Clinical Review & Education

Review

Parkinson Disease Subtypes

Mary Ann Thenganatt, MD; Joseph Jankovic, MD

IMPORTANCE It is increasingly evident that Parkinson disease (PD) is not a single entity but

rather a heterogeneous neurodegenerative disorder.

OBJECTIVE To evaluate available evidence, based on findings from clinical, imaging, genetic
and pathologic studies, supporting the differentiation of PD into subtypes.
EVIDENCE REVIEW We performed a systematic review of articles cited in PubMed between
1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor,
postural instability and gait difficulty, and Parkinson disease subtypes. The final reference list
was generated on the basis of originality and relevance to the broad scope of this review.
FINDINGS Several subtypes, such as tremor-dominant PD and postural instability gait
difficulty form of PD, have been found to cluster together. Other subtypes also have been
identified, but validation by subtype-specific biomarkers is still lacking.
CONCLUSIONS AND RELEVANCE Several PD subtypes have been identified, but the pathogenic
mechanisms underlying the observed clinicopathologic heterogeneity in PD are still not well
understood. Further research into subtype-specific diagnostic and prognostic biomarkers
may provide insights into mechanisms of neurodegeneration and improve epidemiologic and
therapeutic clinical trial designs.
JAMA Neurol. 2014;71(4):499-504. doi:10.1001/jamaneurol.2013.6233
Published online February 10, 2014.

arkinson disease (PD) is a complex neurodegenerative disease with a broad spectrum of motor and nonmotor features. It is increasingly evident that PD is a heterogeneous
disorder with variable clinicopathologic phenotypes and natural history. Subtypes of PD have emerged, with patients classified according to distinct clinical features (Figure). In-depth knowledge about
these subtypes may lead to further insights into mechanisms of disease and pathogenesis-targeted and symptomatic treatments.
We performed a systematic review of articles cited in PubMed
between 1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor, postural instability and gait difficulty, and Parkinson disease subtypes. In this review article, we discuss the most commonly identified PD subtypes and their
distinguishing features.
Parkinson disease can be defined clinically, pathologically, and
genetically.1,2 According to the United Kingdom Parkinson Disease
Society Brain Bank, the clinical criteria for probable PD require the
presence of bradykinesia and at least 1 of the following features: rigidity, rest tremor of 4 to 6 Hz, or postural instability. In addition, 3
supportive features are required.3
With the emergence of new genetic, imaging, and pathologic
findings, coupled with the clinical variability, there is a growing consensus that PD should be considered a syndrome rather than a single
entity and that its diagnostic criteria should be reexamined. A multiple-tier approach may be required, including the core clinical criteria based on United Kingdom Parkinson Disease Society Brain Bank,
jamaneurology.com

Author Affiliations: Parkinson's

Disease Center and Movement
Disorders Clinic, Department of
Neurology, Baylor College of
Medicine, Houston, Texas.
Corresponding Author: Joseph
Jankovic, MD, Parkinsons Disease
Center and Movement Disorders
Clinic, Department of Neurology,
Baylor College of Medicine, 6550
Fannin St, Ste 1801, Houston, TX
77030 (josephj@bcm.edu).
Section Editor: David E. Pleasure,
MD.

pathologic criteria, supported by typical Lewy body (LB) pathology

and genetic criteria (genetic mutations confirmed to cause PD
phenotype).1

Methods of Classification
Traditionally, PD subtypes have been identified empirically based on
clinical observations and analyses of cohort studies, focusing on data
sets that identify clinical features clustered together.4 One of the earliest classifications categorized PD into two subtypes: (1) tremordominant PD and (2) postural instability and gait difficulty (PIGD).4
The DATATOP database, which includes information on more than
800 patients with early, untreated PD, was analyzed to explore the
clinical heterogeneity of PD.4 Using the Unified Parkinsons Disease Rating Scale, an average global tremor score and a mean score
for the complex of PIGD were determined, and patients were assigned to a tremor group and a PIGD group based on the ratio of these
scores.4 This finding was validated with the new Movement Disorder Society Unified Parkinsons Disease Rating Scale in 877 patients with PD, a scale for which cutoff scores reliably differentiate
the two subtypes with optimal sensitivity and specificity.5
A data-driven approach using a process called cluster analysis
has been used to identify PD subtypes.6 This process, based on the
relationship between selected variables without an a priori hypothesis, is still dependent on certain choices, such as variables seJAMA Neurology April 2014 Volume 71, Number 4

