Parkinsonism and Related Disorders 46 (2018) S6eS9

Contents lists available at ScienceDirect

Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Dementia with Lewy Bodies and Parkinson Disease Dementia: It is the

Same Disease!
Joseph H. Friedman, MD a, b, *
a
Dept. of Neurology, Butler Hospital, 345 Blackstone Blvd, Providence, RI 02906, USA
b
Dept of Neurology, Warren Alpert Medical School of Brown University, Providence, RI 02906, USA

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: The question whether DLB and PDD are distinct disorders has been debated in several
Received 15 July 2017 forums. The two disorders, once parkinsonism is present in DLB, cannot be distinguished on clinical or
Accepted 15 July 2017 pathological grounds. The conundrum exists for those DLB patients who do not yet have parkinsonism,
and raises the parallel with patients who have Rapid Eye Movement Behavior Disorder but have not yet
Keywords: manifested parkinsonian signs.
Dementia with Lewy bodies
Methods: A literature review was summarized to justify classification as a single disorder.
Parkinson's disease dementia
Results: Most clinical observations and trials point to these disorders, once parkinsonism is present in
Disease classification
Parkinson's disease progression
DLB, are identical.
Dementia with Lewy bodies disease Conclusion: This article notes the advantage to clinical research and treatment by considering these two
progression syndromes as the same so that medications approved for PDD and for PD psychosis can be extended to
DLB patients and that resources for PD research and support can be also used for DLB.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction Whether DLB and PD with dementia (PDD) are the same disease
or not has been the subject of debate [3]. The Movement Disorders
The first description of DLB was published in 1961 [1]. Two men, Society convened a panel to suggest a revised clinical definition of
ages 69 and 70, one with a 12 month course and the other of un- idiopathic PD, which suggested that DLB, once parkinsonism is
clear duration, had developed dementia associated with severe present, should be considered the “DLB subtype” of PD [4], and that
flexion and rigidity. One had visual hallucinations. The medical the presence of dementia should no longer be exclusionary for the
histories were not well known to the physicians so that clinical diagnosis of PD. The U.K. Brain Bank criteria use “severe dementia”
details were slight. The occurrence of Lewy bodies (LB) in the cor- as an exclusionary criterion, not mild dementia. While both sides of
tex, they noted, had been described previously but only in the the argument agree that the two clinical syndromes are extremely
elderly and had unknown significance. The recognition that this close in all aspects, other than for the timing of the onset of de-
disorder was a significant cause of dementia, was a surprise to the mentia, several expert groups have taken the position that it is
original authors, who had thought their cases a “curiosity.” (per- “useful” to consider the entities as separate [3,5,6], without an
sonal communication). explicitly stated rationale. A summary of arguments against the
Clinically defined DLB is now thought to constitute about 5% of MDS revised criteria that suggested DLB classification as a variant of
dementia cases in the elderly [2] and autopsy studies have found PD was published in 2017 [7]. The current distinguishing feature
that 3e10% of older dementia patients meet pathological criteria between the two disorders remains the temporal sequence of de-
for the diagnosis of DLB [2]. Parkinson's disease (PD) is the second mentia versus motor signs. If dementia precedes or occurs within
most common neurodegenerative disorder in resource wealthy 12 months of the onset of motor features, the disorder is labeled
parts of the world and DLB is the second most common neurode- DLB, the “12 month rule” [8].
generative dementing disorder. There are two questions to consider in attempting to reach an
answer to the question. What criteria should be used to classify a
disease: does the answer to the DLB vs PDD question matter?
* Dept. of Neurology, Butler Hospital, 345 Blackstone Blvd, Providence, RI 02906, The conundrum arises because DLB often presents before motor
USA features of PD. Fifteen to 40% die without motor signs [8]. It is
E-mail address: joseph_friedman@brown.edu.

http://dx.doi.org/10.1016/j.parkreldis.2017.07.013
1353-8020/© 2017 Elsevier Ltd. All rights reserved.
 J.H. Friedman / Parkinsonism and Related Disorders 46 (2018) S6eS9 S7

difficult to distinguish from Alzheimer's disease (AD), a distinction Table 2

important for prognosis and clinical trials. It is difficult [3] for pa- Quotes from expert reviews.

