1.What is RBD?
RBD stands for “Rapid eye movement (REM) sleep Behaviour Disorder”. REM sleep is an important stage of sleep when most dreams happen and memory consolidates. Brain activity in this phase is similar to when we are awake.
RBD may present as a condition on its own, namely isolated RBD (iRBD), or be associated with neurodegenerative diseases, including Parkinson’s disease (PD). It may cause injuries and it has a significant prognostic value.
RBD may present as a condition on its own, namely isolated RBD (iRBD), or be associated with neurodegenerative diseases, including Parkinson’s disease (PD). It may cause injuries and it has a significant prognostic value.
2. What happens in people with RBD?
Unlike healthy people, in whom there is a loss of skeletal muscle tone – called atonia - while dreaming, in people with RBD this loss of muscle tone does not occur during the REM sleep. Consequently, people with RBD act out their dreams. This may manifest in different ways, in relation to dream content, such as shouting, yelling, screaming, orating, singing, laughing, cursing, crying out or jerking, punching, kicking, biting, flailing limb in the air, or falling out of bed while sleeping (Boeve, 2010).
3. Is a person aware of what happens during an RBD event?
Persons with RBD may be woken up by these events, be alert and orientated to their surroundings. Interestingly and so far unexplained is the fact that, during an RBD event, bed-partners of RBD persons have noticed the disappearance of parkinsonism symptoms – e.g. a much stronger voice, normal facial expression, and even symmetrical movements.
4. Is RBD a dangerous condition?
Motor activity while dreaming can lead to sleep-related injury to both the persons with RBD themselves and their sleeping or room partners, in over two-thirds of cases (69%). This may result in contusions, traumatic injuries and subdural haematomas.
5. Is RBD common in Parkinson’s disease?
Sleep disturbances are very common in PD, with 60 to 98% of persons with PD (PwPD) suffering from them. Among these sleep disorders is RBD. The frequency of RBD in PD has been reported to vary from 20 to 72%. So, yes, RBD is rather common in PD. Based on recent metanalyses, approximately, one in two persons with Parkinson’s may be suffering from RBD.
6. If RBD is so common in persons with Parkinson’s disease and can frequently cause injuries, why is it not screened routinely?
Medical professionals are likely to be little aware of RBD, because of its low prevalence in the general population, and the diagnosis of RBD is often missed in regular clinical practice. On the other hand, persons with RBD tend to delay care-seeking as they underestimate its significance and importance. But, as we will see, every PwPD should be screened for RBD.
7. What makes a person with RBD eventually seek health care?
The bedpartner or room-mate is often key to the joint decision of consulting a health care provider. Consultation would usually be triggered by injuries to themselves or the RBD person. The long delay in care-seeking - estimated by some authors to be about 9 years - coupled with health care providers’ limited awareness of RBD, would then contribute to RBD being often underdiagnosed and left untreated.
8. How is RBD diagnosed?
Polysomnography remains the gold standard for the diagnosis of RBD. However, it is not easily accessible and is an in-patient procedure. So, a probable RBD (pRBD) diagnosis is often made based on clinical history using RBD screening questionnaires (RBDSQ), which have been shown to be reliable, practical instruments. When used specifically in Parkinson’s to screen RBD, a sensitivity of 84.2% and a specificity of 96.2% have been reported.
Based on the International REM Sleep Behavior Disorder Study Group, Postuma et al. have proposed just a single screening question (RBD1Q) which has shown to have a very high detection rate for RBD, with a sensitivity of 93.8% and a specificity of 87.2%: “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?” (Postuma, 2012). Boeve et al. have reported a sensitivity of 100% and a specificity of 95% to identify people with RBD (Boeve, 2013).
Based on the International REM Sleep Behavior Disorder Study Group, Postuma et al. have proposed just a single screening question (RBD1Q) which has shown to have a very high detection rate for RBD, with a sensitivity of 93.8% and a specificity of 87.2%: “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?” (Postuma, 2012). Boeve et al. have reported a sensitivity of 100% and a specificity of 95% to identify people with RBD (Boeve, 2013).
9. How frequent are RBD episodes in a person and how long do they last?
The number and duration of RBD episodes vary markedly between people and in the same person. The majority of episodes tend to last less than 2 minutes, with a frequency of less than one per week but which can be even higher (2 or more episodes per week).
As most REM sleep is concentrated during the latter part of the sleep - usually after 3.00 a.m. - RBD events tend to occur mostly in the few hours before waking.
As most REM sleep is concentrated during the latter part of the sleep - usually after 3.00 a.m. - RBD events tend to occur mostly in the few hours before waking.
10. Is there any way to predict when an RBD would occur?
Unfortunately, there isn’t. One may have an episode today and no episodes for the rest of the week or have several episodes during a week and then no episodes the following week. It’s unpredictable.
11. What is the relationship between RBD and Parkinson’s disease?
There is strong, consistent evidence that iRBD is a prodromic, early sign of neurodegenerative diseases, mostly (94%) synucleinopathies. Synucleinopathies, which include PD, are a subgroup of neurodegenerative diseases characterized by the production and intracellular accumulation of abnormal deposits of synuclein. In people with iRBD, decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity have a sensitivity of 100% and specificity of 55% in predicting conversion to a synucleinopathy within 5 years.
Most (96.6%) people with iRBD will in the end (14 years) convert mostly to Parkinson's and dementia with Lewy bodies.
Most (96.6%) people with iRBD will in the end (14 years) convert mostly to Parkinson's and dementia with Lewy bodies.
12. So, is RBD a risk factor for Parkinson’s disease?
Yes, RBD is an important risk factor for PD. Furthermore, there is also substantial evidence that RBD predicts a clinical subtype of PD, which is distinct from PD without RBD. Many authors believe that PDRBD+ and PDRBD- would represent two different clinical entities.
