Parkinsonian syndromes: Parkinson’s disease dementia, dementia

with Lewy bodies and progressive supranuclear palsy

Anca Popescua, Carol F. Lippab,*

aDepartment of Neurology, Temple University Hospital, Philadelphia, PA, USAbDepartment of Neurology, Drexel University College of Medicine, Philadelphia, PA 19129, USA

Abstract

The recognition of dementia in Parkinson’s disease (PDD) is relatively new compared with the first description of ‘shaking palsy’ by James

Parkinson in 1817. Physicians who currently diagnose and manage PDD patients, not uncommonly evaluate mysterious cases having a

variety of cognitive and extrapyramidal features. In this large group, diagnostic uncertainty has limited clinical research, including

pharmaceutical trials. However, the classic teaching still holds ground: typically, dementia in Parkinson’s disease (PD) does not manifest

from the onset of clinical signs. In spite of lacking temporal definition, this clinical criterion is still the one used to make a clinical distinction

between PDD and the closely associated extrapyramidal dementia syndrome, dementia with Lewy bodies (DLB). Patients with PD

developing dementia some years later diagnosed as having PDD, whereas patients presenting with fluctuating cognition, visual hallucinations

and then parkinsonism would be diagnosed with DLB. In DLB, dementia occurs before parkinsonism or shortly thereafter. However, as

discussed below, one might consider this distinction arbitrary. There is active research examining the relationship between DLB and PD

using clinical, genetic, pathologic, and biochemical data.

q 2004 Elsevier B.V. All rights reserved.

Keywords: Alpha-synuclein; Alzheimer’s disease; Dementia with Lewy bodies; Parkinson’s disease

1. Introduction

Clinical and biochemical features of the three most

frequent extrapyramidal dementias (PDD, DLB and PSP)

are summarized below, with the aim of integrating the

clinical and biological features relevant to clinical research.

These conditions may be now classified as CNS proteino-

pathies and grouped according to the pathological protein.

Alpha-synuclein is the signature protein of the synucleino-

pathies, DLB and PDD. Tau is the protein implicated in

progressive supranuclear palsy (PSP), Pick’s disease,

corticobasal degeneration and some of the Parkinson’s

plus dementia syndromes linked to the tau gene on

chromosome 17. The mechanism by which protein abnorm-

alities lead to disease is still a matter of debate.

2. Synucleinopathies: PDD and DLB

Since Frederic Lewy first described PD, Lewy bodies

(LBs) have been the object of intensive research

and scrutiny. LBs are the pathologic hallmark of PD and

DLB, just as neurofibrillary tangles and amyloid plaques are

to Alzheimer’s disease (AD), and polyglutamine aggregates

are to Huntington’s disease [1]. Microscopic specimens

stained with hematoxylin/eosin (the most routine histo-

chemical stain) reveal LBs in the substantia nigra (the

pathognomonic location for idiopathic PD) as round,

eosinophilic masses with a clear halo (Fig. 1A). More

recently, with the development of immunohistochemistry,

the halo has been shown to stain with antibodies against

alpha-synuclein (Fig. 1B). Cortical LBs, the defining feature

of DLB, often appear as homogeneous aggregates of alpha-

synuclein lacking a halo (Fig. 1C).

The description of an alpha-synuclein gene mutation in a

family with PD in 1997 by Polymeropoulos [2] and

colleagues and the identification of alpha-synuclein as the

major constituent of LBs have greatly advanced our

understanding of the neurodegenerative diseases. The

cause of LB formation is puzzling, but their formation

may be associated with lysosomal dysfunction [3]. Their

function, if any, is unclear. Whether they initiate the

pathophysiologic cascade (causal hypothesis) or act as a

protective mechanism combating the neurodegenerative

process (reactional hypothesis) is not known [4].

1566-2772/$ - see front matter q 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.cnr.2004.04.011

Clinical Neuroscience Research 3 (2004) 461–468

www.elsevier.com/locate/clires

* Corresponding author. Tel.: þ1-215-842-7151; fax: þ1-215-849-1645.

