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Background: The G2019S leucine‐rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology. Objective: Describe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies. Method: We present an 89‐year‐old man with a 10‐year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease. Results: Neuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau‐immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging‐related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found. Conclusion: This case illustrates that levodopa‐responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 dementiaLinear and non‐linear mixed modeling analysis of longitudinal data was utilizedFindings have implications for clinical prognostication and trial design [ABSTRACT FROM AUTHOR]

Background: a‐synuclein aggregation is a pathologic hallmark of several Lewy body disorders with differing symptoms. This symptom heterogeneity may be due to varying underlying disease trajectories. Here, we use a data‐driven approach to identify and characterize distinct spatial‐temporal progression patterns of α‐synuclein deposition. Method: The Subtype and Stage Inference (SuStaIn) model evaluates the optimal grouping of individuals into subtypes with distinct orderings of events/stages. We applied Ordinal SuStaIn to post‐mortem Lewy‐type α‐synuclein (LTS) density scores measured in 10 regions (including olfactory bulb and tract [OBT], limbic, brainstem, and cortical regions) of 814 subjects from the Sun Health Research Institute Brain Donation Program (Table‐1). The optimal SuStaIn model was selected according to the Cross‐Validation Information Criteria. We selected 781 subjects with stage>0 (nexcluded = 13) and subtype probability>50% (nexcluded = 20) to assess differences in subtypes. Hierarchical multinomial logistic regressions were performed to compare subtypes on (1) age at death, sex, APOE‐e4 copies, and post‐mortem interval; (2) total amyloid plaque load; and (3) total tau tangle load. In a subset of individuals (n = 355), we additionally compared subtypes on MMSE scores and the motor section of the Unified Parkinson Disease Rating Scale (UPDRS). All models were adjusted for SuStaIn stage and significant predictors of preceding models. Result: SuStaIn identified three subtypes with distinct LTS trajectories, which we termed "OBT/Limbic‐first", "OBT/Brainstem‐first", and "OBT‐sparing/Brainstem‐first" based on the first regions to show deposition (Figure‐1). The majority of individuals were assigned to OBT/Limbic‐first (N = 475,60.8%), followed by OBT/Brainstem‐first (N = 165,21.1%), and OBT‐sparing/Brainstem‐first (N = 141,18.1%) subtypes (Table‐1). We observed a higher frequency of homozygous APOE‐e4 carriers and amyloid and tau burden in the OBT/Limbic‐first subtype compared to the OBT/Brainstem‐first (ßAPOE‐e4 = 0.82±0.40, pAPOE‐e4 =.042; ßamyloid= 0.08±0.42, pamyloid<.001; ßtau= 0.17±0.03, ptau<.001) and OBT‐sparing/Brainstem‐first (ßAPOE‐e4 = 0.98±0.48, pAPOE‐e4 =.042; ßamyloid= 0.14±0.27, pamyloid<.001; ßtau= 0.18±0.03, ptau<.001) subtypes. In addition, the OBT/Brainstem‐first subtype showed a higher amyloid burden (ß = 0.06±0.02, p =.012) and higher MMSE (ß = 0.08±0.04, p = 0.030) compared to the OBT‐sparing/Brainstem‐first (Table‐1, Figure‐2). Conclusion: In this large post‐mortem SuStaIn study, we identified three subtypes of α‐synuclein deposition, possibly reflecting different epicenters and spreading trajectories of misfolded α‐synuclein, where OBT/Limbic‐first was associated with Alzheimer's co‐pathology. Follow‐up work will study how these subtypes differ in clinical diagnosis and symptomatology. [ABSTRACT FROM AUTHOR]

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates have not yet been fully determined. To investigate and compare independent associations between multiple plasma biomarkers (p‐tau181, p‐tau217, p‐tau231, Aβ42/40, GFAP, and NfL) and neuropathologic measures of amyloid and tau, we included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with antemortem plasma samples and a postmortem neuropathological exam, 48 of whom had longitudinal p‐tau217 and p‐tau181. When simultaneously including plaque and tangle loads, the Aβ42/40 ratio and p‐tau231 were only associated with plaques (ρAβ42/40[95%CI] = −0.53[−0.65, −0.35], ρp‐tau231[95%CI] = 0.28[0.10, 0.43]), GFAP was only associated with tangles (ρGFAP[95%CI] = 0.39[0.17, 0.57]), and p‐tau217 and p‐tau181 were associated with both plaques (ρp‐tau217[95%CI] = 0.40[0.21, 0.56], ρp‐tau181[95%CI] = 0.36[0.15, 0.50]) and tangles (ρp‐tau217[95%CI] = 0.52[0.34, 0.66]; ρp‐tau181[95%CI] = 0.36[0.17, 0.52]). A model combining p‐tau217 and the Aβ42/40 ratio showed the highest accuracy for predicting the presence of Alzheimer's disease neuropathological change (ADNC, AUC[95%CI] = 0.89[0.82, 0.96]) and plaque load (R2 = 0.55), while p‐tau217 alone was optimal for predicting tangle load (R2 = 0.45). Our results suggest that high‐performing assays of plasma p‐tau217 and Aβ42/40 might be an optimal combination to assess Alzheimer's‐related pathology in vivo. Synopsis: This study conducted a head‐to‐head comparison between multiple plasma biomarkers and neuropathological measures of amyloid plaques and neurofibrillary tangles. Plasma p‐tau217 and p‐tau181 are independently associated with both amyloid plaques and tau neurofibrillary tangles, the main pathological hallmarks of Alzheimer's disease.Plasma p‐tau217 may be a better Alzheimer's biomarker than p‐tau181 as it shows stronger associations with Alzheimer's pathology and is more sensitive to early pathological changes.Plasma p‐tau217 longitudinal changes may help in predicting the presence of Alzheimer's pathology.Plasma Aβ42/40 and plasma p‐tau231 are specifically associated with amyloid pathology, whereas plasma glial fibrillary acidic protein (GFAP) is specifically associated with tau pathology.Plasma neurofilament light (NfL) is increased in participants with cerebral white matter rarefaction even after accounting for the presence of Alzheimer's disease pathology. [ABSTRACT FROM AUTHOR]

Objectives: Detection of α‐synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α‐synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α‐synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α‐synuclein measures, and investigate within‐subject relationships. Methods: The Systemic Synuclein Sampling Study aimed to characterize α‐synuclein in multiple tissues and biofluids within Parkinson disease subjects (n = 59) and compared to healthy controls (n = 21). Motor and non‐motor measures and dopamine transporter scans were obtained. Four measures of α‐synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin‐fixed paraffin‐embedded submandibular gland, total α‐synuclein quantified in biofluids using enzyme‐linked immunoassay, and aggregated α‐synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within‐subject α‐synuclein measures were compared. Results: Sensitivity and specificity of α‐synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different α‐synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index = 83.1%). 98.3% of all Parkinson disease cases had ≥1 measure of α‐synuclein positive. Interpretation: α‐synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total α‐synuclein measures, and within‐subject relationships of central and peripheral α‐synuclein measures emerged. [ABSTRACT FROM AUTHOR]