13. What about the “body-first” / “brain-first” Parkinson’s subtypes? What are they and how does RBD relate to them?
It has recently been proposed that there could be two major PD subtypes, based on the location where the α-synuclein would aggregate first and its secondary propagation:
A.An enteric, peripheral nervous system (PNS)-first subtype, also called “body-first subtype”, and
B.A Central Nervous System (CNS)-first subtype, also called “brain-first subtype”.
PDRBD+ would belong to the “body-first subtype”.
A.An enteric, peripheral nervous system (PNS)-first subtype, also called “body-first subtype”, and
B.A Central Nervous System (CNS)-first subtype, also called “brain-first subtype”.
PDRBD+ would belong to the “body-first subtype”.
14. What would happen in the body-first and brain-first subtypes?
In the body-first subtype, α-synuclein aggregates would first form in the enteric nervous system. From there, they would spread upwards retrogradely through the autonomic nervous system to the brainstem and then to other parts of the brain, in a more symmetric fashion. So, in the phase preceding the appearance of motor symptoms, the pre-motor phase, RBD and symptoms of autonomic system involvement would precede the nigrostriatal dopaminergic system involvement and clinical motor signs of its dysfunction.
In the brain-first subtype, α-synuclein would aggregate in the brain first, to spread then through neuronal networks to the rest of the brain and to the autonomic nervous system. In this subtype, dopaminergic involvement with no RBD would precede that of the autonomic system. The prodromal phase would be shorter, with less pronounced non-motor symptoms appearing within a shorter interval before motor symptoms.
The presence of RBD, autonomic symptoms - such as constipation and orthostatic hypotension - or hyposmia (reduced sense of smell) during the prodromal, pre-motor phase of PD would tend to imply a body-first ascending propagation.
PDRBD+ - body-first subtype, has been shown to have faster disease progression than PDRBD-.
In support of the existence of the two subtypes, Leclair-Visonneau et al. found α-synuclein aggregates in colonic biopsies in 64% of PDRBD+ subjects compared to only 13% of PDRBD- ones (Leclair-Visonneau, 2017). Also, imaging studies have shown increased colonic volume and delayed colonic transit time in PDRBD+ compared to PDRBD-.
In the brain-first subtype, α-synuclein would aggregate in the brain first, to spread then through neuronal networks to the rest of the brain and to the autonomic nervous system. In this subtype, dopaminergic involvement with no RBD would precede that of the autonomic system. The prodromal phase would be shorter, with less pronounced non-motor symptoms appearing within a shorter interval before motor symptoms.
The presence of RBD, autonomic symptoms - such as constipation and orthostatic hypotension - or hyposmia (reduced sense of smell) during the prodromal, pre-motor phase of PD would tend to imply a body-first ascending propagation.
PDRBD+ - body-first subtype, has been shown to have faster disease progression than PDRBD-.
In support of the existence of the two subtypes, Leclair-Visonneau et al. found α-synuclein aggregates in colonic biopsies in 64% of PDRBD+ subjects compared to only 13% of PDRBD- ones (Leclair-Visonneau, 2017). Also, imaging studies have shown increased colonic volume and delayed colonic transit time in PDRBD+ compared to PDRBD-.
15. How long does it take for a person with RBD to develop a synucleinopathy?
RBD may manifest even 50 years before the synucleinopathy. Over 70% of persons with iRBD will develop parkinsonism or dementia within 12 years of their diagnosis. When hyposmia, severe constipation and orthostatic hypotension are present together with RBD, conversion to PD may occur in less than 5 years.
16. Are there any clinical features which characterise persons with the “PD/RBD+ subtype”?
Most subjects with the PDRBD+ phenotype – about 90% of them - are male. They are older, have a longer duration of the disease and of antiparkinsonian medicines compared with PDRBD-.
Clinical symptomatology is characterized by worse motor and more non-motor symptoms and poorer cognitive performance.
Individuals with PDRBD+ experience a more severe degree of disability with poorer quality of daily living and more functional dependency than those with PDRBD-. A Japanese multi-centre study found that Hoehn and Yahr stage was higher (worse) in the PDRBD+ subtype as were the Unified Parkinson's Disease Rating Scale (UPDRS) part III – motor symptoms – score (worse) and levodopa-equivalent daily dose; more motor fluctuations were also present.
Disease progression is faster with an aggressive clinical course and higher mortality.
This has led some authors to hypothesize that PDRBD+ may result from a different pattern of neurodegeneration than PDRBD-.
Clinical symptomatology is characterized by worse motor and more non-motor symptoms and poorer cognitive performance.
Individuals with PDRBD+ experience a more severe degree of disability with poorer quality of daily living and more functional dependency than those with PDRBD-. A Japanese multi-centre study found that Hoehn and Yahr stage was higher (worse) in the PDRBD+ subtype as were the Unified Parkinson's Disease Rating Scale (UPDRS) part III – motor symptoms – score (worse) and levodopa-equivalent daily dose; more motor fluctuations were also present.
Disease progression is faster with an aggressive clinical course and higher mortality.
This has led some authors to hypothesize that PDRBD+ may result from a different pattern of neurodegeneration than PDRBD-.
17. Which symptoms are more common in the “PD/RBD+ subtype”?
Several symptoms tend to be present more frequently or be more severe in PDRBD+.
Rigidity - PDRBD+ tend to be non-tremor-predominant subtype. Rigidity is more severe.
Olfactory dysfunction - Sense of smell and odour discrimination score are more frequently reduced in RBD, long before Parkinson’s motor symptoms appear. Increased olfactory threshold or dysfunction has been reported in 61 to 97% of iRBD subjects, with a higher frequency and severity of hyposmia found in PDRBD+ than PDRBD-. It has been suggested that olfactory dysfunction may be a sign of a widespread neurodegenerative process.
Those having both RBD and hyposmia are at higher risk for lower cognitive function.
Excessive daytime sleepiness – Excessive daytime sleepiness is a condition in which a PwPD is often unable to remain fully awake and alert during the waking hours of the day, to the extent that s/he may suddenly fall asleep. This condition, which can result in serious accidents and traumas, has a major impact on the quality of life and is also more frequent and worse in PDRBD+ compared with PDRBD-.
