September/October 2024

September/October 2024 Issue

Essential Tremor and Dementia
By Jamie Santa Cruz
Today’s Geriatric Medicine
Vol. 17 No. 5 P. 14

What Clinicians Should Know About the Link Between These Two Conditions

Essential tremor (ET) is one of the most common movement disorders, affecting about 7 million people in the United States.1 Long thought to be strictly a motor disorder, it’s now known that the disease has cognitive impacts as well. Among other things, it raises the risk of dementia, at least in certain patients. Here’s what clinicians should know about the connection between ET and dementia—and how to counsel patients about their risk.

What Is Essential Tremor?
Although ET can occur early in life, sometimes even in childhood, it’s generally linked to older age.2 The prevalence in the population as a whole hovers around 1%, possibly less, but among individuals older than 65, the prevalence is close to 6%.3-5 Approximately one in 17 adults older than 65 has ET.6

ET is a chronic, progressive, neurologic disease, the most typical feature of which is kinetic tremor during voluntary movements. ET almost always involves the hands or arms, but it also often affects the head/neck, voice, or jaw.2 The tremor is usually somewhat asymmetric, but it can sometimes be severely asymmetric or unilateral. It tends to spread over time, and it also worsens with time, with current best estimates suggesting that it worsens at a rate of 2% to 5% per year.7 About 20% of patients also experience tremor at rest.8

ET can cause significant disability. It frequently affects the ability to carry out basic activities of daily life, such as drinking, writing, pouring, signing one’s name, carrying a cup, and using a spoon.6 It’s also frequently associated with gait and balance impairment.9

Although ET’s most obvious symptoms are motor symptoms, there is also a range of nonmotor symptoms.10 These include sensory effects—namely, diminished hearing and/or diminished sense of smell to a greater degree than in age-matched controls. The disease also has psychiatric symptoms, including depression, apathy, anxiety, and personality characteristics. And ET is linked to cognitive changes ranging from mild to severe. Because of the diversity of clinical manifestations and lack of established biomarkers of the disease, diagnosis can be difficult, and misdiagnosis is common.11-13

While ET is distinct from Parkinson’s disease (PD), ET and PD tend to cooccur, and people with ET have a four-fold higher risk of developing PD than do those without ET.14

Causes and Pathways
ET is caused by a combination of genetic and environmental factors. Thirty percent to 70% of patients with ET have a family history of the disease,15 and first-degree relatives have five times the risk of developing ET compared with people who don’t have a close relative with the disease.16 Twin studies show a high concordance in monozygotic twins, suggesting a significant—but not exclusive—role in genetics.17 It’s still not certain what environmental factors play in, but beta-carboline alkaloids and lead exposure are both strong possibilities.2

The mechanisms behind ET still aren’t clear. Originally, the disease was thought to stem from a tremor pacemaker (oscillator) in the inferior olivary nucleus. Later, the theory was expanded to hypothesize a network of multiple oscillators—the inferior olivary nucleus but also the cerebellum, thalamus, and cortex—rather than a single oscillator. This central oscillatory network hypothesis is supported by studies that show a coherence between signals in the aforementioned brain areas and simultaneous signals in muscles affected by tremors.6

A different theory is that ET is a neurodegenerative disease. The main evidence in favor of this theory is that the disease is associated with advanced age, that it worsens in most patients, and that it’s associated with an increased risk of mortality in prospective studies.18,19 The neurodegenerative hypothesis is supported by a variety of studies that demonstrate a large number of degenerative changes in the cerebellum, including but not limited to loss of Purkinje cells in ET.20,21 However, not all studies have replicated the finding of Purkinje cell loss, so this hypothesis is still not universally accepted.22

The Link Between ET and Cognitive Impairment
Since the early 2000s, a range of studies have found a link between ET and cognitive deficits. Cognitive deficits are most frequently reported in the domains of executive function and memory, though they can also appear in other domains. Such deficits have been observed in ET populations across the globe, and they’ve been observed in ET patients, both young and old.10,23 At least one study found that cognitive changes in ET appeared before motor symptoms.24 Other research has found that the link between ET and cognitive deficits isn’t explained by medication side effects or psychiatric symptoms.25

