Parkinson Disease Neuropathology: Later

ORIGINAL CONTRIBUTION Parkinson Disease Neuropathology Later-Developing Dementia and Loss of the Levodopa Response

Hulya Apaydin, MD; J. Eric Ahlskog, PhD, MD; Joseph E. Parisi, MD; Bradley F. Boeve, MD; Dennis W. Dickson, MD

Objective: To investigate the neuropathologic sub- and limbic areas compared with PD patients without de- strate for dementia occurring late in Parkinson disease mentia (PՅ.002). Alzheimer pathology was modest. Only (PD). one patient met the criteria defined by the National In- stitute on Aging and the Reagan Institute Working Group Design: We identified 13 patients with a clinical diag- on the Diagnostic Criteria for the Neuropathologic As- nosis of PD who experienced dementia at least 4 years sessment of Alzheimer’s Disease for “intermediate prob- after parkinsonism onset (mean, 10.5 years) and subse- ability of Alzheimer’s disease.” There were, however, sig- quently underwent postmortem examination. Despite le- nificant correlations between neocortical Lewy body vodopa therapy, 9 patients later became severely im- counts and senile plaques as well as neurofibrillary tangles. paired and nonambulatory, requiring total or near-total Senile plaque counts did not significantly correlate with care; this included 4 patients treated with 1200 mg/d or tangle counts in any of the analyzed nuclei. Arteriolar more of levodopa (with carbidopa), which was consis- disease may have contributed to the clinical picture in 2 tent with loss of the levodopa response. These 13 pa- patients. tients were compared with 9 patients clinically diagnosed as having PD, but without dementia, who had Conclusions: Diffuse or transitional Lewy body dis- undergone autopsies. ease is the primary pathologic substrate for dementia developing later in PD. This same pathologic substrate Results: Twelve of 13 PD patients with dementia had seemed to account for end-stage, levodopa refractory par- findings of diffuse or transitional Lewy body disease as kinsonism. The occurrence of Alzheimer pathology was the primary pathologic substrate for dementia; 1 had pro- modest, but was highly correlated with Lewy body pa- gressive supranuclear palsy. This pathology also appar- thology, suggesting common origins or one triggering the ently accounted for the levodopa refractory state. Among other. the 12 PD patients with dementia, mean and median Lewy body counts were increased nearly 10-fold in neocortex Arch Neurol. 2002;59:102-112

DIOPATHIC Parkinson disease (PD) (Table 1).1-7 However, this range likely un- is a progressive neurodegenera- derestimates the problem. Patients with de- tive disease of undetermined cause mentia are less likely to be referred to or fol- with characteristic motor find- lowed up in PD clinics. In community-based ings that include rest tremor, ri- studies, prevalence figures are a little higher, Igidity, bradykinesia, and postural distur- ranging from 12% to 41% (Table 18-12), but bance. Degeneration of the substantia nigra these numbers too may underestimate the pars compacta is the primary anatomic sub- magnitude of this problem. By definition, strate for the motor symptoms; micro- prevalence studies ascertain cases at a single scopic Lewy bodies within this nucleus are point in time. Dementia may lead to nurs- From the Department of the pathologic hallmark. ing home placement and earlier death; these Neurology, Istanbul University, Dementia may complicate PD after patients will not be counted in subsequent Cerrahpas¸a Medical School, years of an otherwise typical course. This prevalenceanalyses.AmongPDpatientswho Istanbul, Turkey (Dr Apaydin); problem may overshadow the motor as- do not initially experience dementia, the Departments of Neurology pects of parkinsonism and become the pri- yearly incidence of dementia ranges from (Drs Ahlskog and Boeve) and 6,11,13-18 Pathology (Dr Parisi), Mayo mary source of disability. In PD, dementia 2.6% to 9.5% (Table 1 ). Thus, if PD Clinic, Rochester, Minn; and is not a presenting feature, but is common patients live long enough, the risk is substan- Department of Pathology, Mayo later in the disease course. The frequency tial. One series estimated that the cumula- Clinic, Jacksonville, Fla of dementia among patients from clinic- tive risk of dementia among PD patients by (Dr Dickson). hospital cohorts ranges from 6% to 29% the age of 85 years was more than 65%.14

