Background

Olfactory dysfunction in Parkinson's disease (PD) is well-established and may represent one of the earliest signs of the disease.

Objective & methods

The 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).

Results

Mean 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).

Conclusions

These 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.

Objectives

Determine diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard.

Methods

Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to determine the predictive value of a clinical PD diagnosis, using 2 clinical diagnostic confidence levels, PossPD (never treated or not clearly responsive) and ProbPD (responsive to medications). Neuropathologic diagnosis was the gold standard.

Results

Based on first visit, 9 of 34 (26%) PossPD cases had neuropathologically confirmed PD while 80 of 97 (82%) ProbPD cases had confirmed PD. PD was confirmed in 8 of 15 (53%) ProbPD cases with <5 years of disease duration and 72 of 82 (88%) with ≥5 years of disease duration. Using final diagnosis at time of death, 91 of 107 (85%) ProbPD cases had confirmed PD. Clinical variables that improved diagnostic accuracy were medication response, motor fluctuations, dyskinesias, and hyposmia.

Conclusions

Using neuropathologic findings of PD as the gold standard, this study establishes the novel findings of only 26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects, 53% accuracy in early PD responsive to medication (<5 years' duration), and >85% diagnostic accuracy of longer duration, medication-responsive PD. Caution is needed when interpreting clinical studies of PD, especially studies of early disease that do not have autopsy confirmation. The need for a tissue or other diagnostic biomarker is reinforced.

Classification of evidence

This study provides Class II evidence that a clinical diagnosis of PD identifies patients who will have pathologically confirmed PD with a sensitivity of 88% and specificity of 68%.

The pathologic changes of Parkinson's disease (PD) and Progressive Supranuclear Palsy (PSP) have been reported to coexist, but whether PSP pathology modifies the clinical course of those individuals is unknown. The aim of this study was to determine whether clinical features of pathologically confirmed PD subjects with concomitant PSP pathology differ from those with PD alone. Subjects enrolled in the Arizona Study of Aging and Neurodegenerative Disorders had annual movement and cognitive evaluations from enrollment until death/autopsy. All cases between 1997 and 2014 with a final clinicopathological diagnosis of PD with or without PSP at autopsy were analyzed. Overall, 12 of the 125 cases with pathologically confirmed PD had coexisting PSP pathology (9.6%). Those with PD-PSP had more-prominent postural instability, body bradykinesia, difficulty arising from a chair, and falls; asymmetric onset was less common in this group. Downgaze palsy and square wave jerks were infrequent in both groups. Gender, age at death, disease duration, rate of dementia, and presence of rest tremor did not differ between groups. Only 58% of subjects in the PD-PSP group were correctly given a final diagnosis in life of PD, compared to 91% of those with PD alone. The combination of PD and PSP pathology yields a heterogeneous clinical syndrome that often resembles PD, but may be more symmetric at onset and have more-prominent postural instability and falls. Our observations suggest that coexisting PSP pathology may be an important factor contributing to the clinical heterogeneity in PD and a potential confounder in diagnosis.

Background

Clinical diagnostic criteria for PD rely on rest tremor, bradykinesia, and rigidity. These features are non-specific and neuropathological confirmation remains the gold standard for diagnosis. This study presents data on clinical certainty ratings in autopsy-proven PD.

Methods

Subjects were assessed annually by a movement disorders specialist and assigned to a clinical certainty group for PD based on multiple clinical features before autopsy. The three groups considered for analysis are as follows: Group I 0-49% certainty, Group II 50-89% certainty, and Group III 90-100% certainty. All subjects were autopsied and had a standardized neuropathological assessment.

Results

275 subjects were assigned a PD certainty at their last visit before death. Group I had 80 subjects, Group II 56 subjects, and Group III 139 subjects. The clinical features recorded in Group I, II, and III, were as follows: rest tremor, bradykinesia, rigidity, postural instability, asymmetric onset, persistent asymmetry, current response to dopaminergic treatment, motor fluctuations, and dyskinesia. Rigidity, postural instability, asymmetric onset, current response to dopaminergic treatment, motor fluctuation, and dyskinesia were more likely to be present in the group which was rated with higher certainty. The final diagnosis of PD was confirmed by neuropathological assessment in 85% of the patients in Group III as compared to 30% in Group II and 5% in Group I.