In addition to being associated with mild cognitive deficits, ET has also been linked to a higher risk of both mild cognitive impairment (MCI) and dementia. In 2007, a population-based study of older adults in Spain followed participants for an average of 3.8 years and found that 7.8% of participants with ET developed dementia by the end of the follow-up period, compared with only 3.9% of controls.26 In 2009, a separate population-based study of older adults in Manhattan produced roughly similar findings. In this second study—a prospective cohort study with a mean follow-up of 3.8 years—patients with ET were about 60% more likely to develop dementia by the end of the study period compared with controls without ET.27

This year, a new study from researchers at UT Southwestern provided yet further evidence of a link. The new study followed 222 patients with ET (mean age of 79) for an average of five years. At baseline and again at 18-month intervals, each participant was assessed with a comprehensive battery of neuropsychological tests measuring cognitive function across five different domains. At the conclusion of the study, the researchers found that 27% of the participants had MCI—approximately double the prevalence of MCI seen among similarly-aged adults in the general population. Meanwhile, 19% of participants had dementia—about three times the prevalence seen in the general population.28 Based on this, the researchers concluded that ET appears to triple dementia risk.

The new study lacked a contemporary control group and relied instead on historical controls. However, the new study has several major strengths. “It’s a prospective longitudinal study over a 10-year period, which is a far longer period than any of the other studies,” says Elan Louis, MD, MS, a professor and chair of the department of neurology at UT Southwestern Medical Center, and senior author of the new study.

A second strength is that the neurological test battery was carefully chosen. “Most neurological tests are designed for the general population. Some require pencil and paper, and ET patients can’t complete them,” says Ludy Shih, MD, clinical director of movement disorders at Beth Israel Deaconess Medical Center, Harvard Medical School, who was not involved in the research. Furthermore, all participants were meticulously evaluated to confirm that their condition met the criteria for ET. This is an important point, Shih says, considering that misdiagnosis with ET is common and could skew the study results.

Not only did Louis’s group provide evidence of a strong link between ET, MCI, and dementia, but their new study did something else as well: It analyzed the rate at which participants developed MCI and dementia. Louis’s group showed that each year, approximately 4% of those who had previously showed no cognitive impairment developed MCI, and approximately 12% of those who previously had MCI but not dementia developed dementia.28

“This is the first study to ever quantify dynamically what the dementia looks like,” Louis says. “We have quantified for the first time not only the prevalence of MCI and dementia but the yearly conversion rate to MCI and dementia, to give a sense of at what rate is this evolving.”

Importantly, not all studies have found a link between ET and dementia. In 2014, researchers at Banner Sun Health Research Institute in Sun City, Arizona, published findings from a prospective cohort study involving a total of 507 patients (83 with ET and the rest healthy controls), who had been followed for an average of 5.4 years. The researchers found that the incidence of dementia at the end of the study period was 6% for participants with ET and 8% for controls. In this study, then, the participants with ET actually had a lower risk of dementia than that of the controls—although that difference was not statistically significant.29

Why the Inconsistencies Among Studies?
“There are differences in the methodology, there are differences in the study population, and my guess is that’s the reason we see differences,” says Holly Shill, MD, a professor in the department of neurology at the Barrow Neurological Institute in Phoenix, who was involved in both of the Banner studies. One key issue may be how ET is defined: the Banner research that has found no link between ET and dementia relied on less restrictive criteria to determine who has ET compared with studies that have found a link.

That said, even the Banner group has found some link between ET and dementia. In its 2014 study, there was no increased risk of dementia overall for participants with ET, but when the researchers segmented their study population by age of onset of ET, they found that those with ET onset after age 65 had more than double the risk of developing dementia compared with those with onset before age 65.29

This finding regarding the age of onset is consistent with the 2007 Spanish study mentioned previously. The Spanish study showed that ET doubles dementia risk, but in an adjusted model, the researchers found that this was only true for participants who had developed ET after age 65; those who developed ET before the age of 65 had no elevated risk.26

Overall, Shih says, the evidence suggests there’s some link between ET and dementia, but the exact nature of the link is still uncertain. “I think there is probably a nuanced relationship in that certain people with ET are going to be at higher risk. Sometimes studies say, ‘Oh, there’s no link.’ But all the studies say that people who develop ET after age 65 are at higher risk.”

One noteworthy point: Dementia risk doesn’t seem linked to either tremor duration or tremor severity. “That would be a logical thing,” Shill says, but both the Banner group and Louis’s group at UT Southwestern have looked into a potential connection, and they “have really not shown a correlation.”