Decline of olfactory function is frequently observed in aging and is an early symptom of neurodegenerative diseases. As the olfactory bulb (OB) is one of the first regions involved by pathology and may represent an early disease stage, we specifically aimed to evaluate the contribution of OB pathology to olfactory decline in cognitively normal aged individuals without parkinsonism or dementia. This clinicopathological study correlates OB tau, amyloid β (Aβ) and α‐synuclein (αSyn) pathology densities and whole brain pathology load to olfactory identification function as measured with the University of Pennsylvania Smell Identification Test (UPSIT) and clinical data measured proximate to death in a large autopsy study including 138 cases considered non‐demented controls during life. Tau pathology was frequently observed in the OB (95% of cases), while both Aβ (27% of cases) and αSyn (20% of cases) OB pathologies were less commonly observed. A weak correlation was only observed between OB tau and olfactory performance, but when controlled for age, neither OB tau, Aβ or αSyn significantly predict olfactory performance. Moreover, whole brain tau and αSyn pathology loads predicted olfactory performance; however, only αSyn pathology loads survived age correction. In conclusion, OB tau pathology is frequently observed in normally aging individuals and increases with age but does not appear to independently contribute to age‐related olfactory impairment suggesting that further involvement of the brain seems necessary to contribute to age‐related olfactory decline. [ABSTRACT FROM AUTHOR]

Background: Evidence from previous PET imaging studies suggests that increased neocortical tau seen in APOE‐ε4 carriers can be explained by the higher levels of neocortical amyloid‐β (Aβ) pathology also seen in this group. However, these studies also suggest an amyloid‐independent association between APOE‐ε4 and medial temporal lobe (MTL) tau. Using neuropathological data, we investigated whether amyloid‐β in the MTL, which is difficult to accurately measure with PET, may fully mediate the association between APOE‐ε4 carriership and MTL tau burden. Method: Amyloid‐β and tau pathology in MTL and neocortical areas have been measured in a total of 2,704 individuals from two independent neuropathological datasets (Arizona Study of Aging and Neurodegenerative Disorders, Brain and Body Donation Program, n=1,117 and ROSMAP, n=1,587; Table 1). Regression models were used to investigate the associations between APOE‐ε4 carriership and neocortical and local (MTL) amyloid‐β on MTL tau, adjusting for age, sex and presence of co‐pathologies. Based on these results, we also tested whether local (MTL) amyloid‐β mediated the association between APOE‐ε4 carriership and MTL tau. Result: Supporting results from previous studies, APOE‐e4 carriers showed higher tau burden in the MTL (p<0.001) when amyloid‐β was not included in the model in both datasets. In independent models, both local and neocortical amyloid‐β were associated with MTL tau, with local amyloid‐β showing a stronger association with MTL tau in both datasets (Arizona: βMTL=0.93 vs. βneoc=0.76; ROSMAP: βMTL=0.42 vs. βneoc=0.40). When both measures were included in the model, local amyloid‐β also showed a stronger association with MTL tau in ROSMAP (βMTL=0.28 vs. βneoc=0.19). In the Arizona dataset, neocortical amyloid‐β effect became non‐significant (p=0.252) when local amyloid‐β was also included in the model. Finally, with mediation analyses we observed that MTL amyloid‐β fully mediated the APOE‐ε4 effect on MTL tau in both datasets (Figure 1). All statistics are reported in Table 2. Conclusion: In two large neuropathological datasets, we showed that the association between APOE‐ε4 genotype and higher medial temporal lobe tau burden is mediated by higher local amyloid‐β levels. This finding contradicts some previous imaging literature, where only global amyloid‐β burden was considered. [ABSTRACT FROM AUTHOR]

Background: Pathological Lewy body disease (LBD) may commonly present clinically as Parkinson's disease dementia (PDD), Dementia with Lewy bodies (DLB) or Alzheimer's disease dementia (ADD). Neuropathological definitions also include a group in which ADD is present, but the postmortem Lewy pathology does not meet threshold density and distribution levels for the neuropathological diagnosis of DLB (ADLB). Little is known about the cognitive profiles of patients with ADLB and despite common underlying pathology, studies delineating neuropsychological profiles in LBD are fraught with inconsistencies. We characterized the longitudinal cognitive trajectories defined by neuropsychological profiles in cases along the pathological spectrum of LBD. Method: Cases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a cognitive diagnosis of dementia at death and who at minimum, had two neuropsychological evaluations were included. Final neuropathological diagnosis was determined as LBD (neocortical or limbic LB ± AD), ADLB, and AD pathology only. LBD cases were categorized by their cognitive clinical syndromes as PDD and DLB. Global cognition was evaluated using MMSE. Neuropsychological domains of Memory, Executive function, language, attention, and visuospatial were evaluated. Mixed linear methods were used to predict longitudinal change for a given baseline MMSE. Result: 287 participants and 1874 participant‐years of data were included in this study. LBD (n = 115), and ADLB (52) groups were predominantly male, while AD (n = 114) group was primarily female. Baseline MMSE was similar across all pathologic groups. Linear mixed modelling methods showed faster decrease in memory domain scores (decreasing 0.22 units/year – 0.42 units/year faster, p = 0.01) in ADLB group compared to other groups. Significantly faster decline was noted in LBD and ADLB group in clock drawing (p<0.001), fluency scores (declining 1.02 unit/year faster p<0.001) compared to AD group. There was no difference between PDD and DLB clinical subgroups. Conclusion: In autopsy confirmed cases, ADLB had an accelerated trajectory of decline in memory tasks, while AD, and LBD appeared to have similar trajectories. In contrast, all groups with Lewy bodies progressed faster and showed accelerated decline compared to AD in measures of frontal‐subcortical functions. These results may inform antemortem classification of patients and diagnostic accuracy in these groups. [ABSTRACT FROM AUTHOR]

Background: Strong evidence from diverse sources points to adenosine triphosphate‐binding cassette transporter subfamily A member 7 (ABCA7) as a major risk factor in Alzheimer's disease (AD). However, the mode of its involvement with the disease and many aspects of its function are understood incompletely. Method: Human microglia cells C20 and HMC3 and neuronal cells SK‐N‐SH were either depleted in cholesterol using methyl‐β‐cyclodextrin and/or rosuvastatin or treated with pro‐inflammatory cytokines IL‐1β, IL‐6 or TNFα, and ABCA7 protein levels in these cells were then assessed using a validated monoclonal antibody. ABCA7 levels were also assessed using the antibody in the parietal cortex from 170 donors, who were genotyped for the APOE isoforms. Result: Large (∼75%) reductions in intracellular cholesterol and saturating amounts of pro‐inflammatory cytokines IL‐1β and TNFα reduced ABCA7 protein by, respectively, 36.8±9.1% (mean±standard deviation, two‐tailed t test p = 0.0002, n = 4), 53.0±22.6% (p = 0.002, n = 4) and 59.2±8.0% (p = 0.0006, n = 4) in C20 cells and by similar percentages in HMC3 cells. Similarly severe cholesterol depletion had no effect on ABCA7 and IL‐1β and TNFα moderately increased ABCA7 amounts in SK‐N‐SH cells. IL‐6 had no effect on ABCA7 expression in any cell line. IL‐1β and TNFα significantly cross‐induced each other's secretion in C20 cells. We have previously shown that ABCA7 protein levels drop suddenly during AD pathogenesis between Braak and Braak stages I and II in the human brain. Among the individuals without AD pathology or with Braak stage I pathology, ABCA7 levels were lower in APOE4 carriers without reaching statistical significance (0.74, 0.35‐2.51 vs 1.5, 0.30‐3.16 ABCA7/GAPDH ratios; median, 25%‐75% interval; Mann‐Whitney p = 0.44, n = 68 vs 14); among the individuals with Braak stages II‐V, ABCA7 was also lower in APOE4 carriers (0.21, 0.07‐1.07 vs 0.55, 0.11‐1.35; Mann‐Whitney p = 0.18, n = 53 vs 35). The comparison groups were matched for age, sex and PMI. Conclusion: The effect of cholesterol depletion on ABCA7 expression is tissue specific. ABCA7 functions are homeostatic and not compatible with inflammation in microglia. If APOE4 has an effect on ABCA7 levels, it is smaller than the reduction in ABCA7 between Braak stages I and II. These findings improve our understanding of ABCA7 pathophysiology. [ABSTRACT FROM AUTHOR]

