Conjugal Synucleinopathies: A Clinicopathologic Study.

BACKGROUND: While preclinical studies have shown that alpha-synuclein can spread through cell-to-cell transmission whether it can be transmitted between humans is unknown. OBJECTIVES: The aim was to assess the presence of a synucleinopathy in autopsied conjugal couples. METHODS: Neuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies. RESULTS: Ninety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD. CONCLUSIONS: This large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society.

RNA sequencing of olfactory bulb in Parkinson's disease reveals gene alterations associated with olfactory dysfunction.

The olfactory bulb is involved early in the pathophysiology of Parkinson's disease (PD), which is consistent with the early onset of olfactory dysfunction. Identifying the molecular mechanisms through which PD affects the olfactory bulb could lead to a better understanding of the pathophysiology and etiology of olfactory dysfunction in PD. We specifically aimed to assess gene expression changes, affected pathways and co-expression network by whole transcriptomic profiling of the olfactory bulb in subjects with clinicopathologically defined PD. Bulk RNA sequencing was performed on frozen human olfactory bulbs of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative disorders and the Brain and Body Donation Program. Differential expression analysis (19 PD vs 19 controls) revealed 2164 significantly differentially expressed genes (1090 upregulated and 1074 downregulated) in PD. Pathways enriched in downregulated genes included oxidative phosphorylation, olfactory transduction, metabolic pathways, and neurotransmitters synapses while immune and inflammatory responses as well as cellular death related pathways were enriched within upregulated genes. An overrepresentation of microglial and astrocyte-related genes was observed amongst upregulated genes, and excitatory neuron-related genes were overrepresented amongst downregulated genes. Co-expression network analysis revealed significant modules highly correlated with PD and olfactory dysfunction that were found to be involved in the MAPK signaling pathway, cytokine-cytokine receptor interaction, cholinergic synapse, and metabolic pathways. LAIR1 (leukocyte associated immunoglobulin like receptor 1) and PPARA (peroxisome proliferator activated receptor alpha) were identified as hub genes with a high discriminative power between PD and controls reinforcing an important role of neuroinflammation in the olfactory bulb of PD subjects. Olfactory identification test score positively correlated with expression of genes coding for G-coupled protein, glutamatergic, GABAergic, and cholinergic receptor proteins and negatively correlated with genes for proteins expressed in glial olfactory ensheathing cells. In conclusion, this study reveals gene alterations associated with neuroinflammation, neurotransmitter dysfunction, and disruptions of factors involved in the initiation of olfactory transduction signaling that may be involved in PD-related olfactory dysfunction.

Correlation of Presynaptic and Postsynaptic Proteins with Pathology in Alzheimer's Disease.

Synaptic transmission is essential for nervous system function and the loss of synapses is a known major contributor to dementia. Alzheimer's disease dementia (ADD) is characterized by synaptic loss in the mesial temporal lobe and cerebral neocortex, both of which are brain areas associated with memory and cognition. The association of synaptic loss and ADD was established in the late 1980s, and it has been estimated that 30-50% of neocortical synaptic protein is lost in ADD, but there has not yet been a quantitative profiling of different synaptic proteins in different brain regions in ADD from the same individuals. Very recently, positron emission tomography (PET) imaging of synapses is being developed, accelerating the focus on the role of synaptic loss in ADD and other conditions. In this study, we quantified the densities of two synaptic proteins, the presynaptic protein Synaptosome Associated Protein 25 (SNAP25) and the postsynaptic protein postsynaptic density protein 95 (PSD95) in the human brain, using enzyme-linked immunosorbent assays (ELISA). Protein was extracted from the cingulate gyrus, hippocampus, frontal, primary visual, and entorhinal cortex from cognitively unimpaired controls, subjects with mild cognitive impairment (MCI), and subjects with dementia that have different levels of Alzheimer's pathology. SNAP25 is significantly reduced in ADD when compared to controls in the frontal cortex, visual cortex, and cingulate, while the hippocampus showed a smaller, non-significant reduction, and entorhinal cortex concentrations were not different. In contrast, all brain areas showed lower PSD95 concentrations in ADD when compared to controls without dementia, although in the hippocampus, this failed to reach significance. Interestingly, cognitively unimpaired cases with high levels of AD pathology had higher levels of both synaptic proteins in all brain regions. SNAP25 and PSD95 concentrations significantly correlated with densities of neurofibrillary tangles, amyloid plaques, and Mini Mental State Examination (MMSE) scores. Our results suggest that synaptic transmission is affected by ADD in multiple brain regions. The differences were less marked in the entorhinal cortex and the hippocampus, most likely due to a ceiling effect imposed by the very early development of neurofibrillary tangles in older people in these brain regions.

Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology.

Lewy body (LB) disorders, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. By applying data-driven disease progression modelling to regional neuropathological LB density scores from 814 brain donors, we describe three inferred trajectories of LB pathology that were characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) showed earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) exhibited the first abnormalities in brainstem regions. Early limbic pathology was associated with Alzheimer's disease-associated characteristics. Meanwhile, brainstem-first pathology was associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in LBDs.

Longitudinal motor decline in dementia with Lewy bodies, Parkinson disease dementia, and Alzheimer's dementia in a community autopsy cohort.

INTRODUCTION: We examined the progression of extrapyramidal symptoms and signs in autopsy-confirmed dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Alzheimer's disease dementia (AD). METHODS: Longitudinal data were obtained from Arizona Study of Aging and Neurodegenerative Disease, with PDD (n = 98), AD (n = 47) and DLB (n = 48) further sub-grouped as with or without parkinsonism (DLB+ and DLB-). Within-group Unified Parkinson's Disease Rating Scale (UPDRS) -II and UPDRS-III trajectories were analyzed using non-linear mixed effects models. RESULTS: In DLB, 65.6% had parkinsonism. Baseline UPDRS-II and III scores (off-stage) were highest (P < 0.001) for PDD (mean ± SD 14.3 ± 7.8 and 27.4 ± 16.3), followed by DLB+ (6.0 ± 8.8 and 17.2 ± 17.1), DLB- (1.1 ± 1.3 and 3.3 ± 5.5) and AD (3.2 ± 6.1 and 8.2 ± 13.6). Compared to PDD, the DLB+ group had faster UPDRS-III progression over 8-years (Cohen's-d range 0.98 to 2.79, P < 0.001), driven by gait (P < 0.001) and limb bradykinesia (P = 0.02) subscales. DISCUSSION: Motor deficits progress faster in DLB+ than PDD, providing insights about expected changes in motor function. HIGHLIGHTS: Dementia with Lewy bodies has faster motor progression than Parkinson's disease dementia Linear and non-linear mixed modeling analysis of longitudinal data was utilized Findings have implications for clinical prognostication and trial design.

The role of sex differences in depression in pathologically defined Alzheimer's disease.

Introduction: Sex differences in Alzheimer's disease (AD) may contribute to disease heterogeneity and affect prevalence, risk factors, disease trajectories and outcomes. Depression impacts a large number of patients with AD and has been reported to be more prevalent in women. We aimed to better understand the interaction between sex, depression and AD neuropathology, which could have implications for detection of symptoms, earlier diagnosis, therapeutic management, and enhanced quality of life. Methods: We compared 338 cases with clinicopathologically confirmed AD (46% women) to 258 control cases (50% women), without dementia, parkinsonism or a significant pathological diagnosis. Depression was assessed both, using the Hamilton Depression Scale (HAM-D), and as being reported in their medical history combined with treatment with antidepressant medication. Results: In the control group, women showed a higher depression severity, and a higher proportion of women were found to meet the cut-off score for depression on the HAM-D (32 vs. 16%) and having an history of depression (33 vs. 21%), while these sex differences were not observed in AD. Further, in both groups, female sex independently predicted the presence of depression, with covariates for age and cognitive status. AD subjects had higher mean HAM-D scores, were more likely to meet cutoff scores for depression (41 vs. 24%) and have a history of depression than controls (47 vs. 27%). When comparing the increase in frequency of depression in controls versus AD, the difference was significantly greater in men (AD men - control men: 24%) than in women (AD women - control women: 9%). Although subjects with depression were more likely to have higher levels of AD neuropathology, these differences were not observed when investigating the control or AD group separately. Discussion: Control women had a higher likelihood and severity of depression than control men, but this sex difference was not noted when considering only those with pathologically defined AD, emphasizing the importance of considering sex in aging studies. AD was associated with higher rates of depression and men may be more likely to report or be diagnosed with depression once they develop AD indicating the importance of more frequent depression screenings in men.

Low clinical sensitivity and unexpectedly high incidence for neuropathologically diagnosed progressive supranuclear palsy.

The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100 000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (∼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate.

Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy.

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

Neuropathologic validation of the Alzheimer's Questionnaire.

