Young onset Parkinson’s disease (YOPD)

Definition
PD with onset of motor symptoms between ages 21 to 40 years, while onset at or
before age 20 defines juvenile PD and onset after 55/60 defines late onset PD
(LOPD).
The reported maximal age for YOPD has varied from 40 to 55.
3 stages of early PD: preclinical (neurodegeneration without clinical symptoms),
prodromal (symptoms but are not yet sufficient to make a diagnosis), clinical stage.
(Zesiewicz et al., 2020)

Prevalence
The National Institute on Aging notes that although symptoms appear after the age of
60 years in most people with Parkinson’s disease, in 5–10% of cases, it occurs before
the age of 50 years. Doctors refer to these cases as early onset Parkinson’s disease.
(Biddiscombe et al., 2020)
Some people develop juvenile Parkinson’s disease, in which the symptoms start
appearing before the age of 20 years. The American Parkinson Disease Association
(APDA) notes that 10–20% of people with Parkinson’s disease have the early onset
form, meaning that it affects about 6,000–12,000 people in the United States.
Scientists do not know exactly why Parkinson’s disease happens, but they believe that
it results from a combination of environmental and genetic factors. Head injury and
exposure to toxins, such as pesticides, may contribute.
About 10% of all cases have a genetic cause, and most of these involve younger
people. In cases where there is a genetic cause, the disease may be hereditary.
YOPD represents 5 to 7% of PD patients in the western hemisphere, but 10 to 14% in
Japan. (Mehanna et al., 2019)

Genetic
It has been well recognized that the younger the age at onset (AAO), the higher the
risk of genetic predisposition.
Family history: 20% of YOPD vs 6.9% of LOPD
PARK 1: early motor fluctuations
PARK 2: prominent involvement of legs, FOG, dystonia, marked levodopa sensitivity
associated with motor fluctuations and dyskinesia.
Impact of YOPD
Quality of life (QOL)
Motor features
Young onset patients had a more frequent family history of Parkinson’s disease and a
longer survival.
Rigidity and painful cramps were the predominant initial symptoms in 21.7% of the
YOPD and 8.2% of each the MOPD and LOPD patients (p=0.004).
YOPD tend to have severe motor complications (dyskinesia and dystonia). (Calne et
al., 2008)
However, research suggests that a younger person is more likely to have rigidity and
slow movement than a person with late onset Parkinson’s disease. (Pagano et al.,
2016; Mehanna et al., 2014)
Muscle stiffness and contraction, posture maintenance disability, FOG, propulsion.
(Iwasa et al., 2019)
Slower progression of PD symptoms
More side effects from dopaminergic medications
More frequent dystonia (cramping and abnormal postures)

This pattern is consistent with an autosomal recessive contribution to the inheritance

of early but not late-onset PD.
Genetic factors are important in both early- and late-onset PD, but specific genes and
mode of inheritance may differ between the two groups.

Non-motor features
Young onset was also a risk factor for poor emotional well-being independent of
depression status. (Kinpe et al., 2011)
Dementia/cognitive changes: 139 YOPD with median disease duration of 18 years,
only 19% had developed. (Calne et al., 2008)