Background: The brainstem nucleus incertus (NI) or 'uncertain nucleus', was originally described by Streeter in 1903 as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. A century later, the NI has been shown to play a key role in memory formation in rodents, through direct and indirect inhibition of the hippocampus; and the anatomy of the NI and its projections throughout the brain have been systematically mapped in rats, mice, and primates, but not in humans. In these novel studies, we mapped the human NI using the neuropeptide, relaxin‐3 (RLN3), as neurochemical marker. In rodents, RLN3 is produced mostly in NI neurons with some subsidiary positive cells in the periaqueductal gray and an area dorsal to the substantia nigra. Methods: Serial, free‐floating coronal sections of formalin‐fixed postmortem tissue were prepared from the pons of an adult female (aged 96 years) without a history of dementia or other neurological disorders, provided by the Banner Brain and Body Donation Program, Sun City, Arizona, USA. Using immunohistochemistry, we first identified the NI by mapping the distribution of microtubule‐associated protein‐2 (MAP2) and RLN3. The specificity of the RLN3 antibody used was verified in a dot‐blot using native RLN3 peptide. We also investigated the presence of markers detected in the NI of rats ‐ glutamic acid dehydrogenase‐65/67 (GAD65/67) and corticotropin‐releasing factor type 1 receptor (CRF1); and used a phosphorylated‐tau (AT8) to determine if the NI displayed tau accumulation. Results: Detection of MAP2‐immunoreactivity revealed the neuronal distribution throughout the pons. RLN3‐immunoreactivity was detected in neurons in the dorsal, anterior‐medial region, revealing the broad anatomy of the human NI. Neurons within this same area were also positive for GAD65/67‐ and CRF1‐immunoreactivity, in line with previous studies; and AT8‐immunoreactivity was also detected. Conclusions: RLN3 is present in neurons of the human NI and aspects of its anatomy are shared across species, including the macaque. Accumulation of phosphorylated‐tau in the NI suggests its possible involvement in the pathology of Alzheimer's disease and related dementias. Further comparative studies are required to better understand the neurochemical anatomy of the human NI. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by β‐amyloid plaques and tau tangles. Plasma levels of phospho‐tau217 (P‐tau217) accurately differentiate Alzheimer's disease dementia from other dementias, but it is unclear to what degree this reflects β‐amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post‐mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P‐tau217, but P‐tau217 was not elevated in patients with non‐Alzheimer's disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging ("BioFINDER‐2", N = 426), where β‐amyloid and tau PET were independently associated with P‐tau217. P‐tau217 concentrations correlated with β‐amyloid PET (but not tau PET) in early disease stages and with both β‐amyloid and (more strongly) tau PET in late disease stages. Finally, P‐tau217 mediated the association between β‐amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P‐tau217 concentration is increased by both β‐amyloid plaques and tau tangles and is congruent with the hypothesis that P‐tau is involved in β‐amyloid‐dependent formation of neocortical tau tangles. Synopsis: Plasma levels of phosphorylated tau, including P‐tau217, are elevated in Alzheimer's disease (AD). This study explores the underlying processes associated with the increased levels of plasma P‐tau217, using post‐mortem data and positron emission tomography (PET) of β‐amyloid and tau. Plasma P‐tau217 is independently associated with higher levels of both β‐amyloid pathology and tau pathology in the brain.The first changes in plasma P‐tau217 may reflect the early accumulation of β‐amyloid before there is widespread tau aggregation.Once tau aggregation reaches the neocortex, there is a strong correlation between plasma P‐tau217 and the amount of aggregated tau.Plasma P‐tau217 mediates the association between β‐amyloid accumulation and tau accumulation. [ABSTRACT FROM AUTHOR]

Background: An unmet clinical need in Parkinson's disease (PD) is to identify biomarkers for diagnosis, preferably in peripherally accessible tissues such as skin. Immunohistochemical studies have detected pathological α‐synuclein (αSyn) in skin biopsies from PD patients albeit sensitivity needs to be improved. Objective: Our study provides the ultrasensitive detection of pathological αSyn present in the skin of PD patients, and thus, pathological αSyn in skin could be a potential biomarker for PD. Methods: The real‐time quaking‐induced conversion assay was used to detect pathological αSyn present in human skin tissues. Further, we optimized this ultra‐sensitive and specific assay for both frozen and formalin‐fixed paraffin‐embedded sections of skin tissues. We determined the seeding kinetics of the αSyn present in the skin from autopsied subjects consisting of frozen skin tissues from 25 PD and 25 controls and formalin‐fixed paraffin‐embedded skin sections from 12 PD and 12 controls. Results: In a blinded study of skin tissues from autopsied subjects, we correctly identified 24/25 PD and 24/25 controls using frozen skin tissues (96% sensitivity and 96% specificity) compared to 9/12 PD and 10/12 controls using formalin‐fixed paraffin‐embedded skin sections (75% sensitivity and 83% specificity). Conclusions: Our blinded study results clearly demonstrate the feasibility of using skin tissues for clinical diagnosis of PD by detecting pathological αSyn. Moreover, this peripheral biomarker discovery study may have broader translational value in detecting misfolded proteins in skin samples as a longitudinal progression marker. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease is characterized by β‐amyloid plaques and tau tangles. Plasma levels of phospho‐tau217 (P‐tau217) accurately differentiate Alzheimer's disease dementia from other dementias, but it is unclear to what degree this reflects β‐amyloid plaque accumulation, tau tangle accumulation, or both. Method: We studied plasma P‐tau217 in a cohort with post‐mortem neuropathological data (N=88), for correlations with plaque and tangle density, and in a cohort with β‐amyloid and tau PET imaging ("BioFINDER‐2", N=426). Result: In the cohort with post‐mortem neuropathological data, both plaque and tangle density contributed independently to higher P‐tau217 (Fig 1). Several findings were replicated in the cohort with PET imaging, where β‐amyloid and tau PET were independently associated to P‐tau217. P‐tau217 correlated with β‐amyloid PET (but not tau PET) in early disease stages, and with both β‐amyloid and (more strongly) tau PET in late disease stages (Fig 2). Finally, P‐tau217 mediated the association between β‐amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe (Fig 3). Conclusion: These findings support the hypothesis that plasma P‐tau217 is associated with both β‐amyloid plaques and tau tangles and is congruent with the hypothesis that P‐tau is involved in β‐amyloid‐dependent formation of neocortical tau tangles (Fig 4). [ABSTRACT FROM AUTHOR]

Objective: Considering the demonstrated implication of the retina in Parkinson disease (PD) pathology and the importance of dopaminergic cells in this tissue, we aimed to analyze the state of the dopaminergic amacrine cells and some of their main postsynaptic neurons in the retina of PD. Methods: Using immunohistochemistry and confocal microscopy, we evaluated morphology, number, and synaptic connections of dopaminergic cells and their postsynaptic cells, AII amacrine and melanopsin‐containing retinal ganglion cells, in control and PD eyes from human donors. Results: In PD, dopaminergic amacrine cell number was reduced between 58% and 26% in different retinal regions, involving a decline in the number of synaptic contacts with AII amacrine cells (by 60%) and melanopsin cells (by 35%). Despite losing their main synaptic input, AII cells were not reduced in number, but they showed cellular alterations compromising their adequate function: (1) a loss of mitochondria inside their lobular appendages, which may indicate an energetic failure; and (2) a loss of connexin 36, suggesting alterations in the AII coupling and in visual signal transmission from the rod pathway. Interpretation: The dopaminergic system impairment and the affection of the rod pathway through the AII cells may explain and be partially responsible for the reduced contrast sensitivity or electroretinographic response described in PD. Also, dopamine reduction and the loss of synaptic contacts with melanopsin cells may contribute to the melanopsin retinal ganglion cell loss previously described and to the disturbances in circadian rhythm and sleep reported in PD patients. These data support the idea that the retina reproduces brain neurodegeneration and is highly involved in PD pathology. ANN NEUROL 2020;88:893–906 [ABSTRACT FROM AUTHOR]

