Parkinson's Disease

Contents

Preface: Parkinson Disease xiii

Joseph Jankovic

James Parkinson and Other Historical Aspects of Parkinson’s Disease 167

Helen L. Dainton-Howard and Christopher G. Goetz
The history of Parkinson’s disease is long and rich. Here, we discuss an-
cient remedies, James Parkinson’s identification of the disease, Charcot’s
refinement of diagnostic criteria, and multiple other contributions to our
current understanding. We also discuss the multiple treatment methods
we have now and potential developments for the future.

Pathogenesis of Parkinson’s Disease 185

Bin Xiao, ZhiDong Zhou, YinXia Chao, and Eng-King Tan
Both genetic and environmental factors modulate the risk of Parkinson’s
disease. In this article, all these pathophysiologic processes that contrib-
ute to damages at the tissue, cellular, organelle, and molecular levels, and
their effects are talked about.

Prodromal Parkinson’s Disease: A Snapshot of the Landscape 209

Iro Boura, Karolina Poplawska-Domaszewicz, Naomi Limbachiya, Dhaval Trivedi,
Lucia Batzu, and Kallol Ray Chaudhuri
Early observations of specific nonmotor and subtle motor symptoms pre-
ceding clinical diagnosis of Parkinson’s disease (PD) have paved the way
for prodromal PD research, significantly propelling our understanding of
early, subclinical stages of neurodegeneration. Prodromal PD has
emerged as a complex concept with some researchers suggesting that
the period before PD onset is divided into the “at-risk,” “preclinical,” and
“prodromal” phases. Advances in genetic, imaging, laboratory, and digital
technologies have enabled the identification of pathophysiological pat-
terns and the potential development of diagnostic, progressive, and ther-
apeutic biomarkers, which could lead to early PD detection and
intervention.

Biomarkers in Parkinson’s Disease 229

Sarah M. Brooker and Paulina Gonzalez-Latapi
Parkinson’s disease (PD) is a leading cause of disability worldwide, and
there is a pressing need to develop therapeutics to slow or halt disease
progression. The identification of reliable biomarkers of PD at all stages
of disease will be a critical step toward optimizing diagnosis and therapeu-
tic development. For PD, biomarkers could serve multiple important func-
tions. There have been significant advances in biomarker development in
PD in recent years, and in this review, the authors summarize the current
state of the PD biomarker field covering major advances in fluid, tissue,
and neuroimaging biomarkers.

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viii Contents

Atypical Parkinsonian Disorders 249

Nahid Olfati, Fahimeh H. Akhoundi, and Irene Litvan
Atypical parkinsonian disorders (APD) include progressive supranuclear
palsy, corticobasal degeneration, and multiple system atrophy. Identifying
APD is important because they have different pathogenesis, disease
course, and prognosis than Parkinson’s disease (PD), and require different
treatments. Therefore, when encountering patients with parkinsonism, it is
of crucial importance to look for “red flags” or signs, such as impairments
in higher cortical function, oculomotor, cerebellar, balance and other mo-
tor abnormalities including dystonia, myoclonus, and apraxia that help dif-
ferentiate them from PD. Although disease-modifying therapies are not yet
available, treatments targeting specific symptoms may improve the quality
of life in these patients.

Motor Features of Parkinson’s Disease 279

Arjun Tarakad
The most characteristic motor feature of Parkinson’s disease is bradykine-
sia. Other cardinal motor features of Parkinson’s disease include tremor
(particularly rest tremor), rigidity, and postural instability/gait changes. Ad-
ditional motor features common to the disease include dystonia, postural
abnormalities, speech and swallowing dysfunction, and levodopa-related
dyskinesias. The pathophysiology of many of these motor features re-
mains poorly understood. During the natural course of the disease, non-
motor features (discussed elsewhere) often precede the onset of motor
features and meaningfully contribute to motor disability and the gradual
decline in the quality of life.

Non-motor Symptoms and Treatments in Parkinson’s Disease 291

Jennifer G. Goldman
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by
motor and non-motor symptoms. The non-motor features may precede
the onset of motor symptoms and occur throughout all stages of PD.
The non-motor symptoms reflect multisystem involvement of the central
and peripheral nervous systems, multiple neurotransmitters, and multiple
pathologies. PD management necessitates a comprehensive approach
to address non-motor symptoms, including pharmacologic and non-phar-
macological interventions and often multiple different disciplines or spe-
cialists in the PD care team. This review article discusses symptoms and
treatments for the non-motor symptoms of PD including those affecting
mood, cognition, behavior, sleep, autonomic function, and sensory
systems.

