Risks Found Years Before Diagnosis

Article In Brief

A large study that focused on an area of high socioeconomic deprivation in London found that several symptoms usually shared in primary care settings could help identify patients at risk of developing Parkinson's disease up to a decade before such a diagnosis.

Several symptoms in the primary care setting may help identify patients at risk of developing Parkinson's disease (PD) up to a decade before such a diagnosis, a team of researchers in the United Kingdom reported March 7 online in JAMA Neurology.

Investigators at Queen Mary University of London analyzed electronic health care records from primary care practices in East London, an ethnically diverse population with universal health care, but high socioeconomic deprivation.

The study included 1,055 individuals who developed PD, with the investigators noting their clinical signs and symptoms reported at three different time periods prior to diagnosis. They then compared their health history with those in a control group of 1,009,523 individuals matched for age and gender, with 10 controls for each individual in the PD group.

Although PD patients had symptoms years before diagnosis, tremor and memory problems were the most common; tremor up to 10 years before diagnosis, and five years earlier for memory symptoms.

Other potential risks included epilepsy, hearing loss, hypertension, type 2 diabetes, hypotension, constipation, and depression, among others. Although recent research has reported potential associations with epilepsy and hearing loss with later development of PD, the findings have not been well reported, the researchers noted. To test their findings, they were able to replicate their results with data in the UK Biobank, a large biomedical database of genetic and health data on half a million UK residents.

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We, as clinicians, need to be aware of these constellations of symptoms and ask proactively about them if early Parkinsons is suspected.”—DR. CHRISTINA SIMONET

While the investigators could find no associations between ethnicity or deprivation index levels and future PD diagnosis, the review's inclusion of such an ethnically and racially diverse group is important, said lead author Christina Simonet, MD, a neurologist and PhD student at Queen Mary University of London. Dr. Simonet and her colleagues are part of the Preventive Neurology Unit, Wolfson Institute of Population Health.

“Early features of Parkinson's disease have been described through population-based studies that have generally overrepresented affluent White individuals, and may not be generalizable,” she noted.

“GPs [general practitioners] need to consider Parkinson's disease as a multisystemic condition that can be manifested by our movement, but other symptoms such as constipation, erectile dysfunction, depression, and cognitive impairment. We, as clinicians, need to be aware of these constellations of symptoms and ask proactively about them if early Parkinson's is suspected,” she told Neurology Today.

“On the other hand, we saw that people asked for advice to their GPs with symptoms but often did not get a diagnosis until five to 10 years later. Ten years before diagnosis is too long for patients to wait. An early diagnosis would bring a real opportunity to improve the quality of life for patients by treating them early.”

The study had several limitations, including shortcomings inherent in research using electronic health records based on clinical reports, and lacked data on medications that may cause symptoms similar to PD.

In an accompanying editorial, Bhavana Patel, DO; Shannon Y. Chiu, MD; and Melissa Armstrong, MD, FAAN, neurologists at the University of Florida College of Medicine, Gainesville, complimented the researchers, although they agreed with the authors that relying on electronic health records is inexact and may underestimate any findings.

“Despite these limitations, the current study provides important information about PD risk markers in a diverse and often understudied population. With the increasing body of evidence regarding risk and prodromal markers for PD, an opportunity exists to formally identify potentially modifiable risk factors for PD, similar to those modeled for dementia.”

Study Details

The investigators used electronic health records to extract clinical information from primary care practices in East London, recorded between 1990 and February 6, 2018. Individuals with a diagnosis of PD and their clinical history were then compared with controls without PD or other major neurological conditions.

The researchers conducted two analyses—a matched analysis with 10 controls for each patient with PD, matched by age and gender, and an unmatched analysis. Three time periods—less than two years, two to five years, and five to 10 years—before diagnosis were analyzed separately and together. Patients with PD were older than controls (72.9 years versus 40.3 years) and more were male. In the matched analysis (the 1,055 individuals with PD and 10,550 controls), the investigators identified associations of tremor and memory symptoms less than two years before the PD diagnosis.

“This study provides data suggesting that a range of comorbidities and symptoms are encountered in primary care settings before PD diagnosis in an ethnically diverse and deprived population,” said Dr. Simonet.

Temporal associations were observed for epilepsy and hearing loss, a novel finding. “The prominence of memory symptoms suggests an excess of cognitive dysfunction in early PD in this population or difficulty in correctly ascertaining symptoms in traditionally underrepresented groups,” she said.

“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,” she 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. Patients might otherwise wait for up to 10 years for an explanation for their symptoms.”

Although the UK's National Health Service (NHS) provides free care to all patients, Dr. Simonet said that there may still be under-ascertainment of PD, noting that preliminary evidence exists for atypical presentations in ethnic minority groups and a higher likelihood of being mislabeled with vascular conditions that can mimic PD and other neurodegenerative disease.

The lack of prescription information was another limitation, which inhibited developing a more robust definition of PD or inclusion of additional patients not recorded as having PD but who were prescribed anti-parkinsonian medication, nor were the researchers able to exclude those with drug-induced parkinsonism.