Background: The early stage of Alzheimer's Dementia (AD) development has been linked to the breakdown of the blood‐brain barrier (BBB), which is maintained by pericytes and other cell types. Platelet‐derived growth factor receptor‐β (PDGFRβ) has been identified as a novel biomarker of BBB‐associated capillary pericyte damage. Our study aimed to explore the potential association between PDGFRβ and neuropathological diagnosis of Alzheimer's Dementia, as well as GFAP levels‐ a widely recognized AD biomarker that is present in both serum and cerebrospinal fluid (CSF). Method: A cohort of 48 subjects in the Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with serum and CSF samples, obtained at the time of death, were included in this cross‐sectional study. Enzyme‐linked immunosorbent assay (ELISA) was utilized to detect PDGFRβ and GFAP in serum and CSF. Statistical analyses were performed using Spearman's rank correlation and Mann‐Whitney U test. Result: Baseline characteristics were similar between AD (n = 28) and non‐AD groups(n = 20). There was a significant increase in levels of serum PDGFRβ in AD compared to unmatched non‐AD subjects (Mean: 6348.2pg/ml vs 4730.1pg/ml, p<0.05). In addition, PDGFRβ in both CSF and serum correlated with Glial Fibrillary Acidic Protein (GFAP), a well‐known biomarker associated with AD (Spearman's 흆 = 0.42, P< 0.01, Spearman's 흆 = 0.46, P< 0.01, respectively.) Conclusion: PDGFRβ, a putative marker of BBB integrity, is elevated in the serum of individuals with Alzheimer's Dementia (AD) and is correlated with GFAP levels measured in both serum and cerebrospinal fluid (CSF). While these findings are promising and suggest the potential use of PDGFRβ as a blood‐based biomarker for AD pathophysiology, further studies with larger sample sizes are warranted to validate the potential of PDGFRβ as a biomarker for AD. [ABSTRACT FROM AUTHOR]

Background: Accumulation of tau oligomers at the synapses in Alzheimer's disease (AD) disrupts neuronal activities and leads to neurodegeneration. Tau immunotherapy has been actively pursued as a treatment for tauopathies in the past decade. Despite several failed Phase 2 trials of N‐terminus binding antibodies a variety of tau epitopes are being investigated at different stages of clinical trials. APNmAb005 is a humanized monoclonal antibody designed to block synaptic toxicity elicited by tau oligomers. Method: APNmAb005 was selected as a clinical candidate from APRINOIA's antibody discovery platform based on its unique binding properties to pathological tau in vitro immunoassays as well in vivo efficacy studies in rTg4510 mice. Humanized APNmAb005 is in IgG4 backbone and the production was scaled up successfully with good stability and solubility to support preclinical and clinical development. GLP safety study was conducted in cynomolgus monkeys. A Phase 1a randomized, double‐blind, placebo‐controlled study of APNmAb005 in healthy subjects is underway. Result: Epitope‐mapping study reveals that APNmAb005 binds to a conformation‐dependent epitope in the mid‐region, which results in a preferable recognition of pathological tau in early Braak stage (III‐IV) AD brains as well as tau aggregates in astrocytes and oligodendrocytes in brains from progressive supranuclear palsy (PSP) patients but not monomeric tau in normal brains. APNmAb005 blocks in vitro tau seeding at nanomolar concentrations and rescues neuronal loss in rTG4510 mice. Four‐week repeat dosing toxicology study shows no observed adverse effects. Conclusion: APNmAb005 is a conformation selective antibody that binds to tau oligomers and aggregates preferentiually in synapses in pathological brain tissues and inhibits tau spreading. The mid‐region conformation dependent epitope is distinct from all other tau antibodies currently in clinical development. APNmAb005 offers a unique tau immunotherapy for neurodegenerative disorders and is currently in Phase 1 to evaluate its safety and tolerability. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are frequent in Alzheimer's Disease dementia (ADD) but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co‐occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). Previous studies have shown that both ADLB and DLB cases have faster cognitive and/or functional decline compared to AD. However, the differences in NPS severity over disease course and survival in these pathologic subgroups is not well understood. Method: Cases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a final neuropathologic diagnosis of DLB (±AD co‐pathology; n = 65), ADLB (n = 89), AD (without LB) (n = 140), and controls (no neuropathological diagnosis) (n = 82) were included. Total NPI‐Q (scores ranging from 0‐36) at time of enrollment and within 2.5 years of death were calculated for all groups. Statistical analysis utilizing ANCOVA (adjusting for age, sex, baseline MMSE and cognitive symptom duration) with pairwise comparisons, and Kaplan‐Meier curves were completed. Result: Age at onset of cognitive symptoms was not different between pathology groups. NPI‐Q scores at enrollment were highest in ADLB (7.33 ± 4.85), and higher (p<0.001) than DLB (5.10 ± 3.37), AD (4.54 ± 3.63) and controls (1.78 ± 1.70). At final evaluation, NPI‐Q scores were highest in DLB (10.04 ± 6.28), followed by ADLB (8.0 ± 4.), and ADD (7.61 ± 5.05) when compared to controls (2.78 ± 3.97) (all p<0.001). DLB and AD demonstrated significant increases in NPI‐Q severity during follow up (p < 0.001). AD had longer survival time (5.8 years) compared to ADLB (4.0 years) and DLB (3.9 years). Subjects with NPS had a shorter median survival time (3.4 years) compared to subjects without NPS (6.5 years; p = 0.002). Conclusion: A higher NPS burden and shorter survival is seen in both DLB and ADLB, as compared with AD. This suggests that diffuse neocortical LB pathology is not the major driver of either NPS or survival. [ABSTRACT FROM AUTHOR]

The Arizona Study of Aging and Neurodegenerative Disease (AZSAND)/Brain and Body Donation Program (BBDP) is a unique clinicopathological study of aging and neurodegenerative disease based in Sun City, AZ since 1987. The BBDP has made rapid autopsy a priority, with a constitutive 24‐7 rapid autopsy team and a 3.0‐hour median postmortem interval for the entire collection. Tissue quality is correspondingly high, with a median RNA Integrity Number (RIN) for frozen brain tissue of 8.9. The current holdings include fixed and frozen brain and body tissue, as well as biofluids from more than 850 Alzheimer's Disease (AD) cases, 250 Parkinson's Disease (PD) cases and more than 350 elderly control subjects. The program supports and leads national and international research focused on AD, AD related dementias and other debilitating neurodegenerative diseases. It provides basic scientists with de‐identified annual comprehensive standardized cognitive, motor, and non‐motor assessments data and neuropathologically characterized human samples that are suitable for the elucidation of the molecular mechanisms of disease and novel therapeutic targets. The BBDP is committed to distributing human samples and accompanying clinicopathological data to as many researchers as possible. All collected data are available to researchers through the program's website https://www.brainandbodydonationregistration.org/ and personalized consultations. [ABSTRACT FROM AUTHOR]