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 METHODS cortex, nucleus basalis of Meynert, amygdala, entorhinal cortex, hippocampus, thalamus, and multiple brainstem nuclei, including substantia nigra and locus coeruleus. Mi- From the Mayo Health Sciences Research Database, we iden- croscopic sections were stained with hematoxylin-eosin, tified all patients undergoing autopsy between 1976 and modified Bielschowsky and thioflavin S stains, and immu- 1997 with diagnoses in life of PD and dementia. All clini- nohistochemical stains for ␣-synuclein (polyclonal58) and cal histories were reviewed to identify those who met the tau (monoclonal, PHF-1; Peter Davies, PhD, Albert Ein- following criteria: (1) clinical picture of idiopathic PD with- stein College of Medicine, Bronx, NY). Microscopic fea- out features that suggest another parkinsonian disorder; (2) tures of these sections were evaluated independently by 2 an initially favorable response to levodopa therapy, if ad- observers (J.E.P. and D.W.D.). Although attempts were made ministered; and (3) dementia developing at least 4 years to mask these observers to the clinical information, this was after PD motor symptom onset. Initially, we selected 5 years not consistently possible. Assessment of AD-type patho- as the minimum criterion interval between PD motor symp- logic features included determination of Consortium to tom onset and dementia; however, because of the small num- Establish a Registry for Alzheimer’s Disease (CERAD)59 ber of patients, we reduced this to 4 years (adding 2 patients). neuritic plaque scores and Braak and Braak staging.60 Parkinsonism onset was dated from the time the initial symp- The National Institute on Aging and the Reagan Institute toms were experienced by the patient. Onset of dementia Working Group on the Diagnostic Criteria for the Neuro- corresponded to the date when cognitive impairment was pathologic Assessment of Alzheimer’s Disease (NIA- first noted. To qualify as PD, all patients were required to Reagan) diagnostic criteria were used for the diagnosis of have at least 2 of the 3 cardinal PD motor symptoms (ri- AD.61 Criteria for the pathologic diagnosis of Lewy body gidity, rest tremor, and bradykinesia) and have been diag- dementia were from the Consortium on Dementia With nosed as having PD by a Mayo Clinic physician. To qualify Lewy Bodies.41 as having dementia, patients fulfilled criteria for dementia Quantitative analyses included counts of Lewy bod- according to the Diagnostic and Statistical Manual of Men- ies, senile plaques, and neurofibrillary tangles (ϫ200 mi- tal Disorders, Revised Third Edition55 as documented in the croscopic field) in brain regions from patients with and with- medical histories. out dementia. Lewy body counts were performed in the From the same Mayo database, we identified all PD substantia nigra, neocortex, limbic cortex, amygdala, and patients undergoing autopsy between 1976 and 1997 who nucleus basalis of Meynert. Senile plaques and neurofibril- met criteria for absence of dementia and for whom ad- lary tangles were counted in the neocortex, the CA1 re- equate brain tissue specimens were available for analysis. gion of the hippocampus, and the entorhinal cortex with Criteria for PD were the same as in the group with demen- thioflavin S fluorescent microscopy using an Olympus BH2 tia. Nondementia status within the last year of life was docu- microscope (Olympus America Inc, Melville, NY) with a mented by fulfilling 1 of 2 criteria: (1) achieving a score 490-nm bandpass filter. that was within normal limits on the Mini-Mental State Ex- Statistical analyses were performed using JMP com- amination,56 Short Test of Mental Status,57 or formal psy- puter software (JMP Software, version 4.0.4; SAS Institute chometric examinations or (2) having been seen within a Inc, Cary, NC).62 t Tests were used for comparison of the year of death at least twice by Mayo Clinic physicians and clinical demographic data between groups. Preliminary having medical records that documented the clinical im- analyses (Shapiro-Wilks W test) indicated that much of the pression of no dementia. These patients served as the con- pathologic data were not normally distributed, and hence, trol group. Both the patients with and without dementia nonparametric statistical tests were used for these assess- were selected without knowledge of the patient’s neuro- ments. Comparisons between groups were by Wilcoxon rank pathologic condition. sum test or, where appropriate, ␹2 analysis. Spearman rank Brain areas examined included multiple neocortical order statistics were used for correlative assessments. regions (frontal, parietal, and calcarine), anterior cingulate PϽ.05 was considered statistically significant.

The neuropathologic substrate for the dementia that ing concurrently with parkinsonism plus other charac- develops in PD patients has been debated. In the last quar- teristic features (including hallucinations and cognitive ter of the 20th century, more than 20 investigations ad- fluctuations) is now recognized to typically represent de- dressed this issue (Table 2).19-40 Among these publica- mentia with Lewy bodies.41,42 Clinical parkinsonism may tions, there has been no consensus whether this dementia also complicate AD, in which case the dementia is promi- is primarily a cortical or subcortical process or whether nent early in the disease course.43-47 Alzheimer disease (AD) or Lewy body disease is the pri- The uncertainties regarding the neuropathologic sub- mary contributor. In some patients, the pathologic cause strate for dementia that complicates PD may also relate to for dementia was not apparent. Clinical heterogeneity may histologic techniques. Lewy bodies (especially cortical) and explain some of this lack of consensus. In most series, other cellular inclusions were underestimated based on mi- clinical details were sparse, including the temporal re- croscopy with the older hematoxylin-eosin and silver im- lationship between parkinsonism and dementia (Table pregnation techniques. With the application of ubiquitin 2). Some of these series may have included patients in immunohistochemical analysis, these were more easily whom the dementia was a presenting symptom. Early de- identified.48,49 Recently, ␣-synuclein immunohistochemi- mentia may have an entirely different pathologic basis cal analysis was recognized to be a much more sensitive than dementia developing several years after the onset and specific technique for identifying Lewy bodies and dis- of levodopa-responsive PD. In fact, dementia develop- tinguishing these from other cellular inclusions.50,51 The