Autonomic dysfunction – A dysfunction of the autonomic nervous system is common in PD. This dysfunction is responsible for symptoms such as orthostatic hypotension, constipation, urinary incontinence, heat or cold intolerance, to name a few. This dysfunction is associated with, and is more severe in, PDRBD+. Severe cardiac sympathetic denervation – leading to cardiovascular dysfunction - has been described in PDRBD+ compared with PDRBD-. This may result in postprandial hypotension (drop of blood pressure), supine hypertension (increased blood pressure while lying down, e.g. while sleeping at night), increased blood pressure variability and decreased heart rate variability. RBD and dysautonomia symptoms have been reported to be significantly associated with anxiety symptoms over time. Let’s have a look at orthostatic hypotension and constipation.
§ Orthostatic hypotension is defined as a drop of systolic blood pressure by 20 mmHg or more or a drop of the diastolic blood pressure by at least 10 mmHg within 3 minutes of standing up from the lying or sitting position. PwPD often have decreased levels of norepinephrine, which is a neurotransmitter that helps to correct the drop in blood pressure caused by such rapid changes in body position. An impairment of this adjustment response may result in symptoms (symptomatic orthostatic hypotension) which can lead to falls. Orthostatic hypotension is much more common and more severe in the PDRBD+ subtype. Romenets et al. found that a drop in systolic blood pressure greater than 10 mmHg detected PDRBD+ with high sensitivity (81%) and specificity (86%) (Romenets, 2012). Light-headedness upon standing (postural light-headness) has been reported to be significantly more prevalent in PDRBD+ than PDRBD- (52.5% vs 35.7%). A higher prevalence of dizziness has also been reported in PDRBD+ vs. PDRBD- (55.6% vs 19.2%). RBD and orthostatic hypotension have combined negative effects on disability. Yin et al. have proposed that RBD may represent an independent risk factor for orthostatic hypotension (Yin, 2022).
§ Constipation is very common in Parkinson’s (28–80%), with the prevalence increasing as the disease progresses. It is among the first non-motor symptoms to develop in the prodromal phase of PD and can have a great impact on the quality of life of PwPD. Constipation is closely associated with RBD; it is more frequent and severe in PDRBD+, compared with PDRBD-.
Postural instability and gait issues - PDRBD+ is associated with more severe gait issues and a tendency to have gait freezing. Those who develop postural instability and gait issues early in the course of the disease will experience a more rapid progression. Duart Folle et al. have suggested that RBD could serve as a marker for faster cognitive decline and disease progression in PwPD with Postural Instability and Gait Dysfunction (Duarte Folle, 2019).
Speech impairment - Speech impairment, especially articulatory, is present in 88% of persons with RBD.
Falls - The risk of falls is higher in PDRBD+ compared with PDRBD- (38% vs 7%), especially in those with longer disease duration. Romagnolo et al. reported that PwPD with cardiac autonomic neuropathy had a 15-fold risk for falls (Romagnolo, 2019).
There are also some psychiatric symptoms which are more common in PDRBD+.
§ Depression and anxiety - Depression is more common in PDRBD+. The effect of RBD on depression in PD may in part be mediated by autonomic dysfunction, with cardiovascular, gastrointestinal, thermoregulatory and urinary symptoms representing strong predictors of depression in PD. An association between RBD and anxiety is also present.
§ Hallucinations - RBD is often associated with visual hallucinations and cognitive impairment, which are risk factors for each other.
§ Impulsive-compulsive behaviours – These are unplanned behaviours which a person can not resist and which are carried out without thinking of the possible consequences, or behaviours according to which an individual feels the urge to do certain activities which have no purpose, often repetitively. Examples include an uncontrollable, pathological sense to gamble, shop, hoard, binge eat, hypersexuality, punding, hobbying. Such behaviours can result in much harm and have serious consequences. An increased risk of developing impulsive-compulsive behaviours has been described in PDRBD+ in many studies. In a recent metanalysis, PDRBD+ were found to have a 2-fold risk compared with PDRBD-.
Restless Leg Syndrome - RBD may also be a risk factor for the Restless Leg Syndrome in PwPD.
I've left at the end of this list a very important symptom.
Cognitive impairment and dementia - Whether idiopathic or PD-associated, RBD is a risk factor for cognitive impairment, faster cognitive decline and dementia. In a population-based study, people with pRBD were more than 2 times as likely as those without pRBD to develop mild cognitive impairment and parkinsonism within 4 years.
Rigidity - PDRBD+ tend to be non-tremor-predominant subtype. Rigidity is more severe.
Olfactory dysfunction - Sense of smell and odour discrimination score are more frequently reduced in RBD, long before Parkinson’s motor symptoms appear. Increased olfactory threshold or dysfunction has been reported in 61 to 97% of iRBD subjects, with a higher frequency and severity of hyposmia found in PDRBD+ than PDRBD-. It has been suggested that olfactory dysfunction may be a sign of a widespread neurodegenerative process.
Those having both RBD and hyposmia are at higher risk for lower cognitive function.
Excessive daytime sleepiness – Excessive daytime sleepiness is a condition in which a PwPD is often unable to remain fully awake and alert during the waking hours of the day, to the extent that s/he may suddenly fall asleep. This condition, which can result in serious accidents and traumas, has a major impact on the quality of life and is also more frequent and worse in PDRBD+ compared with PDRBD-.
Autonomic dysfunction – A dysfunction of the autonomic nervous system is common in PD. This dysfunction is responsible for symptoms such as orthostatic hypotension, constipation, urinary incontinence, heat or cold intolerance, to name a few. This dysfunction is associated with, and is more severe in, PDRBD+. Severe cardiac sympathetic denervation – leading to cardiovascular dysfunction - has been described in PDRBD+ compared with PDRBD-. This may result in postprandial hypotension (drop of blood pressure), supine hypertension (increased blood pressure while lying down, e.g. while sleeping at night), increased blood pressure variability and decreased heart rate variability. RBD and dysautonomia symptoms have been reported to be significantly associated with anxiety symptoms over time. Let’s have a look at orthostatic hypotension and constipation.
