uncover the potential

In neurogenic orthostatic hypotension (nOH)
associated
with multiple system atrophy

THERE CAN BE POWER IN THE PERIPHERY

Preserved peripheral sympathetic
neurons are a source of norepinephrine1

Illustration of preserved peripheral sympathetic neurons superimposed on top of an image of an older man in a seated position

nOH is a type of autonomic
dysfunction associated with some neurodegenerative disorders, such as multiple system atrophy.1,2

Neurodegenerative disorders associated
with nOH include:

Icon of person with cane, representing multiple system atrophyMultiple system
atrophy,
an atypical parkinsonism2
Icon of person, representing Parkinson's diseaseParkinson's disease2

The highest prevalence of nOH in neurodegenerative disorders occurs in conditions characterized by α-synuclein aggregation, including multiple system atrophy, Parkinson's disease, dementia with Lewy bodies, and pure
autonomic failure.2,3

The pathophysiology of nOH can vary—in some forms it is primarily due to central nervous system degeneration, while in others it is due to peripheral nerve degeneration.1,4

Illustration of central nervous system
Illustration of peripheral nervous system

Neurodegeneration presents on a spectrum of severity and location1,4

Illustration of preserved peripheral sympathetic neurons superimposed on top of an image of an older man standing

Impaired Central
Nervous system, Preserved Peripheral Sympathetic Neurons1,5

MSA is characterized by
central nervous system degeneration
and α-synuclein aggregation.1,5

MSA presents with parkinsonism
and/or
cerebellar ataxia symptoms,
such as tremors
and rigidity, and is
associated with autonomic
dysfunction, most notably nOH.5,6

Icon of an open hand with nerve pathways, symbolizing tremors, a symptom of MSA Icon of bent arm holding elbow, representing rigidity, a symptom of MSA

nOH symptoms may have
a severe impact on patients7

nOH symptoms may have
a severe impact on patients7

Illustration of human brain and spinal cord, the sites of neurodegeneration in MSA Illustration of peripheral nervous system, the site of preservation in MSA

In MSA, neurodegeneration occurs
in the central nervous system,
largely preserving the peripheral
sympathetic neurons.1

In MSA, neurodegeneration occurs
in the central nervous system,
largely preserving the peripheral
sympathetic neurons.1

Illustration of preserved peripheral sympathetic neurons superimposed on top of an image of an older man leaning on a chair
Illustration of norepinephrine release at a nerve synapse

nOH in MSA

For Most Patients Living With MSA, nOH Is Part of the Picture1

Bar graph showing that about 70 to 80 percent of patients with MSA may experience neurogenic orthostatic hypotension

~70%-80%

of patients with MSA may suffer
from nOH in their lifetime

Normally, the peripheral autonomic nervous system raises blood pressure by signaling blood vessels to constrict through the release of norepinephrine.8,9

Outline of a human figure standing

nOH in MSA

Upon standing, blood pressure would
naturally drop due to gravity. Fainting can
occur if blood pressure is not restored.10

Icon with five dots symbolizing norepinephrine, a neurotransmitter released by sympathetic neurons to maintain blood pressure

To maintain blood pressure, peripheral sympathetic neurons release norepinephrine. Within 5 minutes, plasma norepinephrine levels are doubled.8,9,11

Icon of a muscle fiber, indicating where vasoconstriction can occur

Norepinephrine binds to receptors on
blood vessels, leading to vasoconstriction.
This prevents dizziness and fainting.2,8,9,11

In patients with nOH, the peripheral sympathetic neurons fail to release enough norepinephrine upon standing1,12,13

  • Without this signal, blood vessels cannot constrict properly, causing a sudden and sustained drop in blood pressure1,12,13
  • This inadequate response leads to symptoms such as dizziness, lightheadedness, and fainting after moving to an upright position8
  • Other nOH symptoms patients with MSA might face include fatigue, generalized weakness, and cognitive dysfunction7

Summary1,14,15

  • Patients with nOH due to MSA have normal NE levels at rest, but have inadequate NE release upon standing
  • Because degenerated central neurons fail to activate intact peripheral sympathetic neurons, the normal vasoconstrictive response upon standing is blunted
  • This leads to a rapid drop in blood pressure in the brain and other
    vital organs

Circulating NE levels while resting are near normal
in patients with MSA1,14

  • In some neurodegenerative disorders, including MSA, the presence of intact peripheral sympathetic neurons means there is a store of available norepinephrine1,14
  • With the loss of central neurons, the intact peripheral sympathetic neurons do not receive a signal upon standing
    to release their stores of NE1,8,12,13
Close-up of illustrated peripheral nerves with an indicator signaling that there is a source of norepinepherine Visual of brain and spinal cord, sites of MSA neurodegeneration, with an indicator signaling irreversible neuronal death

The neuronal death in the central nervous
system that causes nOH is irreversible.7,16

Illustration of peripheral nervous system in yellow and central nervous system in gray

Pathways to nOH

The underlying pathophysiology of
nOH can differ between patients with neurodegenerative disorders.1,14

Man leaning on a chair, with an icon inset representing inadequate norepinephrine release in nOH

nOH is caused by inadequate NE release upon standing,
but it can arise from different pathophysiology1,14,15

Illustration of peripheral nervous system, the site of preservation in MSA

In some nOH-inducing mechanisms, this lack of NE release stems primarily from central degeneration—this is commonly seen in MSA.

Illustration of human brain and spinal cord, the sites of neurodegeneration in MSA

In other nOH-inducing mechanisms, this lack of NE release stems from both central and peripheral degeneration.

By understanding how preserved peripheral sympathetic neurons function in the absence of central
autonomic input, we can deepen our knowledge of
MSA-related nOH and explore new paths for supporting patients affected by this debilitating condition.15

MSA, multiple system atrophy; NE, norepinephrine;
nOH, neurogenic orthostatic hypotension; PD, Parkinson's disease.