Parkinson's Disease (Non-Motor and Non-Dopaminergic Features) || Clinical Features of Dementia Associated with Parkinson's Disease and Dementia with Lewy Bodies

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Chapter 12Clinical Features of Dementia Associatedwith Parkinson’s Disease and Dementia withLewy Bodies

David J. BurnInstitute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

Introduction

Dementia with Lewy bodies (LBD) and Parkinson’s dis-ease with dementia (PDD) are typically differentiated bythe “1 year rule.” Dementia that develops prior to theonset of PD symptoms, or within 1 year after diagnosis,is referred to as DLB, whereas dementia developing morethan 1 year after the onset of PD features is diagnosedas PDD. In writing a chapter on the clinical features ofdementia associated with PDD and DLB, one imaginesa dog walking out at night in between two lamp-posts.The lamp-post on the left is most frequently visited bythe Movement Disorder specialist, a vicious beast whofiercely guards his territory, while the post on the rightis the domain of the Old Age Psychiatrist, a lean animalwho has had to become increasingly streetwise in orderto survive. Looking at the two near-identical lamp-posts,we ask ourselves, do these territories really matter? Theanswer is probably not. In a recent review on the sub-ject, McKeith wrote: “Other than age of onset, temporalcourse, and possibly levodopa-responsiveness, no majordifferences between DLB and PDD have been found inany variable examined thus far, including cognitive pro-file, attentional performance, neuropsychiatric features,sleep disorder, autonomic dysfunction, type and sever-ity of parkinsonism, neuroleptic sensitivity, and respon-siveness to cholinesterase inhibitors” [1]. Indeed, it isnot unreasonable to consider that they represent differentspectra of the same disease.

Of course, patients with PDD are generally underthe care of movement disorders specialists at the timetheir dementia develops, whereas patients with DLBare usually first referred to geriatric psychiatrists, oftenwith suspected Alzheimer’s disease (AD) as dementiafrequently precedes the onset of parkinsonian features.Hence, despite the fact that the two conditions may be

part of a single disorder, entry into the health care sys-tem frequently differs, and patient support organiza-tions add another element of “identity” to the disorders.Unambiguous diagnostic labels are clearly important.This chapter will concentrate on PDD and DLB as twovery similar conditions and part of a disease spectrum. Itwill consider the clinical features that typify these demen-tias. Where differences exist, or study data are only avail-able for one or the other diagnosis, this will be specified.

The interface between PDD and DLB

PDD refers to dementia developing in the context ofestablished PD. For DLB, dementia is frequently (but notinvariably) the first feature to develop and parkinsonismusually develops (but not always) at a later stage. Theclinical interface between the two is arbitrary and the infa-mous “1 year rule” is frequently invoked for an opera-tional definition [2]. This “rule” states that if extrapyra-midal motor features have been present for 12 months ormore before the onset of dementia, the diagnosis shouldbe PDD, but if dementia precedes the motor features oroccurs within 12 months of the onset of the motor fea-tures, the diagnosis should be DLB. This polarizationbased upon the temporal evolution of clinical features isreasonable in one sense, but ignores the fact that biol-ogy does not work in “straight lines” or “cut-offs” andthere is no reason to think that dementia that begins 11months after the onset of motor features is different to thedementia that begins after a latency of 13 months. Mostclinicians and researchers therefore regard PDD and DLBas a continuum on a spectrum of disorders characterizedby neuronal loss, Lewy-related pathology and synucleindeposition [3]. A useful unifying term for the dementiaassociated with PD and DLB is “Lewy body dementia.”

Parkinson’s Disease: Non-Motor and Non-Dopaminergic Features, First Edition. Edited by C. Warren Olanow, Fabrizio Stocchi, and Anthony E. Lang.c© 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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Clinical Features of Dementia Associated with Parkinson’s Disease and Dementia with Lewy Bodies 135

Unfortunately, “DLB” and “Lewy body dementia” are fre-quently interchanged, leading to further confusion.

Descriptive epidemiology

Prevalence estimates for DLB, depending on case criteria,range from 0 to 5% with regard to the general population,and from 0 to 30.5% of all dementia cases [4]. The onlyestimate for DLB incidence is 0.1% per year for the gen-eral population and 3.2% per year for all new dementiacases [4].

Cognitive deficits are evident even in early PD. Depe-nding upon the neuropsychologic tests used and the cri-teria applied, impairments have been reported in 24–36%of newly diagnosed PD cases [5,6]. People with PD havean increased risk of full-blown dementia of up to six timesthat of age-matched controls [7]. In a systematic review ofprevalence studies of PDD, 24–31% of PD patients havedementia and 3–4% of dementia burden in the popula-tion is due to PDD [8]. The prevalence of PDD in the gen-eral population aged over 65 years has been estimated as0.2–0.5%. Studies providing data for dementia incidencein PD have yielded figures of between 30 and 112 per 1000person-years [9].

