[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: The clinical diagnosis and classification of neurodegenerative diseases based on clinical examination or available biomarkers are currently insufficiently accurate. Although histologic examination is considered the gold standard for diagnosis, brain biopsies have been avoided because of the high risk-benefit ratio. However, brain biopsies have previously been performed with a craniotomy and excision of approximately 1 cm of cerebral cortex tissue, and it is possible that needle core brain biopsies would have a lower morbidity and mortality risk. Here, we compared the ability of simulated needle core biopsy versus simulated open biopsy to detect the frontal cortex histopathology associated with common neurodegenerative diseases in the elderly using 144 autopsy-proven cases. Simulated needle core biopsy, as compared with simulated open biopsy, gave close to 90% sensitivity and specificity for identifying graded densities of β-amyloid and neuritic plaques, neurofibrillary tangles, phosphorylated α-synuclein, and phosphorylated TDP-43 pathology. This study shows that the presence and densities of the most common molecular pathologies may be histopathologically assessed in simulated frontal cortex needle biopsies, with accuracy very close to that obtained by open cortical biopsy. An accurate estimation of the morbidity and mortality risk associated with cortical needle core biopsy will require specifically designed clinical trials in appropriate subjects.
[Show abstract][Hide abstract] ABSTRACT: Background
Hyposmia is common in Parkinson's disease (PD) and is also observed with normal aging. It can be ascertained through objective testing, but it is unclear whether patients are aware of deficits and whether this has implications for cognitive status.Methods
Subjects in the Arizona Study of Aging and Neurodegenerative Disorders were studied with annual motor and cognitive testing with objective smell testing (University of Pennsylvania Smell Identification Test; UPSIT) done every third year beginning in 2002. Those with a baseline UPSIT <25th percentile (hyposmia) were studied for presence of unawareness of hyposmia and cognitive status.ResultsThere were 75 subjects with PD and 143 nonparkinsonian controls with hyposmia. Lack of awareness of hyposmia was present in 16% of PD subjects and 47% of those without PD. In PD, there was no increase in unawareness in PD with dementia. In non-PD controls, unawareness was correlated with presence of dementia. Unawareness of hyposmia correlated most strongly with the neuropsychiatric tests of learning and memory. In controls without dementia or PD, 48% were unaware.Conclusions
Querying patients about anosmia might be useful in parkinsonian disorders without objective testing. However, in elderly controls, it should be followed by objective testing and lack of awareness has implications for worsened cognitive status.
[Show abstract][Hide abstract] ABSTRACT: Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.
[Show abstract][Hide abstract] ABSTRACT: Background: Low-contrast vision is thought to be reduced in Parkinson's disease (PD). This may have a direct impact on quality of life such as driving, using tools, finding objects, and mobility in low-light condition. Low-contrast letter acuity testing has been successful in assessing low-contrast vision in multiple sclerosis. We report the use of a new iPad application to measure low-contrast acuity in patients with PD. Objective: To evaluate low- and high-contrast letter acuity in PD patients and controls using a variable contrast acuity eye chart developed for the Apple iPad. Methods: Thirty-two PD and 71 control subjects were studied. Subjects viewed the Variable Contrast Acuity Chart on an iPad with both eyes open at two distances (40 cm and 2 m) and at high contrast (black and white visual acuity) and 2.5% low contrast. Acuity scores for the two groups were compared. Results: PD patients had significantly lower scores (indicating worse vision) for 2.5% low contrast at both distances and for high contrast at 2 m (p < 0.003) compared to controls. No significant difference was found between the two groups for high contrast at 40 cm (p = 0.12). Conclusions: Parkinson's disease patients have reduced low and high contrast acuity compared to controls. An iPad app, as used in this study, could serve as a quick screening tool to complement more formal testing of patients with PD and other neurologic disorders.
[Show abstract][Hide abstract] ABSTRACT: Background: QEEG could provide physiological biomarkers for changes over time in Parkinson's disease (PD) cognitive decline if they track with longitudinal neuropsychological performance. Objective: Our aim was to correlate longitudinal changes in frequency domain quantitative electroencephalography (QEEG) measures with change in neuropsychological performance testing in PD. Methods: 71 PD subjects, not demented at baseline, were studied from the Arizona Study of Aging and Neurodegenerative Disorders cohort. Baseline and follow-up digital EEG from PD subjects were analyzed for QEEG measures of background rhythm frequency and global relative power in delta (2.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-30 Hz) bands. Baseline and subsequent evaluation included Mini Mental Status Examination and five other neuropsychological tests that load on cognitive domains known to decline in PD. Pearson coefficient was used to assess correlations. Multiple linear regression modeling was used to assess the effect of variable combinations of QEEG and other measures, including age and PD duration. Results: Changes in delta bandpower showed the highest and most consistent pattern of correlations with longitudinal changes in neuropsychological testing. The highest correlation was between delta bandpower increase and decline in the Rey Auditory-Verbal Learning Test (-0.59:p < 0.001). Delta bandpower was also increased in the incident dementia group compared to non-dementia at followup. Conclusions: 1) Longitudinal change in the QEEG frequency domain measure of delta bandpower correlated best with longitudinal neuropsychological performance change in PD; 2) These results constitute preliminary evidence that delta bandpower may be a suitable biomarker for evaluating PD cognitive deterioration longitudinally.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: 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).