Background: We previously reported that in our autopsy‐confirmed cohort of Dementia with Lewy Bodies (DLB), Parkinson's Disease Dementia (PDD) and Alzheimer's Disease (AD), DLB with parkinsonism (DLB+Park) predicted faster progression of UPDRS‐III scores compared to PDD, DLB without parkinsonism (DLB‐Park), and AD. This study examined annualized rate of change of UPDRS‐III subscales in our cohort. Methods: Data included were from participants in Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with clinicopathologic diagnosis of DLB (n = 48), PDD (n = 98) or pure AD (n = 48), and longitudinal movement exams. Mixed effects model (accounting for age, education, and sex) was used to determine predicted mean UPDRS‐III and subscale scores (0‐4) for all groups. Individual UPDRS‐III subscale scores were derived for: Body Bradykinesia, Limb Bradykinesia, Gait, Postural Instability, Limb Rest Tremor, Neck Rigidity and Limb Rigidity. Where applicable, scores for multiple limbs involved were averaged. Results: Longitudinal data was analyzed for over 1430‐participant years. Parkinsonism was present in 65.6% of DLB participants. PDD participants were more likely to be treated with dopaminergic agents (87.8%) compared to (p<0.001) DLB+Park (57.6%), DLB‐park (0%) and AD (2.1%). Frequency (29.4% vs. 29.0%) and severity (mean±SE = 0.4±0.07 and 0.4±0.12) of Limb Rest Tremor was similar for PDD and DLB+park. Limb Bradykinesia frequency and severity were PDD: 100%, 2.4±0.11, DLB+Park: 96.8%, 2.1±0.18, DLB‐Park: 20%, 0.4±0.23, and AD: 62%, 1.1±0.16. Frequency of gait abnormality was 98.5% in PDD, 90.3% in DLB+park, 60% in DLB‐Park and 57.8% in AD. Rigidity was most frequent in the PDD group (88.2%), followed by DLB+Park (71%), AD (19.6%), and none DLB‐park (0%). Over 8 years trajectories for limb bradykinesia and gait were greater for DLB+park than PDD (Figure 1, Cohen's d range 0.89‐2.18 and 0.63‐1.99 over 8 years, p<0.001). Conclusion: Our results suggest that DLB+Park group have faster motor progression predominantly related to gait abnormalities and limb bradykinesia. Future analyses will explore more convergent data, integrated effects of various measures and their differential contributions in this cohort. [ABSTRACT FROM AUTHOR]

Background: The Colombian kindred affected by the autosomal dominant AD causative mutation PSEN1 E280A are an invaluable population in determining the utility of blood biomarkers (BB) and how additional risk factors may affect BB years to decades prior to symptom onset. Neurofilament light (NfL) (Quiroz et al., 2020) and phospho‐tau 217 (p‐tau217) (Palmqvist et al., 2020) diverge about 20 years prior to onset of clinical symptoms in carriers compared to non‐carriers. How APOE4 carriage may influence NfL and p‐tau217 in the kindred is unknown. We assessed cross‐sectional effects of APOE4 carriage on plasma NfL and p‐tau217 in the PSEN1 E280A kindred. Method: We used a single molecule array immunoassay to quantify plasma NfL and a Meso Scale Discovery based plasma immunoassay to quantify p‐tau217. 1428 persons (age 18 to 75, mean 35.8, 23% APOE4 carriers, 54% PSEN1 E280A carriers) had available data for NfL analyses. A total of 612 persons (age 18 to 60, mean 35.9, 25% APOE4 carriers, 62% PSEN1 E280A carriers) had available data for p‐tau217 analyses. Age related trajectories were derived from cross‐sectional log‐transformed p‐tau217 and NfL concentrations modelled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method in E280A mutation and APOE4 carriage defined groups. The primary comparison was made between APOE4 carrier and noncarriers within E280A carriers and noncarriers separately. Result: In PSEN1 E280A mutation carriers, plasma NfL concentrations begin to differentiate those who were APOE4 carriers from non‐carriers at age 47.4 (figure 1). Plasma NfL concentrations did not differentiate APOE4 carriers versus non‐carriers in those without the PSEN1 E280A mutation though concentration of NfL trended higher in APOE4 carriers in the higher age range of the sample. Plasma p‐tau217 concentrations did not differentiate APOE4 carriers from non‐carriers in PSEN1 E280A mutation carriers or non‐carriers. Conclusion: APOE4 carriage results in accelerated NfL plasma increases in PSEN1 E280A mutation carriers starting at about the age of symptom onset. The inability to detect APOE4‐related ptau217 and NfL differences in the other groups may be related to the younger age of participants and limitations in statistical power. [ABSTRACT FROM AUTHOR]

Background: Plasma ptau is a promising indicator of amyloid‐β (Aβ) mediated tau pathophysiology. We previously characterized the ability of Lilly's MesoScale Discovery (MSD)‐based plasma ptau217 and ptau181 assays to discriminate between those with and without the neuropathological diagnosis of Alzheimer's disease (AD) in Banner research participants with near‐end‐of‐life blood samples and extensive postmortem neuropathological assessments. We now extend this work in a head‐to‐head comparison of those assays to the University of Gothenburg's Single molecule array (Simoa)‐based plasma ptau181 and 231 assays. Method: Assays were performed blindly in plasma samples acquired 1.0±0.7 years before death from up to 106 Banner research participants with and without cognitive impairment and different neuropathological diagnoses. ROC analyses were used to discriminate between those with and without the neuropathological diagnosis of AD and presence or absence of neuritic Aβ plaques. Spearman correlations were used to characterize their associations with mean cortical neuritic plaque counts and with mean cortical tau tangle counts in those with and without the diagnosis of AD or neuritic plaques. Result: Lilly's ptau217 assay was better than Lilly's ptau181 and Gothenburg's ptau231 and ptau181 assays in discriminating between the neuropathological diagnosis of Intermediate/High Likelihood versus Low Likelihood/No AD (respective AUCs=0.86, 0.67, 0.62 and 0.61), the diagnosis of High Likelihood versus Low Likelihood/No AD (AUCs=0.95, 0.83, 0.67 and 0.67), and presence or absence of neuritic Aβ plaques (AUCs=0.86, 0.70, 0.61 and 0.62). It also provided better indicators of mean cortical neuritic plaque (r's=0.69, 0.35, 0.26 and 0.29) and tangle counts (r's=0.73, 0.60, 0.19, ‐0.04) in those with the neuropathological diagnosis of AD or at least moderately frequent neuritic plaques (r's=0.71, 0.59, 0.22, 0.01). The assays were not correlated with tangle counts in those without AD or neuritic plaques. Conclusion: Lilly's MSD‐based plasma ptau217 assay performed better than the other three ptau assays in the neuropathological diagnosis of AD, discriminating between those with and without neuritic Aβ plaques, and providing an indicator of Aβ‐related tau tangle burden. Banner Sun Health Research Institute's growing brain donation program resources could help characterize and compare blood‐based biomarkers in the neuropathological diagnosis of AD, Parkinson's disease and related diseases. [ABSTRACT FROM AUTHOR]

Background: PD patients often have visual alterations, for example, loss of visual acuity, contrast sensitivity or motion perception, and diminished electroretinogram responses. PD pathology is mainly characterized by the accumulation of pathological α-synuclein deposits in the brain, but little is known about how synucleinopathy affects the retina.Objective: To study the correlation between α-synuclein deposits in the retina and brain of autopsied subjects with PD and incidental Lewy body disease.Methods: We evaluated the presence of phosphorylated α-synuclein in the retina of autopsied subjects with PD (9 subjects), incidental Lewy body disease (4 subjects), and controls (6 subjects) by immunohistochemistry and compared the retinal synucleinopathy with brain disease severity indicators.Results: Whereas controls did not show any phosphorylated α-synuclein immunoreactivity in their retina, all PD subjects and 3 of 4 incidental Lewy body disease subjects had phosphorylated α-synuclein deposits in ganglion cell perikarya, dendrites, and axons, some of them resembling brain Lewy bodies and Lewy neurites. The Lewy-type synucleinopathy density in the retina significantly correlated with Lewy-type synucleinopathy density in the brain, with the Unified Parkinson's disease pathology stage and with the motor UPDRS.Conclusion: These data suggest that phosphorylated α-synuclein accumulates in the retina in parallel with that in the brain, including in early stages preceding development of clinical signs of parkinsonism or dementia. Therefore, the retina may provide an in vivo indicator of brain pathology severity, and its detection could help in the diagnosis and monitoring of disease progression. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Abstract: 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). [ABSTRACT FROM AUTHOR]

