- More than 10
million people globally have Parkinson’s disease.
- There is currently no cure for Parkinson’s
disease.
- For a few years, researchers have been looking at
the energy molecule nicotinamide adenine dinucleotide (NAD+) as a possible
treatment for the condition.
- A phase 1 clinical trial has found a high dose
supplementation of NR, a form of vitamin B3, helps increase NAD+ levels in
people with Parkinson’s disease.
- The NR supplementation may be associated with
clinical symptom improvement of Parkinson’s disease.
Researchers estimate that more than 10 million people around the world have Parkinson’s
disease, making it the second most prevalent neurodegenerative
disease after Alzheimer’s disease.
There is currently no cure for Parkinson’s disease.
Medications, lifestyle changes. Source, and
sometimes surgery are used to manage symptoms through the disease’s stages.
Over the past few years, researchers have also looked
at nicotinamide adenine dinucleotide (NAD+) — an important molecule that helps the body
create energy — as a possible treatment for Parkinson’s disease.
Previous research suggests people with Parkinson’s may
have a NAD+ deficiency. Source, and increasing. Source NAD+
levels may have a positive effect.
Now, a phase 1 clinical
trial has found that a high dose supplementation of nicotinamide riboside. Source (NR) — a source of vitamin B3 and precursor to
NAD+ — increased whole blood NAD+ levels and expanded the NAD+ metabolome. Source in people with Parkinson’s disease, and may be
associated with clinical symptomatic improvement for those with the condition.
The research is still in its
early stages, and it remains to be conclusively proven that NR supplementation
can improve the symptoms of Parkinson’s disease.
The study was recently
published in the journal Nature Communications. Source.
According to Prof. Charalampos Tzoulis,
professor of neurology and neurogenetics at the University of Bergen and
Haukeland University Hospital, Bergen Norway, and co-lead author of this study,
NR is a form of vitamin B3 and a precursor of NAD+.
“NAD+ is an essential
coenzyme that plays a vital role in multiple cellular processes, including
mitochondrial function — the powerhouses of the cell — and cellular energy
metabolism, regulation of gene expression, and DNA repair,” Dr. Tzoulis
explained to Medical News Today.
“Research has shown that abnormal energy metabolism,
due to dysfunction in the mitochondria, occurs in the Parkinson’s disease brain
and is believed to play a role in the initiation and progression of the
disease,” he added.
Dr. Daniel Truong, a
neurologist and medical director of the Truong Neuroscience Institute at
MemorialCare Orange Coast Medical Center in Fountain Valley, CA, and
editor-in-chief of the Journal of Clinical Parkinsonism and Related
Disorders, who was not involved in this study, told MNT that
NAD+ levels tend to decline with age. Source.
“Some potential benefits and uses associated with NR
include anti-aging, energy metabolism, mitochondrial function, [and] DNA
repair,” Dr. Truong detailed. “Some research suggests that NR might have
neuroprotective properties.”
NR supplementation may help in
Parkinson’s
This study was part of
the ChromaDex External Research Program (CERP™), which donated ChromaDex’s patented NR
ingredient, Niagen®, for the advancement of this research.
The phase 1 clinical trial included 20 study
participants with idiopathic Parkinson’s disease. Participants received either
3,000 milligrams (mg) of NR in oral supplement form, or a placebo each day for
4 consecutive weeks.
Study participants were then assessed based on
clinical and molecular measures, an electrocardiogram, and the severity of
Parkinson’s disease symptoms through the MDS-UPDRS rating scale.
Researchers found that NR
significantly increased NAD+ levels and modified the NAD+ metabolome in whole
blood, compared to those who received the placebo.
Daily supplementation ‘safe’ in the
short term
The study also reportedly found the high-dose NR was
safe and well-tolerated by study participants, and was associated with a
significant improvement of clinical symptoms of Parkinson’s disease, measured
by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS),
suggesting augmenting NAD+ levels may have a symptomatic anti-Parkinson’s
effect.