Significance
如何說明 YOPD 是需要探討 postural control
1. Motor symptoms：但文獻不多，所以要做? (沒有直截了當的說明 posture
control 之類的問題)
2. 或是未來有可能發展出更嚴重 posture control 的問題，所以先以 detect 的方
式去看是不是有 minor changes/已經有問題了 (無論是 EEG 和 force plate)
3. YOPD 對於 levodopa 的反應：motor complications 是可以切入的點嗎?
若可以，做 ON 的意義也許就更大
4. 從 daily life 的 functional activity 角度切入，macro 到 micro：將大活動切分成
簡單且較微小的動作
Experiment
Experiment 1：如果先探討 standing 下的 weight shifting
1. YOPD vs age matched control
2. ML & AP direction: ML 的部分，有做到力板的實驗都是與肩同寬站立；AP
要再確認哪隻腳在前後，之前 tandem 時有探討後面的腳承重較大，但如果
要做 AP 位移是不是需要雙腳都要評估?
3. EO/EC? 有些 PD 文獻有做到這個部分
4. Questionnaire: evaluation
5. GaitUp 目前就是放在 TUG 裡面：可能要思考 GaitUp 的數值要和問卷或是力
板的數據去做 correlation 等等
Experiment 2：做出 weight shifting 的問題後，讓 YOPD 去 track wave + retention
的效果
1. YOPD
2. Pre-test: normal wave (將 experiment 1 的 control 平均數值?)
Training: 個別化數值設計 (由本身的 wave 逐漸練到較難的 wave)
Post-test: 這樣是要以 pre-test 的 evaluation 作為 post 還是要完全沒有出現的
wave (波長不定或波峰波谷的距離不同，頻率的調整之類的，因為 YOPD 本
身還是有 slow motion 的狀況)
Experiment 3：dual task? 類似俊逸的實驗
1. YOPD
2. Single 的部分剛好可以拿來當 experiment 2 的 follow up?
3. Dual task: supraposture 可能也要想比較困難有趣的 (例如做出與 posture 反向)
4. 那這個應該也是要 training 之後做 retention test
[Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory
Disorders]
Vagus nerve & PD
The vagus nerve is the tenth cranial nerve and is composed of 20% motor efferent and
80% sensory afferent fibers. (Sigurdsson)
The vagus nerve has been repeatedly suggested to represent one major route of
disease progression in Parkinson's disease (PD), with an active retrograde transport of
α-synuclein originating in the enteric nervous system ascending the vagus nerve and
eventually reaching the dorsal motor nucleus of the vagus (dmX) in the lower
brainstem.
α-synuclein
PD is characterized by progressive neuronal loss in the substantia nigra (SN) pars
compacta and widespread aggregation of the α-synuclein protein that accumulates in
Lewy bodies (LB) and Lewy neurites.
Premotor phase
Degeneration of the dorsal nucleus of the vagus nerve (VN) has been reported early in
the disease course and it could lead to impaired function of the VN, resulting in
certain non-motor symptoms of PD.
[Noninvasive vagus nerve stimulation in Parkinson’s disease: current status and future
prospects]
- Gait problems are observed in all gait domains according to a validated gait model
in PD, while cognitive dysfunction is noted in several cognitive domains including
visuospatial, attention, and memory: arise due to alterations in cholinergic
neurotransmission (in the nucleus basalis of Meynert (nbM) & the
pedunculopontine nucleus (PPN 橋腦腳間核) in the brainstem, serotonergic
 neurons in the raphe nuclei, decreased neurotropic factor signaling in the SN and
basal ganglia)
- Although dopaminergic (DA) medication is the current gold standard treatment
for PD, compelling evidence has shown that patients respond selectively to DA
treatment, and both gait and cognitive function continue to progressively decline
with time, thus suggesting an alternative pathological basis.
- Novel non-pharmacological interventions mitigating both PD-associated gait and
cognitive impairments are urgently needed
VNS
Rat model
Improving locomotion in a rat model of PD
Gait in PD: step time, step length variability decreased
[Non-invasive vagus nerve stimulation improves clinical and molecular biomarkers of
Parkinson’s disease in patients with freezing of gait]
6 two-minute stimulations (total 12 min/day) of the nVNS/sham device for one month
at home: velocity, step length and step time improved
In one study, 19 participants with mild-to-moderate PD, with and without freezing of
gait (FOG) were assessed using an instrumented walkway technology pre- and post-
stimulation applied twice to the left side of the neck. Step length, count, velocity, and
stride velocity variability were all found to be improved in participants, while in
patients with FOG the number of steps taken to turn was significantly reduced.
(Noninvasive vagus nerve stimulation improves gait and reduces freezing of gait in
Parkinson’s disease. Mov Disord. 2019;34:917–918.)
tcVNS may have beneficial neuromodulatory effects on treatment-resistant gait
characteristics and falls in PD. Potential putative mechanisms could be reduced
neuroinflammation, reduced α-synuclein aggregation, increased neurotropic
factor signaling and/or upregulated cholinergic neurotransmission. The use of a non-
pharmacological adjunct to rehabilitate to improve gait in Parkinson’s is an intriguing
可能機制 result from indirect activation of central neural circuitry, including
noradrenergic projections from locus coeruleus (Johnson, R. L. & Wilson, C. G. A
review of vagus nerve stimulation as a therapeutic intervention. J. Inflamm. Res. 11,
203 (2018).)
[Noninvasive vagus nerve stimulation in Parkinson’s disease: current status and future
prospects]
- Vagus nerve stimulation (VNS) is a neuromodulation technique involving invasive
surgical implantation of a generator subcutaneously, providing direct electrical
stimulation of the left cervical vagus nerve.
- It is more common that the left vagus nerve is stimulated due to the right vagus
 nerve having greater connections to the heart.
- Implantable VNS (iVNS): complications
- A further advantage of the nVNS devices is that they promote further research in
cognitive and clinical neuroscience to objectively identify the technique’s
mechanisms of action specifically in healthy populations without requiring
invasive surgery.
- Transcutaneous auricular VNS (taVNS) is used to stimulate structures of the outer
ear such as the tragus 耳屏 and cymba conchae 耳甲艇, which are innervated by
the auricular branch of the vagus nerve (ABVN); transcutaneous cervical VNS
(tcVNS) is delivered via a hand-held device while indirectly stimulating the (left)
cervical branch of the vagus nerve within the carotid sheath. (auricular branch of
the vagus nerve: Alderman’s nerve or Arnold’s nerve)
- taVNS: The majority of studies utilize monophasic or biphasic rectangular pulses,
with a pulse width between 200 and 300 μs, current intensity at 0.5 mA, and a
frequency of 25 Hz.
- tcVNS: low-voltage 5 kHz sine wave electrical signal bursts lasting 1 ms via two
flat stimulation contact surfaces, which permeates the skin and subcutaneous
structures. These bursts repeat once every 40 ms (25 Hz frequency) for 120
seconds. Stimulation intensity can be adjusted by the patient, and stimulation can
be repeated up to 12 times per day. Headache, epilepsy, depression and anxiety

