Incidental Lewy body disease: Electrophysiological findings suggesting pre-clinical Lewy body disorders

Objective

Evaluate electrophysiologic findings in incidental Lewy body disease (ILBD).

Methods

ILBD, Control, and Parkinson’s disease (PD) subjects had electrophysiological evaluation within 2 years prior to autopsy. Data analyzed included surface electromyography (EMG) of upper extremity muscles during rest and muscle activation, and electroencephalography (EEG) recording at rest. For EMG, gross tracings and spectral peaks were analyzed. EEG measures analyzed were background frequency and power in delta, theta, alpha, and beta bands.

Results

Three of ten ILBD subjects (30%) showed unilateral rhythmic EMG discharges at rest without a visually apparent rest tremor. The ILBD resting EMG frequency was lower than in the Control group with no overlap (P = .03) and close to that of the PD group. The ILBD group had significantly lower background rhythm frequency than the Control group (P = .001) but was greater than the PD group (P = .01).

Conclusions

The electrophysiologic changes in ILBD cases are between those of Control and PD, suggesting that these findings may reflect changes correlating with ILBD as a possible precursor to PD.

Significance

Electrophysiologic changes in ILBD may assist with the identification of a preclinical stage for Lewy body disorders and help the development of a therapeutic agent for modifying Lewy body disease progression.     

Somatic mitochondrial DNA mutations in early Parkinson and incidental Lewy body disease

Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases.     

Reduced striatal tyrosine hydroxylase in incidental Lewy body disease

Incidental Lewy body disease (ILBD) is the term used when Lewy bodies are found in the nervous system of subjects without clinically documented parkinsonism or dementia. The prevalence of ILBD in the elderly population has been estimated at between 3.8 and 30%, depending on subject age and anatomical site of sampling. It has been speculated that ILBD represents the preclinical stage of Parkinson’s disease (PD) and/or dementia with Lewy bodies (DLB). Studies of ILBD could potentially identify early diagnostic signs of these disorders. At present, however, it is impossible to know whether ILBD is a precursor to PD or DLB or is just a benign finding of normal aging. We hypothesized that, if ILBD represents an early stage of PD or DLB, it should be associated with depletion of striatal dopaminergic markers. Eleven subjects with ILBD and 27 control subjects were studied. The ILBD subjects ranged in age from 74 to 96 years (mean 86.5) while the control subjects’ age ranged from 75 to 102 years (mean 86.7). Controls and subjects did not differ in terms of age, postmortem interval, gender distribution, medical history conditions, brain weight, neuritic plaque density or Braak neurofibrillary stage. Quantitative ELISA measurement of striatal tyrosine hydroxylase (TH), the principal enzyme for dopamine synthesis, showed a 49.8% (P = 0.01) reduction in ILBD cases, as compared with control cases. The finding suggests that ILBD is not a benign condition but is likely a precursor to PD and/or DLB.     

The evolution of diagnosis in early Parkinson disease. Parkinson Study Group

CONTEXT: Since there is no diagnostic biological marker for Parkinson disease (PD), the diagnosis is based on the results of clinical assessment. The accuracy of diagnosis improves with time and repeated assessments. Studies that require only inclusion of early cases of PD present a diagnostic challenge. Previous studies concluded that initial diagnoses of PD made by general neurologists were incorrect in 24% to 35% of the cases when patients were examined at autopsy. Experts in movement disorders are expected to have greater accuracy of initial diagnosis of PD. OBJECTIVE: To determine the evolution of clinical diagnosis in patients with early PD made initially by experts in PD. DESIGN: Eight hundred patients with mild parkinsonian symptoms (Hoehn and Yahr stage 1 or 2) who received a diagnosis of PD less than 5 years before the beginning of the study were included in the original Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease study. These patients were followed up prospectively with repeated clinical assessments. The following clinical criteria were used to reassess the initial diagnosis: investigator's confidence in the diagnosis of PD, presence of atypical clinical features, findings of imaging studies, response to levodopa, and results of autopsy examinations. RESULTS: The mean +/- SD duration of illness in the 800 cases at enrollment was 2.2+/-1.3 years, and the mean +/- SD Hoehn and Yahr stage was 1.6+/-0.5. The mean +/- SD follow-up was 6.0+/-1.4 years (range, 0.2-7.6 years). In 5 cases, PD was not confirmed at autopsy, and in 15 patients, the results of imaging studies indicated the presence of other pathological conditions. Of the 550 cases treated with levodopa, 49 (8.9%) had little or no improvement; 6 of these cases overlap with either autopsy or imaging study exclusion criteria. Two other cases had at least 4 of the 6 atypical clinical features arguing against the diagnosis of PD. Thus, of the 800 patients, 65 (8.1%) did not have PD according to the study criteria. Compared with those patients with the final diagnosis of PD, in the diagnoses of 60 patients without autopsy, the duration of symptoms (mean +/- SD, 7.2+/-2.0 years vs. 8.3+/-1.9 years; P<.001) and the duration of follow-up (5.3+/-1.6 years vs. 6.1+/-1.3 years; P<.001) were shorter. CONCLUSIONS: We found that 65 (8.1%) of patients initially diagnosed as having PD were later found to have an alternate diagnosis based on multifactorial clinical diagnostic criteria. This alternate diagnosis indicated that experts in PD changed their diagnoses infrequently during the 7.6-year follow-up.     