“The study showed that treatment with high dose NR 3
gr [grams] daily is short-term safe for a month and may, therefore, be explored
in larger clinical trials,” Dr. Tzoulis said. “It must be stressed that our
study does not establish general safety for this NR dose, or whether it is safe
to take for any period longer than 30 days. This remains to be determined in
longer studies.”
“In addition, the study
showed that NR 3 gr daily leads to a pronounced increase in blood NAD levels
and related metabolites, without causing any adverse metabolic effects after 30
days,” he continued.
However, he cautioned that, “[w]hile NR treatment was
associated with a small clinical improvement in this study, this cannot be
interpreted as a sign of clinical effect, as the study was not designed to
detect clinical improvement.”
Would higher doses of NR be safe?
One of the main purposes of this study was to
determine the short-term safety of 3,000 mg NR daily.
“To harness the full
therapeutic potential of NR, we need to explore higher-dose regimens,” Dr.
Tzoulis said. “This study establishes the short-term safety of 3,000 mg NR
daily and allows high-dose options to be explored in future therapeutic
trials.”
“As for conclusive proof on the therapeutic potential
of NR in Parkinson’s disease, we look forward to the results from our year-long
NO-PARK phase 2/3 study on 400 persons with Parkinson’s disease, which is
already ongoing at our Center and estimated to conclude by the end of 2024,” he
added. “Public information on the NO-PARK study can be viewed at neuro-sysmed.no and at clinicaltrials.gov.”
Larger, long-term studies needed
After reviewing this study, Dr. Rocco DiPaola, movement disorders neurologist at the Hackensack Meridian
Neuroscience Institute at Jersey Shore University Medical Center, told MNT his
first reaction is that it offers a potential treatment that may help slow the
progression of Parkinson’s Disease.
“There [are] currently no treatments that offer
neuroprotection and this would be a treatment that may help prevent some of the
long-term complications related to advancing disease. The current study was on
a small scale and short duration to demonstrate safety. A large-scale trial
with [a] longer duration of treatment would be necessary to further demonstrate
safety and a neuroprotective benefit.”
– Dr. Rocco DiPaola
Dr. Truong agreed, noting that “[the findings are
promising, but this is just one study, and its results need to be replicated
and expanded upon in larger and longer-term trials, especially double-blind
studies.”
“I am intrigued by the mechanism of action proposed in
the study, namely the increase in NAD+ levels and its potential neuroprotective
effects,” he continued. “They would be interested in how this could be
integrated into current treatment protocols for Parkinson’s disease,
considering the safety profile and patient tolerance.”
“Given the current status of treating Parkinson’s
disease, any potential new therapeutic avenue is of interest,” Dr. Truong
added. “The idea of a supplement that could improve clinical symptoms and
potentially slow disease progression is particularly appealing.”
In
Conversation: Why Parkinson's research is zooming in on the gut
Parkinson’s disease affects millions of people around
the world, but it remains unclear exactly what causes it, and there is
currently no cure for this condition. In an effort to better understand the
mechanisms involved, some researchers are now looking to the gut. Why, and what
could this research reveal? In this installment of our In Conversation podcast,
we discuss how gut health may play a role in Parkinson’s.
Millions of people around the world live with Parkinson’s
disease, a neurological condition
that primarily affects mobility, balance, and muscle control, though its
symptoms can include many other issues, from mood changes to gastrointestinal
issues and a deterioration of memory and other cognitive functions.
According to data from the World Health Organization
(WHO), the global prevalence of Parkinson’s has doubled. Source in the past 25 years, and as per the most recent estimates, the
disease has resulted in “5.8 million disability-adjusted life years” globally.
While much of this increase is driven by increasing
numbers of older adults, there is also some evidence that age-adjusted
incidence is also on the rise. Source.