A majority of people with PD will develop demen-tia if followed up for long enough. The cumulative inci-dence of dementia steadily increases with age and dura-tion of PD and, conditional on survival, increases to80–90% by age 90 years [10]. At 20 years of follow-up in acohort of patients recruited in Sydney, Australia, 100 of136 (74%) had died, and 83% of the surviving patientswere demented [11]. This high cumulative incidence wasalso suggested by a clinicopathologic study in which80% of PD cases had been reported with dementia ante-mortem [12].

Predicting dementia in PD

Current age, rather than age at onset, is the most impor-tant determinant of dementia risk in PD [13]. Increasingmotor disability is also predictive of dementia and is syn-ergistic with current age [14]. Non-demented PD patientswith a “postural instability–gait difficulty” motor phe-notype show more rapid cognitive decline [15] and thisphenotype is associated with a fourfold increased riskof dementia [9]. One may speculate that these observa-tions relate to increasing cholinergic neuronal loss and/ordysfunction, particularly within the pedunculopontinenucleus, “modulating” the clinical phenotype and simul-taneously producing a range of non-motor problems,including cognitive impairment.

Longer disease duration and male gender have alsobeen associated with increased risk of PDD. Less well-

established risk factors include low educational attain-ment, depression, excessive daytime somnolence, REMsleep behavior disorder, and orthostatic hypotension(OH). A recent study suggested that cerebrovascular riskfactors may not be associated with incident dementiain PD [16]. This finding is somewhat counterintuitiveand, despite this, cigarette smoking prior to disease onsethas been associated with worse cognitive function in PD[17]. Dementia may be associated with weight loss in PD,together with worsening of parkinsonism, age at diagno-sis, and emergence of visual hallucinations, but the pre-dictive value of antecedent weight loss is not known.

Regarding drug effects, anti-cholinergic agents may bea risk factor for PDD, and prolonged use of these agentshas been associated with an increased frequency of cor-tical plaques and tangles in non-demented PD patients[18]. This is biologically plausible since muscarinic M1receptors have been linked with amyloid precursor pro-tein secretion. Poor response to l-dopa and hallucinationson dopaminergic treatment also predict dementia, whilethere is limited evidence from an observational study thatamantadine may delay and attenuate dementia [19]. l-Dopa-induced elevation in plasma homocysteine levelscould contribute towards cognitive failure, although thishas not been confirmed in prospective studies. Visual hal-lucinations in PD predict more rapid cognitive deteriora-tion [20].

Psychosis requiring anti-psychotic therapy has beenassociated with development and progression of demen-tia, while the use of atypical anti-psychotics may haveadverse effects upon disease progression. Deficits in audi-tory verbal learning and non-verbal reasoning, picturecompletion, Stroop interference, and verbal fluency haveall been independently associated with an increased riskof cognitive failure in PD. Two simple bedside tests,pentagon copying and semantic fluency, may also bepredictive of cognitive decline and dementia. There isan association between apathy and cognitive dysfunc-tion, particularly executive impairment, but it is unknownwhether apathy is independently predictive of dementia.

Cognitive features

The neuropsychologic profile of PDD is covered in detailin Chapter 13, so this aspect will therefore be coveredonly briefly here. Suffice it to say that the dementia syn-drome associated with PD is clinically heterogeneous,presumably reflecting a variable underlying pathologicand neurochemical substrate. Executive deficits are, how-ever, common and typical of PDD [6]. These deficits maybe “subclinical” from an early stage in the disease processand only revealed by formal neuropsychologic testing.Subsequently, they become more disruptive, may be asso-ciated with “word finding” problems, and begin to impact



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upon activities of daily living. Impairment in tasks requir-ing initiation, planning, concept formation, rule finding,set shifting, or set maintenance, together with impairedmental processing speed (bradyphrenia), constitutes exec-utive dysfunction. Such an apparent lack of mental flex-ibility, inability to multitask or complete simple or pre-viously familiar tasks, and mental slowness are frustrat-ing to both patients and carers, yet may be overlooked bythe unwary physician and not captured by performing aMini-Mental State Examination (MMSE). The dysexecu-tive syndrome of PDD may be so severe as to dominateneuropsychologic testing at this stage, making the inter-pretation of other tests difficult (for example, by impact-ing upon memory retrieval strategies and the patient’sapproach to pentagon copying) [21]. Notwithstandingthe executive impairment, memory and visuoperceptualdeficits also typify many cases of PDD [22]. Memory prob-lems may arise via disturbance of retrieval rather thanstorage (in contrast with AD), although not all studieshave confirmed this distinction. In the former case, thememory deficit is classically improved by cueing. Impair-ment in spontaneous and focused attention and poor per-formance on attentional tasks constitute another typicalcomponent in the dementia syndrome associated withPD. This may be recognized clinically by brief or moreprolonged “absences,” with the patient staring into space,or appearing to become distracted. Attentional perfor-mance may fluctuate during the day and from day to day,leading to frustratingly variable levels of function and asignificant impact upon activities of daily living [23,24].