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Clinical Review & Education Review

Parkinson Disease Subtypes

lected for analysis, the clustering technique, and the number of clusters. A recent systematic review6 evaluated the data obtained with
cluster analysis and identified the following common subtypes:
(1) old age at onset and rapid disease progression, (2) young-onset
PD (YOPD) and slow progression, (3) tremor-dominant phenotype
(which may overlap with benign tremulous PD), and (4) PIGD phenotype (also dominated by bradykinesia and rigidity).

Clinical Features
Age at Onset
Although age is the most important risk factor for the development
of PD, disease onset may start at a young age. When we compared
88 patients with YOPD (aged 20-40 years) and 110 with late-onset
PD (LOPD; aged >60 years) evaluated in the Movement Disorders
Clinic at Baylor College of Medicine, we found that patients with
YOPD initially presented more often with rigidity and dystonia and
had a higher frequency of levodopa-related motor complications
than those with LOPD, who presented more often with the PIGD pattern (Figure). Nearly one-third of patients with YOPD represent
PARK2-associated PD, caused by parkin gene (PRKN) mutation, often manifested by early levodopa-induced dyskinesias, hallucinations, dystonic gait, cervical dystonia, dopa-responsive dystonia, leg
tremor at rest and on standing, marked sleep benefit, hyperreflexia, ataxia, peripheral neuropathy, and dysautonomia.7,8 Although parkinsonian symptoms are readily discernible in young individuals, they may be less obvious at onset in the elderly and are
often initially attributed to age-related frailty. Mild parkinsonism may
be seen in older patients without a diagnosis of PD and have been
associated with PD susceptibility loci.9 Patients with LOPD are often characterized by the PIGD subtype.10 Although it is well recog-

Figure. Parkinson Disease (PD) Subtypes

PIGD PD
Poor prognosis with rapid
progression
Bradykinesia and rigidity
Dementia
Depression
Anosmia
Mixed PD
Levodopa
Degeneration in
ventrolateral SN
DAT SPECT
Egg-shaped configuration
on DAT SPECT

Tremor-dominant PD
Good prognosis with slow
progression
Essential tremor
Benign tremulous parkinsonism
Good response to levodopa
Wearing off
Increased fMRI activity in CTC
circuitry
Degeneration in medial SN,
ventral GPi, thalamic serotonin,
and midbrain (A8)
Eagle wing configuration
on DAT SPECT
YOPD

LOPD

Onset between ages

20 and 40 y
Genetic
Dystonia

Onset after age 60 y

Sporadic

Subtypes include postural instability and gait difficulty (PIGD) and

tremor-dominant PD. CTC indicates cerebellothalamocortical; DAT, dopamine
transporter; fMRI, functional magnetic resonance imaging; GPi, globus pallidus
interna; LOPD, late-onset PD; SN, substantia nigra; SPECT, single-photon
emission computed tomography; YOPD, young-onset PD.

500

nized that patients with YOPD have an excellent response to levodopa, it is also clear that they have a greater tendency for early
development of dyskinesias and motor fluctuations.
Several studies have shown that patients with YOPD have a
slower progression of disease than those with LOPD.4,11 The Sydney Multi-Center Study group11 assessed the course of disease in 125
patients with de novo PD and concluded that age at onset was a major determinant of the course of disease. Although the course may
be more protracted in patients with YOPD, the terminal stage, manifested by more rapid physical and cognitive decline, may be similar
across groups irrespective of age at onset.12 Compared with patients with LOPD, the disease in those with YOPD affects quality of
life more adversely in terms of loss of employment, disruption of family life, perceived stigma, and depression.13