tients to understand that they have a variant of PD when no motor “When the clinical picture is fully developed they are indistinguishable” [29]
features are present. Analogies might be made to patients with .,“there is no rational clinical or pathological basis to dictate a definite time
REM sleep behavior disorder [7] who lack motor features of an interval between development of motor symptoms versus onset of dementia”
[5]
alpha synucleinopathy, those with progressive supranuclear palsy “We did not find evidence of or a definitive pathological substrate to support the
who lack the required eye movement abnormality by the time of categorical clinical distinction between PDD and DLB despite the findings of
death, those with autonomic dysfunction prior to developing higher cortical NFT, NP and SYN pathology in DLB compared with PDD, [20].
diagnosable multi-system atrophy, etc. The MDS suggested criteria for the dx of PD “do not consider dementia an
exclusion criterion for PD regardless of when it occurs in relation to
parkinsonism onset” [7].
2. What is a disease and what is the role of disease “no major difference between DLB and PDD have been found in any variable
examined including cognitive profile, attentional performance,
classification?
neuropsychiatric features, sleep disorders, autonomic dysfunction, type and
severity of parkinsonism, neuroleptic sensitivity, and responsiveness to
There are a number of definitions of disease (see Table 1) but cholinesterase inhibitors” [Third report of the DLB consortium]
they share the unifying requirements of “distinguishing signs and “The Working Group agreed unanimously that PDD and DLB are more similar
symptoms” and a “particular,” or distinguishing process. than different. The main difference between the two entities is the timing of
onset of dementia in relation to motor symptoms.” [6]
The first International List of Causes of Death was published in
“Neuropathologic findings do not support an arbitrary cut off between the two
1893 and later taken over by the World Health Organization as The disorders.” [30]
International Classification of Disease. This was always considered
an evolutionary process, as understanding of epidemiology, path-
transporter (DaT) imaging [8]. Thus, studies of DLB are hampered
ophysiology and pathology improved with time. ICD 11 is in
by the need to have either autopsy results or the presence of motor
progress, and “experts and stakeholders are invited to participate in
features to correctly identify those with the disorder. Increasing use
the ICD revision” (WHO ICD Revision website 2017).
of dopamine transporter (DaT) scanning may allow for a higher
Disease classification has followed a standard progression. A
degree of confidence and sensitivity in the diagnosis of pre-motor
syndrome was first described, usually based on symptoms and
DLB, which will increase the number of subjects available to study.
signs, but possibly by changes in laboratory markers or by pathol-
Dementia eventually affects about 80% of PD patients. PDD is
ogy. With increased knowledge came refinements. Classification
characterized primarily by executive dysfunction [10]. Patients
runs into trouble when pathology, or pathological mechanisms,
have problems with planning and multi-tasking. They have a
incompletely understood, produce different syndromes with the
reduced ability to abstract and to adjust to changing requirements.
same pathology or when different pathologies produce clinically
Visuo-spatial dysfunction is an early feature, often preceding the
indistinguishable syndromes. There are family members with
onset of dementia or memory loss. Cortical functions such as lan-