E-mail address: carol.lippa@drexel.edu (C.F. Lippa).

3. Clinical features of PDD

Patients with PD who have a resting tremor with little

action tremor symptoms early in the disease course are

substantially relieved with administration of levodopa

preparations. The presenting motor symptoms are typically

asymmetrical, and among these, tremor is the most common

symptom. Gait abnormalities are also common, but usually

occur later in the disease course.

The prevalence of dementia in PD ranges from 2% in

early onset cases [5] to up to 81% in various patient

populations [6]. On average it is 40% [7]. The prevalence

increases with age; dementia is almost never present in

patients under age 50. Dementia is estimated at 69% in PD

patients over age 80 years [8]. Longitudinal studies have

shown that more than 75% of PD patients develop some

cognitive impairment by 8 years of followup [9]. Risk

factors for dementia in PD include advanced age at onset,

severe motor symptoms, a long disease duration, early

levodopa-related confusion, hallucinations and psychosis.

An akinetic-rigid syndrome, depression, poor verbal fluency

test scores, early autonomic failure, symmetrical disease

presentation, and suboptimal responses to dopaminergic

treatment are also associated with an increased likelihood of

dementia [10].

Cognitive difficulties in PDD may be present early, and

may be domain-specific. These include the classic sub-

cortical deficits such as bradyphrenia. Memory may be

relatively preserved, but with particular difficulty with

spontaneous information retrieval. Usually patients with PD

only meet the DSM-IV-TR criteria for dementia, long after

the diagnosis of PD has been established. Then, dementia

usually remains mild-to-moderate in severity. Cognitive

deficits more typically cortical in nature also occur in PDD

and include impairment of visuospatial abilities, hallucina-

tions, aphasia and apraxias. Dopaminergic medications and

sleep abnormalities may compound fluctuations. Most

patients with PD have cortical LBs, whether demented or

not [11]. The presence of dementia in PD may correlate with

the density of cortical LBs [12] and their presence is often in

eloquent areas for the executive function, such as the frontal

cortex [13]. Patients with PDD may have evidence of

atrophy of the hippocampus [14] and substantia innominata

[15], comparable to or even more severe than that of AD

patients. SPECT perfusion studies in PDD patients have

shown perfusion deficits in the temporal and parietal lobes

that are not seen in non-demented PD patients [16].

However, PET studies with fluorodeoxyglucose often

show decreased glucose metabolism even in non-demented

PD patients, which may be quite diffuse, without

temporoparietal dominance [17]. The pattern of cortical

perfusion deficits in PDD is global, like in non-demented

PD patients, but more severe abnormalities are seen in the

lateral parietal, temporal [17] and frontal association

cortices, and posterior cingulate lobe (a pattern with much

similarity to that of AD) [18]. Persons with PDD also show

decreased N-acetylaspartate on studies using magnetic

resonance spectroscopy [19].

Complicating interpretation of studies of PDD is the fact

that Alzheimer’s disease (AD) pathology is widespread in

PDD subjects. Clinical criteria are used in differentiating

PDD from AD. The pattern of cognitive loss on

Fig. 1. Photomicrographs of Lewy bodies at high magnification (60 £ ). A shows a nigral Lewy body using hematoxylin/eosin stain (A). LBs are rounded,

intraneuronal inclusions with a halo. B shows Lewy bodies stained with antibodies directed against alpha-synuclein. Note that the ring enhances. C and D show

cortical Lewy bodies using alpha-synuclein immunohistochemistry. C is from a subject meeting criteria for DLB. Numerous Lewy bodies and Lewy neurites

are observed in this temporal lobe section. D is also from the temporal lobe, but it is from an Alzheimer’s disease patient with cortical Lewy bodies. Note

that Lewy bodies and Lewy neurites can be numerous in Alzheimer’s disease. Neurofibrillary tangles are also present in affected neurons (compare the

cytoplasm in C and D).