Olfactory dysfunction in incidental Lewy body disease and Parkinson's disease

BackgroundOlfactory dysfunction in Parkinson's disease (PD) is well-established and may represent one of the earliest signs of the disease.Objective & methodsThe objective of this study was to evaluate the relationship of olfactory dysfunction, using the University of Pennsylvania Smell Identification Test (UPSIT), to clinical and pathological parameters of clinicopathologically diagnosed PD (n = 10), incidental Lewy body disease (ILBD) (n = 13), and identically assessed controls who lacked a neurodegenerative disease (n = 69).ResultsMean UPSIT scores were significantly lower in PD (16.3, p < 0.001) and ILBD (22.2, p = 0.004) compared to controls (27.7). Using an UPSIT cutoff score of <22 (the 15th percentile) the sensitivity for detecting PD was 9/10 (90%) and ILBD 6/13 (46%), while the specificity was 86% (Controls with score of <22 = 10/69).ConclusionsThese results add to the growing body of evidence suggesting that olfactory testing could be useful as a screening tool for identifying early, pre-motor PD.     

Prospective study of presynaptic dopaminergic imaging in patients with mild parkinsonism and tremor disorders: part 1. Baseline and 3-month observations.

To record prospectively, from early presentation, the clinical features of parkinsonism and tremor disorders, in relation to evidence of dopaminergic deficit shown with [(123)I]-FP-CIT (DaTSCAN, Amersham Health) single photon emission computerised tomography (SPECT). Clinical signs were recorded in 62 patients, of whom 24 failed standard Parkinson's disease (PD) and essential tremor criteria, and 38 fulfilled UK Brain Bank step 1 PD criteria. Striatal radioligand uptake was graded visually as normal or abnormal, and specific:nonspecific ratios were calculated. Bradykinesia and rigidity showed significant overall association with abnormal scans (P < or = 0.003), but rest tremor did not (P = NS). In the 24 patients not fulfilling specific criteria (mean age 63 [SD 9] years, disease duration 3 [SD 4] years), 10 (42%) had abnormal visual SPECT assessment and 14 (58%) had normal scans. Of 38 patients with early PD by clinical criteria (mean age 60 [SD 9] years, disease duration 3 [SD 1.7] years), 33 (87%) were visually abnormal. Baseline clinical diagnosis corresponded with SPECT imaging results in 51 of 62 cases (82%), which increased to 56 of 62 cases (90%) with amendment of seven clinical diagnoses at 3 months (blind to SPECT results). Akinetic-rigid cardinal diagnostic features of parkinsonism associate well with dopaminergic deficit in patients with early and mild clinical features. When these clinical features are uncertain, or the patient fails clinical diagnostic criteria, testing for dopaminergic deficit with [(123)I]-FP-CIT SPECT may assist the diagnostic process.     

Provisional diagnostic criteria for depression in Parkinson's disease: report of an NINDS/NIMH Work Group.

Mood disorders are the most common psychiatric problem associated with Parkinson's disease (PD), and have a negative impact on disability and quality of life. Accurate diagnosis of depressive disturbances in PD is critical and will facilitate the testing and use of new interventions; however, there are no clear diagnostic criteria for depressive disorders in PD. In their current form, strict Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are difficult to use in PD and require attribution of specific symptoms to PD itself or the depressive syndrome. Additionally, DSM criteria for major depression and dysthymia exclude perhaps half of PD patients with comorbid clinically significant depression. This review summarizes an NIH-sponsored workshop and describes recommended changes to DSM diagnostic criteria for depression for use in PD. Participants also recommended: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of subsyndromal depression in clinical research studies of depression of PD; (3) the specification of timing of assessments for PD patients with motor fluctuations; and (4) the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and intended to be defined further and validated but provide a common starting point for clinical research in PD-associated depression.     

Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders

Involvement of the olfactory bulb by Lewy-type α-synucleinopathy (LTS) is known to occur at an early stage of Parkinson’s disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical α-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included α-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer’s disease with LTS (ADLS), Alzheimer’s disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson’s Disease Rating Scale (Spearman R −0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.     

MDS clinical diagnostic criteria for Parkinson's disease

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances. © 2015 International Parkinson and Movement Disorder Society     

Brain stem pathology in Parkinson's disease: An evaluation of the Braak staging model

The lower brain stem of 25 pathologically‐confirmed Parkinson's disease (PD) cases was examined by alpha synuclein immunohistochemistry to characterize pathological accumulation of alpha synuclein (Lewy‐type α‐synucleinopathy, LTS) in the medulla oblongata, to examine differences between affected regions and test a proposed model of staging of pathology in PD. All cases had LTS in the medulla, including the dorsal motor nucleus of the vagus (dmX), when present. The distribution followed a consistent pattern and appeared to be concentrated in a tyrosine hydroxylase (TH) immunoreactive region, probably representing the dorsal IX/X nuclear complex and the intermediate reticular zone. LTS density was greatest in the dmX. A similar distribution pattern to PD was seen in 14 incidental Lewy body disease (ILBD) cases, five derived from the Queen Square Brain Bank tissue collection and nine identified in separate series of 60 neurologically‐normal individuals, and in three cases with the G2019S mutation of LRRK2. Semiquantitative assessment showed that severity of pathology in the dmX was not correlated with the severity of cortical pathology. Semiquantitative assay of TH and ChAT peptide expression in the medulla showed that TH expression in PD and ILBD did not differ from controls. These findings broadly support the Braak hypothesis of caudo‐rostral development but indicate that the extent of the disease in the cortex and the severity of pathology in the medulla were independent of one another. © 2010 Movement Disorder Society     

Do published criteria improve clinical diagnostic accuracy in multiple system atrophy?

OBJECTIVE: To assess the accuracy of a clinical diagnosis of multiple system atrophy (MSA) and compare it to the Quinn and Consensus criteria for MSA using neuropathologically examined cases from the Queen Square Brain Bank for Neurological Disorders. METHODS: Fifty-nine cases with a neurologic diagnosis of MSA when last assessed prior to death were studied. RESULTS: In 51 (86%) of these cases, the diagnosis of MSA was confirmed pathologically. False positive diagnoses included PD (n = 6), progressive supranuclear palsy (n = 1), and cerebrovascular disease (n = 1). When applying either set of diagnostic criteria, a diagnosis of probable MSA gave lower sensitivity but higher positive predictive value than one of possible MSA. Application of either set of diagnostic criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by the last clinic visit. CONCLUSIONS: This study shows a high diagnostic accuracy for the clinical diagnosis of MSA by neurologists, with PD accounting for most of the false positive diagnoses. Application of either Quinn or Consensus criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by last clinic visit.     

Diagnostic accuracy of parkinsonism syndromes by general neurologists

IntroductionMovement disorder specialists can achieve a high level of accuracy when clinically diagnosing parkinsonism syndromes. However, data about the diagnostic accuracy among general neurologists is limited.ObjectivesThis study investigated the recent diagnostic accuracy of parkinsonism syndromes by general neurologists.MethodsA retrospective examination of 1362 post-mortem cases diagnosed in the years 2000–2012 by neuropathologists was performed. Out of these cases, we identified 111 patients who received a clinical parkinsonism diagnosis during life and 122 patients who received a neuropathological diagnosis of a parkinsonism syndrome post-mortem including 11 incidental cases.ResultsFifty-eight (75.3%) of the 77 patients who had received clinical Parkinson's disease (PD) diagnoses were confirmed after the neuropathological examination. The sensitivity of the clinical diagnosis for idiopathic Parkinson's disease (PD) was 89.2% and the specificity was 57.8%. The corresponding numbers for progressive supranuclear palsy (PSP) were 52.9% and 100%, and for multiple system atrophy (MSA) were 64.3% and 99.0%, respectively.ConclusionsParkinson's disease is heavily overdiagnosed by general neurologists, whereas parkinsonism plus syndromes are underdiagnosed. Despite improvements in the diagnostic methods during recent decades and the development of diagnostic clinical criteria for parkinsonian syndromes, the diagnostic accuracy of Parkinson's disease remains relatively low, and 1/4 of diagnoses are incorrect.     

