3386 PART 13 Neurologic Disorders

PARKINSON’S DISEASE AND

RELATED DISORDERS

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, exceeded only by Alzheimer’s disease (AD). Its

cardinal clinical features were first described by the English physician

James Parkinson in 1817. James Parkinson was a general physician who

captured the essence of this condition based on a visual inspection of

a mere handful of patients, several of whom he only observed walking

on the street and did not formally examine. It is estimated that the

number of people with PD in the most populous nations worldwide

is ~5 million persons, and this number is expected to double within

20 years based on the aging of the population. The mean age of onset of

PD is about 60 years, and the lifetime risk is ~3% for men and 2% for

women. The frequency of PD increases with age, but cases can be seen

in individuals in their twenties and even younger, particularly when

associated with a gene mutation.

Clinically, PD is characterized by rest tremor, rigidity (stiffness),

bradykinesia (slowing), and gait dysfunction with postural instability.

435 Parkinson’s Disease

C. Warren Olanow,

Anthony H.V. Schapira

enteric nervous system and spreads through the vagus nerve to the

heart, lower brainstem, substantia nigra, limbic system, and lastly the

cerebral cortex. PD may also begin in the olfactory bulb and spread

through olfactory system connections or start independently in enteric

and olfactory bulb areas. Evidence from human anatomic pathology

and animal models suggests that LBD may similarly propagate via

a prion-like mechanism. Abnormally folded α-synuclein aggregates

propagate transneuronally following connection pathways of the nervous system. This pathologic propagation from the periphery to the

brain correlates with the evolution of clinical symptoms; PD usually

manifests first with nonmotor features characterized by constipation

and/or hyposmia, followed by anxiety, depression, RBD, parkinsonism,

and lastly dementia. PDD is manifested clinically when limbic and

cortical areas are involved.

A profound cholinergic deficit, owing to basal forebrain and pedunculopontine nucleus involvement, is present in most patients with DLB

and may be associated with the characteristic fluctuations, inattention,

and visual hallucinations. Adrenergic deficits from locus coeruleus

involvement further undermine arousal and alerting.

PATHOGENESIS

Both genes and environmental factors are thought to contribute to

the development of LBD. The presence of alpha-synuclein aggregates

in Lewy bodies led to the discovery of α-synuclein duplications and

triplications that manifest clinically as PD or DLB. There are multiple

genes associated with PD, but mutations of glucocerebrosidase (GBA)

particularly lead to PDD or DLB presentations (Chap. 435).

The origins of LBD in gastrointestinal and olfactory areas suggest

that environmental toxins acting on a susceptible genetic background

may contribute to the LBD pathogenesis (a “double-hit” hypothesis).

Several toxins have been associated with PD (Chap. 435), but epidemiologic studies of risk factors in DLB remain inconclusive.

LABORATORY FEATURES

In patients presenting with cognitive disturbances, it is always necessary to rule out treatable causes of dementia such as drugs, infections,

or metabolic disturbances (Chap. 29). MRI of the brain can be helpful

to rule out vascular parkinsonism or subdural hematomas, or support

the diagnosis of other disorders such as MSA (i.e., pontine “hot-cross

buns” sign; Chap. 440).

Biomarkers that support the diagnosis of LBD include polysomnogram showing RBD with atonia, CSF showing either α-synuclein

oligomers (RT-QuIC) or CSF or blood levels of phospho-tau217,

iodine-123-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy

showing cardiac postganglionic sympathetic denervation, and dopamine

transporter imaging using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) (Table 434-1).

TREATMENT

Dementia with Lewy Bodies

Although there are currently no disease-modifying agents to prevent, slow, or cure LBD-related dementias, several symptomatic

treatments are available. By addressing the substantial cholinergic

deficit in DLB, cholinesterase inhibitors such as rivastigmine (target

dose 6 mg twice daily or 9.5 mg patch daily) or donepezil (target

dose 10 mg daily) often improve cognition, reduce hallucinosis, and

stabilize delusional symptoms. The atypical antipsychotic pimavanserin is frequently helpful to treat the psychosis and does not

worsen parkinsonism; it is approved by the FDA for patients with

PDD and is often used off-label for DLB. Pimavanserin is a selective inverse agonist of the serotonin 5-HT2A receptor that does not

block dopamine receptors but carries an FDA warning regarding

an increase in risk of death, especially in older patients. Low-dose

clozapine (begin at 6.25 mg, increasing up to 25 mg, daily) is also

effective for treating hallucinations and delusions, but requires

frequent blood draws due to the risk of agranulocytosis. Patients

with LBD are sensitive to dopaminergic medications, which must

be carefully titrated; tolerability may be improved with concomitant

use of a cholinesterase inhibitor. Patients with DLB should not be

exposed to typical neuroleptics that can lead to a neuroleptic malignant syndrome and death, or anticholinergics or dopamine agonists

that can exacerbate their symptoms.