Dopaminergic medication, deep brain stimulation, and
speech and occupational therapy are some of the treatments currently available to people with Parkinson’s
disease, but researchers are constantly on the lookout for more and better
treatments.
In order to pave the way to better treatments,
scientists are first seeking to understand more about how Parkinson’s disease
works, and what mechanisms in the body might affect its development.
Several studies from the past 12 months have focused
on one particular aspect of Parkinson’s disease, namely gut health. But why is
gut health important in Parkinson’s, and what could it reveal about the
disease?
To find out more about the current research and how
the disease can affect individuals, Medical News Today welcomed
two guests to the latest installment of our In Conversation podcast: Dr. Ayse Demirkan and Gary Shaughnessy.
Dr. Demirkan is a senior lecturer in AI Multiomics for
Health and Wellbeing at the University of Surrey in the United Kingdom, and
co-author of a paper about the imprint of the microbiome in Parkinson’s
disease, which appeared in Nature Communications. Source in
November 2022.
Gary Shaughnessy is the chair of trustees at Parkinson’s
UK, a research and support
nongovernmental organization. In 2015, Shaughnessy received a diagnosis of
Parkinson’s disease, and since then, he has been taking on regular physical
challenges to raise money for Parkinson’s research.
Over the past few years, an increasing amount of
evidence has come to light indicating that there is a two-way
communication route between the
brain and the gut. Researchers have termed this the gut-brain axis. Source.
The gut-brain axis has been implicated in many health
conditions affecting the brain, from dementia to depression. And while the gut-brain
connection may be less obvious in other conditions, it is, in fact, clearer in
Parkinson’s disease, which, in some people, is also characterized by gastrointestinal symptoms. Source,
such as constipation.
One perspective on Parkinson’s disease, known as the Braak hypothesis. Source,
suggests that, in many cases, an unknown pathogen can reach the brain via two
routes, one of which implicates the gut.
According to this
hypothesis, one way for pathogens to reach the brain could be by being
swallowed, reaching the gut, and then advancing to the brain via the vagus nerve — the longest cranial
nerve that connects the brain with, among others, the intestines. This may then
trigger the onset of Parkinson’s disease.
In our podcast, Dr. Demirkan acknowledged that, at
first, the notion of looking to the gut to understand more about Parkinson’s
disease might seem surprising, but that the Braak hypothesis provides an
intriguing lens through which to assess potential mechanisms at play.
“[Through the Braak hypothesis,] there comes the idea
that the disease actually starts in the intestines, and then through the vagus
nerve, it spreads to the other tissues and toward the brain,” she explained.
According to her, Parkinson’s disease is the
neurological condition most interesting to study in relation to gut health for
one simple reason: Parkinson’s gut microbiome stands out the most.
Gut microbiome is different in
Parkinson’s
Through the recent study they
conducted, Dr. Demirkan and her colleagues saw that individuals with
Parkinson’s disease had distinct gut microbiomes characterized by dysbiosis —
the phenomenon of imbalance between so-called good versus bad bacteria.
Their study suggested that
around 30% of the proportion of gut bacteria in people with Parkinson’s disease
is different from those without Parkinson’s.
“We found one-third of these microbes [in the gut of
people with Parkinson’s] to be different,” Dr. Demirkan said on the podcast.
“So this is a very strong indication of dysbiosis. And also how they [the
bacteria] function, what kind of genes they carry, [these aspects were] also
different. We found a reduced [amount of] short-chain fatty acid producers, for
example, bacteria that [are] known to be gut-friendly […] We found increased
pathogenic bacteria […], including Escherichia coli, and we found a
lot of bacterial pathways disturbed as well, potentially affecting the
well-being of the neuronal tissues.”
– Dr. Ayse Demirkan
Dr. Demirkan and her colleagues found that bacteria
such as Bifidobacterium dentium — which can cause infections
such as brain abscesses — were at significantly elevated levels in the gut of
people with Parkinson’s disease.