The Alzheimer's Questionnaire (AQ) is an informant-based screening tool with good diagnostic accuracy for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). The aim of this study is to validate the AQ with AD-associated neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology. Data from 205 prospectively followed autopsy cases clinically classified as AD (n = 90), aMCI (n = 42), or cognitively unimpaired (CU, n = 73) were used. Semi-quantitative measures of NP and NFT pathology were correlated with the AQ, Clinical Dementia Rating Sum of Boxes (CDR-SOB), and the Mini-Mental State Exam (MMSE). The AQ correlated significantly (p < 0.001) with NP load (r = 0.37) and NFT load (r = 0.57). The MMSE and CDR-SOB showed similar correlations with NP load (r = - 0.37, r = 0.35, respectively) and NFT load (r = - 0.58, r = 0.55, respectively). The AQ correlates well with NP and NFT pathology of AD, which provides additional confidence to clinicians using the AQ to screen for AD-related cognitive impairment.

SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

Olfactory Bulb Amyloid-ß Correlates With Brain Thal Amyloid Phase and Severity of Cognitive Impairment.

The Alzheimer disease (AD) neuropathological hallmarks amyloid ß (Aß) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aß throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aß and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aß was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aß and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aß pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.

Clinical Diagnostic Accuracy of Early/Advanced Parkinson Disease: An Updated Clinicopathologic Study.

OBJECTIVE: To update data for 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 (AZSAND) were used to determine the predictive value of a clinical PD diagnosis. Two clinical diagnostic confidence levels were used, possible PD (PossPD, never treated or not responsive) and probable PD (ProbPD, 2/3 cardinal clinical signs and responsive to dopaminergic medications). Neuropathologic diagnosis was the gold standard. RESULTS: Based on the first visit to AZSAND, 15/54 (27.8%) PossPD participants and 138/163 (84.7%) ProbPD participants had confirmed PD. PD was confirmed in 24/34 (70.6%) ProbPD with <5 years and 114/128 (89.1%) with ≥5 years disease duration. Using the consensus final clinical diagnosis following death, 161/187 (86.1%) ProbPD had neuropathologically confirmed PD. Diagnostic accuracy for ProbPD improved if included motor fluctuations, dyskinesias, and hyposmia, and hyposmia for PossPD. CONCLUSIONS: This updated study confirmed lower clinical diagnostic accuracy for elderly, untreated or poorly responsive PossPD participants and for ProbPD with <5 years of disease duration, even when medication responsive. Caution continues to be needed when interpreting clinical studies of PD, especially studies of early disease, that do not have autopsy confirmation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a clinical diagnosis of ProbPD at the first visit identifies participants who will have pathologically confirmed PD with a sensitivity of 82.6% and a specificity of 86.0%.

Clinicopathological Correlation: Dopamine and Amyloid PET Imaging with Neuropathology in Three Subjects Clinically Diagnosed with Alzheimer's Disease or Dementia with Lewy Bodies.

BACKGROUND: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer's disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. OBJECTIVE: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). METHODS: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. RESULTS: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. CONCLUSION: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.

Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease.

The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal ß-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.

Increased Risk of Autopsy-Proven Pneumonia with Sex, Season and Neurodegenerative Disease.

There has been a markedly renewed interest in factors associated with pneumonia, a leading cause of death worldwide, due to its frequent concurrence with pandemics of influenza and Covid-19 disease. Reported predisposing factors to both bacterial pneumonia and pandemic viral lower respiratory infections are wintertime occurrence, older age, obesity, pre-existing cardiopulmonary conditions and diabetes. Also implicated are age-related neurodegenerative diseases that cause parkinsonism and dementia. We investigated the prevalence of autopsy-proven pneumonia in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study, between the years 2006 and 2019 and before the beginning of the Covid-19 pandemic. Of 691 subjects dying at advanced ages (mean 83.4), pneumonia was diagnosed postmortem in 343 (49.6%). There were 185 subjects without dementia or parkinsonism while clinicopathological diagnoses for the other subjects included 319 with Alzheimer's disease dementia, 127 with idiopathic Parkinson's disease, 72 with dementia with Lewy bodies, 49 with progressive supranuclear palsy and 78 with vascular dementia. Subjects with one or more of these neurodegenerative diseases all had higher pneumonia rates, ranging between 50 and 61%, as compared to those without dementia or parkinsonism (40%). In multivariable logistic regression models, male sex and a non-summer death both had independent contributions (ORs of 1.67 and 1.53) towards the presence of pneumonia at autopsy while the absence of parkinsonism or dementia was a significant negative predictor of pneumonia (OR 0.54). Male sex, dementia and parkinsonism may also be risk factors for Covid-19 pneumonia. The apolipoprotein E4 allele, as well as obesity, chronic obstructive pulmonary disease, diabetes, hypertension, congestive heart failure, cardiomegaly and cigarette smoking history, were not significantly associated with pneumonia, in contradistinction to what has been reported for Covid-19 disease.