Less commonly, the pattern of dementia in PD is sim-ilar to that encountered in AD. The exact frequency ofsuch a phenotype has not been established, although inan incident community-based PD cohort, 8% of cases haddeficits on a pattern recognition task at first assessment,believed to be sensitive to temporal lobe dysfunction [5].It may be speculated that this clinical phenotype is deter-mined by a greater burden of Alzheimer-type pathologyin the medial temporal lobe. In a study of PD to character-ize dementia and its relationship to visual hallucinations,this “AD” dementia phenotype was encountered in only5% of prevalent PDD cases [25].

Regarding DLB, the cognitive profile is also typifiedby marked impairments in visuospatial, attentional, andexecutive function, with relative sparing of memory incomparison with AD [26]. Several studies have comparedthe cognitive profiles of DLB and PDD. No significantdifferences were found, although DLB cases may havegreater executive dysfunction [27]. When assessed usingthe Mattis Dementia Rating Scale, 56 and 55% of patientswith PDD and DLB, respectively, were classified as hav-ing a so-called “subcortical” cognitive profile comparedwith only 33% of patients with AD [28]. Conversely, 30%of patients with PDD and 26% of those with DLB had a“cortical” profile.

In summary, both PDD and DLB are typified bya dysexecutive–visuoperceptual dementia syndrome,although there may be heterogeneity. There is no signif-icant difference in the dementia profile between the twoLewy body dementias, and where differences exist theyare more likely to represent temporal effects rather thanfundamental biological differences.

Neuropsychiatric features

Neuropsychiatric disturbances are extremely common inPDD and DLB. In a study of 537 PDD patients, 89% pre-sented with at least one neuropsychiatric symptom whenassessed using the Neuropsychiatric Inventory, and 77%had two or more symptoms [29]. Hallucinations occurin 45–65% of PDD patients and 60–70% of DLB patients,considerably more commonly than in AD (where typi-cally fewer than 10% are affected). One study has sug-gested that the frequency of visual hallucinations in PDDmay be as high as 87% [25], although this requires confir-mation. Visual hallucinations in the Lewy body demen-tias are at least twice as frequent as auditory hallucina-tions, the majority being complex formed hallucinations.The characteristics of recurrent visual hallucinations aresimilar in PDD and DLB, with phenomenology sug-gesting involvement of dorsal and ventral visual path-ways in their generation [30]. Tactile hallucinations areuncommon. Visual hallucinations, which are commonlypreceded by illusionary phenomena (that is, the misin-terpretation of visual stimuli) may be simple and ill-defined – a feeling that someone is behind the patient(“presence”), or that someone has passed across theirvisual field (“passage”). Subsequently, the hallucinationsbecome more formed and detailed, often in color, static,and centrally located. Both anonymous people and familymembers (living or dead) are common, as are animals. Asinsight is lost, delusional misinterpretation of the halluci-nations may occur. Delusions have a frequency in PDD of25–30% and 55–70% in DLB [27]. Paranoid ideation, suchas spousal infidelity and “phantom boarder” (believingstrangers are living in the house) are common themes.Capras syndrome, characterized by a delusional beliefthat a person has been replaced by an imposter, is alsocommon in the Lewy body dementias, and frequentlyaccompanied by visual hallucinations [31]. In a prospec-tive study of 30 PDD cases, delusional misinterpretationwas found in 16.7% of patients [32]. In common withthe previous study, all of these cases also experiencedvisual hallucinations that were significantly more severethan in PDD cases without delusional misinterpretation.There is some evidence that PDD patients with Caprasand related syndromes have more severe memory andlanguage deficits, possibly implicating greater temporallobe involvement [32].




The frequency of major depression in PDD has beenfound to be 13%, compared with 9% for non-dementedPD patients [33]. Major depression occurs in 19% of DLBcases at presentation, with nearly 50% of patients experi-encing depressive symptoms at some stage of their illness[34]. Both severity of depressed mood and prevalence ofmajor depression may be higher in PDD and DLB than inAD. Anxiety is also common in the Lewy body demen-tias (30–50%) and tends to cluster with depressed mood.Irritability and aggression, common in AD, are not promi-nent features in PDD or DLB. Apathy affects over 50% ofpeople with PDD, and in 70% this may be severe [29].This contrasts with a previously reported frequency of17% for non-demented PD. Demented PD patients are sig-nificantly more likely to underestimate their apathy com-pared with non-demented cases, so an informant assess-ment is important [35].