RBD usually responds to melatonin, requiring at times 20 mg/

day. If melatonin is not effective, clonazepam, gabapentin, or

codeine can be used with caution due to the possibility of worsening cognition or falls. Antidepressants, especially those with strong

anxiolytic properties (escitalopram, paroxetine, duloxetine, or venlafaxine; see Chap. 452), are often necessary for mood and anxiety

symptoms. Orthostatic hypotension may require treatment with

nonpharmacologic measures (diet high in salt and liquids, a 30°

elevation of the head of the bed) or pharmacologic therapies (i.e.,

fludrocortisone, midodrine, droxidopa). Physical therapy can maximize motor function and protect against fall-related injury. Home

safety assessments and transfer instruction should also be provided.

Education for patients and caregivers and social worker support are

also important. Therefore, the care of patients with LBD requires a

multidisciplinary approach.

■ FURTHER READING

Emre M et al: Clinical diagnostic criteria for dementia associated with

Parkinson’s disease. Mov Disord 22:1689, 2007.

Litvan I et al: Diagnostic criteria for mild cognitive impairment in

Parkinson’s disease: Movement Disorder Society Task Force guidelines. Mov Disord 27:349, 2012.

Mckeith IG et al: Diagnosis and management of dementia with Lewy

bodies: Fourth consensus report of the DLB Consortium. Neurology

89:88, 2017.

Mckeith IG et al: Research criteria for the diagnosis of prodromal

dementia with Lewy bodies. Neurology 94:743, 2020.

Rossi M et al: Ultrasensitive RT-QuIC assay with high sensitivity and

specificity for Lewy body-associated synucleinopathies. Acta Neuropathol 140:49, 2020.

Sonni I et al: Clinical validity of presynaptic dopaminergic imaging

with 123I-ioflupane and noradrenergic imaging with 123I-MIBG in

the differential diagnosis between Alzheimer’s disease and dementia

with Lewy bodies in the context of a structured 5-phase development

framework. Neurobiol Aging 52:228, 2017.

3387Parkinson’s Disease CHAPTER 435

inclusions in cell bodies and axons that stain for α-synuclein (known

as Lewy bodies and Lewy neurites, collectively as Lewy pathology)

(Fig. 435-1). While interest has focused on the dopamine system,

neuronal degeneration with Lewy pathology can also affect cholinergic

neurons of the nucleus basalis of Meynert (NBM), norepinephrine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei

of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system. This

“nondopaminergic” pathology is likely responsible for the nonmotor

clinical features listed above and in Table 435-1. It has been postulated

that Lewy pathology can begin in the peripheral autonomic nervous

system, olfactory system, and dorsal motor nucleus of the vagus

nerve in the lower brainstem, and then spread in a predictable and

sequential manner to affect the SNc and cerebral hemispheres (Braak

staging). These studies thus suggest that the classic degeneration of

SNc dopamine neurons and the cardinal motor features of PD develop

at a midstage of the illness. Indeed, epidemiologic studies suggest that

clinical symptoms reflecting early involvement of nondopaminergic

neurons such as constipation, anosmia, rapid eye movement (REM)

behavior sleep disorder, and cardiac denervation can precede the onset

of the classic motor features of PD by several years if not decades.

Originally it was considered that these are risk factors for developing

PD, but based on pathological findings it is now considered likely that

they represent an early premotor form of the disease. Intense efforts

are underway to accurately define a premotor stage of PD with high

sensitivity and specificity. This will be of particular importance when a

neuroprotective therapy is available as it would be desirable to initiate

disease-modifying treatment at the earliest possible stage of the disease.

TABLE 435-1 Clinical Features of Parkinson’s Disease

CARDINAL MOTOR

FEATURES

OTHER MOTOR

FEATURES NONMOTOR FEATURES

Bradykinesia

Rest tremor

Rigidity

Postural instability

Micrographia

Masked facies

(hypomimia)

Reduced eye

blinking

Drooling

Soft voice

(hypophonia)

Dysphagia

Freezing

Falling

Anosmia

Sensory disturbances (e.g., pain)

Mood disorders (e.g., depression)

Sleep disturbances (e.g., fragmented

sleep, RBD)

Autonomic disturbances

Orthostatic hypotension

Gastrointestinal disturbances

Genitourinal disturbances

Sexual dysfunction

Cognitive impairment/dementia

Abbreviation: RBD, rapid eye movement sleep behavior disorder.

These are known as the classical or “cardinal” features of the disease.

Additional clinical features can include freezing of gait, speech difficulty, swallowing impairment, and a series of nonmotor features that

include autonomic disturbances, sensory alterations, mood disorders,

sleep dysfunction, cognitive impairment, and dementia (see Table 435-1

and discussion below).

Pathologically, the hallmark features of PD are degeneration

of dopaminergic neurons in the substantia nigra pars compacta

(SNc), reduced striatal dopamine, and intraneuronal proteinaceous

FIGURE 435-1 Pathologic specimens from a patient with Parkinson’s disease (PD) compared to a normal control demonstrating (A) reduction of pigment in SNc in PD (right)

versus control (left), (B) reduced numbers of cells in SNc in PD (right) compared to control (left), and (C) Lewy bodies (arrows) within melanized dopamine neurons in PD.