- The most common adverse events related to the use of the noninvasive devices
include headaches, nasopharyngitis, dizziness, oropharyngeal, and neck pain, skin
irritation. The attrition rate due to adverse events is approximately 2.6% in studies
employing nVNS.
High-resolution ultrasound: Some studies have found that both left and right vagus
nerves are significantly smaller in patients relative to age-matched controls, while
others have shown a comparable size of the vagus nerve between patients and
controls.
BOLD: nucleus tractus solitaries (NTS 孤束核) and LC (locus coeruleus, 藍斑核)
Using taVNS, some but not others showed increased BOLD response in the nucleus
tractus solitarius (NTS) and LC. Conversely, Kraus and colleagues reported decreased
BOLD response in both regions during taVNS.
VNS & neurotransmitters
- NE: (Colzato et al., 2020) via the activation of the LC
Support neural plasticity by inducing long-term potentiation in the hippocampus:
memory formation (McIntyre et al., 2012; Sara 2009)/ associative memory (LC to
hippocampus areas, amygdala in the case of emotional memory formation)
Modulation of NE & GABAergic system: alters inhibitory control processes
PES
- GABA: primary inhibitory neurotransmitter, higher levels of GABA decrease
cortical excitability. Neuromodulation of action control processes, in the
regulation of motor functions and in motor learning
tVNS enhance performance in multitasking condition, via GABA
higher order goal-directed behavior
implicit motor sequence learning relies on response selection
automatic motor inhibition
related to PFC and motor cortex
- Dopamine: tVNS increased post-error slowing (PES), depends on catecholamine
activity (Moeller et al., 2012; Wardle et al., 2012)
- Ach: VNS may boost the cholinergic system and modulate neuroinflammation in
PD/ efferent fibers are colinergic
- BDNF has been studied widely as a peripheral biomarker of neuroplasticity in
various neurodegenerative disorders including PD
- tVNS has been proposed as a means to further investigate in healthy humans the
neuromodulation of cognitive processes related to norepinephrine (NE), gamma-
aminobutyric acid (GABA), and acetylcholine (ACh), the three main
neurotransmitters likely targeted by this intervention (Van Leusden et al. 2015)
[The Safety and Efficacy of Transdermal Auricular Vagal Nerve Stimulation Earbud
Electrodes for Modulating Autonomic Arousal, Attention, Sensory Gating, and
Cortical Brain Plasticity in Humans]
VNS in depression and anxiety: PD 還沒有人做
Depression can predate the motor features of PD for up to several years
- changes in areas of the brain that are implicated in depression, enhanced levels of
NE and serotonin, and increased BDNF, which may in turn decrease the neuronal
loss associated with depressive disorders
- Heart rate variability (HRV): reduced HRV and vagus nerve activity have been
associated with increased morbidity and mortality, and greater prevalence of
psychiatric conditions, such as depression and anxiety.

(Farmer AD, Strzelczyk A, Finisguerra A, et al. International consensus based review

and recommendations for minimum reporting standards in research on transcutaneous
vagus nerve stimulation (Version 2020). Front Hum Neurosci. 2021;14:1–47.)

Inclusion criteria
Exclusion criteria
With early signs of atypical Parkinsonism e.g. supranuclear gaze palsy
Significant visual impairment of coexisting local or systemic diseases likely to affect
gait
Who underwent deep brain stimulation surgery or those with an implanted cardiac
pacemaker, as were patients with metallic implants near the stimulation site
With known or suspected cardiovascular disease, uncontrolled hypertension or recent
myocardial infarction

Intervention
The nVNS device (provided without restriction by electroCore, Inc.) generated a
proprietary frequency-modulated electrical stimulus at low voltage (maximum 24 V)
with a maximum current output of 60 mA. The signal consisted of 1ms bursts of 5
kHz sine waves repeated at 25 Hz.
Usually, these are equipped with the following fixed parameters: frequency of 25
Hz, 200-us pulse width, 30-s on cycle/30-s off cycle, and current intensities up to 3
mA.
Yakunina et al. (2017) has shown that stimulating the cymba conchae, the ear canal,
and the tragus activate vagal afferent areas such as the NTS and the LC in the
brainstem. However, the strongest activation was reached when the electrode was
located on the cymba conchae.