Conclusions

High certainty (90-100%) had strong positive predictive value (85%) for autopsy-proven PD as compared to either lower certainty groups (0-49% and 50-89%) which had lower predictive value (5% and 30% respectively).

Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were women; the median age of study entry was 83.5 years (range, 67-99 years), and the median duration from the first visit until death was 4.3 years (range, 0-10 years). At autopsy, clinicopathological diagnoses were made in 30 cases (25%). These diagnoses included 20 with Alzheimer disease (AD) (17%), 7 with vascular dementia (6%), 4 with progressive supranuclear palsy (3%), 3 with Parkinson disease and 1 each with dementia with Lewy bodies, corticobasal degeneration, or multiple system atrophy (0.8% each). Of the 87 subjects still clinically normal at death (73%), 33 had extensive AD pathology (preclinical AD) (38%), 17 had incidental Lewy bodies (20%), and 4 had incidental pathology consistent with progressive supranuclear palsy (5%). The diagnoses were not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period.

Introduction

Finding a peripheral tissue biopsy site to diagnose early PD would be of value for clinical care, biomarker validation, and as research enrollment criteria. Whereas autopsy and advanced PD studies suggest that the submandibular gland is an important biopsy site, there are no studies in early PD. The aim of this study was to determine whether needle biopsy of the submandibular gland reveals Lewy type alpha-synucleinopathy in early PD.

Methods

Twenty-five early PD (duration < 5 years) and 10 controls underwent transcutaneous needle core biopsies of the submandibular gland. Tissue was stained for phosphorylated alpha-synuclein, reviewed blind to clinical diagnosis, and only nerve element staining was considered positive.

Results

Mean (standard deviation) age was 69.5 (8.3) for the PD group, 64.8 (8.0) years for controls, and disease duration 2.6 (1.1) years. Six PD and 1 control subject had inadequate glandular tissue. Positive staining was found in 14 of 19 (74%) PD and 2 of 9 (22%) control subjects. PD-positive and -negative cases did not differ clinically. Adverse events (mainly swelling and bruising) were common (77% of cases), but were minor and transient.

Conclusions

Submandibular gland needle biopsies identified phosphorylated alpha-synuclein staining in 74% of early PD subjects. False positives may be true false positives or may represent prodromal PD. If confirmed in larger studies with eventual autopsy confirmation, the potential value of submandibular gland biopsies for early PD may be to aid in clinical trial inclusion/exclusion and eventually serve as a gold standard for biomarker studies short of autopsy confirmation.

Objective

Previous research has linked complex or formed visual hallucinations (VH) to Lewy-type alpha-synucleinopathy (LTS) in neocortical and limbic areas. As Alzheimer's disease pathology often co-occurs with LTS, we questioned whether this pathology - amyloid plaques and neurofibrillary tangles - might also be linked to VH.

Methods

We performed a semi-quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), or dementia with Lewy bodies (DLB). 173 subjects - including 50 with VH and 123 without VH - were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini-mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities.

Results

A significant relationship was found between the density of LTS and the presence of VH in PD, AD, and DLB. Plaque and tangle densities also were associated with VH in PD (p = .003 for plaque and p = .004 for tangles) but not in AD, where densities were high regardless of the presence of hallucinations. Furthermore, with DLB cases excluded, comorbidity of PD and AD was significantly more prevalent among subjects + VH than subjects -VH (p < .001).

Conclusion

These findings suggest that both AD and PD neuropathology contribute to the pathogenesis of VH. Incident VH could be predictive of concomitant AD/PD pathology even when criteria are not met for a second diagnosis.