A. Popescu, C.F. Lippa / Clinical Neuroscience Research 3 (2004) 461–468462

neuropsychological testing may help determine whether

dementia in PDD subjects is related to cortical LBs or AD

pathology. PD patients have more prominent retrieval

memory deficits compared with AD patients who experience

prominent storage deficits. This clinical observation may be

explained by relative biochemical insufficiency of the

prefrontal cortex, (and correspondingly less involvement

of the temporal cortex) owing to the dopaminergic deficit in

the basal ganglia which are connected to the prefrontal areas.

Dementia in PD compounds the disability of the

disease. There are effective medications for most motor

features of uncomplicated PD, including levodopa and

dopaminergic agonists, but few options for affecting the

dementia symptoms of PDD. In the temporal evolution of

PD, increasingly higher levodopa doses are needed to control

the motor symptoms, and their benefit is frequently offset by

confusion and psychosis. Greater degrees of improvement

and fewer side effects occur with acetylcholinesterase

inhibitors. These include donepezil hydrochloride (with

improved scores on the Mini-mental State Examination,

MMSE, and the Clinician’s Interview Based Impression of

Change plus Caregiver Input [20]) and galantamine

hydrochloride (improved global smental status, MMSE,

verbal fluency and clock drawing test scores [21]). Other

neurotransmitter systems may also be deficient in PDD,

including the monoaminergic systems. A variety of hypoth-

eses have been proposed linking particular neurotransmitters

to cognitive-specific domains. The dopaminergic system is

involved in the dysexecutive syndrome, the cholinergic

system in attention and memory, norepinephrine deficit in

impairment of attention and serotonin in depression [22].

However, such hypotheses cannot always be translated into

practice with specific pharmacological agents.

Compared with the non-demented PD patient, the PDD

subject experiences a poorer quality of life [23], earlier

nursing home placement [24,25], and higher mortality [26].

In PDD, depression often accompanies dementia and may

be severe. Depression in PD in general is more prominent in

‘off’ states and may be improved by optimization in the dose

of levodopa or other dopamine agents [27].

Pharmacotherapy for parkinsonian features is difficult in

PDD because dopaminergic therapy worsens confusion and

psychotic features [28] and an atypical antipsychotic

frequently needs to be added to an antidepressant, increas-

ing the risk of drug–drug interactions. Antipsychotic drugs,

including even atypical agents, may worsen the extrapyr-

amidal features [27]. Therefore, there is a critical need to

better understand the mechanisms by which PD patients

develop dementia to devise more targeted pharmacological

approaches.

4. Clinical features of DLB

The hallmark features of DLB include fluctuations,

visual hallucinations and spontaneous parkinsonism.

Patients with DLB may present with cognitive symptoms,

or with motor and cognitive symptoms together [29].

Occasionally, motor symptoms occur first. However, in

these cases cognitive symptoms develop within the

following year. When parkinsonism is present, symptoms

include a symmetrical, rigid-akinetic syndrome. Patients

with DLB have a more severe action tremor, bradykinesia,

difficulty arising from a chair, facial expression, gait, and

rigidity symptoms than PD patients. Postural imbalance and

tremor at rest do not differ between the two categories. The

severity of extrapyramidal features correlates with age,

duration of disease, and cognitive impairment in PD patients

but not in DLB patients [30]. Fluctuations may occur

spontaneously or be triggered by medications, infections, or

electrolyte imbalances. Their pathophysiologic substrate is

not understood, but is thought to be neurochemical since PD

patients with levodopa-induced psychosis experience simi-

lar symptoms [31].

Psychiatric symptoms in DLB are similar to those of

levodopa-induced psychosis (which occurs in patients with

both advanced PD and PDD). Visual hallucinations of small

persons and animals, visual illusions, metamorphopsia,

personal or topographical misidentification, reduplicative

paramnesia and the Capgras syndrome occur. It is possible

that these represent dysfunction of the nigro-amygdaloid-

occipital lobe connections [32].