Possible Mechanisms
It’s still unclear exactly how ET might increase the risk for cognitive impairment and dementia. But there’s likely more than one mechanism at play.

“One of the things we have learned from looking at ET brains over the last 20 years is that there is clear evidence of cerebellar dysfunction,” Louis says. “Cerebellar dysfunction is associated with cognitive-affective syndrome. So, it’s highly likely that some of the mild cognitive difficulties in ET simply relate to the fact that the cerebellum is not normal. It’s degenerating.”

The more pressing question, however, is what causes moderate and severe cognitive disturbances, especially dementia. Recent postmortem studies have found that the brains of ET patients show evidence of greater-than-normal tau pathology.30 Changes in tau protein have been linked to a variety of neurodegenerative disorders, including AD, raising the question of whether there are shared mechanisms behind ET and Alzheimer’s.

Putting these two points together, then, it’s likely that two distinct mechanisms lie behind the milder vs more severe cognitive impacts seen in ET. “The cerebellar degeneration, which is at the root of ET, is responsible for some of the milder cognitive problems, and the increased risk for comorbid neurodegenerative disease is responsible for some portion—maybe a large portion—of the severe cognitive disturbances, like dementia,” Louis says.

Takeaways for Clinicians
The new research coming out on ET and its connection to cognitive impairment and dementia has several implications for clinicians:

1. Don’t sweep cognitive complaints from ET patients under the rug. According to Louis, patients with ET who complain of cognitive difficulties are sometimes just told, “Well, you’re old. It’s just because you’re old.” But current research makes plain that cognitive impairments are common in ET, and doctors should take complaints about cognition seriously, he says.

2. Talk to ET patients about the potential for future cognitive impairment and dementia. Because her own research has found evidence of a link between ET and dementia only in patients with ET onset after 65, Shill herself remains uncertain whether all patients with ET are at elevated dementia risk. Still, she says, the topic is likely to come up with patients, and clinicians should be prepared to address it.

“Patients are smart,” Shill says. They are likely reading about research on this topic, and they want to know, “‘I’ve got a tremor now, but what about five years from now? Am I going to get Parkinson’s? Am I going to get dementia?’” She doesn’t believe in worrying patients unnecessarily, but she does discuss the subject candidly and tells her patients, “‘We’re going to keep an eye on you. I’m going to ask you about cognitive changes. And if you’re worried about something, we will do additional testing and formal cognitive assessments if needed.’”

According to Louis, conversations about the potential for cognitive impairment and dementia are important because they allow patients to better prepare for their own future. “Doctors need to be aware [of the potential for cognitive impairment], screening for it, advising patients of what their risks might be so that they can plan for it.”

3. Talk to ET patients who don’t yet show cognitive impairments about how to protect their brains. “Practically speaking, any patient I’m seeing in my clinic, especially if they are in midlife—mid-40s, 50s, and above—I’m always counseling; you have to protect your brain,” Shih says. “Think about all the evidence base of what protects you from dementia—a healthy diet, exercise, getting hearing impairment addressed.” Counseling on protecting brain health is important for all patients, but it may be especially important for those with ET.

Looking Ahead
According to Louis, there’s a pressing need for more studies on the underlying mechanisms behind cognitive impairment and dementia in ET so that researchers can devise better treatments.

The identification of blood-based biomarkers that could help diagnose and categorize ET patients with MCI and dementia would be a major help, as such biomarkers would help researchers better understand what is happening in the brain in ET. Again, several studies have shown evidence of AD pathology (or AD-like pathology) in the brains of ET patients. “It could be in a couple of years that a patient could walk into a doctor’s office complaining of cognitive impairment, and with a simple blood test, we can diagnose them with Alzheimer’s disease or provide information about what their risk is for developing Alzheimer’s.” If future research continues to show a link between ET and AD, there’s a possibility that new immunotherapies rolling out for people with AD might be beneficial for ET patients—a truly encouraging prospect.

Fortunately, according to Louis, researchers are actively investigating all of these points, and there’s likely to be a lot of new data within two to three years. “Things are moving quickly,” Louis says. “It’s an exciting time.”

— Jamie Santa Cruz is a health and medical writer based in Parker, Colorado.

References
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