Inability to accurately diagnose Lewy type alpha-synucleinopathy (LTS) pre-mortem has been a major obstacle to clinical care and research. Probable REM sleep behavior disorder (PRBD) diagnosed with support of instruments such as the Mayo Sleep Questionnaire (MSQ) may provide a cost effective means of predicting LTS. Since 2007, 602 subjects in the Arizona Study of Aging and Neurodegenerative Disorders had clinician assessment for PRBD (298 with, 304 without support of the MSQ), completed cognitive and movement examinations, and had neuropathological assessment. Mean age at death was 84.8 years. Histological evidence of LTS was found in 80/101(79.2%) cases with PRBD and 198/501 (39.5%) without PRBD (p < 0.001). Overall sensitivity for predicting LTS by PRBD diagnosis was 28.8%, specificity 93.5%, positive predictive value (PPV) 79.2%, negative predictive value (NPV) 60.5%. Diagnosis of PRBD was less frequently present in subjects without LTS [4/105 (3.8%) of healthy controls, 42/255 (16.5%) AD, 2/33 (6.1%) progressive supranuclear palsy (PSP) without LTS] than in subjects with LTS [11/46 (23.9%) DLB, 58/104 (55.8%) PD, and 4/16 (25.0%) PSP with LTS.] PRBD was not present in any of 46 subjects with incidental Lewy body disease (ILBD). MSQ-supported diagnosis of PRBD appears useful for predicting LTS in manifest neurodegenerative disease, but not necessarily ILBD. Additional prospective autopsy research, including well-characterized polysomnogram-confirmed RBD subjects, is needed to elucidate the earliest tissue abnormalities in the "idiopathic" (premotor/pre-dementia) stage of RBD.

Objective

Identify clinical features predictive of Lewy body pathology in Alzheimer's disease (AD) patients in an ongoing longitudinal clinicopathologic study.

Material and methods

We queried the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) database for dementia cases with AD pathology (1997-2015). Subjects received longitudinal comprehensive clinical evaluations including motor/neuropsychological assessment and Apo-E4 genotyping. All cases were autopsied and had standard neuropathological assessments for AD and Lewy-type synucleinopathy (LTS). Subjects were categorized based on standardized pathological criteria with AD cases that had LTS but did not meet DLB pathologic criteria being categorized as ADLB. We performed pairwise comparison between the different diagnoses and multivariable modelling to identify clinical symptoms that predict the pathological diagnosis.

Results

We identified 32 DLB/AD, 54 ADLB, 70 AD only and 41 PDD/AD cases. AD subjects with LTS pathology had higher UPDRS II and III total scores as well as generally higher individual scores compared to AD alone. While depression scales and Trail-making Test A correlated significantly with LTS, other neuropsychological variables were not significantly different. Apo E4 occurrence was similar in all groups (40%-49%).

Conclusions

Our study suggests that the presence (or absence) of LTS influences motor and non-motor clinical findings in AD patients. These findings may lead to biomarkers that allow for more targeted treatment of AD.

Background

Although there are studies investigating the pathologic origins of mild cognitive impairment (MCI), they have revolved around comparisons to normal elderly individuals or those with Alzheimer's disease (AD) or other dementias. There are few studies directly comparing the comprehensive neuropathology of amnestic (aMCI) and nonamnestic (naMCI) MCI.

Methods

The database of the Brain and Body Donation Program ( www.brainandbodydonationprogram.org ), a longitudinal clinicopathological study of normal aging and neurodegenerative disorders, was queried for subjects who were carrying a diagnosis of aMCI or naMCI at the time of autopsy. Neuropathological lesions, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy bodies (LBs), infarcts, cerebral white matter rarefaction (CWMR), cerebral amyloid angiopathy (CAA), and concurrent major clinicopathological diagnoses, including Parkinson's disease (PD) were analyzed.

Results

Thirty four subjects with aMCI and 15 naMCI met study criteria. Subjects with aMCI were older at death (88 vs. 83 years of age, p = 0.03). Individuals with naMCI had higher densities of LBs within the temporal lobe (p = 0.04) while subjects with aMCI had a propensity for increased NFTs in parietal and temporal lobes (p values = 0.07). After adjusting for age at death, the only significant difference was greater densities of temporal lobe NFTs within the aMCI group. Other regional pathology scores for plaques, NFTs, and LBs were similar between groups. Subjects met clinico-pathological criteria for co-existent PD in 24 % aMCI and 47 % naMCI while neuropathological criteria for AD were met in equal percentages of aMCI and of naMCI cases (53 %); these proportional differences were not significant (p values > 0.35). Furthermore, regardless of amnestic status, there was a greater presence of CAA (71 % of MCI with executive dysfunction vs. 39 % without p = 0.03) and a greater presence of CWMR (81 % of MCI with executive dysfunction and 54 % without p = 0.046) in MCI cases with executive dysfunction.

Conclusions

No single pathologic entity strongly dichotomized MCI groups, perhaps due to the pathologic heterogeneity found within both entities. However, these data suggest the possibility for naMCI to have a propensity for increased LBs and aMCI for increased NFTs in select anatomic regions.