The rs17070145-T variant of the WWC1 gene, coding for the KIBRA protein, has been associated with both increased episodic memory performance and lowered risk for late onset Alzheimer's disease, although the mechanism behind this protective effect has not been completely elucidated. To achieve a better understanding of the pathways modulated by rs17070145 and its associated functional variant(s), we used laser capture microdissection (LCM) and RNA-sequencing to investigate the effect of rs17070145 genotypes on whole transcriptome expression in the human hippocampus (HP) of 22 neuropathologically normal individuals, with a specific focus on the dentate gyrus (DG) and at the pyramidal cells (PC) of CA1 and CA3 sub-regions. Differential expression analysis of RNA-seq data within the HP based on the rs17070145 genotype revealed an overexpression of genes involved in the MAPK signaling pathway, potentially driven by the T/T genotype. The most important contribution comes from genes dysregulated within the DG region. Other genes significantly dysregulated, and not involved in the MAPK pathway (Adj P < 0.01 and Fold Change > |1.00|) were: RSPO4 (HP); ARC, DUSP5, DNAJB5, EGR4, PPP1R15A, WBP11P1, EGR1, GADD45B (DG); CH25H, HSPA1A, HSPA1B, TNFSF9, and NPAS4 (PC). Several evidences suggested that the MAPK signaling pathway is linked with memory and learning processes. In non-neuronal cells, the KIBRA protein is phosphorylated by ERK1/2 (involved in the MAPK signaling) in cells as well as in vitro. Several of the other dysregulated genes are involved in memory and learning processes, as well as in Alzheimer's Disease. In conclusion, our results suggest that the effect of the WWC1 rs17070145 polymorphism on memory performance and Alzheimer's disease might be due to a differential regulation of the MAPK signaling, a key pathway involved in memory and learning processes. [ABSTRACT FROM AUTHOR]

Background: Neurofibrillary tau pathology spread in Alzheimer's disease (AD) mostly shows a stereotypical pattern of topographical progression. Atypical patterns have also been described and associated with interhemispheric asymmetry. As histopathological studies that used bilateral sampling are limited, this study aimed to assess interhemispheric tau pathology differences and the presence of topographically atypical cortical spreading patterns. Method: Immunohistochemical staining for detection of tau pathology was performed in 23 regions of interest of 57 autopsy cases and compared between cortical regions and hemispheres. Result: Frequent mild (82% of cases) and occasional moderate (32%) interhemispheric density discrepancies were observed while marked discrepancies were uncommon (7%) and restricted to occipital regions. Left and right hemispheric tau pathology dominance was observed with similar frequencies, except in Braak stage VI that favored a left dominance. Interhemispheric Braak stage differences were observed in 16% of cases and was more frequent in advanced (IV‐VI) than early stages (I‐III). One atypical lobar topographical pattern, where occipital tau pathology density exceeded frontal lobe scores, was identified in 4 cases, favoring a left dominant asymmetry. Conclusion: We speculate that asymmetry and atypical topographical progression patterns may be associated with described atypical AD clinical presentations and progression characteristics, which should be tested by comprehensive clinicopathological correlations. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Questionnaire (AQ) is a brief, informant‐based screening tool that has demonstrated good diagnostic accuracy in identifying clinical Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). The AQ has been further validated by its correlations with established informant‐ and performance‐based cognitive assessments as well as with standard neuropsychological tests. Recent evidence has also demonstrated that the AQ correlates well with PET‐based measures of amyloid plaque. The aim of this study is to validate the AQ with the hallmark neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology of AD. Method: Data from 205 prospectively‐followed autopsy cases classified as AD (n=90), aMCI (n=42), or cognitively unimpaired (CU, n=73) were used in this analysis. The average age at death was 87.07±7.84 years with the average interval between the last clinical assessment and death of 16.48±14.32 months. Semi‐quantitative measures of NP and NFT pathology from five brain regions were used to assess total plaque and total tangle loads which were then correlated with the AQ, Clinical Dementia Rating Sum of Boxes (CDR‐SOB), and the Mini‐Mental State Exam (MMSE). Spearman correlations were used in the primary analyses and were followed up with robust regression models that adjusted for age at death, sex, education, and APOE ε4 carrier status. Result: The AQ correlated significantly with NP load (r=0.37, p<0.001) and NFT load (r=0.57, p<0.001). These associations remained significant after covariate adjustment (NP: β=0.28, 95% CI: (0.21, 0.34), p<0.001; NFT: β=0.22, 95% CI: (0.17, 0.28), p<0.001). 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). Conclusion: These findings extend previous clinical and neuroimaging findings of the AQ showing that it correlates well with the hallmark NP and NFT pathology of AD and provide additional confidence to clinicians who use the AQ to screen for AD‐related cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Although parkinsonism is a core feature of Parkinson's Disease Dementia (PDD) and Dementia with Lewy bodies (DLB), its evolution is less delineated. We aimed to assess differences in severity and progression of parkinsonian motor symptoms and signs in a community autopsy cohort with clinicopathologic diagnosis of DLB, PDD or Alzheimer's Disease (AD). Method: Data included were from 194 participants in the Arizona study of Aging and Neurodegenerative Disorders with clinicopathologic diagnosis of DLB (n=48), PDD (n=98) (±AD co‐pathology) or pure AD (n=48), and at least two movement exams performed by movement disorders subspecialists who classified PD and parkinsonism according to MDS‐UPDRS criteria. DLB was subgrouped by presence or absence of parkinsonism at final exam (DLB+Park and DLB–Park). Between group trajectory of UPDRS‐II and UPDRS‐III scores were explored using piecewise‐linear and non‐linear MMRM multivariate analysis. Result: Over 1435 participant‐years of longitudinal data were included in the analyses (Figure 1). Mean±SD age at baseline movement exam and death were 76.0±7.5 and 83.4±6.8 years, respectively. At baseline, most participants did not have dementia or substantial motor abnormalities (except motor abnormalities in PDD). DLB (73.9%) and PDD (69.2%) groups had more males than AD (33.3%). Parkinsonism was present in 65.6% of DLB at last exam. Piecewise‐linear MMRM analysis showed baseline UPDRS‐II and UPDRS‐III scores were highest (p<0.001) for PDD (mean±SE: 14.3±0.78 and 27.4±1.64), followed by DLB+Park (5.0±1.05 and 17.4±3.10), DLB‐Park (3.7±2.54 and 3.8±1.35) and AD (3.2±0.88 and 8.0±1.94). Annual rate of increase in UPDRS‐II was greatest for DLB+Park (1.44±0.20) and PDD (1.04±0.08), followed by DLB‐Park (0.89±0.18) and AD (0.30±0.11). Annual rate of increase in UPDRS‐III was highest for PDD and DLB+Park (2.12±0.20 vs 2.64±0.42), followed by DLB‐Park and AD (1.31 ± 0.38 and 0.64 ± 0.22). Preliminary non‐linear MMRM models (Figure 2) further supported substantial between group/subgroup differences in motor trajectories, and progression in DLB‐Park. Conclusion: These preliminary results in a large, well‐characterized clinicopathological community‐based autopsy cohort support that DLB+Park experience comparable, or greater, parkinsonian motor progression to PDD. Future modeling/sensitivity analyses will better delineate expected trajectories of motor progression to add prognostication value in clinic and design of DLB clinical trials. [ABSTRACT FROM AUTHOR]