Although levodopa preparations are commonly pre-

scribed in DLB, these patients do not respond consistently

to dopaminergic medications. Moreover, dopaminergic

agents may worsen the hallucinations and cause somno-

lence. Patients with DLB may also have significant adverse

effects from other medications. Exposure to neuroleptic

agents may lead to marked degrees of ‘freezing’ of the

movements, cognition and even death [33]. For this reason it

is recommended that typical neuroleptic agents be avoided

in this patient population. If necessary, atypical neuroleptic

agents may be used at low doses.

From the pharmacologic perspective, DLB subjects have

greater cholinergic losses than AD patients [34–36], so their

symptoms may respond dramatically to cholinesterase

inhibitors. Donepezil hydrochloride [37] and rivastigmine

tartrate [38] may have favorable effects on confusion,

psychosis, hallucinations, anxiety, apathy, and delusions

similar to those of PDD patients.

5. Are PDD and DLB distinct clinicopathologic entities?

Despite the above mentioned elements to aid in the

distinction between PDD and DLB, the clinician often has

difficulty distinguishing these disorders based on physical

examination alone. Hallucinations in both DLB and PDD

may be associated with more severe dementia, off/on states,

age and sleep disturbances, e.g. restless legs, sleep–wake

cycle reversal, REM sleep behavior disorder [39–41].

Typical hallucinations are vivid images of people or

A. Popescu, C.F. Lippa / Clinical Neuroscience Research 3 (2004) 461–468 463

animals, dramatic settings, formed and recurrent as opposed

to hallucinations in delirium, stroke and seizures. At the

anatomic level, hallucinations may be related to occipital

hypoperfusion [42] and to the LB density in temporal cortex

[43]. At a biochemical level, hallucinations and aggressive

behavior may be significantly related to the prominent

cholinergic deficit [44]. At the genetic level, delusions may

be related to a DRD3 dopamine receptor gene polymorph-

ism [45].

There is a growing trend to group DLB and PDD together

as a spectrum of LB disorders since many of the clinical

distinctions between them are arbitrary. The notion that the

clinical symptoms reflect the regional distribution of

pathology in identical disease processes is gaining popular-

ity since no clear-cut biochemical differences exist between

LBs in PD and DLB [46]. Global cortical LB densities do

not distinguish pathoanatomically between PDD and DLB,

but LB density is higher in the temporal cortex in DLB cases

[47]. Current research efforts are directed at clarifying the

relationship between PDD and DLB so the relevant

diagnosis can be established and appropriate interventions

applied.

6. PDD/DLB and their relationship to the AD epidemic

Further confounding diagnosis in the extrapyramidal

dementias, AD patients frequently develop parkinsonism,

including even early onset presenilin-1 related genetic AD

cases [48]. Parkinsonian features in AD include bradykinesia,

rigidity and gait disorder, but typically do not include

resting tremor. In sporadic cases, bradykinesia and rigidity

may be marked late in the course of AD, when neurofi-

brillary tangles form in the substantia nigra. There are cases

where motor slowing occurs in a stage-dependent manner in

the absence of other signs of extrapyramidal dysfunction

[49]. Rarely, PD may present with dementia early without

significant extrapyramidal features and mimic AD [50].

All dementia patients will have some memory and

naming deficits. In early DLB, in contrast to cortical

dementias such as AD, encoding/immediate recall is more

severely impaired than delayed recall/retrieval. Visuospatial

ability and executive function is significantly affected

earlier in DLB than in AD [32]. Spatial cognition may be

affected even in PD [51]. Vivid visual hallucinations are rare

in AD but a diagnosis of AD needs to be considered

alongside with DLB when they are present early in the

evolution of a patient with a parkinsonian syndrome [52].

AD patients may have agitation, disinhibition, irritability or

apathy which are uncommon in PDD. In end-stage disease,

clinical features of AD, DLB and PDD are often similar

[53]. This is due to progressive involvement of eloquent

cortical areas with LBs and extension of AD pathology to

subcortical nuclei.