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Frequency, Prevalence, and Incidence of Dementia Among Patients With Parkinson Disease (PD)*

Incidence Prevalence in Initially Among PD Nondemented Frequency Patients in PD Cohort Relative Risk No. of PD in PD Community-Based (Incidence Compared Source, y Patients Design Patient Cohort, % Study, % per Year) With Controls Brown and . . . Meta-analysis, studies up 25 (Authors thought ...... Marsden,1 1984 to 1984, prevalence or this was frequency overestimate) Taylor et al,2 1985 100 Cohort from clinic 8-15 ...... Elizan et al,3 1986 203 Cohort from clinic 29 ...... Girotti et al,4 1988 147 Cohort from clinic 14 ...... Mayeux et al,5 1988 339 Hospital-clinic cohort 11 (Later corrected ...... to 16) Biggins et al,6 1992 87 Cohort in clinic, initially Initially 6; after . . . 12 Throughout ... and after 54 months 54 months, 19 54 months (2.7 per year) Friedman and 88 Cohort in clinic 22 ...... Barcikowska,7 1994 Sutcliffe et al,8 1985 226 Community based . . . 12 ...... Mayeux et al,9 1992 179 Community based . . . 41 ...... Tison et al,10 1995 60 Random sampling of ... 18 ... 4.6 community Marder et al,11 1995 279 Community based; . . . 37 19 Throughout 1.7 prevalence initially; 2 years incidence was among (9.5 per year) nondemented patients followed up for 2 years Aarsland et al,12 242 Community based . . . 28 ...... 1996 Rajput et al,13 1987 103 Community based, ...... 21 Throughout 3.7 cumulative probability of 5 years, developing dementia by Kaplan-Meier 5 years after initial PD analysis diagnosis (4.2 per year) Mayeux et al,14 1990 249 Hospital-clinic cohort of ...... 26 Throughout ... initially nondemented 57 months patients followed up for (5.5 per year) 57 months Mahieux et al,15 81 Initially nondemented cohort ...... 23 Throughout ... 1998 in clinic followed up for 3.5 years 3.5 years (6.6 per year) Hughes et al,16 2000 83 Initially nondemented cohort ...... 38 Throughout ... from clinic followed up for 122 months, 122 months Kaplan-Meier analysis (3.7 per year) Aarsland et al,17 171 Community based, following ...... 33 Throughout 5.9 2001 up nondemented PD 4 years patients (n = 130 after (8.3 per year) 4 years) Breteler et al,18 1995 . . . Data from nationwide ...... 3.0 morbidity registers, cumulative incidence throughout 8 years after index date

*Ellipses indicate no relevant study data.

studies presented in Table 2 were performed before sonism preceded dementia by at least 4 years and (2) the ␣-synuclein immunohistochemical testing was available. histologic techniques included ␣-synuclein immunohis- We were interested in a specific subset of patients tochemical analysis. A preliminary report of our find- whom we commonly see in our PD clinics—those with ings has been published, documenting diffuse or transi- typical early PD who later experience dementia. We an- tional Lewy body disease as the primary substrate for the ticipated that the neuropathologic basis for this demen- dementia in all but one of these patients (the exception tia should be apparent and may be fairly uniform if (1) having progressive supranuclear palsy).52 Hurtig et al53 we restricted our PD patients to those in whom parkin- and Mattila et al54 have also reported similar findings.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Clinicopathologic Studies of Dementia Occurring in PD Before ␣-Synuclein Immunohistochemical Analysis*