Background: In many neurodegenerative diseases including Alzheimer's disease (AD), specific subpopulations of cells and brain regions are more sensitive to dysfunction and degeneration than others. For example, excitatory neurons in the layer 2/3 of middle temporal gyrus (MTG) is particularly vulnerable to degeneration in early AD. The mechanisms underpinning this selective cellular and regional vulnerability, however, are unclear. Recently, the spatially resolved transcriptomics has been used in AD‐like mouse models to identify genes altered in the vicinity of amyloid plaques and genes differentially expressed in those vulnerable regions in AD. Here we report that spatial transcriptomics of human postmortem MTG reveals differential gene expression in layer 2/3 of early AD compared to non‐AD cases. Methods: Human MTG frozen sections from 2 non‐AD and 2 early AD cases were mounted over the capture areas with poly T probes on the 10x Visium Gene Expression slide. The cDNA libraries were generated by following the 10x Visium Spatial Gene Expression Reagent Kits user guide. Then cDNA libraries from 4 samples were pooled in a NovaSeq6000 SP v1.0 flowcell and paired end sequencing were performed on an Illumina NovaSeq6000 sequencer. The sequence data were analyzed via 10x Genomics software (Space Ranger v 4.0.0 and Loupe Browser v 4.1.0) and Seurat (v 3.2.2). Results: Uniform Manifold Approximation and Projection (UMAP) analysis of spatial transcriptomics data generated seven cell clusters, which correspond to the cortical layers 1‐6 and the white matter in MTG. In the identified differentially expressed genes (DEGs) in layer 2/3, we found many signatures associated with AD including plaque‐induced genes, disease associated microglia genes, oligodendrocyte response genes, A1 astrocyte genes, as well as tangle‐associated genes. GO enrichment analysis of these DEGs revealed important functional pathways that may be implicated in the pathogenesis of AD, such as synapse structure or activity, protein folding and stability, neuronal apoptosis, autophagy, ER stress, oxidative stress, response to amyloid‐beta, microglial activation, neuroinflammatory response, regulation of chemotaxis, and myelination. Conclusions: Taken together, we demonstrate that the genome‐wide the spatially resolved transcriptomics provide an unprecedented and unbiased approach to untangle the selective cellular and regional vulnerability in early AD. [ABSTRACT FROM AUTHOR]

Background: Pathological tau accumulates in patients with Alzheimer's disease (AD) and related tauopathies. However, it remains unclear why specific neuronal subtypes and brain regions are vulnerable to pathological tau in early AD. Recently we found excitatory neurons expressing the Wolframin (WFS1) in the entorhinal cortex and the CA1 of hippocampus are particularly vulnerable to pathological tau in tau transgenic mice and human AD. However, the role of WFS1 in mediating this selective neuronal vulnerability is unknown. Method: The tau aggregates in live cells were imaged as individual tiles and stitched via the Zeiss Observer 7 fluorescent microscope, and then the area with tau aggregates in each stitched image was quantitated by Image J. The tau pathology in mouse brain was visualized by MC1‐positive and conformation‐dependent tau via the immunofluroscent staining. The protein interaction between WFS1 and tau was measured by the Duolink Proximity ligation assay (PLA) and co‐immunoprecipitation (CO‐IP) assay. Result: Here we reported that overexpression of human WFS1 significantly reduced DS9 tau seeding in SH‐SY5Y cells stably transfected with P301S mutant tau, while overexpression of mutant P724L WFS1 did not. Also, overexpression of human WFS1 significantly reduced exogenous tau aggregation in primary mouse mixed neurons treated with P301S tau‐YFP lentivirus, while overexpression of mutant WFS1 did not. Furthermore, the heterozygotes of PS19 tau;NestinCre/+; Wfs1f/+ brain‐specific knock‐out mice and PS19 tau;Wfs1+/‐ knock‐out mice have much more tau pathology in the Dentate gyrus, CA1 and entorhinal cortex compared with PS19 tau and PS19 tau;Wfs1f/+mice. The homozygotes of PS19 tau;NestinCre/+;Wfs1f/f brain‐specific knock‐out mice and PS19 tau;Wfs1‐/‐ knock‐out mice have even more tau pathology than those heterozygotes. We further identified that WFS1 interacts with both total tau and pathological tau in primary cultured neurons, wild‐type and tau transgenic mice, and human non‐AD and AD cases. The interaction is first enhanced as tau pathology increases, however, it is reduced as tau pathology further increases. Conclusion: Taken together, we demonstrate that deficiency of Wfs1 increases vulnerability to pathological tau in vitro and in vivo, indicating WFS1 may be a therapeutic target for preventing or delaying the tau pathology in AD. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) p‐tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD) reflecting abnormal tau metabolism in the brain. We have recently shown that also plasma p‐tau181 is a promising biomarker for AD (Janelidze et al, Nature Medicine, 2020). We now evaluate whether CSF p‐tau217 or plasma p‐tau217 are even better biomarkers. Methods: We compared CSF p‐tau217 to CSF p‐tau181 in the Swedish BioFINDER‐1 cohort (n=194). We next evaluated plasma p‐tau217 and plasma p‐tau181 in three cohorts with 1,438 participants: an Arizona‐based neuropathology cohort, including 34 AD and 47 non‐AD participants; the Swedish BioFINDER‐2 cohort, including cognitively unimpaired (n=312) participants, and clinically diagnosed patients with mild cognitive impairment (MCI, n=188), AD dementia (n=126), and other non‐AD neurodegenerative diseases (n=109); a Colombian autosomal‐dominant AD kindred, including 365 PSEN1E280A‐carriers and 257 non‐mutation carriers. Results: CSF p‐tau217 had stronger correlations with the tau‐PET tracer, and more accurately identified individuals with abnormal tau‐PET scans (AUC=0.93) than CSF P‐tau181. CSF P‐tau217 correlated better than p‐tau181 with CSF and PET measures of neocortical amyloid‐β burden and more accurately distinguished AD dementia from non‐AD neurodegenerative disorders. Antemortem plasma P‐tau217 differentiated individuals with intermediate‐to‐high likelihood of AD according to neuropathology from those without AD (AUC=0.89) and performed significantly better than plasma P‐tau181. Plasma P‐tau217 also differentiated clinical AD dementia from non‐AD neurodegenerative diseases (AUC=0.96) significantly better than plasma P‐tau181, plasma neurofilament light, and established MRI measures, and similar to CSF P‐tau217, CSF P‐tau181, CSF Aβ42/40, and tau‐PET. Increased plasma P‐tau217 was observed already in the pre‐symptomatic stages of AD. In PSEN1 mutation carriers the increase started at age 25, about 20 years prior to estimated onset of MCI. Plasma P‐tau217 correlated with cerebral tau tangle densities in subjects with neuritic plaques (r=0.64). It predicted abnormal tau‐PET scans (AUC=0.95) significantly better than plasma P‐tau181, plasma neurofilament light, CSF P‐tau181 and CSF Aβ42/Aβ40, and similar to CSF P‐tau217. Conclusions: Plasma and CSF P‐tau217 reflect brain tau burden, increases early in AD, and differentiates AD from other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Idiopathic rapid eye movement sleep behavior disorder (RBD) is a strong known predictor of a final clinicopathological diagnosis of a Lewy type α‐synucleinopathy (LTS). Olfactory dysfunction is an early symptom of synucleinopathies and has been repeatedly associated with the presence of post‐mortem LTS.To assess the combined value of a clinician diagnosis of probable RBD (PRBD) and hyposmia in predicting the post‐mortem presence of LTS in a broader, less‐selected, volunteer elderly population.We studied 652 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders, which were evaluated for PRBD, had completed annual movement and cognitive assessments, and had at least one the University of Pennsylvania Smell Identification Test (UPSIT) olfactory test.Histological evidence of LTS was significantly more frequent in those who had PRBD (112/152: 73.7%) than those without (177/494: 35.8%) (P < 0.001). LTS was more frequent in cases with PRBD and a low UPSIT score (90.8%) compared to cases with PRBD only (73.7%) (P < 0.001) or cases with a low UPSIT score only (69.4%) (P < 0.001). Sensitivity of PRBD diagnosis for predicting LTS was 38.8% and specificity 88.8%, whereas sensitivity of a low UPSIT score was 74.4% and specificity 73.4% (Youden's index = 0.276 for PRBD, 0.478 for UPSIT). When combining both measures, sensitivity was 34.3% and specificity increased to 97.2%.PRBD, diagnosed without sleep study confirmation, combined with a reduced olfactory performance is highly specific for predicting post‐mortem presence of LTS. The combination of both measures may provide a cost‐effective means of predicting LTS in a broader community. [ABSTRACT FROM AUTHOR]