REM disorders and dysautonomia help distinguish

individuals with synucleinopathies from those with AD.

REM sleep behavior disorder has been associated with

subsequent development of PD and DLB, although early

REM sleep behavior disorder is more classically associated

with DLB [54]. DLB and PDD patients may be aware of the

unreality of these symptoms or they may find them

distressing and incorporate them into their delusional

beliefs. Sleep disorders reflect neuronal loss in locus

coeruleus and substantia nigra [40]. Although the locus

coeruleus has neuronal loss in AD and DLB [55], REM

sleep behavior disorder is extremely rare in persons with

pure in AD [56]. Early dysautonomic symptoms are more

frequent in DLB than PD, and absent in AD. DLB patients

may develop carotid sinus hypersensitivity with bradycardia

and hypotension, syncope and early urinary incontinence,

while patients with AD less frequently develop such

symptoms [57].

Unfortunately, there is no biomarker that will distinguish

AD from DLB with perfect sensitivity and specificity. In

cases where the clinical diagnosis is uncertain between DLB

and AD, nuclear medicine studies using I123-FDP-CIT may

identify DLB with high sensitivity (88%) and specificity

(91%) by showing decreased bilateral uptake in the striatum

in DLB but not in AD [58].

Overlap pathology AD–PD is more the rule than the

exception [59–61]. LBs frequently occur in AD (Fig. 1D)

and AD pathology is present in the majority of cases with

DLB [56]. According to some autopsy series, 37–80% DLB

cases show concomitant AD [61,62]. Merdes [61] recently

pointed out that the clinical features of DLB are affected by

concurrent neuritic pathology. There is significant corre-

lation between the number of neocortical LBs, amyloid

plaques and neurofibrillary tangles [12] and focal LBs are

present in the majority of patients with AD [46,63]. It is

possible that PD and AD pathology are epiphenomena of the

same disease process. Alternatively, one pathologic feature

may promote development of the other. One idea is that tau

inclusions present in neurofibrillary tangles may promote

LB formation [64]. Another hypothesis regarding the

widespread occurrence of dual pathology is that genetic

influences play a role [65]. When both features are present,

the intensity of each feature is intermediate. Moreover, there

may be genetic ‘cross-talk’ between genes for alpha-

synuclein and AD [66]. It is important to better understand

the reasons why AD and LB pathology co-occur because

overlap pathology influences the clinical phenotype in DLB

and AD. AD with LBs is a more devastating condition than

AD alone [67].

Cholinergic agents are the standard of care for mild-to-

moderate AD. Cholinergic losses are, however, earlier and

more widespread in DLB compared with AD [35,36,44].

The anatomical pattern of cholinergic loss is different: in the

mesiofrontal region in DLB as opposed to hippocampal

region (as seen in AD) [68]. This is in keeping with the

clinical observation that patients who respond more

prominently to cholinesterase inhibitors are more likely to

have DLB than AD.

A. Popescu, C.F. Lippa / Clinical Neuroscience Research 3 (2004) 461–468464

7. Progressive supranuclear palsy

Similar to DLB, the diagnosis of PSP is often missed by

inexperienced clinicians despite established diagnostic

criteria [69]. Here, AD pathology is usually absent, and so

potential for diagnostic specificity is higher for PSP than

DLB. Since Steele et al. described the disease in 1964, it has

been held that the triad of vertical supranuclear ophthalmo-

plegia, postural instability/parkinsonism and mild dementia

is a very reliable combination for the diagnosis of PSP.

Lately, however, there have been reports that DLB may

present in a similar way [65]. Neuropsychological testing

facilitates to distinguish PSP and PDD. Screening with

batteries of tests specific to subcortical dementias show that

more than 50% of PSP patients have cognitive and

behavioral deficits in the first year after disease onset [70].