No. of PD Patients Interval From Initial Conditions Causing With Parkinsonism to Levodopa or Associated Source, y Dementia Dementia, y Responsiveness Pathologic Findings With PD Dementia Hakim and 19 Dementia after ? Alzheimer changes in both demented and Concurrent Alzheimer disease Mathieson,19 1979 parkinsonism in nondemented PD (not distinguishable only 4 of 19 patients on that ground) Boller et al,20 1980 16 Ͻ2, 4 Patients; ? Alzheimer disease in all 9 with severe Cortical Alzheimer changes unclear, 6 patients; dementia and 3 of 7 with mild Ͼ2, 6 patients dementia Mann and Yates,21 3 ? ? Reduced cell counts, compared with Degeneration of noradrenergic 1983 nondemented PD, in LC, NBM, and cholinergic systems supraoptic nucleus, and paraventricular nucleus of hypothalamus; no Alzheimer changes Whitehouse et al,22 5 ? ? Loss of NBM neurons NBM degeneration 1983 Gaspar and Gray,23 18 7.5 ? No cortical Lewy bodies in any patient; Cortical Alzheimer changes; 1984 among demented, cortical Alzheimer neuronal loss, NBM, and LC changes, cell loss in NBM and LC were more pronounced, but overlap with nondemented patients Perry et al,24 1985 10 ? ? In contrast to nondemented PD and NBM degeneration Alzheimer disease, all with marked reductions of NBM cell counts; all had reduced choline acetyltransferase in cortex; Alzheimer changes in 3 of 10 Chui et al,25 1986 4 3-18 ? Three fourths had no evidence of Subcortical degeneration (NBM, Alzheimer changes but Lewy body LC, SN); no cortical or degenerative changes in SN, LC, and hippocampal plaques or NBM; other patient had tangles but no tangles Lewy bodies in hippocampus and subcortical nuclei Jellinger,26 1987 104 ? ? Severity of dementia correlates with Different conditions: (1) Alzheimer changes in majority but concurrent Alzheimer changes; not all; demented had much greater (2) primarily NBM cell loss in NBM degeneration; (3) degeneration in LC, dopaminergic ventral tegmentum, raphe; (4) rarely, Alzheimer plus diffuse Lewy body disease Yoshimura,27 1988 37 ? ? 65% explained by Alzheimer changes, Multiple contributors, including but these patients also had cortical degeneration in NBM, LC, Lewy bodies; 22% no obvious cause mesolimbic system, plus although greater NBM degeneration; Alzheimer disease 14% with vascular and “senile” changes Rinne et al,28 1989 11 ? ? Dementia correlated with neuronal loss Medial nigral degeneration in medial SN Braak and Braak,29 10 ? ? Abundant cortical amyloid plaques Localized entorhinal 1990 but without cortical neurofibrillary neurofibrillary changes changes; localized tangles in layer (suggest possible pre-␣ of entorhinal cortex disconnection of isocortex from hippocampus); Alzheimer disease not otherwise present in cortex

(continued)

RESULTS mainder had dementia documented early in the disease course). From the cohort of 162 PD patients who had DEMOGRAPHICS AND PRETERMINAL undergone autopsy, we included all 9 who met criteria CLINICAL CHARACTERISTICS for absence of dementia (5 men, 4 women). Mayo Clinic neurologists were involved in the diagnosis and care of From the Mayo database, 162 PD patients were identi- all patients except for a single PD patient without de- fied who had undergone autopsy between 1976 and 1997. mentia who had rest tremor–predominant PD. As given Dementia had been coded in 64 of these patients. Of these, in Table 3, there was a trend toward earlier onset of par- 13 patients (6 men, 7 women) met the inclusion criteria kinsonism in the group with dementia, whereas the age for PD with later-developing dementia (most of the re- at death was similar. Parkinsonism duration was signifi-

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No. of PD Patients Interval From Initial Conditions Causing With Parkinsonism to Levodopa or Associated Source, y Dementia Dementia, y Responsiveness Pathologic Findings With PD Dementia Xuereb et al,30 1990 17 ? ? 14 of 17 with no cortical disease Subcortical disease (Lewy bodies or Alzheimer changes) Zweig et al,31 1993 7 ? ? Neuronal loss in LC, ventral tegmental Degenerative changes within area, NBM, and medial SN (excluded multiple subcortical areas cases with Alzheimer disease) Duyckaerts et al,32 1993 10 ? ? Cortical Alzheimer changes (plaques and Cortical disease, Alzheimer tangles) accounted for some but not greater than Lewy body all; diffuse Lewy body disease in one changes (but did not account demented patient; severe degenerative for all demented cases) changes in SN, LC, or NBM, but also in nondemented patients Hughes et al,33 1993 31 9.1 73% had good 55%, No cause; 29%, Alzheimer disease; No identifiable cause in majority; or excellent 10%-26%, Lewy body disease; 6%, remainder with Alzheimer or response vascular disease diffuse Lewy body diseases Sugiyama et al,34 1994 4 ? ? All 4 had cortical Lewy body disease and Cortical Lewy body disease; one fourth with concurrent Alzheimer unclear if dementia was changes presenting feature de Vos et al,35 1995 12 5.5 (2 patients, 0) 9 of 12 responded Both demented and nondemented Alzheimer disease patients had cortical Lewy bodies; only in 2 demented patients were the numbers high enough to suggest a causative factor; Alzheimer changes appeared to account for majority of dementia Jendroska et al,36 1996 23 ? ? Cortical amyloid ␤-peptide deposition did Heterogeneous conditions, but not distinguish demented PD patients primarily cortical Lewy body from controls; heterogeneous causes and Alzheimer degeneration for dementia: cortical Lewy bodies, Alzheimer changes, cerebrovascular, hydrocephalus, and nonspecific pathologic conditions Jellinger,37 1997 153 ? ? 85%, Alzheimer changes; 8%, vascular Cortical Alzheimer disease; disease; demented patients had more degenerative changes in profound NBM degenerative changes subcortical nuclei insufficient Brown et al,38 1998 6 ? ? All had cortical Lewy bodies, marked in 2; Cortical Lewy bodies Alzheimer changes mild in 2 and nonexistent in others Mattila et al,39 1998 41 ? ? 43% Met criteria for Alzheimer disease; Cortical Lewy bodies, either cortical Lewy bodies correlated with independent from or in cognitive impairment, especially addition to Alzheimer disease among those without Alzheimer disease SantaCruz et al,40 1999 8 ? ? Cortical Lewy body counts same in Primarily Alzheimer disease demented vs nondemented patients; plaques and tangles were significantly greater in demented patients