Motor Phenotype
Several studies have confirmed that patients presenting with tremor
at onset have a slower progression of disease than those with a PIGD
subtype4,14 The tremor-dominant form of PD is often initially misdiagnosed as essential tremor, particularly if the patients have had
a long-standing history of tremor. The overlap between clinical features of PD and essential tremor and the possible pathogenic link
between the two disorders has been a subject of several recent
reviews.15,16
An entity named benign tremulous parkinsonism has been described in patients with predominant rest tremor, mild nontremor
signs, absence of gait disorder, and mild progression of parkinsonism other than tremor despite many years of disease.17 A case series of 16 such patients were found to have a lower mean age at onset (58.5 years) than most PD series and a poor response to
levodopa.18 An autopsy evaluation of 21 such cases found less severe neuronal loss in the substantia nigra than in pathologically
proven PD controls, indicating a slower progression of neuronal
degeneration.18 Others have argued against the term benign tremulous parkinsonism and proposed the term monosymptomatic tremor
at rest19 because patients with advanced cases have troublesome
symptoms along with imaging evidence of dopaminergic deficit;
hence, the condition is not benign.
Nonmotor symptoms, such as cognitive impairment, also vary
according to motor subtype. The PIGD form of PD is associated with
a faster rate of cognitive decline and a higher incidence of
dementia.20 One study demonstrated that patients with tremordominant PD may start to show signs of dementia only after PIGD
symptoms develop.20 In addition to cognitive decline, depression
and apathy are often associated with the nontremor-dominant PD
subtype.21,22 Olfaction among PD subtypes has been the focus of
few studies, demonstrating more impaired olfaction in the akineticrigid subtype than in the tremor-dominant group.23

Imaging Findings
Various imaging modalities, including positron emission tomography (PET), single-photon emission computed tomography (SPECT),
and functional magnetic resonance imaging, are increasingly used
to identify the neural circuits and connectivity involved in specific
PD signs.
Fluorodopa PET scans have been shown to correlate well with
certain PD signs and symptoms, particularly bradykinesia, and with
postmortem nigral cell count.24 In terms of age at onset, a study using

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Parkinson Disease Subtypes

Review Clinical Review & Education

3 presynaptic dopamine markers, (6) dihydrotetrabenazine labeled with carbon 11 (11C), [11C]d-threo-methylphenidate, and
6-fluoro-L-dopa labeled with fluorine 18 (18F) found that younger
patients have a greater decrease of dihydrotetrabenazine putaminal binding at onset than older patients; however, the rate of dihydrotetrabenazine binding loss progressed more slowly in patients
with YOPD.25
Scanning with SPECT can be used to evaluate the presynaptic
dopaminergic system by measuring the density of striatal dopamine transporter. Several dopamine transporter SPECT studies
have found a significant correlation between striatal iodine 123
(123I) fluoropropyl (FP) carbomethoxy-3 -(4-iodophenyltropane)
(CIT) uptake and the severity of akinetic-rigid symptoms but not
with tremor.26,27 One FP-CIT SPECT study comparing 24 patients
with tremor-dominant PD and 28 with akinetic-rigid PD found that
uptake in the contralateral putamen was significantly lower in the
akinetic-rigid phenotype than in the tremor-dominant
phenotype.26 Another study comparing FP-CIT SPECT findings in
122 patients with PD found different patterns of dopamine uptake
based on visual analysis.27 The tremor-dominant patients had an
eagle wing striatal configuration, corresponding to dopamine
loss in the caudate and lateral putamen. In contrast, the patients
with akinetic-rigid PD had an egg-shaped configuration, corresponding to dopaminergic loss in the dorsal putamen.27 These
findings, however, require validation by other studies using larger
samples and different imaging techniques, such as PET tracer
[18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]AV-133), targeting vesicular monoamine transporter 2.28
Several imaging studies have demonstrated that loss of neurotransmitters other than dopamine contribute to the pathophysiologic mechanism of parkinsonian tremor and other parkinsonian
motor and nonmotor features. For example, loss of thalamic serotonin has been implicated in the generation of rest tremor.29,30
One PET study involving 23 patients with PD found a 27% reduction in raphe 5-HT1A receptor binding compared with controls;
this reduction correlated with Unified Parkinsons Disease Rating
Scale tremor scores but not with rigidity or bradykinesia.29 With
[ 11 C]dihydrotetrabenazine dopaminergic and [ 11 C]methyl-4piperidinyl propionate acetylcholinesterase PET imaging, cortical
cholinergic denervation was found to correlate more with slowing
of gait in PD than with nigrostriatal denervation.31 Thus, the various cardinal signs of PD may be related to different neurotransmitter deficiencies: whereas dopaminergic deficiency correlates well
with bradykinesia and rigidity, serotonin seems to play a role in
tremor, and cholinergic deficit seems to contribute to gait disorder
associated with PD.
One study used functional magnetic resonance imaging to
compare the activation of striatothalamocortical and cerebellothalamocortical circuits in 17 patients with PD (9 with tremordominant and 8 with akinetic-rigid PD) and 14 controls and found
that patients with tremor-dominant PD had significantly more
activity in contralateral cerebellothalamocortical circuits, supporting the differential involvement of the two circuits in PD
subtypes.32 Another study, including 44 patients with PD (21 with
tremor-dominant and 23 with nontremor-dominant PD) and 36
controls, used functional magnetic resonance imaging and
[123I]FP-CIT to investigate the interplay between the basal ganglia
and the cerebellothalamic circuitry in generating rest tremor and
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found that pallidal dopamine depletion was correlated with