SNc, substantia nigra pars compacta.

A

B C

3388 PART 13 Neurologic Disorders

■ DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Parkinsonism is a generic term that is used to define a syndrome

manifest by bradykinesia with rigidity and/or tremor. It has a differential diagnosis (Table 435-2) that reflects differences in the site of

involvement within the basal ganglia, the nature of the pathology,

and the clinical picture. The basal ganglia are comprised of a group

of subcortical nuclei that include the striatum (putamen and caudate

nucleus), subthalamic nucleus (STN), globus pallidus pars externa

(GPe), globus pallidus pars interna (GPi), and the SNc (Fig. 435-2).

Among the different forms of parkinsonism, PD is the most common

(~75% of cases). Historically, PD was diagnosed based on the presence

of two of three parkinsonian features (tremor, rigidity, bradykinesia).

However, postmortem studies found a 24% error rate when diagnosis

was based solely on these criteria. Clinicopathologic correlation studies

subsequently determined that parkinsonism (bradykinesia and rigidity) associated with rest tremor, asymmetry of motor impairment, and

a good response to levodopa is much more likely to predict the correct

pathologic diagnosis. With these revised criteria (known as the U.K.

Brain Bank Criteria), a clinical diagnosis of PD could be confirmed

pathologically in >90% of cases. Imaging of the dopamine system (see

below) further increases diagnostic accuracy. The International Parkinson’s Disease and Movement Disorder Society (MDS) has suggested

revised clinical criteria for PD (known as the MDS Clinical Diagnostic

Criteria for Parkinson’s disease), which are thought to increase diagnostic accuracy even further, particularly in early cases where levodopa

has not yet been tried. While motor parkinsonism has been retained

as the core feature of the disease, the diagnosis of PD as the specific

type of parkinsonism relies on three additional categories of diagnostic

features: supportive criteria (features that increase confidence in the

diagnosis of PD), absolute exclusion criteria, and red flags (which must

be counterbalanced by supportive criteria to permit a diagnosis of PD).

Utilizing these criteria, two levels of certainty have been delineated;

clinically established PD and clinically probable PD (see Berg et al.

Movement Disorders 30:1591, 2015 in Further Reading).

Imaging of the brain dopamine system in patients with PD can

be performed using positron emission tomography (PET) or singlephoton emission computed tomography (SPECT). These studies

typically show reduced and asymmetric uptake of striatal dopaminergic biomarkers, particularly in the posterior putamen with relative

sparing of the caudate nucleus (Fig. 435-3). These findings reflect the

degeneration of nigrostriatal dopaminergic neurons and the loss of

their striatal terminals. Imaging can be useful in patients where there

is diagnostic uncertainty (e.g., early stage, essential tremor, dystonic

tremor, psychogenic tremor) or in research studies in order to ensure

accuracy, but is not necessary in routine practice. This may change in

the future when there is a disease-modifying therapy and it is critically

important to make a correct diagnosis as early as possible. There is also

some evidence that the diagnosis of PD, and even pre-PD, may be made

based on the presence of increased iron in the SNc using transcranial

sonography or special MRI protocols.

Genetic testing can be helpful for establishing a diagnosis but is not

routinely employed as monogenic forms of PD are relatively rare and

likely account for no more than 10% of cases (see discussion below).

A genetic form of PD should be considered in patients with a strong

positive family history, early age of onset (<40 years), a particular ethnic background (see below), and in research studies. Genetic variants

of the glucocerebrosidase gene (GBA) are the most common genetic

association with PD. They are present in 5–15% of PD patients, and

in 25% of Ashkenazi PD patients. However, only about 30% of people

with GBA variants will develop PD by age 80 years. Genetic variants

TABLE 435-2 Differential Diagnosis of Parkinsonism

Parkinson’s Disease

Sporadic

Genetic

Dementia with Lewy bodies

Atypical Parkinsonism

Multiple-system atrophy (MSA)

 Cerebellar type (MSA-c)

 Parkinson type (MSA-p)

Progressive supranuclear palsy

 Parkinsonism variant

 Richardson variant

Corticobasal syndrome

Frontotemporal dementia

Secondary Parkinsonism

Drug-induced

Tumor

Infection

Vascular

Normal-pressure hydrocephalus

Trauma

Liver failure

 Toxins (e.g., carbon monoxide,

manganese, MPTP, cyanide, hexane,

methanol, carbon disulfide)

Neurodegenerative disorders that are

associated with parkinsonism

Wilson’s disease

Huntington’s disease

 Neurodegeneration with brain iron

accumulation

SCA 3 (spinocerebellar ataxia)

 Fragile X–associated

ataxia-tremor-parkinsonism

Prion diseases

X-linked dystonia-parkinsonism

 Alzheimer’s disease with

parkinsonism

Dopa-responsive dystonia

Abbreviation: MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.

Striatum

(Putamen and

Caudate)

Globus Pallidus

A B SNc

STN

SNc

Striatum

Globus Pallidus

FIGURE 435-2 Basal ganglia nuclei. Schematic (A) and postmortem (B) coronal sections illustrating the various components of the basal ganglia. SNc, substantia nigra

pars compacta; STN, subthalamic nucleus.