clinical PD, but not all of whom have LB, for example [9]. There are
guage and praxis are generally not involved early. Memory prob-
currently three “variants” of FTD and several variants of Alz-
lems tend to be more a problem of recall than a failure to lay down a
heimer's disease, phenomenologically quite dissimilar.
memory trace. The neuropsychological profile on formal testing of
The importance of classification is in avoiding confounding one
the two disorders is the same [6,11]. As the dementia progresses
disease with another. Pre-motor DLB is often indistinguishable
however, the overlap with “cortical” dementias, particularly Alz-
from Alzheimer's disease [6], but observations on one do not
heimer's disease became more pronounced, with language
translate to the other.
dysfunction, apraxia and failure to lay down a memory trace
becoming more evident [5].
3. Are DLB and PDD the same? (see Table 2) Behavior problems, particularly depression, anxiety, fatigue,
apathy and sleep behavior disorder are so common in PD, that their
3.1. Clinical manifestations absence is considered a “red flag” for its diagnosis [4]. These are
common in DLB as well [8].
DLB may present with purely behavioral symptoms or purely Psychotic symptoms, hallucinations and delusions are common
motor signs, with dementia being recognized later. The rationale in PDD. These are typically visual hallucinations, although other
for the 12 month designation [8] were not provided with the sensory hallucinations also occur [12]. Although hallucinating PDD
consensus guidelines. The most recent Consensus statement [8] patients are almost always on medications known to psychotic
simply notes that “this arbitrary cutoff remains useful, particu- symptoms, this is not always the case [13]. These psychotic symp-
larly in clinical practice.” Sensitivity for pre-motor DLB has been toms are common in DLB, as well, although these patients are
low, but promises to be much higher with the addition of dopamine usually not on medications for PD motor dysfunction. Minor hal-
lucinations,” transient peripheral field hallucinations or “presence”
hallucinations,” are not uncommon in early, untreated PD patients
Table 1
Definitions of “disease”. even without dementia [14]. These symptoms, occurring prior to
diagnosis, illustrates the continuum of the psychotic syndrome,
1. “A condition of the living animal or plant body or one of its parts that impairs
analogous to the presence of MCI in 10e20% of PD patients at the
normal functioning and is typically manifest by distinguishing signs and
symptoms” Merriam Webster Unabridged Dictionary 2017 (www.merriam- time of PD diagnosis [15].
webster.com/dictionary/disease) Cognitive fluctuations, a diagnostic feature of DLB is seen
2. “A particular abnormal condition, a disorder of structure or function, that commonly in PDD [16]. REM sleep behavior disorder is also com-
affects part or all of an organism” Wikipedia 2007
mon in both. Even the prevalence of daytime sleepiness appears to
3. A particular destructive process in an organ or organism, with a specific cause
and characteristic symptoms. Webster's New World College Dictionary
be the same [5]. Thus, the core [8] features of DLB, dementia,
(www.websters.yourdictionary.com) cognitive fluctuations, hallucinations and parkinsonism are present
4. A definite pathological process having a characteristic set of signs and in both disorders.
symptoms. [Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing Autonomic dysfunction is equivalent in the two conditions
and Allied Health, Seventh Edition. 2005. Saunders Press.
[17,18].
S8 J.H. Friedman / Parkinsonism and Related Disorders 46 (2018) S6eS9