Serum p97 levels as an aid to identifying Alzheimer's disease

Background: The application of formal clinical diagnostic criteria for the identification of Alzheimer's Disease (AD) has improved diagnostic sensitivity. However, there remains a need for non-invasive biological markers and laboratory tests, which can facilitate case identification, and the assessment of treatment response. The p97 protein is a secreted protein specifically expressed by amyloid plaque associated reactive microglia that may have AD diagnostic ability. Methods: A quantitative radioimmunoassay was developed to measure serum p97. This study, under a double blind protocol, evaluated the utility of serum p97 as diagnostic test for AD. All subjects were referred to the UBC Clinic for Alzheimer's Disease and Related Disorders (CADRD) for clinical assessment of dementia. A serum p97 sample was obtained at the time of assessment but diagnosis of disease was determined independently of p97 examination. Results: "Possible" and "probable" AD cases (n = 41) and cognitively normal controls (n = 64) showed a highly significant difference in mean p97 concentration (41 vs. 20 ng/ml, p<0.001). There was some overlap in p97 distributions between AD cases and control subjects. The area under the curve (AUC) for the receiver operator curve (ROC) was 0.812. Conclusions: These results further support the specificity of high serum p97 levels in AD and its potential utility as a biological marker in AD. The reproducible elevation of serum p97 in AD underlines the need to further determine its role as a biological marker and diagnostic adjunct for AD.     

Personality disorder-not otherwise specified evidence of validity and consideration for DSM-5

Personality disorder-not otherwise specified (PD-NOS) has received little study despite being a very prevalent diagnosis of personality disorder (PD). Although some studies suggest that PD-NOS is intermediate in severity between subjects with, and without, formal PD, studies examining a comprehensive set of measures and control subjects have not been reported. Nearly 800 subjects were studied with semi-structured diagnostic interviews and with a variety of measures of temperament, character, and specific dimensions of personality and behavior. The subjects were divided into healthy controls (n = 176), Axis I controls (n = 87), PD subjects (n = 344) and PD-NOS subjects (n = 177). Subjects who met General Diagnostic Criteria for Personality Disorder (GDCPD), but not criteria for any one, specific PD, were designated as PD-NOS. On nearly all measures, PD-NOS differed from Healthy and from Axis I Controls in the direction of more pathology. Although subjects meeting criteria for specific PDs appeared more pathological than PD-NOS, this was always due to severity of PD as reflected by the Structured Interview for the Diagnosis of DSM Personality 4 severity score. When compared with subjects with only one specific PD diagnosis, subjects with PD-NOS did not differ in any way. When diagnosed by GDCPD, subjects with PD-NOS are similar to subjects with specific personality disorders and differ, as expected, from Healthy and Axis I Controls on measures of psychosocial function and on various dimensions of personality and related behavior. Accordingly, PD-NOS by GDCPD is as valid a PD as any other specific PD by DSM criteria.     

The syndromal validity and nosological position of apathy in Parkinson's disease

Although apathy is among the most frequent behavioral changes in Parkinson's disease (PD), its diagnosis is still problematic, and the overlap with depression and dementia poorly studied. Aim of the study was validate specific criteria to diagnose apathy in PD, and to examine its association with subsyndromes of depression and dementia. A series of 164 patients with PD, 44 patients with “primary” depression and no PD, 23 patients with Alzheimer's disease, and 26 age‐comparable healthy controls underwent a comprehensive psychiatric assessment that included a structured psychiatric interview and the Apathy Scale. A set of seven diagnostic criteria showed high sensitivity and specificity for clinically diagnosed apathy. Fifty‐two of the 164 patients with PD (32%) met diagnostic criteria for apathy. Eighty‐three percent of patients with apathy had comorbid depression and 56% had dementia. Only 5 of the 40 PD patients (13%) with neither depression nor dementia had apathy. We validated a set of standardized criteria for the diagnosis of apathy in PD. About one third of a series of patients attending a Movement Disorders Clinic showed apathy. Both depression and dementia were the most frequent comorbid conditions of apathy in PD. © 2009 Movement Disorder Society     

The diagnostic challenge of primary dystonia: Evidence from misdiagnosis

Although the understanding of dystonia has improved in recent years, primary dystonia is still insufficiently recognized and patients may not receive the correct diagnosis, leading to transient or permanent misclassification of their symptoms. We reviewed cases of primary dystonia who were at first misdiagnosed and analyzed the reasons why the correct diagnosis was first missed and later retained. Primary dystonia is misdiagnosed mainly, but not exclusively, in favor of other movement disorders: Parkinson's disease (PD), essential tremor, myoclonus, tics, psychogenic movement disorder (PMD), and even headache or scoliosis. Accounts are more numerous for PD and PMD, where diagnostic tests, such as DAT scan and psychological assessment, support clinical orientation. The correct diagnosis was achieved in all cases following the recognition of inconsistencies in the first judgment and of distinctive clinical features of dystonia. These clues have been collected here and assembled into a diagnostic epitome. © 2010 Movement Disorder Society     

Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines

Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.     