Motor, sleep, and other neurologicfeatures

Given the predisposition of patients with a “postu-ral instability–gait disorder” phenotype to go on anddevelop dementia in PD, it is not surprising that this phe-notype is over-represented in PDD and DLB comparedwith more standard forms of PD [36]. Although parkin-sonism is common in DLB, it is not invariable, occur-ring in 70–92% of cases during the disease course [37,38].Although some reports have suggested reduced l-doparesponsiveness in PDD patients, this has not been for-mally established, particularly after controlling for con-founders such as subcortical small vessel disease. Nosignificant difference in mean improvement on UPDRSmotor score to a single-dose 200 mg l-dopa challengewas recorded in one study, although more non-dementedpatients experienced greater than 20% improvement com-pared with those with PDD (90% versus 65%) [39].Another study included patients with DLB, PD, and PDDand failed to detect differences in l-dopa responsivenessbetween PD and PDD groups [40]. Approximately one-third of the DLB patients were found to respond to l-dopa, and these tended to be younger than the non-responders. The use of l-dopa did not appear to haveadverse cognitive or neuropsychiatric effects in the DLBcases over 3 months of follow-up [41]. There are insuffi-cient data to infer differences in the occurrence of l-dopa-induced motor complications in PDD and DLB patientscompared with PD, but they might be expected to be lessas PDD patients tend to be older.

Falls are common in the Lewy body dementias andare likely to be multi-factorial in nature, resulting fromnot only cognitive and neuropsychiatric factors, but alsomotor and autonomic impairments. Over one-third ofDLB patients suffer more than 20 falls per year [42].

The risk of gait and balance disorder is higher in non-Alzheimer’s dementia [vascular dementia (VaD), PDD,and DLB] than in an AD (odds ratio = 15, 95% confi-dence interval 6–37) [43]. Moreover, if a gait disorder ispresent in mild dementia, this may be diagnostic of non-Alzheimer’s dementia, with sensitivity of 78% and speci-ficity of 100%.

Electro-oculography has demonstrated that PDD andDLB patients have impairment in both reflexive and com-plex saccades, compared with AD patients who showdeficits only in complex saccades, although such distinc-tions cannot be made on bedside testing [44]. Using theEpworth Sleepiness Scale, 57% of PDD, 50% of DLB,and 41% of PD subjects were classified as having exces-sive daytime somnolence, compared with only 18% ofAD patients and 10% of controls [45]. Furthermore, sleepquality was poorer in PDD, PD, and DLB patients com-pared with AD and normal controls.

Rapid eye movement (REM) sleep behavior disorder(RBD), a common sleep disturbance in neurodegenerativedisorders, is characterized by loss of normal skeletal mus-cle atonia during REM sleep with resultant motor activ-ity and “acting out of dreams” [46]. Behaviors range fromverbal outbursts to pugilistic movements and even moredramatic motor activity. Injuries to bed partners and thepatients themselves are common. Estimates from special-ist centers place the frequency of RBD in DLB at 50–80%[47]. Prospective population-based studies are needed toassess the true incidence and prevalence of RBD in DLB.A recent cross-sectional study of 65 PD patients using theMayo Sleep Questionnaire for RBD determined that 24met the criteria for a clinical diagnosis of RBD. Of the 24patients with RBD, 10 (42%) also met Diagnostic and Sta-tistical Manual (4th edition) (DSM-IV) criteria for PDD.The frequency of RBD was significantly higher in the PDDgroup (77%) compared with the non-demented PD cases(27%) [48]. Cognitive impairment in non-demented PDpatients may also be closely related to the presence ofRBD [49]. Patients with PD and concomitant RBD showsignificantly poorer performance on standardized testsmeasuring episodic verbal memory, executive functions,and visuospatial and visuoperceptual processing as com-pared with PD patients without RBD and control sub-jects. Although suggestive, therefore, prospective studiesare required to confirm whether the occurrence of RBDin PD is an independent risk factor for incident demen-tia. A higher frequency of symptomatic orthostasis hasbeen reported in association with cognitive impairment inPD [50]. In a cross-sectional study of cardiovascular auto-nomic function in PDD, DLB, AD, and VaD, comparedwith elderly controls, significant differences were foundin severity of cardiovascular autonomic dysfunctionbetween the four dementias [51]. PDD and DLB groupshad considerable impairment, whereas the VaD groupshowed limited evidence of autonomic dysfunction



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and in AD, apart from orthostatic hypotension, auto-nomic function was relatively normal. The PDD patientsshowed consistent impairment of both parasympatheticand sympathetic function tests in comparison with con-trols and AD. Moreover, higher autonomic symptomscores in PDD are associated with poorer outcomes inall measures of physical activity, activities of daily living,depression, and quality-of-life [52].

Urologic symptoms and urodynamic abnormalities arevery common in DLB and result not only from demen-tia and immobility but also from central and peripheralsomato-autonomic dysfunction [53]. Urgency and urgeincontinence, suggesting detrusor overactivity, are morefrequent in DLB cases compared with AD, with up to90% of DLB patients being affected [54]. This may relateto greater subcortical pathology in DLB, leading to disin-hibition of pontine micturition centers. In common withPD, anosmia is frequent in DLB [55]. Adding anosmia asa core feature to diagnostic criteria improved sensitivityfor detecting DLB, but did not improve discriminationbetween AD and DLB owing to a concomitant increasein false positives.