The course of the dementia in the disorders is the same [19,20]. training. Currently the dementing illness are studied by both psy-
Kramberger reported longitudinal scores of the mini-mental state chiatrists and neurologists. DLB patients are cared for by dementia
exam in 835 DLB patients, 198 PDD patients, with 3 years follow up, specialists when the dementia precedes motor dysfunction, and
revealed mean annual declines that were not statistically or clini- probably by movement disorder specialists if it develops within or
cally significantly different. A British study reported similar results. shortly after motor signs are evident (personal observation). In the
The response to anti-dementia drugs is the same [21]. A 2017 U.S. the different National Institutes of Health are funded at
meta-analysis [21] of clinical trials of anti-dementia dugs for DLB different rates and each Institute has its own funding priorities. This
and PDD found similar responses, both in terms of benefits and side author has been told at different times that “neuropsychiatric”
effects, although individual trials often had mildly different problems may fall between the cracks in funding priorities when
outcomes. one Institute believes the other should be responsible.
There is a significant genetic overlap between PDD and DLB Commercial interests will be better served by the merger of PDD
[22,23], although there are far fewer studies of DLB than PD or PDD. with DLB. The sensitivity of diagnosis of DLB before parkinsonism
Abnormalities of the GBA gene, for example is associated with a emerges is so poor, that pharmaceutical trials on pre-motor DLB
higher incidence of dementia in PD, and has been associated with patients are difficult to carry out. If DLB and PDD were a single
DLB, as well [22]. Most studies have focused on genes known to be disorder, there is likely to be a greater commercial research in-
associated with PD, or AD, and may thus be biased. These found vestment since treatments would not have to be carried out on
such associations with SNCA, SCARB2 or AD, APOE, and possible separate populations. Pimavanserin, approved for PD psychosis,
associations with MAPT [22]. rivastigmine, approved for PDD, and droxidopa, approved for
Imaging findings, using morphometry and fMRI on the disorders orthostatic hypotension in PD would automatically be approved for
are comparable [24]. DLB, hence covered by insurers.
Pathologists cannot distinguish these disorders. Neuropa-
thology in general, particularly in the elderly, is always confounded 4. Conclusion
by the variety of accumulated insults as well as the usually over-
looked fact that pathological understanding is more limited than The arguments in favor of considering DLB and PDD as distinct
we like to think. In DLB and PDD comparisons are confounded by but related disorders seems to be based more on the historical
the concurrence of variable degrees of Alzheimer pathology as well development of the clinical concepts of DLB and PD than on clinical
as other disorders [19]. criteria. There are differences between the two entities, but
Irwin et al. [25] found no evidence for a pathological distinction certainly less than one sees among the variants of Alzheimer's
between DLB and PDD after reviewing 213 autopsied cases despite disease, fronto-temporal dementias, or multisystem atrophies.
having clinical information. They found a correlation between de- There is less difference between DLB with parkinsonism and PDD
mentia and shorter survival with the severity of Alzheimer pa- than there is between the PIGD and tremor dominant subtypes of
thology in both disorders. PD. If one considers the analogy with RBD, middle aged adults with
The largest autopsy series of DLB comes from the National RBD and a normal neurological exam are thought to have idiopathic
Alzheimer Coordination Center, with 807 brains, indicating that the RBD, but, in time, are likely to be re-diagnosed with PD or DLB. At
variable degree of AD pathology in both PDD and DLB most likely this time it make more sense to diagnose DLB when motor features
explains much of the spectrum of clinical presentations [19]. are absent, as many of these cases will actually be variants of AD,
The major question concerning dementia in both Lewy body and PDD when motor features are present. Calling these variants
disorders is how much is due to AD pathology versus LB related different diseases will, in the end, be useful once their distinct
pathology? One study found that a majority of PDD cases meet pathophysiologies and treatments become known. Until then, we
neuropathological criteria for a diagnosis of Alzheimer's disease are overlooking the distinct advantages of lumping over splitting
[26]. Looking at the occurrence of LB in AD, as study of 145 brains that come with the extension of clinical trials data, hence insurance
found 56e61% had LB, although rarely in the substantia nigra [24]. covered treatments of PDD to DLB. It is also reassuring to patients
The nature of the relationship between the two types of pathology who carried the diagnosis of DLB before motor features emerged to
is currently the central pathological issue since the presence of one learn that their condition is a variant of PD, and that they have not
seems to increase the risk of the other being present [26,27]. developed a second independent disorder.

3.2. Does the answer matter? Author declaration

There are consequences to classification [28]. Different “stake- I have no competing interests. I have been a paid consultant to
holders” may have strongly held beliefs. It is possible that including Acadia Pharmaceuticals and have received research funding from
DLB as the dementia variant of PD would mean a “loss” for the NIH and M J Fox foundation.
dementia community. It might alter funding mechanisms for
research, by moving requests into PD funding mechanisms rather Funding
than dementia funding. Alzheimer's disease is clearly the most
important of the neurodegenerative disorders, and it may be ad- Butler Hospital.
vantageous for DLB research if funds came from a dementia
resource rather than a PD resource. Alternatively, funds appro-
Acknowledgment
priated for AD may be less available for DLB, a different disorder,
than funds focused on PD research, once PDD and DLB are
To John Growdon, MD, who provided generous and thoughtful
considered a single disorder. The types of doctors who pursue
critical comments.
research may shift from one group to another depending on clas-
sification. For example, most publications on psychiatric aspects of
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