*Data are for cases with a clinical diagnosis of Parkinson disease (PD) and substantia nigra Lewy bodies. ? Indicates data unknown; LC, locus coeruleus; NBM, nucleus basalis of Meynert; and SN, substantia nigra.

cantly longer in the demented group and much more se- vodopa treatment, we elected to include her. One pa- vere in the last year of life (based on the Hoehn and Yahr tient without dementia had mild clinical symptoms with scores). The mean interval from parkinsonism onset to rest tremor–predominant parkinsonism and had not been dementia was 10.5 years. All patients in the PD group administered levodopa therapy. with dementia had been administered levodopa therapy Dementia severity and the clinical state within a year and initially were at least moderately responsive, except of death are summarized in Table 4. Dementia was docu- for one. That patient (patient 3) developed parkinson- mented by formal psychometric or office mental status ism in 1959 and did not receive levodopa until 13 years testing in 7 of the 13 patients. In the rest, the clinical later, by which time she was experiencing dementia and records revealed confusion and unequivocal cognitive hallucinating; levodopa was mildly beneficial in lower impairment; these observations are summarized in Table doses but exacerbated her psychosis. In view of the oth- 4. Hallucinations or delusions were experienced by 10 erwise typical PD and the long interval from onset to le- of the 13 patients after dementia onset. Dementia was at

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Time From PD Onset Time From Motor Symptoms Hoehn and Yahr Score Patient No./Sex Age at PD Onset, y Age at Death, y to Death, y to Dementia Onset, y in Last Year of Life PD Patients With Dementia 1/M 46 64 18 14 5 2/F 73 84 11 5 5 3/F 41 69 28 7 5 4/F 73 89 16 12 4-5 5/M 63 80 17 10 5 6/M 71 81 10 5 4-5 7/M 54 72 18 18 3 8/F 80 85 5 4 4 9/M 62 77 15 10 5 10/F 61 75 14 11 5 11/F 77 83 6 4 3 12/F 33 68 35 27 5 13/M 74 88 14 9 5 Mean (SD) 62.2 (14.8) 78.1 (8.0) 15.9 (8.2) 10.5 (6.6) 5 (Median) PD Patients Without Dementia 14/M 76 77 1 . . . 2-3 15/F 67 76 9 . . . 2 16/F 63 70 7 . . . 4 17/M 81 92 11 . . . 3 18/M 75 90 15 . . . 3 19/M 75 77 2 . . . 2 20/F 89 92 3 . . . 4 21/F 64 66 2 . . . 2 22/M 70 74 4 . . . 2 Mean (SD) 73.3 (8.4) 79.3 (9.7) 6.0 (4.8) ... 2-3 (Median) P Value .054 .74 .004 ... .001

*PD indicates Parkinson disease; ellipses, data not applicable.

least moderately severe in all, sufficient to substantially NEUROPATHOLOGY interfere with activities of daily living, and very apparent to family and caregivers. Fluctuations in cognition On neuropathologic evaluation, one patient with demen- were clearly documented in 2; these could have been tia who had an initially favorable response to levodopa present in others but not documented. In the group with- therapy demonstrated typical histopathologic features of out dementia, absence of dementia within a year of death progressive supranuclear palsy. One patient without de- was supported by normal performances on an office men- mentia had striatonigral degeneration (multiple system tal status examination (5 patients) or formal psychomet- atrophy); she also had responded to levodopa therapy, rics (1 patient). Nondemented status was inferred from although late in the disease course she developed marked the medical records in the remaining 3 patients, all of imbalance. These 2 patients are not included in the sub- whom had been seen at least twice within the last year sequent analysis. The remainder of the patients in both of life by a Mayo Clinic physician. groups had typical Lewy body PD within the substantia Of the 13 patients with dementia, 8 had Hoehn nigra. and Yahr stage 5 disease at the end of their life, were Median and mean Lewy body counts were approxi- severely impaired, and required total or near-total care. mately 10 times higher among the 12 PD patients with Only 3 were ambulatory without assistance (patients 7, dementia compared with the 8 PD patients without de- 8, and 11), including 1 who was ambulatory until pre- mentia in the neocortex, limbic cortex, and amygdala (all terminal hip fracture. All 13 patients with dementia statistically significant; Table 5). In the nucleus basa- continued levodopa therapy but most had a poor lis and substantia nigra, the median and mean Lewy body response (Table 4). Among the patients with Hoehn counts were almost twice as high in the group with de- and Yahr stage 5 disease, 4 were treated with relatively mentia, but this failed to reach statistical significance high doses of carbidopa levodopa-therapy (1200-2200 (Table 5). mg/d) and clearly had lost their levodopa responsive- All 12 PD patients with dementia had pathologic ness. This contrasts with the group without dementia in findings consistent with either diffuse (neocortical) or which the median Hoehn and Yahr score in the last transitional Lewy body disease.41 Transitional Lewy body year of life was 2 to 3. All 8 levodopa-treated patients disease, in which the Lewy body pathology is primarily who did not have dementia remained responsive to confined to limbic areas with sparse neocortical involve- levodopa, although incompletely responsive in some ment, was found in 7 patients; the remaining 5 patients patients, including 2 with medication refractory im- had widespread Lewy body pathology that included neo- balance. cortex.