The cognitive symptoms in PSP are suggestive of a

prominent frontal lobe syndrome [71]. Apathy, decreased

attention, social withdrawal, irritability, depression, stereo-

typy, dependence on social and physical environment, lack

of concern for personal behavior or others’ behavior,

bulimia, disinhibition, inappropriate sexual behavior,

aggressiveness, or a pseudobulbar affect may occur. This

is in addition to the cognitive slowing (bradyphrenia) and

retrieval difficulties that typify PDD and DLB [72]. The

apathy, disinhibition and executive dysfunction correspond

to dysfunction of the orbitofrontal, mesiofrontal and

dorsolateral prefrontal circuitry, respectively [72]. These

are, in turn, due to loss of afferent input from the subcortical

regions affected by PSP (brainstem reticular nuclei,

neocerebellum, globus pallidus internum, thalamus). Severe

impairment of executive function with preserved global

cognitive skills is suggestive of the subcortical, frontal

dementia of PSP. The dysexecutive syndrome can be

elicited by neuropsychological tests looking at task shifting

ability, problem solving, attention, comprehension of

abstract concepts, programming, following set rules, and

self-guided behavior. PSP patients involuntarily grasp and

utilize objects presented to them in the absence of any

explicit task. Neuropsychological tests will elicit deficits in

short term memory (working memory tasks) and long term

memory (remote recall). There may be word finding

difficulty using word-list generation tasks. This domain-

specific dysfunction is more related to difficulty of following

a preset program than amnesia because it may be improved

with cueing, a process that bypasses the defective fronto-

striatal encoding system.

Non-cognitive symptoms in PSP are distinctive. The

patients with PSP have striking inertia. Their face often

show a distinctive grin or frown. Blink frequency is

decreased, even when compared with PD, and eyelid

abnormalities are conspicuous and include blepharospasm

and apraxia of eye opening. Eye movement testing to verbal

commands reveals a delay in initiating eye movements in

early PSP. Prominent eye movement abnormalities are

usually present in PSP, but are uncommon in early DLB or

PD. Diplopia sometimes occur in PSP, but is distinctly rare

in DLB or PD. Vestibuloocular reflex abnormalities and

abnormal optokinetic nystagmus also may help to diagnose

PSP since abnormalities in these findings are almost never

seen in early PD. Complete gaze palsies are seen almost

exclusively in more advanced PSP [73]. Most PSP patients

have slow, hypophonic, dysarthric speech with poor bulbar

control, proportional to the amount of atrophy in brainstem

nuclei [74]. The development of dysarthria and dysphagia

within one year of the onset of a parkinsonian syndrome is

more common in PSP and argues against the diagnosis of

PD/PDD because the synucleinopathies typically spare the

medullary nuclei until late in the disease course.

Assessment of motor features is paramount in differ-

entiating PSP from other extrapyramidal disorders. The PSP

patient is often hyper-erect while the patient with a

synucleinopathy typically has a stooped posture. Increased

muscle tone is axial in PSP and asymmetric and appendi-

cular in PD. PSP and DLB patients show symmetrical motor

findings whereas in PD the findings are usually asymme-

trical. Tremor is less universal in PSP and DLB than PD.

When present, it is a postural or action tremor, not the

resting tremor of PD. In PSP, gait is impaired early in the

course with loss of postural reflexes; this is an intermediate

stage finding in DLB and a late stage finding in PD.

Presence of Babinski responses is more common in PSP

[75]. Other reflex abnormalities including palmomental

responses and glabellar responses occur in both synuclei-

nopathies and PSP, and are not useful in differentiating these

conditions.

Differential diagnosis with PD and PDD is facilitated by

trying to distinguish early symptoms and signs. Several

features in the clinical history will aid in making the

diagnosis of PSP. The age-at-onset of illness in PSP is often

later than that of PD but similar to that of DLB; onset of PSP

before 60 years is unusual [75]. Non-specific symptoms

such as slowing, withdrawal and depression sometimes

herald overt PSP. However, patients often lack insight about

their extrapyramidal and cognitive symptoms, so caregiver

input is crucial when any of these diagnoses are suspected.