This document is a list of references to various scientific studies and articles related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The studies cover a range of topics including diagnostic tools, biomarkers, genetic research, and imaging techniques. The authors of the document have different affiliations and financial disclosures related to their research. The references provide a comprehensive overview of the current research in the field and may be useful for library patrons conducting research on these topics. [Extracted from the article]

Background: Progranulin (PGRN) and prosaposin (PSAP) have lysosomal and neurotrophic properties. Reduced amounts of PGRN in mutant tau‐expressing Alzheimer's disease (AD) model mice exacerbated phosphorylated tau pathology. The implication of PGRN in tangle formation in AD is not understood nor the association of PSAP with AD. Both features need further research. Method: Fixed human brain tissue sections of middle temporal gyrus (MTG) from low plaque (LP)(n=4), high plaque (HP)(n=4) non‐demented (ND), and AD (n=4) cases, and superior frontal gyrus from a presenilin‐1 mutated case and frontal temporal lobar degeneration (FTLD) cases (n=3) with heterozygous granulin mutations were employed in this study. The interaction of PGRN and PSAP was identified with proximity ligation assay (PLA). The colocalization of PGRN and PSAP with tangle was identified by fluorescent immunohistochemistry and triple‐color confocal microscopy with antibodies to phosphorylated tau (p‐tau). PGRN and PSAP fluorescence intensity was measured in p‐tau positive neurons and compared to adjacent p‐tau negative neurons. Result: Different p‐tau positive structures were measured and related to the levels of PGRN and PSAP. Extracellular neuropil threads appeared to have no association with these proteins. Reduced levels of PGRN and PSAP were detected in p‐tau positive neurons compared to control neurons in all groups. Average levels of PGRN in control neurons were decreased as disease developed. In the AD group, reduced signals of these proteins were observed overall in neurons without p‐tau, and absent in fully matured neurofibrillary tangles. The levels of PGRN and PSAP negatively correlated with p‐tau immunoreactivity. The presenilin‐1 mutated case with numerous tangles in frontal cortex had absence of PGRN and PSAP in tangles, but colocalization of PGRN and PSAP was evident in adjacent neurons. FTLD cases showed absence of PGRN in most neurons, but continued expression of PSAP. The interaction of PGRN and PSAP in neurons was verified with a PLA assay. Conclusion: P‐tau positive neurons had significantly less PGRN and PSAP even in the non‐demented groups, which suggests this could be an early event of tangle formation. The insufficiency of both PGRN and PSAP in neurons might lead to accumulation of p‐tau protein due to deficits in lysosomal activity. [ABSTRACT FROM AUTHOR]

Background: Post‐mortem assessment remains the only option and a gold standard for a definitive diagnosis of Parkinson's disease (PD). The antemortem diagnosis is challenging due to a variable clinical presentation and the abundance of mimicking conditions, obscuring the clinical picture and delaying the treatment. It is well established that while PD pathologically manifests in central nervous system with aggregation of α‐synuclein as Lewy bodies and Lewy neurites, this pathology is also found in the peripheral nervous system. Peripheral Lewy‐type synucleinopathy (LTS) is present in early PD, suggesting its utility as a diagnostic and prognostic biomarker. We have previously confirmed that detection of LTS in submandibular gland (SMG) biopsies is sensitive (.75) and specific (.90) for early PD. However, the assessment by a neuropathologist of multiple levels of such biopsy is laborious and time‐consuming. Method: Here work we applied two Convolutional Neural Networks (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total number of 8,386 LTS were annotated following the interrater reliability study with kappa=.7. We used transfer learning to train a CNN model to classify image patches (40‐by‐40 pixels at 20x) with and without presence of LTS objects. Result: The trained CNNs showed the following performance on image patches: sensitivity:.982/.988, specificity:.998/.999, precision:.852/.950, accuracy:.995/.998, and F‐1 score.912/.968 for ResNet30/InceptionV4 respectively. On test WSI the sensitivity in detecting LTS was.963/.971 respectively. Conclusion: This work is first to demonstrate the practical utility of an CNN for screening for LTS, which can further translate into a practical screening tool facilitating the antemortem diagnosis of PD. We further plan to develop neural networks for accurate and precise detection and quantification of LTS in antemortem SMG biopsies. This, altogether, would offer a screening, confirmatory, prognostic, and quantitative tool for clinical assessment of early PD. [ABSTRACT FROM AUTHOR]

Background: Avid Radiopharmaceuticals conducted a prospective case‐control clinicopathological study of flortaucipir F18 PET Imaging (AV‐1451‐A16) from October 2015 through June 2018. This presentation is an initial report of the detailed neuropathological findings of the 67 primary study subjects. Method: Sixty‐seven valid study autopsies were performed. The cerebral patterns of flortaucipir PET images were visually assessed and compared to the patterns of immunohistochemical tau pathology. The study met pre‐specified success criteria, with imaging predicting an NIA‐AA B3 level of tau pathology (Braak V/VI) and a high level of Alzheimer's disease neuropathologic change. Result: There were 35 females and 32 males, mean age 82.6 (SD 9.4). Fifty‐three cases met intermediate or high ADNC levels, consistent with AD as a cause of cognitive impairment. Of these, many had additional major neuropathological findings (not mutually exclusive), meeting neuropathological diagnostic criteria for dementia with Lewy bodies (DLB; n=7), Parkinson's disease (PD; n=1), progressive supranuclear palsy (PSP; n=5), hippocampal sclerosis (HS; n=5), vascular dementia (n=3) and corticobasal degeneration (CBD; n=1), while others had lesser findings of TDP‐43 proteinopathy restricted to the mesial temporal lobe (n=19), Lewy body pathology not meeting criteria for DLB or PD (n=18), age‐related tau astrogliopathy (ARTAG; n=15) or remote cerebral infarcts (n=10). Cases with less than intermediate ADNC (n=14) met neuropathological diagnostic criteria (not mutually exclusive) for PD (n=2), HS (n=2), DLB (n=1), PSP (n=1), CBD (n=1) and others had additional neuropathological findings of TDP‐43 proteinopathy restricted to the mesial temporal lobe (n=2), Lewy body pathology not meeting criteria for DLB or PD (n=4), ARTAG (n=3) or remote cerebral infarcts (n=2). Conclusion: This high proportion of mixed neuropathology is typical of what has been published for other elderly autopsied subjects. Correlations of flortaucipir F18 PET imaging with these varied neuropathological types will be undertaken. [ABSTRACT FROM AUTHOR]