Other infection-causing bacteria more abundant in
people with Parkinson’s were E. coli, Klebsiella pneumoniae, which can cause pneumonia, and Klebsiella quasipneumoniae, which
can cause similar infections.
The study conducted by Dr. Demirkan was not the only
recent research to zoom in on the differences in gut bacteria.
Research from the University of Helsinki — published in May 2023 in Frontiers — in animal models of Parkinson’s disease,
suggests that Desulfovibrio bacteria may be
implicated in this condition. These bacteria produce hydrogen sulfide, which
may lead to forms of inflammation.
Desulfovibrio also
came up in a study from The Chinese University of Hong Kong, which appeared in
May 2023 in Nature Communications. Source. This study, whose aim was to
find a method of diagnosing Parkinson’s earlier, identified an “overabundance”
of these bacteria in people with REM sleep
behavior disorder and early
markers of Parkinson’s.
REM sleep behavior disorder is a deep sleep
disturbance tied to a
higher risk of Parkinson’s
disease. In people with this disorder, the usual brain mechanisms that prevent
them from “acting out” the content of their dreams no longer work, which means
that they perform uncontrolled movements in their sleep.
Shaughnessy told us that he, too, experiences deep
sleep disturbances. “[O]ver the last few years, I have very really vivid
dreams, and […] I’ve fallen out of bed a few times because I’m turning over
doing something, you know, sort of dealing with whatever it is in the dream,”
he described.
What are the potential mechanisms?
If gut bacteria do play a role in Parkinson’s disease,
the question that arises is: What mechanisms might mediate their impact on
neurological health?
One hypothesis hinted at in
the studies on the link between the gut and the brain in Parkinson’s is that
systemic inflammation may be one of the mechanisms involved, since some of the
bacteria that are overabundant in this condition are pro-inflammatory, meaning
that they can trigger inflammation.
There is research indicating that immunosuppressant medication is associated with a
lower risk. Source of
Parkinson’s disease, which suggests that a similar type of medication may also
help manage the condition.
Indeed, chronic brain inflammation. Source is
an important part of Parkinson’s disease, and some studies seem to indicate
that systemic inflammation. Source may worsen brain inflammation and thus
contribute to disease progression.
Some inflammatory conditions have actually been linked
with a higher risk of Parkinson’s. For example, one Danish study from
2018 suggested that people
with inflammatory bowel disease (IBD) have
a 22% higher risk of Parkinson’s disease than peers without this inflammatory
condition.
In the podcast, Dr. Demirkan agreed that inflammation
linked to Parkinson’s disease may start in the gut, caused by “bad” bacteria.
However, she emphasized that this potential mechanism is not yet confirmed, and
further research on this topic is necessary to draw firm conclusions.
Could diet fight dysbiosis in
Parkinson’s?
If gut bacteria may play a role in Parkinson’s
disease, it may seem reasonable to infer that diet could help fight gut
dysbiosis and perhaps provide an easy option for symptom management.
While there are some dietary recommendations and nutritional supplements that
may help provide some symptom relief for some people, it remains unclear just
how much diet can actually do to alter the course of this disease.
One study from 2022 suggests that diets high in flavonoids — natural pigments found in
many fruits — are linked to a lower risk of mortality in Parkinson’s disease.
And an older
study, from 2018, argued that a
protein found in many types of fish, called “parvalbumin,” may help prevent
Parkinson’s disease by stopping alpha-synuclein. Source from
collecting into clumps in the brain — which is what happens in the brains of
people with Parkinson’s, disrupting signals between brain cells.
However, when asked about the potential of diet and
supplements to regulate gut bacteria in people with Parkinson’s, Dr. Demirkan
expressed some reservations.