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).
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.
[Show abstract][Hide abstract] ABSTRACT: A robust top down proteomics method is presented for profiling alpha-synuclein species from autopsied human frontal cortex brain tissue from Parkinson's cases and controls. The method was used to test the hypothesis that pathology associated brain tissue will have a different profile of post-translationally modified alpha-synuclein than the control samples. Validation of the sample processing steps, mass spectrometry based measurements, and data processing steps were performed. The intact protein quantitation method features extraction and integration of m/z data from each charge state of a detected alpha-synuclein species and fitting of the data to a simple linear model which accounts for concentration and charge state variability. The quantitation method was validated with serial dilutions of intact protein standards. Using the method on the human brain samples, several previously unreported modifications in alpha-synuclein were identified. Low levels of phosphorylated alpha synuclein were detected in brain tissue fractions enriched for Lewy body pathology and were marginally significant between PD cases and controls (p = 0.03).
[Show abstract][Hide abstract] ABSTRACT: 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%.
[Show abstract][Hide abstract] ABSTRACT: The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue- such as the inability to biopsy or test tissue from the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess disease progression and therapeutic efficacy.
PLoS ONE 05/2014; 9(5):e94839. DOI:10.1371/journal.pone.0094839 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Many clinicopathological studies do not specify the presence of other pathologies located within the brain, so disease heterogeneity may be under appreciated.
The purpose of this study was to determine the frequencies of concomitant pathologies among parkinsonian disorders.
Data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), an ongoing longitudinal clinical-neuropathological study, was used to analyze concomitant pathologies, including Alzheimer’s disease (AD), argyrophilic grains (Arg), cerebral amyloid angiopathy (CAA), cerebral white matter rarefaction (CWMR) and overlap of each parkinsonian disorder in clinico-pathologically defined Parkinson’s disease (PD; N=140), dementia with Lewy bodies (DLB; N=90), progressive supranuclear palsy (PSP; N=64), multiple system atrophy (MSA; N=6), corticobasal degeneration (CBD; N=7); and normal elderly (controls; N=166).
Of the neuropathologically-confirmed PD cases, 38% had a concomitant diagnosis of AD, 9% PSP, 25% Arg, and 44% CWMR, and 24% CAA. For DLB, 89% had AD, 1% PSP, 21% Arg, and 51% CWMR, and 50% CAA. For PSP cases, 36% had AD, 20% PD, 1% DLB, 44% Arg, 52% CWMR and 25% CAA. Similar heterogeneity was seen for MSA and CBD cases. Many cases had more than one of the above additional diagnoses.
These data demonstrate a great deal of concomitant pathologies among different types of parkinsonian disorders; this may help explain the heterogeneity of clinical findings.
[Show abstract][Hide abstract] ABSTRACT: Visual symptoms are relatively common in Parkinson's disease (PD) and optical coherence tomography has indicated possible retinal thinning. Accumulation of aggregated α-synuclein is thought to be a central pathogenic event in the PD brain but there have not as yet been reports of retinal synucleinopathy. Retinal wholemounts were prepared from subjects with a primary clinicopathological diagnosis of PD (N=9), dementia with Lewy bodies (DLB; N=3), Alzheimer's disease (N=3), progressive supranuclear palsy (N=2) as well as elderly normal control subjects (N=4). These were immunohistochemically stained with an antibody against α-synuclein phosphorylated at serine 129, which is a specific molecular marker of synucleinopathy. Phosphorylated α-synuclein-immunoreactive (p-syn IR) nerve fibers were present in 7/9 PD subjects and in 1/3 DLB subjects; these were sparsely distributed and superficially located near or at the inner retinal surface. The fibers were either long and straight or were branching, often with multiple en-passant varicosities along their length. The straight fibers most often had an orientation that was radial with respect to the optic disc. Together, these features are suggestive of either retinopetal/centrifugal fibers or of ganglion cell axons. In one PD subject there were sparse p-syn IR neuronal cell bodies with dendritic morphology suggestive of G19 retinal ganglion cells or intrinsically photosensitive ganglion cells. There were no stained nerve fibers or other specific staining in any of the non-PD or non-DLB subjects. It is possible that at least some of the observed visual function impairments in PD subjects might be due to α-synucleinopathy.