tremor severity.33 These findings suggest that rest tremor involves
cerebellothalamocortical circuitry, which is driven largely by the
dopamine-depleted basal ganglia.
In a study using functional magnetic resonance imaging and
voxel-based morphometry to examine functional and structural
differences between 20 patients with tremor-dominant or
nontremor-dominant PD and healthy controls, both voxel-based
and region-of-interest analyses showed that patients with
nontremor-dominant PD had reduced brain activity in the prefrontal cortex and globus pallidus compared with both patients with
tremor-dominant PD and controls. 34 Another study found
decreased gray matter volume in the cerebellum of patients with
PD and rest tremor compared with patients with PD without rest
tremor. 35 These and other studies provide evidence for the
involvement of the cerebellothalamocortical circuitry in parkinsonian tremor. In contrast, voxel-based morphometry showed
smaller gray matter and presupplementary motor volume in the
PIGD subgroup, particularly in areas involving motor, cognitive,
limbic, and associative functions.36 This pattern suggests that
degeneration of cortical areas involved in motor planning may
contribute to the PIGD phenotype.

Biomarkers
Refinements in genomics, proteomics, lipidomics, and metabolics
applied to blood, cerebrospinal fluid, and other tissues may lead to
early identification of PD and aid in differentiating the various
subtypes.37 There are emerging data on blood and cerebrospinal fluid
markers that correlate with motor or nonmotor symptoms associated with PD. For example, low plasma levels of epidermal growth
factor have been found to correlate with baseline cognitive impairment in patients with PD.38 Furthermore, lower cerebrospinal fluid
A1-42 and P-tau181 concentrations were associated with PIGD PD
but not with the tremor-dominant form.39