3389Parkinson’s Disease CHAPTER 435

FIGURE 435-3 [

11C]Dihydrotetrabenazine positron emission tomography (a marker

of VMAT2) in healthy control (A) and Parkinson’s disease (B) patient. Note the

reduced striatal uptake of tracer, which is most pronounced in the posterior

putamen and tends to be asymmetric. (Courtesy of Dr. Jon Stoessl.)

A

B

MSA manifests as a combination of the atypical parkinsonian features described above, as well as cerebellar and autonomic features.

Clinical syndromes can be divided into a predominantly parkinsonian

(MSA-p) or cerebellar (MSA-c) form. Clinically, MSA is suspected

when a patient presents with features of atypical parkinsonism in

conjunction with cerebellar signs and/or prominent autonomic dysfunction, usually orthostatic hypotension (Chap. 440). Pathologically,

MSA is characterized by degeneration of the SNc, striatum, cerebellum,

and inferior olivary nuclei coupled with characteristic glial cytoplasmic

inclusions (GCIs) that stain positively for α-synuclein (Lewy bodies)

particularly in oligodendrocytes rather than in SNc neurons as in

PD. MRI can show pathologic iron accumulation in the striatum on

T2-weighted scans, high signal change in the region of the external

surface of the putamen (putaminal rim) in MSA-p, or cerebellar and

brainstem atrophy (the pontine “hot cross bun” sign [Fig. 440-2]) in

MSA-c. There is currently no established evidence for any gene mutation/genetic risk factor for MSA.

PSP is a form of atypical parkinsonism that is characterized by parkinsonism as noted above coupled with slow ocular saccades, eyelid

apraxia, and restricted vertical eye movements with particular impairment of downward gaze. Patients frequently experience hyperextension

of the neck with early gait disturbance and falls. In later stages, speech

and swallowing difficulty and cognitive impairment may become

evident. Two clinical forms of PSP have been identified; a “Parkinson”

form that can closely resemble PD in the early stages and can include a

positive response to levodopa, and the more classic “Richardson” form

that is characterized by the features described above with little or no

response to levodopa. MRI may reveal a characteristic atrophy of the

midbrain with relative preservation of the pons on midsagittal images

(the so-called hummingbird sign). Pathologically, PSP is characterized

by degeneration of the SNc, striatum, STN, midline thalamic nuclei,

and pallidum, coupled with neurofibrillary tangles and inclusions that

stain for the tau protein. Mutations in the MAPT gene that encodes for

the tau protein have been detected in some familial cases.

CBS is a relatively uncommon condition that usually presents with

asymmetric dystonic contractions and clumsiness of one hand coupled

with cortical sensory disturbances manifest as apraxia, agnosia, focal

limb myoclonus, or alien limb phenomenon (where the limb assumes

a position in space without the patient being aware of its location or

recognizing that the limb belongs to them). Dementia may occur at

any stage of the disease. Both cortical and basal ganglia features are

required to make this diagnosis. MRI frequently shows asymmetric

cortical atrophy, but this must be carefully sought and may not be

obvious to casual inspection. Pathologic findings include achromatic

neuronal degeneration with tau deposits. Considerable overlap may

occur both clinically and pathologically between CBS and PSP, and

they may be difficult to distinguish without pathologic confirmation.

Secondary parkinsonisms occur as a consequence of other etiologic

factors such as drugs, stroke, tumor, infection, or exposure to toxins

(e.g., carbon monoxide, manganese) that cause basal ganglia dysfunction. Clinical features reflect the region of the basal ganglia that has

been damaged. For example, strokes or tumors that affect the SNc may

have a clinical picture that is largely identical to the motor features of

PD, whereas toxins such as carbon monoxide or manganese that damage the globus pallidus more closely resemble atypical parkinsonism.

Dopamine-blocking agents such as neuroleptics are the most common

cause of secondary parkinsonism. These drugs are most widely used in

psychiatry, but physicians should be aware that drugs such as metoclopramide which are primarily used to treat gastrointestinal problems are

also neuroleptic agents and may induce secondary parkinsonism. These

drugs can also cause acute and tardive dyskinesias (see Chap. 436).

Other drugs that can cause secondary parkinsonism include tetrabenazine, calcium channel blockers (flunarizine, cinnarizine), amiodarone,

and lithium.

Parkinsonism can also be seen as a feature of dopa-responsive

dystonia (DRD), a condition that results from a mutation in the GTPCyclohydrolase 1 gene, which can lead to a defect in a cofactor for

tyrosine hydroxylase with impairment in the manufacture of dopa and

dopamine. While it typically presents as dystonia (Chap. 436), it can

of the LRRK2 gene have also attracted particular interest as they are

responsible for ~1% of typical sporadic cases of the disease. LRRK2

mutations are a particularly common cause of PD (~25%) in Ashkenazi

Jews and North African Berber Arabs; however, there is considerable

variability in penetrance and many carriers never develop clinical

features of PD. Genetic testing is of particular interest for identifying

at-risk individuals in a research setting and for defining enriched populations for clinical trials of therapies directed at a particular mutation.