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Condition in Last Year of Life

Typical Comments Levodopa, Patient and Observations Degree of mg/d (With Nursing No. Psychosis on Dementia Dementia* Carbidopa) Home Stay Ambulatory General Condition 1 Hallucinations, Mental state “fluctuates Severe 500 Yes No Required feeding delusions very much”; assistance; disoriented; didn’t contractures recognize wife 2No “Incompetent,” Severe 500 Yes With assistance Required feeding “confused” of 2 assistance; “no spontaneous speech” 3 Paranoia, “Combative” At least moderate 500 Yes No Required total care; hallucinations, psychosis required delusions neuroleptics 4 Delusions “Confused”; “Can’t Moderate-severe 300 Yes No Wheelchair confined; remember why she is required total care, in the nursing home”; including assistance “Unable to give for transfers history” 5 Hallucinations “Confusion,” Moderate-severe 800 Yes No Required total care; “disorientation”; minimal response “Too confused to to levodopa do complete mental status exam” 6 Hallucinations, Multiple evaluations Moderate-severe 800 Yes With much Required assistance with delusions because of confusion, assistance care; thioridazine psychosis 7 Hallucinations “Dementia,”“confusion” Moderate 300 No Yes Living at home with wife 8 Hallucinations “Very confused” Moderate 300 Yes Yes, until Living with family till hip preterminal fracture just before hip fracture death; then nursing home; needed assistance with care 9 Hallucinations “Oriented only Severe 2200 Yes No Rigid and bed bound to person” with only minimal levodopa responsivity 10 No “Not oriented to person, Severe 1250 No, but total No Bed bound, levodopa place, or time” care by unresponsive, family requiring tube feeding; minimally communicative and responsive 11 Hallucinations, Hospitalized 4 months Moderate with 200 No, supervised Yes Responsive to levodopa delusions before death with fluctuations living therapy; supervised fluctuating confusion, living delusions, and hallucinations 12 Hallucinations “Confusion,”“dementia” Moderate 2000 No, but total No “Very parkinsonian” care by despite levodopa; family unable to sit up without help; wheelchair confined for last 8 years 13 No “Confused,”“befuddled”; Severe 1200 No, but total With assistance Severe dysphagia; disoriented; didn’t care by of 2 required total care recognize family family

*Dementia was sufficient to substantially interfere with normal interactions and activities in all patients in this group, which we categorized as at least “moderate” dementia. When it was clear from the history that patients had little recognition of their surroundings and were completely disoriented, this was graded as “severe.”

Among the PD patients with dementia, there was a Only one PD patient with dementia met criteria for trend toward increased senile plaque and neurofibril- early AD as defined by (1) NIA-Reagan criteria for “in- lary tangle counts in the neocortex, the CA1 region of termediate probability of AD,”61 with the presence of the hippocampus, and the entorhinal cortex (Table 6). neocortical neurofibrillary tangles (Braak and Braak stage However, compared with the patients without demen- IV),60 and (2) a moderate (CERAD B) plaque score. In tia, this was only significant for neurofibrillary tangles all other patients, neurofibrillary tangles were confined in the CA1 region. The CERAD59 neuritic plaque scores to entorhinal and hippocampal areas (Braak and Braak ranged from sparse (CERAD A) to moderate (CERAD B). stage II-III; NIA-Reagan “low probability of AD”).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 5. Mean Lewy Body Counts per ؋200 Microscopic Table 7. Association of Lewy Body Counts Field in Patients With Parkinson Disease (PD) in Different Brain Nuclei for All Patients With Parkinson Disease PD and Dementia PD (n = 12) (n=8) Correlation ␳ P Value* P Median Mean±SD Median Mean±SD Values Neocortex and Limbic cortex 0.90 Ͻ.001 Neocortex 0.9 2.3±2.4 0.1 0.2±0.2 .002* Amygdala 0.80 Ͻ.001 Ͻ Limbic cortex 5.5 6.9±4.5 0.7 0.7±0.7 .001* Nucleus basalis 0.62 .01 Amygdala 17.5 18.2±12.8 1.5 1.9±2.0 .006* Substantia nigra 0.74 Ͻ.001 Nucleus basalis 14.5 16.1±8.2 8.5 7.5±4.5 .06 of Meynert Limbic cortex and Substantia nigra 5.8 5.7±2.5 3.3 3.3±2.1 .05 Amygdala 0.86 Ͻ.001 Nucleus basalis 0.69 .005 Ͻ *P .05, Wilcoxon rank sum test. Substantia nigra 0.74 Ͻ.001