§ Orthostatic hypotension is defined as a drop of systolic blood pressure by 20 mmHg or more or a drop of the diastolic blood pressure by at least 10 mmHg within 3 minutes of standing up from the lying or sitting position. PwPD often have decreased levels of norepinephrine, which is a neurotransmitter that helps to correct the drop in blood pressure caused by such rapid changes in body position. An impairment of this adjustment response may result in symptoms (symptomatic orthostatic hypotension) which can lead to falls. Orthostatic hypotension is much more common and more severe in the PDRBD+ subtype. Romenets et al. found that a drop in systolic blood pressure greater than 10 mmHg detected PDRBD+ with high sensitivity (81%) and specificity (86%) (Romenets, 2012). Light-headedness upon standing (postural light-headness) has been reported to be significantly more prevalent in PDRBD+ than PDRBD- (52.5% vs 35.7%). A higher prevalence of dizziness has also been reported in PDRBD+ vs. PDRBD- (55.6% vs 19.2%). RBD and orthostatic hypotension have combined negative effects on disability. Yin et al. have proposed that RBD may represent an independent risk factor for orthostatic hypotension (Yin, 2022).
§ Constipation is very common in Parkinson’s (28–80%), with the prevalence increasing as the disease progresses. It is among the first non-motor symptoms to develop in the prodromal phase of PD and can have a great impact on the quality of life of PwPD. Constipation is closely associated with RBD; it is more frequent and severe in PDRBD+, compared with PDRBD-.
Postural instability and gait issues - PDRBD+ is associated with more severe gait issues and a tendency to have gait freezing. Those who develop postural instability and gait issues early in the course of the disease will experience a more rapid progression. Duart Folle et al. have suggested that RBD could serve as a marker for faster cognitive decline and disease progression in PwPD with Postural Instability and Gait Dysfunction (Duarte Folle, 2019).
Speech impairment - Speech impairment, especially articulatory, is present in 88% of persons with RBD.
Falls - The risk of falls is higher in PDRBD+ compared with PDRBD- (38% vs 7%), especially in those with longer disease duration. Romagnolo et al. reported that PwPD with cardiac autonomic neuropathy had a 15-fold risk for falls (Romagnolo, 2019).
There are also some psychiatric symptoms which are more common in PDRBD+.
§ Depression and anxiety - Depression is more common in PDRBD+. The effect of RBD on depression in PD may in part be mediated by autonomic dysfunction, with cardiovascular, gastrointestinal, thermoregulatory and urinary symptoms representing strong predictors of depression in PD. An association between RBD and anxiety is also present.
§ Hallucinations - RBD is often associated with visual hallucinations and cognitive impairment, which are risk factors for each other.
§ Impulsive-compulsive behaviours – These are unplanned behaviours which a person can not resist and which are carried out without thinking of the possible consequences, or behaviours according to which an individual feels the urge to do certain activities which have no purpose, often repetitively. Examples include an uncontrollable, pathological sense to gamble, shop, hoard, binge eat, hypersexuality, punding, hobbying. Such behaviours can result in much harm and have serious consequences. An increased risk of developing impulsive-compulsive behaviours has been described in PDRBD+ in many studies. In a recent metanalysis, PDRBD+ were found to have a 2-fold risk compared with PDRBD-.
Restless Leg Syndrome - RBD may also be a risk factor for the Restless Leg Syndrome in PwPD.
I've left at the end of this list a very important symptom.
Cognitive impairment and dementia - Whether idiopathic or PD-associated, RBD is a risk factor for cognitive impairment, faster cognitive decline and dementia. In a population-based study, people with pRBD were more than 2 times as likely as those without pRBD to develop mild cognitive impairment and parkinsonism within 4 years.
18. Can we elaborate more on the risk for cognitive impairment in “PD/RBD+”?
Mild Cognitive Impairment (MCI) or a reduction in attention, memory, executive functions, verbal fluency and visuospatial abilities are more frequently present in persons with RBD, irrespective of whether or not they have PD. In a study on RBD, MCI was present in 50% of iRBD and in 73% of PDRBD+, compared with just 11% of PDRBD- and 8% of control subjects. A higher prevalence and severity of, or risk for, cognitive impairment in PDRBD+ has been confirmed in many studies. Its prevalence in PDRBD+ was found to be up to three times as high as in PDRBD- (66% vs. 23%). The risk of developing MCI/parkinsonism over 4 years in those with pRBD+ was estimated to be more than twice as much as in those with no pRBD- in a population-based study. Neuropsychological test scores in those with RBD are worse than in those without RBD.
The coexistence of olfactory dysfunction or orthostatic hypotension with RBD is associated with worse cognitive function.
RBD is also associated with the development of dementia, representing a risk factor for cognitive impairment deterioration and faster progression to dementia in PDRBD+ compared with PDRBD-. PDRBD+ had a higher rate of dementia compared to those without RBD (42% Vs 7.3%).
The coexistence of olfactory dysfunction or orthostatic hypotension with RBD is associated with worse cognitive function.
RBD is also associated with the development of dementia, representing a risk factor for cognitive impairment deterioration and faster progression to dementia in PDRBD+ compared with PDRBD-. PDRBD+ had a higher rate of dementia compared to those without RBD (42% Vs 7.3%).
19. After this description of the symptoms, the clinical course in the “PD/RBD+ subtype” seems to be rather aggressive …
Yes, that’s correct. The combination of RBD with selected other symptoms further aggravates the prognosis.
We have already seen that RBD and hyposmia (reduced sense of smell) are a risk for lower cognitive function and faster disease progression and that RBD and orthostatic hypotension have combined negative effects on disability.