Atypical, Secondary, and Other Forms of Parkinsonism

Atypical parkinsonism refers to a group of neurodegenerative conditions that are usually associated with more widespread pathology

than found in PD (e.g., degeneration of striatum, globus pallidus, cerebellum, and brainstem, as well as the SNc). These conditions include

multiple system atrophy (MSA; Chap. 440), progressive supranuclear

palsy (PSP; Chap. 432), and corticobasal syndrome (CBS; Chap. 432).

As a group, they tend to present with parkinsonism (rigidity and

bradykinesia) but manifest clinical differences from PD reflecting

their more widespread pathology. These include early involvement of

speech and gait, absence of rest tremor, lack of motor asymmetry, poor

or no response to levodopa, and a more aggressive clinical course. In

the early stages, some cases may show a modest benefit from levodopa

and can be difficult to distinguish from PD, but the diagnosis becomes

clearer as the disease evolves over time. Neuroimaging of the dopamine

system is usually not helpful, as striatal dopamine depletion can be seen

in both PD and atypical parkinsonism. By contrast, metabolic imaging

of the basal ganglia/thalamus network (using 2-F-deoxyglucose) may

be helpful, showing a pattern of decreased activity in the GPi with

increased activity in the thalamus, the reverse of what is seen in PD.

3390 PART 13 Neurologic Disorders

present as a biochemically based form of parkinsonism (due to reduced

synthesis of dopamine) that closely resembles PD and responds to levodopa but is not associated with abnormalities on fluoro-dopa positron

emission tomography (FD-PET) nor neurodegeneration. This diagnosis should be considered in individuals aged <20 years who present

with parkinsonism particularly if there are dystonic features.

Finally, parkinsonism can be seen as a feature of a variety of other

neurodegenerative disorders such as Wilson’s disease, Huntington’s

disease (especially the juvenile form known as the Westphal variant),

certain spinocerebellar ataxias, and neurodegenerative disorders with

brain iron accumulation such as pantothenate kinase (PANK)–

associated neurodegeneration (formerly known as Hallervorden-Spatz

disease). It is particularly important to rule out Wilson’s disease, as

progression can be prevented with the use of copper chelators.

Some features that suggest that parkinsonism might be due to a

condition other than classic PD are shown in Table 435-3.

■ ETIOLOGY AND PATHOGENESIS

Most PD cases occur sporadically (~85–90%) and are of unknown

cause. Gene mutations (see below) are the only known causes of PD.

Twin studies performed several decades ago suggested that environmental factors might play an important role in patients with an

age of onset ≥50 years, with genetic factors being more important in

younger-onset patients. However, the demonstration of later-onset

genetic variants (e.g., LRRK2 and GBA) argues against the emphasis

on environmental factors, even in individuals >50 years of age. The

environmental hypothesis received some support in the 1980s with

the demonstration that MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine), a by-product of the illicit manufacture of a heroin-like

drug, caused a PD syndrome in addicts in northern California. MPTP

is transported into the central nervous system, where it is oxidized

to form MPP+, a mitochondrial toxin that is selectively taken up by,

and damages, dopamine neurons, but typically without the formation

of Lewy bodies. Importantly, MPTP or MPTP-like compounds have

not been linked to sporadic PD. Epidemiologic studies have reported

an increased risk of developing PD in association with exposure to

TABLE 435-3 Features Suggesting an Atypical or Secondary Cause of

Parkinsonism

SYMPTOMS/SIGNS

ALTERNATIVE DIAGNOSIS TO

CONSIDER

History

Early speech and gait impairment (lack

of tremor, lack of motor asymmetry,

early falls)

Atypical parkinsonism

Exposure to neuroleptics Drug-induced parkinsonism

Onset prior to age 40 years Genetic form of PD, Wilson’s disease,

DRD

Liver disease Wilson’s disease, non-Wilsonian

hepatolenticular degeneration

Early hallucinations and dementia with

later development of PD features

Dementia with Lewy bodies

Diplopia, impaired vertical gaze PSP

Poor or no response to an adequate

trial of levodopa

Atypical or secondary parkinsonism

Physical Examination

Dementia as first or early feature Dementia with Lewy bodies

Prominent orthostatic hypotension MSA-p

Prominent cerebellar signs MSA-c

Slow saccades with impaired

downgaze

PSP

High-frequency (6–10 Hz) symmetric

postural tremor with a prominent

kinetic component

Essential tremor

Abbreviations: DRD, dopa-responsive dystonia; MSA-c, multiple-system atrophy–

cerebellar type; MSA-p, multiple-system atrophy–Parkinson’s type; PD, Parkinson’s

disease; PSP, progressive supranuclear palsy.

pesticides, rural living, farming, and drinking well water. Dozens of

other associations have also been reported in individual studies, but

results have been inconsistent, and no environmental factor has yet

been proven to be a cause or contributor to PD. Some possible protective factors have also been identified in epidemiologic studies including

caffeine, cigarette smoking, intake of nonsteroidal anti-inflammatory

drugs, and calcium channel blockers. The validity of these findings and

the responsible mechanism remain to be established.