Diagnosis of PDD and DLB

Usually, when dementia develops in the context of well-established PD, there is no doubt about the diagnosis. Incertain situations, for example a new referral where thetemporal sequence of events is unclear, there is signifi-cant co-morbid illness, or when the clinical course is atyp-ical (e.g., a rapid onset of confusion), the differential mayinclude DLB (since a distinction is usually expected in theclinic), vascular parkinsonism, AD with or without drug-induced parkinsonism, delirium, and depressive pseudo-dementia or other coincidental causes of dementia. Manyof these conditions are excluded by taking a careful collat-eral history, blood tests, structural (e.g., computed tomog-raphy) and functional (e.g., dopamine transporter) imag-ing. In one recent clinicopathologic study, features thatdistinguished PDD from AD included cognitive fluctua-tions, but also several neuropsychiatric features, includ-ing visual and auditory hallucinations, depression, andsleep disturbance [12]. Mild depression or dysthymia haslittle, if any, impact on cognition in PD, whereas signif-icant depression appears to impair executive functionsand memory [56].

Diagnostic criteria for PDDUntil recently, there were no disease-specific diagnosticcriteria for PDD. As mentioned above, reliance upon asingle MMSE score less than the traditional value of 24out of 30 is insensitive because this instrument is heavilybiased towards mnemonic deficits and does not include

robust measures of executive function. Hence PD patientsmay still be demented with scores above this cut-off.Furthermore, as described above, variability in sponta-neous and focused attention may mean that at the timeof assessment, “spuriously” high or low scores may beobtained that are not representative of day-to-day impair-ment. DSM-IV criteria subsume PDD under “dementiadue to other medical conditions,” and the section fails tocapture the spectrum of cognitive and neuropsychiatricproblems associated with this disorder.

New diagnostic criteria for PDD, produced by a TaskForce commissioned by the Movement Disorder Soci-ety, have recently been proposed [21] (Boxes 12.1 and12.2). These criteria were developed through a com-prehensive literature review in which the characteris-tic cognitive, behavioral, motor and other features ofPDD were defined. On the basis of this review, fourgroups of features were derived (Box 12.1). Two levelsof certainty (probable or possible PDD) were then sug-gested, based upon the presence and/or absence of thesefeatures (Box 12.2). The diagnosis of PD, according toQueen Square Brain Bank criteria, before the develop-ment of dementia symptoms is an essential first step inthe process. The diagnosis of dementia must be basedon the presence of deficits in two or more of the fourcore cognitive domains (attention, memory, executive,and visuospatial functions) and should be severe enoughto impact upon normal daily activities, independent ofthe influence of motor and other impairments. Neu-ropsychiatric and behavioral symptoms are frequent inPDD, but are not invariable, and this is reflected in thecriteria.

In a second paper, also commissioned by the MovementDisorder Society, practical guidelines were provided as tohow the diagnostic criteria might be operationalized [57].These guidelines offer two diagnostic levels, dependingupon the clinical scenario and the expertise of the eval-uator. The level I assessment is aimed primarily at theclinician with no particular expertise in neuropsychologicmethods, but who requires a simple, pragmatic set of teststhat are not excessively time consuming (Box 12.3). Thus,in addition to a clinical history and caregiver account, theMMSE [58], supplemented by a clock drawing test andthe four-item Neuropsychiatric Inventory [59], are suffi-cient to complete a level I assessment. Fluctuating atten-tion, which, as described above, is a dominant factor indetermining disability in PDD, is examined by asking thepatient to give the months of the year backwards, startingfrom December, or by repeatedly subtracting 7, startingat 100. It remains to be determined whether these testsare sufficiently sensitive to detect this feature, or whetheradditional instruments such as the “Ferman four-itemtest,” which has been shown to be highly sensitive fordiscriminating DLB from AD, may also be necessary [60].




Box 12.1 Features of dementia associated with Parkinson’s disease [21]

I. Core features1) Diagnosis of PD according to Queen Square Brain Bank criteria2) A dementia syndrome with insidious onset and slow progression, developing within the context of established PD and

diagnosed by history, clinical and mental examination, defined as:– Impairment in more than one cognitive domain– Representing a decline from pre-morbid level– Deficits severe enough to impair daily life (social, occupational or personal care), independent of the impairment

ascribable to motor or autonomic symptoms

II. Associated clinical features

1) Cognitive features:

– Attention: Impaired. Impairment in spontaneous and focused attention, poor performance in attentional tasks;performance may fluctuate during the day and from day to day

– Executive functions: Impaired. Impairment in tasks requiring initiation, planning, concept formation, rule finding, setshifting or set maintenance; impaired mental speed (bradyphrenia)