Also, the simultaneous presence of mild cognitive impairment and orthostatic hypotension with RBD at baseline defines a more malignant “phenotype” with faster progression and predicts the development of dementia.
We have already seen that RBD and hyposmia (reduced sense of smell) are a risk for lower cognitive function and faster disease progression and that RBD and orthostatic hypotension have combined negative effects on disability.
Also, the simultaneous presence of mild cognitive impairment and orthostatic hypotension with RBD at baseline defines a more malignant “phenotype” with faster progression and predicts the development of dementia.
20. Is there any laboratory test that may herald the development of, or conversion to, Parkinson’s in persons with RBD?
Serum uric acid in RBD has been proposed as a biomarker of the conversion from prodromal to clinical PD. Serum uric acid levels are initially higher in RBD in pre-motor PD and have been associated with no conversion to PD. Levels decrease when Parkinson’s clinical motor symptoms manifest. This is consistent with previous studies which have shown a similar inverse relationship of urate levels with the risk of developing Parkinson’s disease (PD) and the rate of disease progression. A recent meta-analysis including 15 studies with 449,816 participants and 14,687 cases has confirmed a reduced risk of PD for higher urate levels.
21. To sum up, can we draw a clinical profile of a person with the “PD/RBD+ subtype”?
A person with PDRBD+ could be described as a person who is more likely to have several clinical features and risks compared with a PDRBD- person.
·Age: older
·Gender: Male
·Duration of disease: longer
·Type: Non-tremor-predominant
·Duration of antiparkinson’s medicines: longer
Symptoms:
·Impairment of cognitive function
·Olfactory dysfunction (anosmia)
·Excessive daytime sleepiness
·Autonomic dysfunction, including orthostatic hypotension and more severe constipation
· Speech impairment
Quality of life:
·Higher impairment of daily living
Higher risk for:
·Worsening cognitive performance and dementia
·Gait freezing
·Higher number of falls
·Depression
·Visual hallucinations
Prognosis:
·Clinical course: faster, more aggressive disease progression
·Higher disability
Higher mortality
·Age: older
·Gender: Male
·Duration of disease: longer
·Type: Non-tremor-predominant
·Duration of antiparkinson’s medicines: longer
Symptoms:
·Impairment of cognitive function
·Olfactory dysfunction (anosmia)
·Excessive daytime sleepiness
·Autonomic dysfunction, including orthostatic hypotension and more severe constipation
· Speech impairment
Quality of life:
·Higher impairment of daily living
Higher risk for:
·Worsening cognitive performance and dementia
·Gait freezing
·Higher number of falls
·Depression
·Visual hallucinations
Prognosis:
·Clinical course: faster, more aggressive disease progression
·Higher disability
Higher mortality
22. Does the prognosis differ if RBD occurs before or after Parkinson’s clinical motor manifestations?
In a very small clinical study, researchers found no difference in disease symptoms between PwPD in whom RBD preceded the disease and those with PDRBD-. However, PwPD in whom RBD developed after the diagnosis of PD showed a significantly higher disease stage, took significantly higher dopaminergic therapy, and had a longer disease duration. Bovenzi et al. in a longitudinal retrospective study described faster disease progression in PDRBD+ than PDRBD- and pRBD (Bovenzi, 2024). Nomura et al. also found that PwPD in whom RBD developed after the PD diagnosis had more severe cognitive dysfunction than those in whom RBD preceded it (Nomura, 2017). These findings however contrast with those of another clinical study showing that PwPD in whom RBD occurred before the onset of motor symptoms would represent a subtype with a more severe cognitive phenotype and a higher risk of developing hallucinations along the disease course. An increased frequency of symptoms such as excessive daytime sleepiness and constipation was reported in PwPD in whom RBD developed before PD compared with those in whom RBD manifested after PD or with those with no RBD.
23. Are there any structural and functional brain differences between PD/RBD+ and PD/RBD-?
Yes. Overall, PDRBD+ shows more widespread structural and functional alterations in several brain areas compared with PDRBD-, based on clinical, neuroimaging and autopsy studies. I’ll give some examples.
The brainstem is the key site of the neural circuits involved in REM sleep. Regulation of REM sleep involves neurons located in several areas in the brain, such as the medulla, pons, midbrain, and hypothalamus. Among them, GABAergic neurons – which have a role in REM modulation – are present in large numbers in the pons, midbrain and lateral hypothalamus. A review of twenty-nine studies, involving a total of 3,347 PD subjects, found changes in PDRBD+ in the brainstem, limbic structures, frontotemporal cortex, and basal ganglia, compared with PDRBD- and healthy controls.
Compared with the brain-first subtype, changes in RBD describe a damage which involves not only the brainstem and a disruption of the pathways regulating REM sleep and atonia, but also many other areas in the brain and the autonomous system.
In line with the clinical description of a more severe phenotype, PDRBD+ is associated with extensive cortical thinning and subcortical abnormalities compared with PDRBD-, “suggesting more severe neurodegeneration” (Rahayel, 2019; Dodet, 2023). On autopsy, PDRBD+ showed significantly increased synuclein deposition in nine of 10 regions of the brain examined in a study compared with PDRBD-, suggesting a more extensive synuclein pathology.
Impaired cognitive function, which is clinically associated with PDRBD+, is also linked to gray matter atrophy in PDRBD+, like reduced thalamus, hippocampus, and putamen volumes, and has been shown to be related to the marked increase in the thinning in the left insula and caudate nucleus in PDRBD+ compared with PDRBD-.
In PwPD, changes in the cholinergic system occur in different brain regions, in line with clinical features. As the system regulates cognition, locomotion and sleep, this would explain why
“its disruption has been associated in PD with cognitive decline, postural instability and gait problems, falls, RBD, neuropsychiatric manifestations, and olfactory dysfunction” (Pasquini, 2021).