Genetics
In the past decade, there has been an explosion of knowledge
about the genetics of PD, and 18 PD-related gene loci have been
identified40 (Table). Both autosomal dominant and autosomal
recessive genetic forms of PD have been identified, with distinct
and overlapping phenotypes. The first gene associated with PD
was identified in 1997 as a missense mutation in the -synuclein
(SNCA) gene with an autosomal dominant mode of inheritance.41
Later, duplications or triplications of the SNCA gene were found in
patients with PD phenotypes.42 Seven SNCA mutations have since
been identified and found to be associated with early-onset parkinsonism, moderate response to levodopa, rapid progression,
pyramidal signs, frequent psychiatric symptoms, and prominent
cognitive dysfunction.41-43
The most common autosomal dominant form of parkinsonism
involves missense mutations in the leucine-rich repeat kinase 2
(LRRK2) gene.44 The G2019S LRRK2 mutation is highly prevalent in
the Ashkenazi Jewish and North African populations.44 The phenotype associated with LRRK2 mutation is highly variable but is quite
similar to sporadic PD, particularly asymmetric parkinsonism with
tremor, but with a decreased risk of cognitive and olfactory impairment, although atypical features such as orthostatic hypotension,
dementia, hallucinations, and sleep disturbance have been deJAMA Neurology April 2014 Volume 71, Number 4

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Clinical Review & Education Review

Parkinson Disease Subtypes

Table. Genetically Determined Parkinsonism

Locus

Inheritance

Gene

Protein

PARK1

AD

SNCA

-Synuclein

PARK2

AR

PARK2

Ubiquitin ligase

PARK3

AD

PARK4

AD

SNCA

-Synuclein

PARK5

AD

UCHL1

Ubiquitin cyclohydrolase A

PARK6

AR

PINK1

PTEN-induced kinase 1

PARK7

AR

DJ-1

DJ-1

PARK8

AD

LRRK2

LRRK2 (dardarin)

PARK9

AR

ATP13A2

Lysosomal type 5
P-type ATPase

PARK10

AD

PARK11

AD

GIGYF2

GRB10-interacting GYF protein 2

PARK12

X-linked

PARK13

AD

HTRA2

Serine protease

PARK14

AR

PLA2G6

Phospholipase A2

PARK15

AR

FBXO7

F-box protein 7

PARK16

PARK17

AD

VPS35

VPS35

PARK18

AD

EIF4G1

EIF4G1

scribed in LRRK2 cases. In contrast, based on a study of patients with

YOPD, G2019S mutation carriers were more likely to have a PIGD phenotype and less tremor.45 The pathologic changes in the brains of
patients with LRRK2-associated PD are quite variable and may include pure nigral degeneration without LBs, typical -synuclein LB
disease, and even neurofibrillary tangle disease with TDP-43 (transactive response DNA-binding protein 43 kDa) inclusions and -amyloid deposits in anterior horn cells. Mutations in two new genes causing autosomal dominant PD have been recently identified: vacuolar
protein sorting 35 homologue gene (VPS35)46 and eukaryotic translation initiation factor 4G1.47
The autosomal recessive forms of parkinsonism include mutations in the parkin gene (PARK2),48 the phosphatase and tensin homologueinduced putative kinase 1 gene (PINK1),49 and the DJ1
gene.50 These mutations are generally associated with YOPD and
manifested by a good response to levodopa and early development of dyskinesias.40 Although early cognitive impairment is uncommon, psychiatric comorbid conditions have been reported to be
present in PINK1-associated and DJ1-associated PD. Both PARK2 and
PINK1 genes have been reported to play a role in mitochondrial function, suggesting that mitochondrial dysfunction plays a role in PD
pathogenesis. Furthermore, mutations in the glucocerebrosidase
gene have been found to be a risk factor for PD in the Ashkenazi Jewish population. Patients with these mutations have been shown to
have an earlier onset of disease and more prominent cognitive
dysfunction.51 The loss of function mutations in glucocerebrosidase suggests a role for lysosomal dysfunction in the pathogenesis
of PD.52

Pathologic Findings
A definite diagnosis of PD requires autopsy confirmation of pathologic findings typical for PD. The core pathologic findings underlying PD are degeneration of melanin and dopamine-containing
neurons, especially in the zona compacta of the substantia nigra,
and the presence of LBs, eosinophilic cytoplasmic inclusions, and
502

Abbreviations: AD, autosomal

dominant; AR, autosomal recessive;
ATPase, adenosine triphosphatase;
EIF4G1, eukaryotic translation
initiation factor 4G1;
LRRK2, leucine-rich repeat kinase 2;
PTEN, phosphatase and tensin
homologue; VPS35, vacuolar protein
sorting 35; ?, unknown.