– Visuospatial functions: Impaired. Impairment in tasks requiring visual-spatial orientation, perception or construction– Memory: Impaired. Impairment in free recall of recent events or in tasks requiring learning new material, memory

usually improves with cueing, recognition is usually better than free recall– Language: Core functions largely preserved. Word finding difficulties and impaired comprehension of complex

sentences may be present

2) Behavioral features:

– Apathy: decreased spontaneity; loss of motivation, interest and effortful behavior– Changes in personality and mood including depressive features and anxiety– Hallucinations: mostly visual, usually complex, formed visions of people, animals or objects– Delusions: usually paranoid, such as infidelity, or phantom boarder (unwelcome guests living in the home)

delusions– Excessive daytime sleepiness

III. Features which do not exclude PD-D, but make the diagnosis uncertain

1) Co-existence of any other abnormality, which may by itself cause cognitive impairment, but judged not to be the cause ofdementia, e.g., presence of relevant vascular disease in imaging

2) Time interval between the development of motor and cognitive symptoms not known

IV. Features suggesting other diseases as cause of mental impairment, which when present make it impossible to diagnosePD-D reliably1) Cognitive and behavioral symptoms appearing solely in the context of other conditions such as acute confusion due to:

– systemic diseases or abnormalities– drug intoxication– major depression according to DSM IV

2) Features compatible with “probable vascular dementia” criteria according to NINDS-AIREN (dementia in the context ofcerebrovascular disease as indicated by focal signs in neurologic examination such as hemiparesis, sensory deficits, andevidence of relevant cerebrovascular disease by brain imaging and a relationship between the two as indicated by thepresence of one or more of the following: onset of dementia within 3 months after a recognized stroke, abruptdeterioration in cognitive functions, and fluctuating, stepwise progression of cognitive deficits)

The four questions in the Ferman instrument are admin-istered to the caregiver and comprise: Does the patientexperience excessive daytime sleepiness? Does the patientsleep for more than 2 hours during the day? Are theretimes when his/her words occasionally come out jumbledup? Does the patient sometimes stare into space for peri-ods of time? Informant endorsement of three out of fourof these items has been shown to have a positive predic-

tive value of 83% for diagnosis of DLB versus AD [60],but the sensitivity of the instrument in detecting fluctuat-ing attention in PDD is not yet known.

The level I assessment can be used alone or in combina-tion with level II, which is better suited to the case whenthere is the need to specify the pattern and the severity ofdementia associated with PD [57]. The level II assessmentis appropriate for detailed clinical monitoring, research



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Box 12.2 Criteria for the diagnosis ofprobable and possible PD-D [21]

Probable PDD

A Core features: both must be present

B Associated clinical features:Typical profile of cognitive deficits includingimpairment in at least two of the four core cognitivedomains (impaired attention which may fluctuate,impaired executive functions, impairment invisuospatial functions and impaired free recall memorywhich usually improves with cueing).The presence of at least one behavioral symptom(apathy, depressed or anxious mood, hallucinations,delusions, excessive daytime sleepiness) supports thediagnosis of Probable PDD; the lack of behavioralsymptoms, however, does not exclude the diagnosis

C None of the group III criteria present

D None of the group IV criteria present

Possible PDD

A Core features: both must be present

B Associated clinical features:Atypical profile of cognitive impairment in one or moredomains, such as prominent or receptive-type (fluent)aphasia, or pure storage-failure type amnesia (memorydoes not improve with cueing or in recognition tasks)with preserved attention.Behavioral symptoms may or may not be presentOR

C One or more of the group III criteria present

D None of the group IV criteria present

studies, or pharmacologic trials. It requires neuropsycho-logic expertise and is much more time consuming thanlevel I assessment.

Both the diagnostic criteria and the accompanyingdiagnostic procedures need to be validated in carefullyconducted, prospective studies, preferably with patho-logic confirmation of diagnosis. It is almost inevitable thatthey will require refinement, but at least represent a solidattempt at deriving “disease-specific” criteria for definingthe dementia syndrome associated with PD, with prac-tical suggestions for their application in routine clinicaluse.

