Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

TDP-43 pathology occurs infrequently in multiple system atrophy.

AIMS AND METHODS: The α-synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological 43-kDa transactive response DNA-binding protein (TDP-43) or fused in sarcoma (FUS) aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico-pathological features. Consequently, we examined MSA for evidence of TDP-43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients. RESULTS: TDP-43 pathology was generally rare, and there were no FUS lesions. The TDP-43 lesions were located predominantly in medio-temporal lobe and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions. CONCLUSIONS: The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP-43 or FUS pathology, but rather from widespread white matter α-synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary α-synuclein-mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP-43.

Novel CSF biomarkers for frontotemporal lobar degenerations.

OBJECTIVE: To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau). METHODS: CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD. RESULTS: CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases. CONCLUSIONS: Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.

Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease.

OBJECTIVES: Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. METHODS: A total of 55 subjects with PD and an Inventory of Depressive Symptomatology-Clinician (IDS-C) score > or = 22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (> 50% decrease in IDS-C score or Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. RESULTS: There were no between-groups differences in a priori-defined response rates. Using a more liberal response criterion of > 40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated. CONCLUSIONS: Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. CLASSIFICATION OF EVIDENCE: This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.

Longitudinal decline in autopsy-defined frontotemporal lobar degeneration.

BACKGROUND: The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively. METHODS: We examine longitudinal decline in cognitive functioning in an autopsy-proven cohort of patients with the clinical diagnosis of a FTLD spectrum disorder or FTLD pathology using a panel of neuropsychological measures. Patients are categorized according to findings at autopsy into tau-positive FTLD, tau-negative FTLD, and frontal variant-Alzheimer disease (fvAD) subgroups. RESULTS: Patients decline significantly over time on all neuropsychological measures. Moreover, several measures differentiate between histopathologically distinct subgroups throughout the course of the disease process. This includes a significant double dissociation involving relative difficulty on a visual constructional measure in tau-positive patients compared to relatively impaired visual confrontation naming in tau-negative patients. Longitudinal measures of FAS naming fluency and animal naming fluency also distinguish tau-positive patients and tau-negative patients with FTLD from patients with fvAD. Other measures show significant decline but do not distinguish between histopathologic groups longitudinally. CONCLUSION: Our findings suggest different longitudinal patterns of cognitive decline in pathologically defined subgroups of patients. Measures consistently distinguishing between patient subgroups can be used to bolster diagnostic accuracy throughout the course of these diseases, while measures demonstrating undifferentiated longitudinal decline may serve as useful endpoints in treatment trials.

Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations.

BACKGROUND: Mutations in the LRRK2 gene are an important cause of familial and nonfamilial parkinsonism. Despite pleomorphic pathology, LRRK2 mutations are believed to manifest clinically as typical Parkinson disease (PD). However, most genetic screens have been limited to PD clinic populations. OBJECTIVE: To clinically characterize LRRK2 mutations in cases recruited from a spectrum of neurodegenerative diseases. METHODS: We screened for the common G2019S mutation and several additional previously reported LRRK2 mutations in 434 individuals. A total of 254 patients recruited from neurodegenerative disease clinics and 180 neurodegenerative disease autopsy cases from the University of Pennsylvania brain bank were evaluated. RESULTS: Eight cases were found to harbor a LRRK2 mutation. Among patients with a mutation, two presented with cognitive deficits leading to clinical diagnoses of corticobasal syndrome and primary progressive aphasia. CONCLUSION: The clinical presentation of LRRK2-associated neurodegenerative disease may be more heterogeneous than previously assumed.

Cognitive and motor assessment in autopsy-proven corticobasal degeneration.

OBJECTIVE: To investigate the clinical features of autopsy-proven corticobasal degeneration (CBD). METHODS: We evaluated symptoms, signs, and neuropsychological deficits longitudinally in 15 patients with autopsy-proven CBD and related these observations directly to the neuroanatomic distribution of disease. RESULTS: At presentation, a specific pattern of cognitive impairment was evident, whereas an extrapyramidal motor abnormality was present in less than half of the patients. Follow-up examination revealed persistent impairment of apraxia and executive functioning, worsening language performance, and preserved memory. The motor disorder emerged and worsened as the condition progressed. Statistical analysis associated cognitive deficits with tau-immunoreactive pathology that is significantly more prominent in frontal and parietal cortices and the basal ganglia than temporal neocortex and the hippocampus. CONCLUSION: The clinical diagnosis of corticobasal degeneration should depend on a specific pattern of impaired cognition as well as an extrapyramidal motor disorder, reflecting the neuroanatomic distribution of disease in frontal and parietal cortices and the basal ganglia.

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers.

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Glucocerebrosidase mutations are an important risk factor for Lewy body disorders.