An initial exploration of the convergent and ecological validity of the UDS 3.0 neuropsychological battery in Parkinson's Disease.

OBJECTIVE: The Uniform Data Set 3.0 neuropsychological battery (UDS3NB) is well developed for research with Alzheimer's disease and related dementias, and may serve as a common set of measures of cognitive decline across neurodegenerative diseases. However, the battery has not been formally assessed in persons with Parkinson's disease (PD). The current research provides initial information on the convergent and ecological validity of the UDS3NB in individuals with PD. METHODS: Participants included 75 individuals diagnosed with PD from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical dementia ratings, administered independently from the cognitive measures, identified individuals as having normal cognition (n = 38), Mild Cognitive Impairment (MCI; n = 25) and dementia (n = 12). UDS3NB measures were compared between these groups, and correlations between UDS3NB measures, gold standard neuropsychological measures, and informant rated activities of daily living ability (ADL) were evaluated. RESULTS: At the group-level, UDS3NB scores followed the expected pattern with higher scores in participants with PD but no cognitive diagnosis and lower in those with dementia; scores in the MCI group were between these extremes. Convergent validity was suggested by moderate correlations between UDS specific measures (i.e., Craft story) and measures such as the RAVLT. Ecological validity was suggested by statistically significant correlations between UDS3NB performance and caregiver ratings of ADLs, with speed and executive functioning measures (Trailmaking A; r = -.51, p < .01; Trailmaking B; r = -.51, p < .01) most strongly related to reported daily functioning. CONCLUSIONS: Findings provide initial support for the convergent and ecological validity of the UDS3NB in individuals with PD. Implications and future directions for this battery are discussed.

Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer's disease dementia.

Many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed during life, instead being categorized as Alzheimer's disease dementia (ADD) or unspecified dementia. Unrecognized DLB therefore is a critical impediment to clinical studies and treatment trials of both ADD and DLB. There are studies that suggest that olfactory function tests may be able to distinguish DLB from ADD, but few of these had neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 257 subjects that went on to autopsy and neuropathological examination. Consensus clinicopathological diagnostic criteria were used to define ADD and DLB, as well as Parkinson's disease with dementia (PDD), with (PDD+AD) or without (PDD-AD) concurrent AD; a group with ADD and Lewy body disease (LBD) not meeting criteria for DLB (ADLB) and a clinically normal control group were also included. The subjects with DLB, PDD+AD and PDD-AD all had lower (one-way ANOVA p < 0.0001, pairwise Bonferroni p < 0.05) first and mean UPSIT scores than the ADD, ADLB or control groups. For DLB subjects with first and mean UPSIT scores less than 20 and 17, respectively, Firth logistic regression analysis, adjusted for age, gender and mean MMSE score, conferred statistically significant odds ratios of 17.5 and 18.0 for the diagnosis, vs ADD. For other group comparisons (PDD+AD and PDD-AD vs ADD) and UPSIT cutoffs of 17, the same analyses resulted in odds ratios ranging from 16.3 to 31.6 (p < 0.0001). To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically-confirmed LBD and ADD. Olfactory function testing may be a convenient and inexpensive strategy for enriching dementia studies or clinical trials with DLB subjects, or conversely, reducing the inclusion of DLB subjects in ADD studies or trials.

Cardiac sympathetic denervation and synucleinopathy in Alzheimer's disease with brain Lewy body disease.