Diagnostic criteria for DLBConsensus clinical diagnostic criteria were first publishedin 1996 and were updated in 1999 and, most recently,in 2005 (Box 12.4). The central feature of DLB is char-acterized as a progressive dementia in which episodic

Box 12.3 Guidelines for diagnosis of PDD atlevel I [57]

1 A diagnosis of PD based on the Queen’s Square BrainBank criteria

2 PD developed prior to the onset of dementia

3 MMSE score below 26

4 Cognitive deficits severe enough to impact upon dailyliving (elicited via caregiver interview or “PillQuestionnaire”a)

5 Impairment in at least two of the following cognitivedomains:– months reversed or subtract seven backwards– lexical fluency or clock drawing– MMSE pentagons– MMSE three-word recall– The presence of one of the following behavioral

symptoms: apathy or depressed mood or delusions orexcessive daytime sleepiness supports the diagnosisof probable PDDb

– The presence of major depression or delirium or anyother abnormality which may by itself causesignificant cognitive impairment makes the diagnosisuncertainc

a This item, described in an Appendix in reference 50,requires validation. In brief, the patient is asked to describeverbally their treatment and its time schedule. Even if thepatient does not manage their own treatment, it is sug-gested that they have lost at least a part of their autonomy ifthey can no longer describe their treatment. The criterion ofimpairment is met if the patient is no longer able to explaintheir daily PD medication, or if errors are made that areconsidered clinically significant.bThese can be assessed with the four-item NeuropsychiatricInventory [52], which includes hallucinations, depression,delusions, and apathy. A cut-off score of ≥3 for each itemis proposed. Excessive daytime sleepiness may be assessedby specific questions.cShould be absent to permit diagnosis of “Probable” PDD.

memory impairment is often minimal in the early stages,whereas attentional, executive, and visuospatial deficitsmay be disproportionately prominent [2,61,62]. The pres-ence of two or more of three core clinical features(fluctuating attention and alertness, recurrent visual hal-lucinations, parkinsonism), together with the variablepresence of suggestive or supportive features, indicatesprobable DLB. This, of course, means that the presence ofparkinsonism is not necessary for the diagnosis of DLB.In addition, the criteria refer to “spontaneous features”of parkinsonism to differentiate drug-induced (mostcommonly the use of neuroleptics) from degenerativeparkinsonism.




Box 12.4 Revised criteria for the clinical diagnosis of DLB [2]

1 Central feature (essential for a diagnosis of possible or probable DLB)Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupationalfunction. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evidentwith progression. Deficits on tests of attention, executive function, and visuospatial ability may be especially prominent.

2 Core features (two core features are sufficient for a diagnosis of probable DLB, one for possible DLB)Fluctuating cognition with pronounced variations in attention and alertnessRecurrent visual hallucinations that are typically well formed and detailedSpontaneous features of parkinsonism

3 Suggestive features (if one or more of these is present in the presence of one or more core features, a diagnosis of probable DLB can bemade. In the absence of any core features, one or more suggestive features is sufficient for possible DLB. Probable DLB should not bediagnosed on the basis of suggestive features alone)REM sleep behavior disorderSevere neuroleptic sensitivityLow dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging

4 Supportive features (commonly present but not proven to have diagnostic specificity)Repeated falls and syncopeTransient, unexplained loss of consciousnessSevere autonomic dysfunction, e.g., orthostatic hypotension, urinary incontinenceHallucinations in other modalitiesSystematized delusionsDepressionRelative preservation of medial temporal lobe structures on CT/MRI scanGeneralized low uptake on SPECT/PET perfusion scan with reduced occipital activityAbnormal (low uptake) MIBG myocardial scintigraphyProminent slow wave activity on EEG with temporal lobe transient sharp waves

5 A diagnosis of DLB is less likelyIn the presence of cerebrovascular disease evident as focal neurologic signs or on brain imagingIn the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical pictureIf parkinsonism only appears for the first time at a stage of severe dementia

6 Temporal sequence of symptomsDLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). The termParkinson’s disease dementia (PDD) should be used to describe dementia that occurs in the context of well-establishedparkinsonian disease. In a practice setting, the term that is most appropriate to the clinical situation should be used andgeneric terms such as LB disease are often helpful. In research studies in which a distinction needs to be made between DLBand PDD, the existing 1 year rule between the onset of dementia and parkinsonism DLB continues to be recommended.Adoption of other time periods will simply confound data pooling or comparison between studies. In other research settingsthat may include clinicopathologic studies and clinical trials, both clinical phenotypes may be considered collectively undercategories such as LB disease or α-synucleinopathy.

“Suggestive features” now included in the criteriaare RBD, severe neuroleptic sensitivity, and abnormaldopamine uptake on single photon emission computedtomography (SPECT) or positron emission tomography(PET) imaging. These have a similar diagnostic weightingas the core features but require further validation beforebeing considered sufficient for a diagnosis of probableDLB without the presence of core features. Features listedin Box 12.4 and considered as supportive of a diagnosisof DLB lack specificity because they may also occur in avariety of other disorders.

When DLB presents as a primary dementia syndrome,the main differential diagnoses are AD, VaD, delirium

secondary to systemic or pharmacologic toxicity, priondisease, or other neurodegenerative syndromes. Whenapplied correctly, consensus guidelines for the clinicaldiagnosis of DLB have prospective diagnostic accuracyat least as good as those for AD. One of the main rea-sons for reduced sensitivity in the diagnosis of DLB isthe failure to enquire about, or elicit, fluctuations in atten-tion. The discriminating value of the diagnostic criteria isgreatest in the early stages, suggesting that DLB shouldbe considered in any new dementia presentation [63]. Theinability of moderately impaired DLB patients to copypentagons accurately has been reported to have a sensi-tivity of 88% and a specificity of 59% compared with AD,



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suggesting this as a useful screening test [64]. The bestmodel for differentiating DLB from AD in the earliest dis-ease stages may include visual hallucinations and visu-ospatial/constructional dysfunction, but not spontaneousextrapyramidal signs, as predictors [65].