dystrophic Lewy neurites.1,53,54 There is growing appreciation for

pathologic involvement in PD not only of brain dopaminergic systems but also of nondopaminergic systems in the brain as well as
peripheral and autonomic systems. Several studies have drawn
attention to the involvement of cardiac, gastrointestinal, submandibular gland, cutaneous, and other body regions, all of which
have been found to have LB disease with deposition of abnormal
-synuclein.55-57
There is also growing evidence that the initial site of disease in
PD may not necessarily be in the substantia nigra but may be in the
nuclei of the caudal brainstem or even in the peripheral nervous system and peripheral organs.54 The hypothesis that progression of neurodegenerative disease is mediated via seeding of misfolded proteins, also known as templating, with intracerebral and transynaptic
propagation of fibrils has extended to a broad range of proteins, including -synuclein, tau, huntingtin, superoxide dismutase 1, and
TDP-43.58 Furthermore, in the central nervous system there is evidence for striatonigral rather than nigrostriatal progression, with the
initial disease site in the striatum and dying-back axonopathy resulting in retrograde degeneration and neuronal loss in the substantia nigra.59
Postmortem studies have examined differences between PD
subtypes, particularly tremor-dominant vs akinetic-rigid
phenotypes.60-63 In a clinicopathologic study involving 166 cases
collected over 39 years, 26% of pathologically confirmed PD cases
were classified as akinetic-rigid, 8% as tremor dominant, and 66%
as mixed. 64 Another clinicopathologic study of 72 autopsyconfirmed cases at a tertiary care center found that 16% of
patients had PIGD at onset and 49% had tremor at onset.65 In a
neuropathologic study of 27 patients with akinetic-rigid PD and 18
with tremor-dominant PD, those in the former group had greater
neuronal loss in the substantia nigra pars compacta, especially the
lateral portion, and the locus coeruleus.60 Another clinicopathologic study found degeneration of a subgroup of midbrain (A8)
neurons in patients with tremor-dominant PD, but this region was

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Parkinson Disease Subtypes

Review Clinical Review & Education

spared in patients with PD without tremor.61 This is consistent

with the finding of greater loss of neurons in the retrorubral A8
field, which contains predominantly calretinin-staining cells but
few tyrosine hydroxylase and dopamine transporter immunoreactive neurons.62 Patterns of striatal and pallidal dopamine loss
seem to vary among the different PD motor subtypes. 63 For
example, in contrast to severe loss of dopamine in the ventral globus pallidus internus, near-normal dopamine levels were found in
the basal ganglia of patients with tremor-dominant PD. Studies
have also demonstrated more severe cortical LB disease in
patients with nontremor-dominant PD than in those with tremordominant PD.66,67
ARTICLE INFORMATION
Accepted for Publication: December 13, 2013.
Published Online: February 10, 2014.
doi:10.1001/jamaneurol.2013.6233.
Author Contributions: Drs Thenganatt and
Jankovic had full access to all the data in the study
and take responsibility for the integrity of the data
and the accuracy of the data analysis.
Study concept and design: Both authors.
Acquisition of data: Both authors.
Analysis and interpretation of data: Both authors.
Drafting of the manuscript: Thenganatt.
Critical revision of the manuscript for important
intellectual content: Both authors.
Administrative, technical, or material support: Both
authors.
Conflict of Interest Disclosures: None reported.
REFERENCES

Conclusions
As we learn more about PD, it is becoming abundantly clear that PD
is a heterogeneous disorder with variable clinical characteristics and
imaging findings, as well as different genetic and other underlying
neuropathologic mechanisms. Identifying subtype-specific biomarkers will enhance our ability to categorize various PD phenotypes into
subtypes, which will lead to a better understanding of pathogenesis, clinical progression, and prognosis. The existence of the various PD subtypes should be considered in the design and interpretation of epidemiologic studies and clinical trials.

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