Lewy body‐related α‐synucleinopathy in the spinal cord of cases with incidental Lewy body disease

Incidental Lewy body disease (ILBD) represents the early asymptomatic phase of Lewy body diseases (LBD), including idiopathic Parkinson's disease (PD). Although pathological disturbances in the spinal cord, which connects the brain to the peripheral nervous system, plays an important role, the pathology of ILBD has not been adequately examined. Eighteen ILBD and eight age‐matched LBD cases were enrolled in the present study. LB‐related pathology was immunohistochemically evaluated using anti‐phosphorylated α‐synuclein (pαSyn) antibodies, revealing LB‐related pathology in the spinal cords of 15 (83.3%) of the ILBD cases. Attempts were made to identify the early pattern of pαSyn deposition in the spinal cord by comparing the cervical, thoracic, lumbar and sacral segments in detail. Most pαSyn‐positive structures were distributed in and around the autonomic nuclei of the spinal cord. The intermediolateral nuclei in the thoracic segments (Th/IML) were the most frequently and severely affected region, suggesting that Th/IML are the first structures affected. Furthermore, following analysis of the distribution pattern of the pαSyn‐positive structures, it is suspected that LB‐related pathology progresses toward the caudal vertebrae by involving neurons in the spinal cord that are vulnerable to αSyn. It should be noted that the ILBD cases enrolled in the present study were in an earlier stage than the PD cases enrolled in the previous study, and that the present study provides new, previously undescribed information.     

Different diagnostic criteria for Parkinson disease: what are the pitfalls?

As there are no definite diagnostic tests or reliable biomarkers for Parkinson disease (PD), its diagnosis still relies on the presence of a combination of cardinal motor features, along with the exclusion of other causes of Parkinsonism and the presence of some of supportive features. To date, several diagnostic criteria have been developed for different purposes through expert opinions or comprehensive review of the literature. However, none of them are without limitations. In this article, we review different diagnostic criteria for PD which have been published in the English medical literature, highlighting specific limitations and pitfalls. With considerable progress in the understanding of PD, particularly in a view of diverse clinical symptomatology and its evolution, it will be difficult to establish a single criterion that is capable of capturing all cases at different disease stages. Rather, we should aim to develop a set of criteria which include a consensus on clinical gold standard or reliable biomarkers at different levels of diagnostic certainty for different purposes. Despite a more refined set of criteria that may aid in the recognition of PD, the accuracy of its diagnosis still largely depends on the observational skills and clinical sensitivity of the treating physician.     

THE SIGNIFICANCE OF THE LEWY BODY IN THE DIAGNOSIS OF IDIOPATHIC PARKINSON''S DISEASE

A retrospective study of 269 patients with a clinical diagnosis of Parkinson's syndrome was carried out. Seventy-eight were selected as cases of Parkinson's disease on the basis of generally accepted criteria. Of these, 73 were found to have Lewy bodies and cell loss in the substantia nigra, two had the pathological changes of striatonigral degeneration, two had extensive neurofibrillary tangles and nigral cell loss compatible with post-encephalitic parkinsonian syndrome, and one had Lewy bodies and striatonigral degeneration. Pathological examination of the remaining brains revealed Lewy bodies with cell loss in the nigra, a different pathological diagnosis, or normal basal ganglia. No unclassifiable 'senile' patients, or cases with neurofibrillary tangle degeneration or extranigral pathology of unknown cause were found. As a result of these findings clinico-pathological diagnostic criteria for Parkinson's disease are proposed. All patients with this diagnosis had Lewy bodies in surviving neurons of two unilateral 7 microns sections of the mid-part of the substantia nigra. The frequency of Lewy bodies in multiple system atrophy, Steele-Richardson-Olszewski syndrome and Alzheimer's disease was low and similar to that in age-matched 'normal' controls. Pathological findings were compatible with the notion that these individuals have preclinical or coincidental Parkinson's disease.