Comorbid Lewy body pathology is very common in Alzheimer's disease and may confound clinical trial design, yet there is no in vivo test to identify patients with this. Tissue (and/or radioligand imaging) studies have shown cardiac sympathetic denervation in Parkinson's disease and dementia with Lewy bodies, but this has not been explored in Alzheimer's subjects with Lewy bodies not meeting dementia with Lewy bodies clinicopathological criteria. To determine if Alzheimer's disease with Lewy bodies subjects show sympathetic cardiac denervation, we analysed epicardial and myocardial tissue from autopsy-confirmed cases using tyrosine hydroxylase and neurofilament immunostaining. Comparison of tyrosine hydroxylase fibre density in 19 subjects with Alzheimer's disease/dementia with Lewy bodies, 20 Alzheimer's disease with Lewy bodies, 12 Alzheimer's disease subjects without Lewy body disease, 19 Parkinson's disease, 30 incidental Lewy body disease and 22 cognitively normal without Alzheimer's disease or Lewy body disease indicated a significant group difference (P < 0.01; Kruskal-Wallis analysis of variance) and subsequent pair-wise Mann-Whitney U tests showed that Parkinson's disease (P < 0.05) and Alzheimer's disease/dementia with Lewy bodies (P < 0.01) subjects, but not Alzheimer's disease with Lewy bodies subjects, had significantly reduced tyrosine hydroxylase fibre density as compared with cognitively normal. Both Parkinson's disease and Alzheimer's disease/dementia with Lewy bodies subjects also showed significant epicardial losses of neurofilament protein-immunoreactive nerve fibre densities within the fibre bundles as compared with cognitively normal subjects (P < 0.01) and both groups showed high pathologic alpha-synuclein densities (P < 0.0001). Cardiac alpha-synuclein densities correlated significantly with brain alpha-synuclein (P < 0.001), while cardiac tyrosine hydroxylase and neurofilament immunoreactive nerve fibre densities were negatively correlated with the densities of both brain and cardiac alpha-synuclein, as well as Unified Parkinson's Disease Rating Scale scores (P < 0.05). The clear separation of Alzheimer's disease/dementia with Lewy bodies subjects from Alzheimer's disease and cognitively normal, based on cardiac tyrosine hydroxylase fibre density, is the first report of a statistically significant difference between these groups. Our data do not show significant sympathetic cardiac denervation in Alzheimer's disease with Lewy bodies, but strongly confirm that cardiac nuclear imaging with a noradrenergic radioligand is worthy of further study as a potential means to separate Alzheimer's disease from Alzheimer's disease/dementia with Lewy bodies during life.

Do Parkinson disease subject and caregiver-reported Epworth sleepiness scale reponses correlate?

OBJECTIVE: Subjective excessive daytime sleepiness, commonly measured with the Epworth Sleepiness Scale (ESS), is associated with cognitive impairment in Parkinson disease (PD). Significant correlation between subject and informant responses has been reported in neurologically healthy individuals. We sought to assess this correlation in patients with PD. PATIENTS AND METHODS: 854 individuals in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) had subject as well as informant-completed ESS completed within one year of a movement disorder exam and cognitive assessment. Correlations were evaluated using Spearman's rank correlation coefficients. RESULTS: Overall, 397/854(46.5 %) were female with mean age of 77.5 (SD 8.3). 572 (67 %) were cognitively normal (CogNL), 135 (15.8 %) had mild cognitive impairment (MCI) and 147 (17.2 %) dementia. Spearman R correlations (all with p < 0.001) between subject and informant ESS responses were 0.73 overall, 0.67 for the CogNL group, 0.79 for the MCI group, 0.79 for those with dementia. Of 175 with clinically probable PD, 115 (65.7 %) were CogNL, 38 had MCI, and 22 (12.6 %) dementia. For subjects with PD correlations (all with p < 0.001) were 0.65 for PD-CogNL, 0.83 for PD-MCI, and 0.70 for those with PD-dementia. CONCLUSION: These significant correlations between subject and informant-completed ESS can be useful in guiding clinical trials designed to assess efficacy of potential treatments for excessive daytime sleepiness for the general population and for patients with PD, even those having cognitive impairment.

Neuropathological Findings in Parkinson's Disease With Mild Cognitive Impairment.

OBJECTIVE: There are few neuropathological studies on Parkinson's disease with mild cognitive impairment (PD-MCI). Those published reveal coexisting Lewy body and Alzheimer's disease pathology. Our objective is to determine the pathology that underlies PD-MCI. METHODS: We used data from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study. Of 736 autopsied subjects with standardized movement and cognitive assessments, 25 had PD-MCI. Neuropathological findings, including Lewy body and Alzheimer's disease pathology, were compared in PD subjects with amnestic MCI (A-MCI) and nonamnestic MCI (NA-MCI). RESULTS: Significant pathological heterogeneity within PD-MCI was found. This included varying Lewy body stages, Alzheimer's disease pathology, and cerebral amyloid angiopathy. There was a significant increase in the severity of Lewy body pathology (meeting The Unified Staging System for Lewy Body disorders neocortical stage) in nonamnestic MCI (7/1, 63%) when compared with amnestic MCI (3/14, 21%, P = 0.032). CONCLUSION: Although a small study, distinct pathological changes may contribute to PD-MCI phenotype. © 2020 International Parkinson and Movement Disorder Society.