Amygdala and Table 6. Senile Plaque and Neurofibrillary Tangle Counts Nucleus basalis 0.76 .003 per ؋200 Microscopic Field in Patients Substantia nigra 0.77 Ͻ.001 With Parkinson Disease (PD) Nucleus basalis and Substantia nigra 0.65 .009 PD and Dementia PD (n = 12) (n=8) P *PϽ.05. Median Mean±SD Median Mean±SD Values Senile plaques Neocortex 4.0 9.6±10.4 0.7 1.5±1.8 .08 Table 8. Association of Lewy Body Counts With Counts CA1, hippocampus 0.0 0.5±0.9 0.0 0.0±0.0 .10 of Senile Plaques and Neurofibrillary Tangles Entorhinal cortex 4.7 7.0±7.9 0.0 1.1±2.0 .14 in All Patients With Parkinson Disease Neurofibrillary tangles Neocortex 0.0 0.1±0.2 0.0 0.0±0.0 .18 Correlation ␳ P Value CA1, hippocampus 0.8 0.9±0.8 0.0 0.0±0.1 .02* Entorhinal cortex 3.0 6.9±8.6 1.3 3.6±5.1 .67 Neocortex Lewy bodies and senile plaques 0.66 .002* *PϽ.05, Wilcoxon rank sum test. Lewy bodies and neurofibrillary tangles 0.51 .03* Senile plaques and neurofibrillary tangles 0.19 .44 CA1, hippocampus Senile plaques and neurofibrillary tangles 0.18 .53 Coexisting large and small vessel disease (atherosclero- Entorhinal cortex sis, arteriolosclerosis) was present in all patients, with Senile plaques and neurofibrillary tangles −0.34 .20 and without dementia, as commonly seen in elderly patients. Among the patients with dementia, 2 had white *PϽ.05. matter pallor and 1 of these had small white matter in- farcts (lacunes). Among the PD patients with dementia, 3 remained (Table 7). Patients with high counts in one brain re- ambulatory before death (patients 7, 8, and 11), with less gion were likely to have high counts in the others. The advanced parkinsonism than the other patients with de- analysis given in Table 7 includes all PD patients (with mentia (Table 4). Pathologically, these could not be dis- and without dementia); however, similar values were also tinguished from the other PD patients with dementia. found when the analysis was restricted to only the pa- Mean Lewy body counts were similar to the group with tients with dementia (although less robust; data not dementia as a whole, as were the counts of senile plaques shown). and neurofibrillary tangles. The neuropathologic diagnosis was diffuse Lewy body disease in 2 (patients 7 and ASSOCIATION OF LEWY BODY COUNTS WITH 8) and transitional Lewy body disease in the other (pa- SENILE PLAQUES AND NEUROFIBRILLARY tient 11). TANGLES Among the PD patients without dementia, no sub- stantial neuropathologic change was found beyond the In the neocortex, Lewy body counts were highly corre- brainstem. Among these patients, Lewy bodies were sparse lated with counts of senile plaques and, to a slightly lesser in the neocortex and limbic cortex; none had more than extent, neurofibrillary tangles (Table 8). This was not minimal evidence of AD pathologic change. an artifact of age, since age at death was not correlated with neocortical counts of Lewy bodies, senile plaques, ASSOCIATIONS OF LEWY BODY COUNTS or neurofibrillary tangles (Spearman ␳ values all Յ0.1 and WITHIN BRAIN REGIONS P Ͼ.60). Furthermore, senile plaque counts were not correlated with counts of neurofibrillary tangles within any Lewy body counts in each of the analyzed brain regions of the analyzed brain regions (neocortex, CA1 area of hip- were highly correlated with counts in the other areas pocampus, or entorhinal cortex). The analysis given in