Disease-Modifying Therapies in Parkinson’s Disease 319

Margherita Fabbri, Jean Christophe Corvol, and Olivier Rascol
A “disease-modifying” treatment is defined as an intervention capable of
slowing the progressive worsening of clinical symptoms of a neurodege-
nerative disease. Over the last couple of decades, many efforts have
been spent on disease-modifying compounds development in Parkinson’s
disease (PD). Herein, the authors present an overview of recent and

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 Contents ix

ongoing clinical trials on PD disease-modifying therapies, stratified by

mechanism of actions. Overall, several trials have been run to
target alpha-synuclein in different ways, with disappointing results so
far, despite preclinical positive findings. In the next few years, results on
precision trials targeting genetic population or pathways (as b-glucocere-
brosidase [GBA] or leucine-rich repeat kinase 2 mutations) are expected.

Treatment of Motor Symptoms of Parkinson’s Disease 341

Luca Marsili, Matteo Bologna, Lily Y. Chen, and Alberto J. Espay
The most effective pharmacologic intervention used to treat motor symp-
toms in Parkinson’s disease is levodopa, which is available in various for-
mulations, including newer continuous subcutaneous infusions. Dopamine
agonists, monoamine oxidase-B enzyme inhibitors, catechol-O-methyl-
transferase enzyme inhibitors, amantadine, istradefylline, and anticholiner-
gics can be used as adjuncts to levodopa. With disease progression,
pharmacologic interventions alone may not suffice to manage motor
symptoms, making it necessary to consider device-aided therapies (eg,
levodopa-carbidopa intestinal gel infusion, continuous subcutaneous infu-
sions of apomorphine, levodopa, or foslevodopa) or invasive surgical tech-
niques (eg, deep brain stimulation or MRI-guided high-frequency focused
ultrasound).

Precision Medicine in Parkinson’s Disease 365

Gadi Maayan Eshed and Roy N. Alcalay
The continually accumulating knowledge of Parkinson’s disease (PD)
genetics presents potential disease modification opportunities through
targeting specific genes and associated metabolic pathways. Glucosyl-
ceramidase beta 1-associated PD and leucine-rich repeat kinase 2-asso-
ciated PD are attractive drug targets, since their respective mutations
significantly increase PD risk and, at the same time, are relatively
prevalent in the PD population. Here, we review clinical trials and
preclinical efforts whose mechanisms target genetic forms of PD, focus-
ing on these 2 genes and their metabolic pathways. Such therapies
could also potentially modify sporadic (ie, without a clear genetic risk
factor) PD.

Surgical Treatments of Parkinson’s Disease 383

Ariane Veilleux Carpentier and Michael S. Okun
Surgical interventions have become an integral part of the treatment arma-
mentarium for Parkinson’s disease in cases where medication manage-
ment alone has proven inadequate. Ablative techniques, deep brain
stimulation, levodopa-carbidopa intestinal gel infusion, and subcutaneous
pump systems offer unique advantages and disadvantages, and the
choice of surgical therapy should be individualized. As newer techniques
and technologies emerge, the landscape for surgical therapies continues
to evolve. A multidisciplinary approach is necessary to establish appropri-
ate candidacy and to determine the most appropriate surgical intervention
for each patient. Regular follow-up is essential to assess efficacy, manage
complications, and to adjust and optimize treatment.

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x Contents

Experimental Therapeutics in Parkinson’s Disease: A Review 399

Priti Gros, Laura Armengou Garcia, and Susan H. Fox
The prevalence and burden of Parkinson’s disease (PD) is rising. Motor
symptoms are primarily treated with dopamine replacement, although
with limitations and complications over time. Advances in PD research in-
clude new drug candidates and innovative repurposing of existing drugs
targeting various molecular mechanisms. Several agents are under Food
and Drug Administration review, highlighting the dynamic progress in the
field. This review summarizes the latest experimental therapies for PD, in-
cluding both motor and nonmotor symptom treatments. A total of 147
studies were included, examining new dopaminergic and nondopaminer-
gic therapies, innovative drug formulations, and approaches to managing
motor complications and nonmotor symptoms.

Physiotherapy and Exercise in Parkinson’s Disease 427

Steven Bellows
Physiotherapy is an important treatment strategy in Parkinson’s disease.
Guidelines recommend early and regular physiotherapy referrals, which
may improve a variety of symptoms, including falls. There are multiple
types of physiotherapy with different goals and benefits. Exercise as well
can improve symptoms and may alter disease trajectory. Studies are
limited by heterogenous interventions and outcome measures, and further
research is needed in generating high-quality research and expanding
physical therapy access.

Palliative Care in Parkinson’s Disease 445

Steven Bellows
Palliative care aims to alleviate suffering from symptoms not often ad-
dressed in typical clinic visits, including nonmotor symptoms, psychoso-
cial and caregiver burden, and advanced care planning. Palliative care is
appropriate at any point in Parkinson’s disease, but hospice care is an im-
portant potential therapy for end-of-life care. Palliative care remains
underutilized, and work is underway on developing palliative care delivery
models.

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