About 10% of PD cases are familial in origin, and mutations in

several PD-linked genes have been identified (Table 435-4). While

monogenic mutations have been shown to be causative of PD, several

genetic risk factors that increase the risk of developing PD have also

been identified. Large-size genome-wide association studies (GWASs)

have identified more than 25 independent gene variants (singlenucleotide polymorphisms) as PD risk factors including variants in the

SNCA, LRRK2, MAPT, and GBA genes as well as in the HLA region

on chromosome 6. It has been proposed that many cases of PD may

be due to a “double hit” involving an interaction between (a) one or

more genetic risk factors that induce susceptibility coupled with (b)

exposure to a toxic environmental factor that may induce epigenetic

or somatic DNA alterations or has the potential to directly damage the

dopaminergic system. In this scenario, both factors are required for

PD to ensue, while the presence of either one alone is not sufficient to

cause the disease. Notably, however, even if a genetic or environmental

risk factor doubles the risk to develop PD, this results in a lifetime risk

of only 4% or lower, and thus cannot presently be used for individual

patient counseling.

Several factors have been implicated in the pathogenesis of cell

death in PD, including oxidative stress, inflammation, excitotoxicity,

mitochondrial dysfunction, lysosomal/proteasomal dysfunction, and

the accumulation of misfolded proteins with consequent proteolytic

stress. Studies also suggest that with aging, dopamine neurons switch

from sodium to calcium pacing through calcium channels, potentially

making these high-energy neurons vulnerable to calcium-mediated

neurotoxicity. Whatever the pathogenic mechanism, cell death appears

to occur, at least in part, by way of a signal-mediated apoptotic or “suicidal” process. Each of these mechanisms offers a potential target for

putative neuroprotective drugs. In addition, a role for inflammation

is implicated by the genetic association of PD with the class II HLA

gene DRB1 (variants of which are associated with either protection or

risk for PD), and that autoreactive T-cells recognizing peptides derived

from alpha-synuclein are present in PD patients. However, it is not

clear which of these factors is primary, if they are the same in all cases

or specific to individual (genetic) subgroups, if they act by way of a

network such that multiple insults are required for neurodegeneration

to ensue, or if the findings discovered to date merely represent epiphenomena unrelated to the true cause of cell death that still remains

undiscovered (Fig. 435-4).

Although gene mutations cause only a minority of cases of PD, they

have been very helpful in pointing to specific pathogenic pathways and

molecular mechanisms that are likely to be central to the neurodegenerative process in the sporadic form of the disease. To date, most interest has focused on pathways implicated by mutations in α-synuclein

(SNCA), GBA, LRRK2, and PINK1/Parkin.

SNCA was the first PD-linked gene mutation and the most intensely

investigated with respect to causative mutations, risk variants, as well

as function of the gene and its encoded protein. Shared clinical features

of patients with SNCA mutations include earlier age of disease onset

than in nongenetic PD, a faster progression of motor signs that are

mostly levodopa-responsive, early occurrence of motor fluctuations,

and presence of prominent nonmotor features, particularly cognitive

impairment. Intriguingly, SNCA constitutes the major component

of Lewy bodies implicating the protein in sporadic forms of PD as

well (Fig. 435-1). Importantly, duplication or triplication of the wildtype SNCA gene also causes PD with triplication carriers being more

severely affected than carriers of duplications. These findings indicate

that increased production of the normal protein alone can cause PD.

Lewy pathology was discovered to have developed in healthy embryonic dopamine neurons that had been implanted into the striatum of

3391Parkinson’s Disease CHAPTER 435

TABLE 435-4 Confirmed Genetic Causes of Parkinson’s Disease*

DESIGNATION* AND

REFERENCE GENEREVIEWS AND OMIM REFERENCE CLINICAL CLUES INHERITANCE

PREVIOUS LOCUS

SYMBOL

1. Classical PD

PARK-SNCA GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1223/

OMIM 168601

Missense mutations cause classical

parkinsonism. Duplication or triplication

mutations in this gene cause early-onset

parkinsonism with prominent dementia.

AD PARK1

PARK-LRRK2 GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1208/

OMIM 607060

Clinically typical PD AD PARK8

PARK-VPS35 GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1223/

OMIM 614203

Clinically typical PD AD PARK17

PARK-GBA GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1223/

OMIM 168600/606463

Clinically typical PD—possibly faster

progression and greater risk of cognitive

impairment

AD

2. Early-onset PD

PARK-Parkin GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1155/

OMIM 600116

Often presents with dystonia, typically in a

leg

AR PARK2

PARK-PINK1 GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1223/

OMIM 605909

Often presents with psychiatric features AR PARK6

PARK-DJ1 GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1223/

OMIM 606324

AR PARK7

3. Parkinsonism

PARK-ATP13A2 GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1223/

OMIM 606693

Kufor-Rakeb syndrome with parkinsonism

and dystonia; additional features:

Supranuclear gaze palsy, spasticity/

pyramidal signs, dementia, facial-faucialfinger mini-myoclonus, dysphagia, dysarthria,

olfactory dysfunction

AR PARK9

PARK-FBXO7 GeneReviews

http://www.ncbi.nlm.nih.gov/books/NBK1223/

OMIM 260300

Early-onset parkinsonism with pyramidal

signs

AR PARK15

PARK-DNAJC6 GeneReviews: n/a

OMIM 615528

May present with mental retardation and

seizures

AR PARK19

PARK-SYNJ1 GeneReviews: n/a

OMIM 615530

May have seizures, cognitive decline,

abnormal eye movements, and dystonia

AR PARK20

According to the recommendations of the International Parkinson’s and Movement Disorder Society (C Marras: Mov Disord 31:436, 2016).

PD patients, suggesting that the abnormal protein had transferred from

affected cells to healthy unaffected dopamine neurons. Based on these

findings, it has been proposed that the SNCA protein may be a prion,

and PD a prion or prion-like disorder (Chaps. 424 and 438). Like

the prion protein PrPC, SNCA can misfold to form β-rich sheets, join

to form toxic oligomers and aggregates, polymerize to form amyloid

plaques (i.e., Lewy bodies), and cause neurodegeneration with spread

to involve unaffected neurons. Indeed, injection of SNCA fibrils into

the striatum of both transgenic and wild-type rodents leads to the

development of Lewy pathology in host neurons, neurodegeneration,

behavioral abnormalities, and spread of SNCA pathology to anatomically connected sites. Further support for this hypothesis comes from

the demonstration that inoculation into the striatum of homogenates

derived from human Lewy bodies induces dopamine cell degeneration

and widespread Lewy pathology in mice and primates. Exciting new

evidence also suggests that SNCA pathology might begin peripherally

in the enteric nervous system within the GI tract and spread by way

of the vagus nerve to the lower brainstem (dorsal motor nucleus of

the vagus) and ultimately to the SNc to cause the motor features of

PD. There is growing interest in the possibility that the gut microbiome in PD patients causes inflammatory changes that promote

alpha-synuclein misfolding and spread. The gut-brain axis might

therefore offer a mechanism by which alpha-synuclein pathology

might spread to the brain and cause PD, and therefore provides a novel

target for therapeutic intervention.

Collectively, this evidence supports the concept that neuroprotective

therapies for PD might be developed based on inhibiting the accumulation or accelerating the removal of SNCA aggregates, knocking down

levels of host SNCA, preventing the spread of misfolded SNCA, or

blocking the templating phenomenon whereby misfolded SNCA promotes misfolding of the native protein in a prion-like chain reaction.

Many of these approaches are currently being tested in the laboratory

and preliminary clinical trials have already been initiated.

Mutations in the GBA gene represent the most important risk factor

in terms of effect size for the development of PD. GBA encodes for

the enzyme glucocerebrosidase (GCase), which promotes lysosomal

function and enhances the clearance of misfolded proteins such

as SNCA. Experimentally, there is a direct pathophysiological link

between increased levels of SNCA and reduced levels of GBA. The

identification of GBA as a risk gene for PD resulted from the clinical

observation that patients with Gaucher’s disease (GD) and their relatives commonly show signs of parkinsonism. This clinical observation

3392 PART 13 Neurologic Disorders

led to the discovery that literally hundreds of mutations in GBA confer risk for the development of PD. Further, it has been shown that

reduced levels of GCase activity due to GBA variants impair lysosomal

function, which results in the accumulation of SNCA. Conversely, the

accumulation of SNCA can lead to inhibition of lysosomal function

and a further reduction in levels of GBA/GCase by interfering with

endoplasmic reticulum-to-Golgi trafficking. Thus, experimentally

there is a vicious cycle in which decreased GBA activity leads to the

accumulation of SNCA, and increased levels of SNCA lead to a further

impairment in lysosomal function. In this regard, it is noteworthy

that lysosomal function is impaired and levels of GCase are reduced

in patients with sporadic PD, and not just in those with GBA variants.

These bidirectional effects of SNCA and GBA form a positive feedback loop that, after surpassing a theoretical threshold, could lead to

self-propagating disease. These findings suggest that this molecular

pathway may not only apply to patients with a GBA variant, but also

to patients with sporadic PD or other synucleinopathies who have two

normal wild-type GBA alleles. Some studies suggest that patients with

GBA variants have a faster rate of progression and increased frequency

of cognitive impairment. Studies of drugs that enhance GCase activity

and promote lysosomal function are currently being tested in the clinic.