The synucleinopathies are neurodegenerative disorders defined by inclusions composed of aberrantly fibrillized alpha-synuclein, but factors contributing to this process remain largely unknown. The authors examined the glucocerebrosidase gene in 75 autopsy specimens with different synucleinopathies and identified mutations in 23% of cases of dementia with Lewy bodies, expanding on previous findings in subjects with Parkinson disease. Mutations in this lysosomal protein may interfere with the clearance or promote aggregation of alpha-synuclein.

[99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease.

BACKGROUND: In vivo imaging of the dopamine transporter with [99mTc]TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in Parkinson disease (PD). OBJECTIVE: To evaluate the relationship between TRODAT SPECT imaging, odor identification skills, and motor function in patients with early PD. METHODS: Twenty-four patients with a clinical diagnosis of early-stage PD (mean Hoehn & Yahr stage = 1.4) underwent TRODAT imaging, Unified PD Rating Scale (UPDRS) ratings of motor function, and administration of the University of Pennsylvania Smell Identification Test (UPSIT). Brain images were obtained using a standardized processing protocol and specific uptake ratios for striatal regions of interest were calculated. Partial correlations between the imaging indices, disease duration, UPSIT scores, and UPDRS motor scores were then calculated. RESULTS: UPSIT scores were correlated with TRODAT uptake in the striatum as a whole (r = 0.66, p = 0.001). The putamen showed the strongest correlation with the UPSIT (r = 0.74; p < 0.001). The correlation between dopamine transporter density in the caudate and UPSIT was moderate (r = 0.36, p = 0.11), but was not significant. CONCLUSIONS: Olfactory function is highly correlated with dopamine transporter imaging abnormalities in early Parkinson disease (PD). Further studies are warranted to determine whether changes over time in these two measures are also correlated in early PD.

Diagnostic accuracy of [99mTc]TRODAT-1 SPECT imaging in early Parkinson's disease.

We evaluated the diagnostic accuracy of SPECT imaging using [(99m)Tc]TRODAT-1 (TRODAT), a relatively inexpensive technetium-labeled dopamine transporter ligand, in distinguishing 29 patients with early PD from 38 healthy volunteers. Mean TRODAT uptake values were significantly decreased in the caudate (p=0.0097) and anterior and posterior putamen (p < 0.0001) of PD patients compared to controls. Using the posterior putamen as the main region of interest resulted in the greatest accuracy (sensitivity 0.79, specificity 0.92). These findings show that TRODAT imaging can accurately differentiate early PD patients from controls and has the potential to improve the diagnosis of patients with early signs of PD.

Grammatical and resource components of sentence processing in Parkinson's disease: an fMRI study.

BACKGROUND: Sentence comprehension requires linguistic processing as well as cognitive resources such as working memory (WM) and information-processing speed (IPS). The authors hypothesize that sentence comprehension difficulty in patients with mild PD is due to degradation of the large-scale neural network that supports cognitive resources during sentence processing. OBJECTIVE: To understand the neural basis for sentence comprehension difficulty in PD. METHOD: Regional brain activity with blood oxygenation level-dependent fMRI was monitored while seven PD patients and nine healthy seniors answered a simple probe about written sentences that vary in their grammatical and cognitive resource properties. RESULTS: Healthy seniors recruited posterolateral temporal and ventral inferior frontal regions of the left hemisphere, brain regions associated with grammatical processing that were also activated by PD patients. Healthy seniors also recruited left dorsal inferior frontal, right posterolateral temporal, and striatal regions that are associated with cognitive resources during sentence processing. Direct contrasts showed that striatal, anteromedial prefrontal, and right temporal regions are recruited to a significantly lesser degree in PD, but these patients have increased activation of right inferior frontal and left posterolateral temporal-parietal areas during sentence comprehension. CONCLUSION: These findings associate impaired sentence comprehension in PD with interruption of a large-scale network important for cognitive resources during sentence processing. These results also imply compensatory up-regulation of cortical activity that allows patients with mild PD to maintain sentence comprehension accuracy.

Dopamine supports sentence comprehension in Parkinson's Disease.

OBJECTIVE: To determine the role of dopamine in the executive resource component of sentence comprehension. METHODS: We studied sentence-picture matching in 20 right-handed, non-demented, native English speakers with mild Parkinson's disease (PD) when 'on' and 'off' their levodopa, taking into account disease duration to control for endogenous dopamine metabolism. We also administered a verbal working memory measure that does not involve specific grammatical manipulations. RESULTS: PD patients 'off' levodopa demonstrated a significant discrepancy in their comprehension of grammatically complex sentences compared to grammatically simpler sentences that was not evident when PD patients were 'on' levodopa. An error analysis demonstrated that impaired comprehension of grammatically complex sentences when 'off' levodopa was associated with poorer performance on foils requiring working memory resources. Performance on an independent measure of verbal working memory correlated only with comprehension of grammatically complex sentences during levodopa supplementation, but working memory according to this measure did not differ during 'on' and 'off' states. CONCLUSION: Dopamine supports the executive resources contributing to sentence comprehension in PD.

Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies.

Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated alpha-synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that alpha-synuclein is nitrated in pathological lesions. The widespread presence of nitrated alpha-synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.

Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.

Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha-synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.

Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy.

Although alpha-synuclein (alpha-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length alpha-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout alpha-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the alpha-syn epitopes detected in GCIs. Notably, carboxy-terminal alpha-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of alpha-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal alpha-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight alpha-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that alpha-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in alpha-syn.

Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology.

Neurodegeneration with brain iron accumulation, type 1 (NBIA 1), or Hallervorden-Spatz syndrome, is a rare neurodegenerative disorder characterized clinically by Parkinsonism, cognitive impairment, pseudobulbar features, as well as cerebellar ataxia, and neuropathologically by neuronal loss, gliosis, and iron deposition in the globus pallidus, red nucleus, and substantia nigra. The hallmark pathological lesions of NBIA 1 are axonal spheroids, but Lewy body (LB)-like intraneuronal inclusions, glial inclusions, and rare neurofibrillary tangles also occur. Here we show that there is an accumulation of alpha-synuclein (alphaS) in LB-like inclusions, glial inclusions, and spheroids in the brains of three NBIA 1 patients. Further, beta-synuclein (betaS) and gamma-synuclein (gammaS) immunoreactivity was detected in spheroids but not in LB-like or glial inclusions. Western blot analysis demonstrated high-molecular weight alphaS aggregates in the high-salt-soluble and Triton X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1 brain. Significantly, the levels of alphaS were markedly reduced in the Triton X-100-soluble fractions compared to control brain, and unlike other synucleinopathies, insoluble alphaS did not accumulate in the formic acid-soluble fraction. These findings expand the concept of neurodegenerative synucleinopathies by implicating alphaS, betaS, and gammaS in the pathogenesis of NBIA 1.

Cognitive resource limitations during sentence comprehension in Parkinson's disease.

Patients with idiopathic Parkinson's disease (PD) were asked to identify the agent of the action in orally presented sentences with subject-relative or object-relative center-embedded clauses while simultaneously performing a secondary task that was less resource-demanding (finger tapping) or more resource-demanding (recognition span). We found that a subgroup of PD patients with impaired sentence comprehension at baseline (no secondary task) did not differ from random in their accuracy understanding all types of sentences during the more demanding (recognition span) condition and also had difficulty understanding the most complex sentences during the less demanding (finger tapping) condition. Control subjects and PD patients without baseline sentence comprehension difficulty were random only in their comprehension of the most complex sentences under the more demanding (recognition span) secondary task condition. Examination of response latencies for accurately understood sentences revealed only an effect for the type of sentence, and this was equally evident across all groups of subjects and regardless of the condition under which the sentences were administered. The sensitivity of PD patients' sentence comprehension accuracy to secondary task resource demands is most consistent with the hypothesis that limited cognitive resources contribute to sentence comprehension difficulty in PD.

Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease.

BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.

Loss of dopamine D2 receptors in Alzheimer's disease with parkinsonism but not Parkinson's or Alzheimer's disease.

A significant proportion of patients with Alzheimer's disease (AD) exhibit extrapyramidal features that are referred to as parkinsonism (AD/Park) to distinguish the clinical and pathological features that differ from Parkinson's disease (PD). Previous results from this laboratory have shown that, although the presynaptic components of the dopamine (DA) system are markedly affected in AD/Park, the pathology is not similar to PD (Murray et al. 1995; Joyce et al. 1997). In the present study, we determined whether the parkinsonian symptoms in AD/Park might also reflect changes in numbers of postsynaptic DA receptors. We analyzed the binding of [125I]epidepride biding to DA D2/D3 receptors and [3H]SCH 23390 to D1 receptors by autoradiography in the striatum of six patients with PD, nine patients with AD, seven patients with AD/Park, and 14 neurologically intact control subjects. D2 receptors were reduced in the caudate and putamen of the AD/Park group (by 42 and 27% of controls, respectively) but not reduced in AD or PD. D1 receptors were elevated by 36% in the putamen of the PD group. Dopamine receptor changes are, therefore, not similar in PD, AD, and AD/Park. The elevation in D1 receptors in PD may contribute to the unwanted side effects of L-dopa treatment. The loss of D2 receptors in AD/Park, not observed in AD lacking overt parkinsonian symptomatology, may contribute to the presence of parkinsonian features and lack of responsiveness to L-dopa.