MRI (magnetic resonance imaging) scans have confirmed the presence of more atrophy in the pontomesencephalic tegmentum in PDRBD+ than in PDRBD- and healthy controls. In this area, there are cholinergic, GABAergic and glutamatergic neurons, involved in REM sleep modulation. Cholinergic neurons here decrease significantly and so do those in the substantia nigra, cortical and subcortical gray areas in PDRBD+ compared with PDRBD- and healthy controls. Concerning GABAergic, glutamatergic and monoaminergic systems, their dysfunction has been reported as part of significant alterations in neurotransmission in PDRBD+.
In addition to the alteration to the cholinergic system, neuroimaging studies have found alterations also to the dopaminergic system in both RBD and PDRBD+. Beyond the brainstem, structural and functional changes have involved the nigrostriatal system, limbic system and the cortex suggesting a more complex neurodegenerative process.
Nigrostriatal degeneration is more symmetrical in PDRBD+ compared with PDRBD-. This is consistent with the body-first subtype proposed mechanism of propagating retrogradely through vagal innervation, more symmetrically, which in turn would result in a more symmetric involvement of the brainstem.
Marked substantia nigra hyperechogenicity, which is a typical, distinctive feature in Parkinson’s, has also been observed in iRBD (37%) compared with the control group (11%).
RBD has been linked with reduced noradrenergic function in PD, which may contribute also to the high prevalence of orthostatic hypotension and cognitive dysfunction in PD.
Many studies have demonstrated that most people with iRBD (92%) show features linked to sympathetic denervation, which are also more evident in PDRBD+ compared to PDRBD-. Cardiac sympathetic denervation is present early in body-first PD while it is less evident in PDRBD-. PDRBD+ may result from a more widespread α-synuclein deposition, including reduced cardiac sympathetic ganglia function, as reflected by a lowered MIBG (123I-mIBG Scintigraphy) uptake.
An impairment of mitochondrial respiration in fibroblasts facing energy demand - in people with RBD - was more evident in PDRBD+.
An in-depth review has recently been published by Horsager et al. on the body-first and brain-first PD subtypes, looking at structural and functional differences between the two forms (Horsager, 2022).
The brainstem is the key site of the neural circuits involved in REM sleep. Regulation of REM sleep involves neurons located in several areas in the brain, such as the medulla, pons, midbrain, and hypothalamus. Among them, GABAergic neurons – which have a role in REM modulation – are present in large numbers in the pons, midbrain and lateral hypothalamus. A review of twenty-nine studies, involving a total of 3,347 PD subjects, found changes in PDRBD+ in the brainstem, limbic structures, frontotemporal cortex, and basal ganglia, compared with PDRBD- and healthy controls.
Compared with the brain-first subtype, changes in RBD describe a damage which involves not only the brainstem and a disruption of the pathways regulating REM sleep and atonia, but also many other areas in the brain and the autonomous system.
In line with the clinical description of a more severe phenotype, PDRBD+ is associated with extensive cortical thinning and subcortical abnormalities compared with PDRBD-, “suggesting more severe neurodegeneration” (Rahayel, 2019; Dodet, 2023). On autopsy, PDRBD+ showed significantly increased synuclein deposition in nine of 10 regions of the brain examined in a study compared with PDRBD-, suggesting a more extensive synuclein pathology.
Impaired cognitive function, which is clinically associated with PDRBD+, is also linked to gray matter atrophy in PDRBD+, like reduced thalamus, hippocampus, and putamen volumes, and has been shown to be related to the marked increase in the thinning in the left insula and caudate nucleus in PDRBD+ compared with PDRBD-.
In PwPD, changes in the cholinergic system occur in different brain regions, in line with clinical features. As the system regulates cognition, locomotion and sleep, this would explain why
“its disruption has been associated in PD with cognitive decline, postural instability and gait problems, falls, RBD, neuropsychiatric manifestations, and olfactory dysfunction” (Pasquini, 2021).
MRI (magnetic resonance imaging) scans have confirmed the presence of more atrophy in the pontomesencephalic tegmentum in PDRBD+ than in PDRBD- and healthy controls. In this area, there are cholinergic, GABAergic and glutamatergic neurons, involved in REM sleep modulation. Cholinergic neurons here decrease significantly and so do those in the substantia nigra, cortical and subcortical gray areas in PDRBD+ compared with PDRBD- and healthy controls. Concerning GABAergic, glutamatergic and monoaminergic systems, their dysfunction has been reported as part of significant alterations in neurotransmission in PDRBD+.
In addition to the alteration to the cholinergic system, neuroimaging studies have found alterations also to the dopaminergic system in both RBD and PDRBD+. Beyond the brainstem, structural and functional changes have involved the nigrostriatal system, limbic system and the cortex suggesting a more complex neurodegenerative process.
Nigrostriatal degeneration is more symmetrical in PDRBD+ compared with PDRBD-. This is consistent with the body-first subtype proposed mechanism of propagating retrogradely through vagal innervation, more symmetrically, which in turn would result in a more symmetric involvement of the brainstem.
Marked substantia nigra hyperechogenicity, which is a typical, distinctive feature in Parkinson’s, has also been observed in iRBD (37%) compared with the control group (11%).
RBD has been linked with reduced noradrenergic function in PD, which may contribute also to the high prevalence of orthostatic hypotension and cognitive dysfunction in PD.
Many studies have demonstrated that most people with iRBD (92%) show features linked to sympathetic denervation, which are also more evident in PDRBD+ compared to PDRBD-. Cardiac sympathetic denervation is present early in body-first PD while it is less evident in PDRBD-. PDRBD+ may result from a more widespread α-synuclein deposition, including reduced cardiac sympathetic ganglia function, as reflected by a lowered MIBG (123I-mIBG Scintigraphy) uptake.
An impairment of mitochondrial respiration in fibroblasts facing energy demand - in people with RBD - was more evident in PDRBD+.
An in-depth review has recently been published by Horsager et al. on the body-first and brain-first PD subtypes, looking at structural and functional differences between the two forms (Horsager, 2022).