Multiple LRRK2 mutations have also now been clearly linked

to PD, with p.G2019S being the most common, possibly due to a

founder effect in the Ashkenazi Jewish and North African Arab

populations. Mutations in LRRK2 account for 3–41% of familial PD

cases (depending on the specific population) and are also found in

apparently sporadic cases, albeit at a lower rate. The phenotype of

LRRK2 p.G2019S mutations is largely indistinguishable from that of

sporadic PD, although tremor appears to be more common; leg tremor

may be a useful diagnostic clue. The penetrance of LRRK2 mutations

is incomplete (30–74% depending on the ethnic group), and patients

tend to run a more benign course. The mechanism responsible for cell

death with this mutation is not conclusively known but is thought to

involve enhanced kinase activity with altered phosphorylation of target

proteins (including autophosphorylation) with possible impairment of

lysosomal function. Kinase inhibitors can block toxicity associated with

LRRK2 mutations in laboratory models, and there has also been much

interest in developing drugs directed at this target. However, nonselective kinase inhibitors are potentially toxic to the lungs and kidneys.

Fortunately, LRRK2 inhibitors have now been developed that have good

preclinical safety and are currently being tested in PD populations.

Mutations in Parkin and PINK1 have also been identified as a cause

of PD. Parkin mutations are the more common, and the major cause

of autosomal recessive and early-onset PD, accounting for up to 77%

of cases of juvenile PD with an age of onset <20 years, and for 10–20%

of early-onset PD patients in general. The disease is slowly progressive, responds well to antiparkinsonian treatment, and is commonly

complicated by dystonia, but very rarely by dementia. At pathology,

neurodegeneration tends to be restricted to the SNc and LC in patients

with Parkin mutations, and Lewy bodies are typically absent. The

reason for these differences from classic PD is not known but may be

related to impaired ubiquitination of damaged proteins (parkin is a

ubiquitin ligase that is required for Lewy body formation but may be

impaired in the mutant form). The clinical phenotypes of Parkin- and

PINK1-linked PD are similar. Parkin and PINK1 proteins are involved

in cell-protection mechanisms and in the turnover and clearance of

damaged mitochondria (mitophagy). Mutations in Parkin and PINK1

cause mitochondrial dysfunction in transgenic animals that can be

corrected with overexpression of Parkin. Improving mitochondrial

function is a particularly attractive potential therapeutic target because

postmortem studies in PD patients show a defect in complex I of the

respiratory chain in SNc neurons.

Thus, evidence is accumulating that genetic factors play an important role in both familial and “sporadic” forms of PD. It is anticipated

that better understanding of the pathways responsible for cell death

caused by these mutations will permit the development of more relevant animal models of PD and better-defined targets for the development of gene-specific neuroprotective drugs. A precision medicine

approach in which therapies are directed specifically at patients who

carry a mutation is of great interest, but it should also be appreciated

that these same targets may also prove to be of importance for therapies

directed at patients with sporadic PD.

■ PATHOPHYSIOLOGY OF PD

The classic model of the organization of the basal ganglia in the normal and PD states is provided in Fig. 435-5. With respect to motor

function, a series of neuronal circuits with multiple feedback and

feedforward loops link the basal ganglia nuclei with corresponding

cortical and brainstem motor regions in a somatotopic manner. The

striatum is the major input region of the basal ganglia, while the GPi

and SNr are the major output regions. The input and output regions are

connected via direct and indirect pathways that have reciprocal effects

on the activity of the basal ganglia output. The output of the basal ganglia provides inhibitory (GABAergic) tone to thalamic and brainstem

neurons that in turn connect to motor systems in the cerebral cortex

and spinal cord that control motor function. An increase in neuronal

activity in the output regions of the basal ganglia (GPi/SNr) is associated with poverty of movement or parkinsonism, while decreased

output results in movement facilitation and involuntary movements

such as dyskinesia. Dopaminergic projections from SNc neurons serve

to modulate neuronal firing and to stabilize the basal ganglia network.

Normal dopamine innervation thus serves to facilitate the selection of

the desired movement and to suppress or reject unwanted movements.

Cortical loops integrating the cortex and the basal ganglia are now

thought to also play an important role in regulating other systems as

well such as behavioral, emotional, and cognitive functions.

In PD, dopamine denervation with loss of dopaminergic tone leads

to increased firing of neurons in the STN and GPi, excessive inhibition

of the thalamus, reduced activation of cortical motor systems, and the

development of parkinsonian features (Fig. 435-5). The current role of

surgery in the treatment of PD is based on this model, which predicted

that lesions or high-frequency stimulation of the STN or GPi might

reduce this neuronal overactivity and improve PD features. The model

has proven less useful in understanding the origins of dyskinesia (see

Fig. 435-5).

TREATMENT

Parkinson’s Disease

LEVODOPA

Since its introduction in the late 1960s, levodopa has been the

mainstay of therapy for PD. Experiments in the late 1950s by

Etiology

Oxidative stress

Mitochondrial

dysfunction

Cell death

Inflammation Protein aggregation Excitotoxicity

FIGURE 435-4 Schematic representation of how pathogenetic factors implicated

in Parkinson’s disease interact in a network manner, ultimately leading to cell

death. This figure illustrates how interference with any one of these factors may

not necessarily stop the cell death cascade. (Reproduced with permission from

CW Olanow: The pathogenesis of cell death in Parkinson’s disease–2007. Mov Dis

22:S335, 2007.)