She emphasized that since people have different risk
factors for Parkinson’s, as well as different iterations of the disease, it is
difficult to make general recommendations that would actually prove helpful:
“It’s very difficult for me to advise anyone anything
[…] because we are all very individual, our gut microbiome is individual. So
prevention [of the condition] is [one thing] I think, and the long-term maintenance
is something else, together with the other complications of the disease. So I
cannot really advise anything, but studies show there is a problem with increased sugar consumption. Source […] There are some intervention studies on diet indeed, but it’s
very difficult [to conclude anything], as the studies are not really […]
finalized. [It is difficult to know] how to advise an individual with a certain
genetic and lifelong history of exposure to different things, because we don’t
know what is in [them].”
Can exercise help with Parkinson’s?
There is, nevertheless, some research suggesting that
exercise can be an effective means of managing the symptoms of Parkinson’s
disease.
One study from 2022, published in Neurology, suggested that participating in regular, moderate-to-vigorous exercise
could help slow down the progression of Parkinson’s disease for those in the
early stages.
Research from
2017 advised that at least 2 and
a half hours of exercise per week could help people with Parkinson’s improve
their mobility while slowing down disease progression.
Dr. Demirkan agreed that exercise can be a helpful
strategy for managing Parkinson’s disease. “[E]xercise itself is an amazing way
of shaping our brain and body,” she said.
“[I]n terms of reversing [Parkinson’s] pathology,
there are some large physiological effects that we can think about. If you’re
running a marathon, for example, it’s a big thing that your body has to go through.
[…] [F]or instance, one thing is that your heat increase for a long time in
like a […] feverish way, right? There is a long-term increase in the core heat,
that’s one thing, and that should definitely have an important effect [on the
gut],” she explained.
Indeed, some research suggests that the heat stress taking place
during exercise could reduce intestinal blood flow, which eventually may impact
the gut microbiome by potentially suppressing some bacteria and making room for
others to expand.
As to which form of exercise is best for people with
Parkinson’s disease, a Cochrane review published in January 2023 concluded that pretty much all forms of exercise can
help improve life quality for those living with this condition.
According to the review authors, existing evidence
suggests that aqua-based training “probably has a large beneficial effect” on
quality of life. Endurance training is also helpful, both in improving life
quality, in general, and in managing motor symptoms, in particular.
When it comes to managing motor symptoms, the authors
write that dance, aqua-based exercise, gait/ balance/ functional exercise, and
multi-domain training could all be equally helpful.
And some past
research — in women with
overweight but without Parkinson’s — has suggested that endurance training
results in an increase in beneficial bacteria called Akkermansia,
which contribute to improved metabolic function.
Shaughnessy, who regularly takes part in demanding and
arduous marathons and other sports challenges to raise funds for Parkinson’s research told us that exercise
has helped him more than anything in maintaining his well-being.
“[E]xercise has become a big part — was already a part
of my life before [the diagnosis], but it’s become […] a big way of helping me
to manage and control the condition,” he told us in the podcast.
“I gradually went from, you know, a bit of running to
marathons. And then the latest thing I’ve done was a 14-day cycle from
Liverpool to Ukraine — 1,400 miles, which was probably a little bit beyond my
capability, to be honest,” he mused.
But challenging himself in
this way, he said, truly helped him on a mental level. “[W]hile I’m exercising,
I don’t feel like I have Parkinson’s, quite often,” Shaughnessy told us.
For him, it is all about focusing on what you are
actually able to achieve at any given point in time, and aiming for that.
“[A big part] of managing the condition, I think, is
around your mental attitude. Because when I first was diagnosed, I actually
found it very difficult, running. And I’d go running as part of being on
business trips abroad and so on, I’d run in cities I went to, and I did decline
in the first months, quite rapidly in terms of my running.
But my wife actually said to me, ‘just focus on what
you can do, not what you can’t do.’ And that was a bit of a turning point for
me. And, you know, by not worrying about [it], I’ve got to get better and go
quicker, and just focus on enjoying my running. And, you know, actually,
ironically, I have got better and I ran my personal best in the marathon in May
this year — so, 8 years after diagnosis.”
– Gary Shaughnessy
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