The degree of concomitant Alzheimer tangle pathologyhas a major influence upon diagnostic accuracy for DLB.Thus, the greater the “Alzheimerization” of the DLB case,the less likely it is that the final clinical diagnosis will becorrect [66]. In DLB patients with a low neurofibrillarytangle burden, visual hallucinations occurred in 65% ofcases, compared with only 33% of those cases with hightangle counts in one study [66]. Not surprisingly, diag-nostic accuracy was therefore greater in the low tangleburden cases (75%) compared with high neurofibrillarytangle load cases (39%).

Natural history and determinantsof prognosis

Overall, women live with PD longer than men and spendmore years with dementia [10]. In a recent register-basedstudy of 10 347 PD subjects with a mean age of 77 yearsreceiving dopaminergic agents, 35% had required an anti-psychotic drug by 7 years into their disease [67]. In turn,psychosis (and visual hallucinations in particular) fre-quently progresses to dementia over a 2 year period [68].Using data from a population-based study in Norwayand 12 years of follow-up, progression from PD to PDDand death has been modeled, using a three-state irre-versible Markov model [10]. From this model, for exam-ple, it may be predicted that at age 70 years, a man withPD but no dementia has a life expectancy of 8 years,of which 5 years would be expected to be dementiafree and 3 years would be expected to be with demen-tia. A mean annual rate of decline of 2.3 MMSE pointshas been reported for PDD once it has developed [69].Visual hallucinations in PDD predict more rapid cognitivedeterioration [20].

Rate of progression for DLB, as evidenced by changein global cognitive measures such as the MMSE or Cam-bridge Cognitive Examination (CAMCOG), is equivalentto or faster than that seen in AD and VaD, with a declineof 4–5 MMSE points per year [70–72]. The neuropsy-chologic changes as DLB progresses are not well char-acterized, although differences from AD are more pro-nounced in the early stages and lessen as the dementiaprogresses.

A retrospective study of 243 autopsy-confirmed Lewybody (predominantly DLB) dementia cases found amedian survival of 5 years from symptom onset [73].Older age at disease onset, fluctuating cognition, andvisual hallucinations predicted shorter survival. Interest-ingly, after adjusting for the presence of age, gender, and

Alzheimer-type pathology, fluctuating cognition at symp-tom onset was identified as the best predictor of a pooroutcome.

Future directions

The Lewy body dementias represent a vigorous researcharea at present, particularly as we strive to discoverbetter symptomatic treatments and, ultimately, disease-modifying strategies. There is more work to be doneto validate clinical diagnostic criteria for PDD, prefer-ably through longitudinal clinicopathologic studies. Suchstudies will also help to determine the pathologic andneurochemical basis for phenotypic variability in PDDand DLB. The development of functional imaging tech-niques utilizing ligands such as PIB which binds β-amyloid with high affinity, also offers the possibility ofdetermining in vivo the correlates of clinical features withthe burden and topography of pathologic protein aggre-gation. Fluctuating attention, which is such a key symp-tom in determining the patient’s ability to perform activ-ities of daily living, yet which is often overlooked in theclinical assessment, requires further study, especially invalidating simple clinical instruments for its detection.Although current age is probably a dominant factor indetermining risk for dementia in PD, it should be possibleto derive better predictive models for this complication,thus identifying patient groups at high risk and suitablefor putative dementia-modifying approaches at an earlystage.

Conclusion

Both PDD and DLB have come to the attention of the med-ical community in recent years. With regard to PDD, thefrequency of dementia in PD is far higher than was previ-ously imagined. In part, this relates to the secular trend foran increasingly aged society, but also the fact that demen-tia is now being systematically considered in the contextof PD and not being dismissed as “co-existing AD.” ForDLB, the main battleground has been differentiating thesyndrome from AD, and it is now accepted that there aremajor clinical differences, largely dependent upon under-lying α-synuclein pathology and strategic cell loss. Fur-thermore, as the worlds of the geriatric psychiatrist andneurologist have collided, the clinical similarities betweenthe two Lewy body dementias have become apparent. It isno longer helpful to defend jealously our respective lamp-posts, as collaborative working and patient managementwill pay far greater dividends. It is therefore time to sharethe same kennel!




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Parkinson's Disease (Non-Motor and Non-Dopaminergic Features) || Clinical Features of Dementia Associated with Parkinson's Disease and Dementia with Lewy Bodies