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 8 included PD patients with and without demen- underscore the increasing recognition of the overlap of tia. When restricted to only those patients with demen- AD and Lewy body pathologies with a continuum of clini- tia, the outcomes were similar, except that the correlation cal deficits from pure dementia to pure parkinsonism, between neocortical Lewy body counts and neurofibril- but often with combinations.47,63-65 lary tangles did not reach statistical significance (␳=0.49, The results of this study suggest that a generalized P=.11). process that simultaneously affects widespread brain regions is responsible for the dementia. This is in contrast COMMENT to what has been suggested by some prior investigators who have focused on specific brain nuclei22,24,28 (Table Lewy body disease, either transitional or diffuse, seemed 2). Lewy body counts in the 5 analyzed brain regions were sufficient to account for dementia in 12 of 13 patients. The highly correlated (Table 7) with most Spearman ␳ val- exception was the single patient with progressive supra- ues more than 0.7 (neocortex, limbic, amygdala, nucleus nuclear palsy. Two patients also had white matter pallor, basalis, and substantia nigra). The evolving clinical state one with multiple lacunar infarctions, which could have of the PD patients with dementia also suggests a gener- contributed to the dementia. Overall, these findings alized brain disorder. Initially, the clinical picture was suggest that the primary cause for dementia that devel- that of a focal process, with typical levodopa-responsive ops later in the course of otherwise typical PD is the un- PD. However, with time, most patients in this series not derlying Lewy body disease. This finding is consistent with only developed dementia, but also became levodopa re- 2 recent series that reported similar results.53,54 In con- fractory, nonambulatory, and unable to care for them- trast to multiple prior publications (Table 2), major Alz- selves. heimer changes were not found among our PD patients These findings also provide insight into the neuro- with dementia. Only one patient met NIA-Reagan crite- pathologic substrate for underlying loss of the levodopa ria for intermediate probability of AD61; the remainder of motor response. Prior PD clinicopathologic studies have the patients fell into the NIA-Reagan category of “low prob- obviously included levodopa refractory, bed-bound pa- ability of AD.” tients (Hoehn and Yahr stage 5). However, this specific The mean age was similar in the groups with and group of PD patients has not been singled out for neu- without dementia, suggesting that simple aging was not ropathologic analysis. In the present study, 8 of the 12 the cause for the pathologic differences. However, the PD patients fit into this category; 3 had been treated with group with dementia had significantly longer disease du- more than 1200 mg/d of levodopa (with carbidopa), sug- rations. This was likely a factor in both the clinical and gesting a levodopa refractory state. Thus, the same neu- neuropathologic differences; in progressive neurodegen- ropathologic process that accounts for dementia seems erative syndromes, longer disease durations typically re- to play a critical role in the loss of the motor response to sult in more severe outcomes. levodopa therapy. Patient 13 also had Hoehn and Yahr Although AD did not seem to be the primary sub- stage 5 disease late in the disease course, was unrespon- strate for dementia in these patients, it clearly was a com- sive to high-dose levodopa therapy, and had progres- ponent of the neuropathologic process. There were trends sive supranuclear palsy. toward higher senile plaque and neurofibrillary tangle Heterogeneous pathologic explanations for demen- counts in most of the analyzed nuclei of the group with tia developing within the context of PD have been re- dementia, although this was only statistically signifi- ported (Table 2). This contrasts with the present study in cant for tangles within the hippocampal CA1 region (Table which the predominant pathologic findings were fairly con- 6). Remarkably, neocortical Lewy body counts were sig- sistent among patients. At least 3 factors account for this nificantly correlated with counts of senile plaques and, discrepancy. First, many of the earlier investigations sum- to a lesser extent, neurofibrillary tangles (Table 8). This marized in Table 2 were performed before the availability is not explained by age-related changes, since there were of more modern immunohistochemical techniques. In fact, no trends linking age at death to counts of any of these all of the studies listed in Table 2 predate the availability neuropathologic markers. Senile plaque counts did not of ␣-synuclein immunohistochemical testing. This is now correlate with counts of neurofibrillary tangles within any recognized to be the most sensitive and specific method of the analyzed nuclei. for identifying Lewy bodies.50,51 Second, patients included The present findings of predominant diffuse or tran- in these prior studies were likely heterogeneous. As is ap- sitional Lewy body disease, combined with lesser Alz- parent in Table 2, basic clinical features were typically not heimer changes, are remarkably similar to the findings reported and perhaps may not have been available to the in patients prospectively diagnosed as having dementia investigators. It was the rare series in which such basic in- with Lewy bodies.42 In the latter condition, patients pre- formation as latency from parkinsonism to dementia or le- sent with dementia with visual hallucinations. Parkin- vodopa responsiveness was reported (Table 2). For those sonian motor findings may develop early or later in the series that included patients in whom dementia was a pre- disease course, in contrast to the present series with senting feature, one might expect different neuropatho- initial parkinsonism and later dementia. Despite the dif- logic conditions, including AD. In the present series, the ference in clinical course, the postmortem pathologic fea- patients were clinically homogeneous in that dementia was tures are similar, with Lewy body pathology predomi- a later development and all initially presented with what nantly of the transitional and diffuse type, plus, a mixture seemed to be typical levodopa responsive PD. The only ex- of AD pathology that in most patients does not meet ception was patient 3, who presented with typical PD be- NIA-Reagan criteria for AD. The findings reported herein fore levodopa was available; when initiated 13 years later,

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 the response was limited by hallucinations. Third, many 12. Aarsland D, Tandberg E, Larsen JP, Cummings JL. Frequency of dementia in Par- prior investigators reporting Alzheimer changes as the sub- kinson disease. Arch Neurol. 1996;53:538-542. 13. Rajput AH, Offord KP, Beard CM, Kurland LT. A case-control study of smoking strate for PD dementia (Table 2) used the older Khacha- habits, dementia, and other illnesses in idiopathic Parkinson’s disease. Neurol- 66 turian neuropathologic criteria. Recent consensus crite- ogy. 1987;37:226-232. ria for the AD neuropathologic substrate61 emphasize the 14. Mayeux R, Chen J, Mirabello E, et al. An estimate of the incidence of dementia in importance of neurofibrillary tangles, in addition to neu- idiopathic Parkinson’s disease. Neurology. 1990;40:1513-1517. ritic plaques. The Khachaturian criteria focused primarily 15. 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