One biochemical signature of PSP is a deficiency in the

cholinergic system in some affected areas (basal ganglia,

cell groups of the mesencephalon and pons but not in the

cerebral cortex) thus providing an anatomically defined

basis for motor and supranuclear oculomotor syndromes

characteristic of PSP [76]. Again, the translation of basic

science into clinical research is fraught with discrepancies:

trials of cholinesterase inhibitors have shown only slight

improvement in memory and worsening in motor scores

[77]. Low doses of antidepressants, especially serotonin

reuptake inhibitors, may improve depression, apathy and the

PSP patient’s pseudobulbar affect.

PSP, PDD and DLB rarely occur in kindreds. Molecular

genetic research has shown that PSP is associated with H1

tau haplotype (also seen in some familial cases of PD)

and with the genotype A0/A0 representing an intronic

A. Popescu, C.F. Lippa / Clinical Neuroscience Research 3 (2004) 461–468 465

polymorphism of the tau gene. The H1 haplotype increases

the expression of the tau gene promoter and tau transcrip-

tion. Patients with PSP and other tauopathies have an

increased likelihood of having the H1/H1 genotype.

However, the H1 haplotype is common throughout all

populations (60% of unaffected population has it) and is

therefore not useful for clinical differentiation of a

tauopathy from a synucleinopathy or amyloidopathy [78].

The etiology of PSP is unknown. Toxic etiologies,

oxidative stress, free radical formation and a multitude of

other causes have been implicated. Pathoanatomically, the

brain areas that are most vulnerable in PSP include

the dorsal midbrain and lower brainstem nuclei. But the

mechanism linking abnormal tau processing with neuronal

degeneration in specific brain areas is poorly understood.

It is now recognized that tau dysfunction can lead to

neuronal degeneration. Tau protein occurs in a variety of

isoforms which can be classified as three-repeat (3R) and

four-repeat. Normally, the ratio of 3R to 4R tau isoforms is

about 1:1. In PSP, corticobasal degeneration, and some

other tauopathies, this ratio is altered with a relative increase

in proportion of 4R tau isoform. It is possible that future

therapies aimed at affecting relative isoform expression

could be beneficial to PSP patients.

There are occasional reports of alpha-synuclein aggre-

gates in basal forebrain, amygdala and substantia nigra in

PSP. However, this is comparable to that found in some

control cases [78] so treatments geared toward reducing

alpha-synuclein aggregation are less likely to be useful in

PSP. Before we can develop a rational approach to early

intervention for PSP, we must first better understand the

pathogenesis and etiology of this tau-related disorder.

8. Conclusions

In summary, the diagnosis of extrapyramidal dementia

remains largely clinical. Diagnostic criteria for these con-

ditions remain imperfect. As more clinicopathologic corre-

lation studies are being published, it seems that there is a

spectrum of Lewy body diseases—with PD at one end, and

DLB at the other. Individuals with disorders in this Lewy body

spectrum also frequently have concurrent AD or vascular

pathology. Some investigators who tend towards ‘splitting’

have identified three subtypes of PDD: subcortical pathology,

limbic/cortical LB-type degeneration, and cases with coinci-

dent AD pathology. Those with tendency towards ‘lumping’

lean more towards AD pathology triggering abnormal

synuclein aggregation and LB formation (probably because

AD is the more prevalent of the two), and the term Lewy body

variant of AD has been used [62]. Genetic testing and other

biomarkers, not well understood at present, may have a

diagnostic or prognostic role in the future. It is possible that

interactions between genotype and environmental factors and

variations in the biochemical milieu throughout life sway

a neurodegenerative process more towards an alpha-synu-

clein-dominant or tau-dominant pathway.

Identification of useful biomarkers for PSP, PDD and

DLB, fine-tuning clinical diagnostic criteria, and acquiring a

better understanding the relationship of PDD to DLB and to

AD pathology are all crucial issues for those undergoing

clinical research in this area. Pharmaceutical development

efforts focused on preventing or correcting alpha-synuclein

and tau protein abnormalities will provide a pivotal role in

altering the course of these diseases.

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