24. Following the “body-first” hypothesis, are there any changes in the microbiome in PD/RBD+?
In the body-first subtype, the pathological process of aggregation of misfolded α-synuclein is believed to start in the enteric nervous system, with microbiome alterations. The intestinal microbiome is part of the microbiota-gut-brain axis, in which the enteric nervous system, autonomic nervous system, central nervous system and gastro-intestinal tract interact to influence key aspects of gut physiology. The intestinal microbiome is markedly altered in PD. Gut dysbiosis is likely to contribute to the leaky gut, neuroinflammation, and over-activated microglial cells found in PD. RBD belongs to the body-first subtype and we have already seen that constipation is very frequent and more severe in PDRBD+ than PDRBD-.
Differences in bacterial composition in RBD and PD vs normal controls have been reported, although altered bacterial taxa are not consistent across studies.
A depletion of butyrate-producing bacteria is a common and important feature in PD, relevant in RBD and early PD. Faecalibacterium is a key butyrate-producing bacterium and has been found to be decreased in PD, and in RBD and PDRBD+. Butyrate is a short-chain fatty acid (SCFA). SCFAs have many health benefits, among which are anti-inflammatory effects, reduction of oxidative stress, support of gastrointestinal barrier integrity, immunoregulatory and neuroprotective. Some authors have suggested that the reduction of SCFA-producing bacteria in PD may start from genus Faecalibacterium. A decrease of the genus Faecalibacterium may thus be a marker predicting conversion from iRBD to PD. A decrease in Faecalibacterium correlated with a higher severity of RBD and was found in persons with RBD and in those with RBD converting to PD.
Also, the genus Akkermansia has been found to be consistently increased in PD, more abundant in PDRBD+ compared to PDRBD-, and in RBD and early PD.
Persons with RBD, PDRBD+ and PDRBD- have been found to be Ruminococcus-dominant, unlike normal controls.
Differences in bacterial composition in RBD and PD vs normal controls have been reported, although altered bacterial taxa are not consistent across studies.
A depletion of butyrate-producing bacteria is a common and important feature in PD, relevant in RBD and early PD. Faecalibacterium is a key butyrate-producing bacterium and has been found to be decreased in PD, and in RBD and PDRBD+. Butyrate is a short-chain fatty acid (SCFA). SCFAs have many health benefits, among which are anti-inflammatory effects, reduction of oxidative stress, support of gastrointestinal barrier integrity, immunoregulatory and neuroprotective. Some authors have suggested that the reduction of SCFA-producing bacteria in PD may start from genus Faecalibacterium. A decrease of the genus Faecalibacterium may thus be a marker predicting conversion from iRBD to PD. A decrease in Faecalibacterium correlated with a higher severity of RBD and was found in persons with RBD and in those with RBD converting to PD.
Also, the genus Akkermansia has been found to be consistently increased in PD, more abundant in PDRBD+ compared to PDRBD-, and in RBD and early PD.
Persons with RBD, PDRBD+ and PDRBD- have been found to be Ruminococcus-dominant, unlike normal controls.
25. Is it possible to control RBD?
Persons with RBD are at risk of injuries. Better sleep also reduces PD motor symptoms. It would therefore be imperative to control RBD events. Low-dose clonazepam and high-dose and rapid-acting melatonin taken at bedtime are currently the medicines most commonly used, to reduce the frequency and severity of RBD events - and the resulting, potential injuries, and improve sleep quality. Clonazepam has been reported to be effective in decreasing the intensity of dream-enacting behaviors. These medicines are thought to prevent injury to patients and bed partners, although results are not consistent across studies. Small randomized placebo-controlled trials have reported an effect comparable to placebo and the overall effects of treatment are still unsatisfactory. It is unclear whether such treatment protects against RBD severity and adverse outcomes in the long run. Furthermore, chronic use of drugs increases the risk of cognitive impairment, dementia and falls, for which PDRBD+ is already at higher risk than PDRBD-. Finally, treatment-associated side effects make some patients stop taking clonazepam. The critical importance of adopting measures to create a safe sleeping environment is an equally key strategic intervention.
26. Does thiamine (b1) have an effect on sleep disorders? Does it play any potential role in “Parkinson’s with RBD”?
Low thiamine intake and thiamine deficiency have been found to be associated with sleep disorders.
Data analysis from 15,384 participants from the Korea National Health and Nutrition Examination Survey 2012-2016 found that low thiamine intake was associated with oversleeping. The lower the intake of thiamine, the higher the likelihood of oversleeping.
Another study found that thiamine intake was significantly lower in people affected by insomnia than in normal sleepers.
Similarly, in another study using data from the National Health and Nutrition Examination Survey (NHANES), 2007–2008, the researchers found an association between low intake of thiamine and very short sleep duration (<5 hours).
There are also some indications from a few clinical studies that thiamine supplementation may positively influence sleep, particularly in the presence of thiamine deficiency.
In a clinical double-blinded trial in elderly women with mild thiamine deficiency, thiamine supplementation (10 mg/day) reduced daytime sleep time and improved sleep patterns. A randomized double-blind, placebo-controlled trial showed that thiamine supplementation (10 mg/day) given also in this case to an elderly population - 65 years old or older - with subclinical thiamine deficiency had a positive effect on sleep.
In a preclinical study in rats, thiamine administration reversed the effects caused by thiamine deficiency - induced by pyrithiamine – on slow-wave sleep (increase) and paradoxical sleep and wakefulness (decrease).
In a small pilot study, a supplement containing 4 different nutrients, including thiamine (1.65 mg), led to remarkable improvements in sleep quality, according to the authors. Although the supplement contained also melatonin, the amount of melatonin (1 mg) was much lower than the one considered effective in RBD. Finally, the presence also of two other ingredients makes it difficult to separate the effects of each substance from each other or any potential combined effects on sleep.