Expert Commentary

Kelly A. Mills, MD, associate professor of neurology and director of the movement disorders division at Johns Hopkins department of neurology, said the increased odds of epilepsy even five to 10 years before the diagnosis of PD is probably the most impactful new finding from the study for most neurologists.

“The magnitude of association between PD diagnosis and a presentation with memory or mood complaints may not be well known by many neurologists,” Dr. Mills told Neurology Today.

“The association with preceding epilepsy should warrant closer physical examination and questioning by clinicians about prodromal non-motor symptoms in persons with epilepsy in this age range, though the direction of causality cannot be inferred from this approach, such as shared predisposing risk factors versus drug-induced parkinsonism from AED's.”

The finding of memory symptoms predating PD diagnosis should also further motivate neurologists to routinely include screening for PD signs and symptoms as part of their work-up for memory complaints, he said.

“Compared to another report done in [a wealthier White cohort], the present study showed lower rates of non-motor symptoms like constipation, fatigue, insomnia, and erectile dysfunction. In detecting and treating non-motor symptoms in more diverse, less resourced populations, neurologists may want to consider ethnic, language, or educational barriers that may lead to under-reporting so that these treatable symptoms are not missed,” he noted.

“As we move into an era of disease-modifying therapy for PD, early diagnosis will be more essential than ever to maximally intervene on neurodegeneration,” explained Dr. Mills. “Including PD in the differential for late-life depression, cognitive complaints, or epilepsy may lead to earlier diagnosis and treatment with symptomatic or, hopefully, disease-modifying therapies.”

Rodolfo Savica, MD, PhD, FAAN, a clinical neurologist at Mayo Clinic in Rochester, MN, who studies early-life predictors of neurodegeneration and mechanisms that lead to disorders such as PD, said he was encouraged by the findings but noted that they need to be confirmed by other studies and in different settings before they can be used in clinical practice.

“The findings are really interesting, and they provide confirmation of what it is already known regarding sex differences and cardiovascular risk factors,” Dr. Savica said. “Also, I think that it is quite relevant and novel the association of hearing loss and epilepsy: such comorbidities have not been studied extensively in the past, and it is quite important to confirm it in other cohorts,” he told Neurology Today.

The role of cardiovascular risk factors needs to be assessed by the practicing physicians to improve the general well-being and potential progression of Parkinson's disease, he added.

Dr. Savica agreed that primary care clinicians may not recognize certain symptoms as PD risk markers, which may affect whether individuals are subsequently diagnosed with PD, or when such a diagnosis occurs.

“A diagnosis of PD is still not that obvious, and there is still a long delay from symptoms onset to diagnosis. Many early manifestations are not specific and can be present in other diseases. Therefore, primary clinicians may surely not easily recognize and diagnose PD.”

He also agreed that population studies that rely exclusively on diagnostic codes can miss important data, as the authors noted. “The use of diagnostic codes may overcount cases and identify cases that are wrongfully diagnosed. Exclusive reliance only on codes is an absolute suboptimal manner to track and identify PD.”

Michele Tagliati, MD, FAAN, professor and chair in movement disorders at Cedars-Sinai Medical Center, Los Angeles, was less sure of the findings' impact on clinicians.

“Several of the associations came as a surprise, particularly epilepsy and hearing loss. While these were statistically significant, the incidence of the associations was very low (2-3 percent for hearing loss and 3-5 percent for epilepsy), he said.

“Given their relatively low incidence, I'm not sure whether these associations might be incorporated into clinical practice. However, they should spur research questions investigating possible pathogenetic relevance, at least in some cases of PD,” he told Neurology Today.

“Pre-motor symptoms associated with high risk of developing PD, including constipation, loss of smell, REM-sleep behavior disorder, and depression among others, have already been characterized,” he noted. “These symptoms are relatively non-specific, at least in isolation, and often temporally very distant (several years) from the neurological diagnosis, and this reduces the practical value of their recognition.

“In addition, the lack of established neuroprotective strategies deprives their recognition of any immediate management value in current clinical practice. That said, the recognition of ‘red flags’ possibly heralding what may be an ongoing neurodegenerative process is of tremendous value, which is at this time mostly limited to research settings.”

Link Up for More Information

• Simonet C, Bestwick J, Jitlal M, et al. Assessment of risk factors and early presentations of Parkinson disease in primary care in a diverse UK Population https://jamanetwork.com/journals/jamaneurology/fullarticle/2789505. JAMA Neurol 2022; Epub 2022 Mar 7.
    • Patel B, Chiu S, Armstrong MJ, et al. Identifying Parkinson risk markers in primary care—old associations and new insights https://jamanetwork.com/journals/jamaneurology/fullarticle/2789509. JAMA Neurol 2022; Epub 2022 Mar 7.
      • Chahine LM, Chin I, Caspell-Garcia C, et al. Comparison of an online-only Parkinson's disease research cohort to cohorts assessed in-person https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242834/. J Parkinsons Dis 2020;10:677–691.