Anecdotal reports made by PwPD have included “sleep” among the symptoms that had improved with high-dose thiamine (Bryan, Parkinson’s and the b1 therapy, 2022). In a small survey among PwPD in a Facebook group, 38 persons with pRBD – screened through the RBD1Q - volunteered to participate. Sixteen of them had already found their b1 sweet spot, that is they were taking a dose of thiamine able to control their PD symptoms. Eleven of these 16 (69%) PwPD with RBD reported an improvement also of RBD, in terms of reduction in the frequency (10/11) and severity of episodes (7/11) and “feeling more rested” when waking up (4/11). Five persons among them were using melatonin in addition to thiamine to control RBD.
It seems from the above studies that thiamine may play a role in sleep, including REM, more so when a deficiency is present. The information available is very scanty and more studies are needed.
Data analysis from 15,384 participants from the Korea National Health and Nutrition Examination Survey 2012-2016 found that low thiamine intake was associated with oversleeping. The lower the intake of thiamine, the higher the likelihood of oversleeping.
Another study found that thiamine intake was significantly lower in people affected by insomnia than in normal sleepers.
Similarly, in another study using data from the National Health and Nutrition Examination Survey (NHANES), 2007–2008, the researchers found an association between low intake of thiamine and very short sleep duration (<5 hours).
There are also some indications from a few clinical studies that thiamine supplementation may positively influence sleep, particularly in the presence of thiamine deficiency.
In a clinical double-blinded trial in elderly women with mild thiamine deficiency, thiamine supplementation (10 mg/day) reduced daytime sleep time and improved sleep patterns. A randomized double-blind, placebo-controlled trial showed that thiamine supplementation (10 mg/day) given also in this case to an elderly population - 65 years old or older - with subclinical thiamine deficiency had a positive effect on sleep.
In a preclinical study in rats, thiamine administration reversed the effects caused by thiamine deficiency - induced by pyrithiamine – on slow-wave sleep (increase) and paradoxical sleep and wakefulness (decrease).
In a small pilot study, a supplement containing 4 different nutrients, including thiamine (1.65 mg), led to remarkable improvements in sleep quality, according to the authors. Although the supplement contained also melatonin, the amount of melatonin (1 mg) was much lower than the one considered effective in RBD. Finally, the presence also of two other ingredients makes it difficult to separate the effects of each substance from each other or any potential combined effects on sleep.
Anecdotal reports made by PwPD have included “sleep” among the symptoms that had improved with high-dose thiamine (Bryan, Parkinson’s and the b1 therapy, 2022). In a small survey among PwPD in a Facebook group, 38 persons with pRBD – screened through the RBD1Q - volunteered to participate. Sixteen of them had already found their b1 sweet spot, that is they were taking a dose of thiamine able to control their PD symptoms. Eleven of these 16 (69%) PwPD with RBD reported an improvement also of RBD, in terms of reduction in the frequency (10/11) and severity of episodes (7/11) and “feeling more rested” when waking up (4/11). Five persons among them were using melatonin in addition to thiamine to control RBD.
It seems from the above studies that thiamine may play a role in sleep, including REM, more so when a deficiency is present. The information available is very scanty and more studies are needed.
27. What can we conclude?
PDRBD+ may represent a distinct phenotype with a higher disease burden, more severe and aggressive disease progression, poorer cognitive function, and a higher disability and mortality. This subtype must be identified early, even by the RBD1Q, and followed up more closely.
Thiamine at high doses which are effective in controlling PD symptoms in a particular PwPD seems to have a positive effect on RBD, with a reported reduction in frequency and severity of episodes. More information is needed to confirm this potential benefit.
It is critical to identify PDRBD+ when conducting research, as response to different approaches may depend on the RBD sub-type, compared with the non-RBD subtype.
Thiamine at high doses which are effective in controlling PD symptoms in a particular PwPD seems to have a positive effect on RBD, with a reported reduction in frequency and severity of episodes. More information is needed to confirm this potential benefit.
It is critical to identify PDRBD+ when conducting research, as response to different approaches may depend on the RBD sub-type, compared with the non-RBD subtype.
28. References
The list of the over 200 selected references on which this Q&A is based is provided in the related document in the Member area of our website at: https://b1parkinsons.org/members/login
List of b1parkinsons.org documents of the Technical Basis Series on the Rationale for the High-dose B1 Therapy Protocol for Parkinson’s disease
1. Safety of thiamine – The evidence (March 2023)
2. Thiamine and cancer – Is there a relationship? (April 2023)
3. Thiamine and magnesium (May 2023)
4. Diagnosing Parkinson’s disease: How accurate is the clinical diagnosis? (July 2023)
5. Screening for testing for vitamin B12 deficiency in Parkinson’s disease B1 therapy (September 2023)
6. Thiamine and the blood-brain barrier – Hypothesis (October 2023)
7. Q&A on benfotiamine - Does benfotiamine have any role in the treatment of neurologic conditions? (February 2024)
8. Q&A on Rapid Eye Movements (REM) sleep Behaviour Disorder (RBD) – Is there any role for thiamine? (September 2024)
These technical documents are in the pdf format and are accessible to everybody, after registration in the Member area of our website at: https://b1parkinsons.org/members/login .
2. Thiamine and cancer – Is there a relationship? (April 2023)
3. Thiamine and magnesium (May 2023)
4. Diagnosing Parkinson’s disease: How accurate is the clinical diagnosis? (July 2023)
5. Screening for testing for vitamin B12 deficiency in Parkinson’s disease B1 therapy (September 2023)
6. Thiamine and the blood-brain barrier – Hypothesis (October 2023)
7. Q&A on benfotiamine - Does benfotiamine have any role in the treatment of neurologic conditions? (February 2024)
8. Q&A on Rapid Eye Movements (REM) sleep Behaviour Disorder (RBD) – Is there any role for thiamine? (September 2024)
These technical documents are in the pdf format and are accessible to everybody, after registration in the Member area of our website at: https://b1parkinsons.org/members/login .
Sergio Pièche
