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AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet the relationship between aCasp-6, different forms of tr-tau and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies.ResultsCasp-6 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies.ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.

Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Proteolytic cleavage of tau by active caspases, including caspase-6, represents an underexplored tau PTM implicated in tau pathology. Caspase-cleaved tau is toxic and prone to self-aggregation in experimental models. To elucidate the presence and temporal course of caspase activation, tau cleavage, and neuronal death, we generated two neoepitope monoclonal antibodies (mAbs) against caspase-6 tau proteolytic sites and cortical neurons from induced pluripotent stem cells (iPSCs) with the frontotemporal dementia (FTD)-causing V337M MAPT mutation. FTLD V337M MAPT and AD postmortem brains showed positivity for both cleaved tau mAbs as well as active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons showed a time-dependent increase in pathogenic tau in the form of tau oligomers, caspase-cleaved tau, and p-tau. Accumulation of toxic tau species in 3-month V337M MAPT neurons also increased vulnerability to stress, which was pharmacologically rescued by caspase inhibition. We propose a model in which time-dependent accumulation of caspase-cleaved tau in V337M MAPT neurons promotes neurotoxicity that is reversed by caspase-6 inhibition. Caspase-cleaved tau may be a biomarker of tauopathy, and caspases could be viable targets for therapeutic intervention against tau pathogenesis in FTLD and other tauopathies.SignificanceThe mechanisms leading to tau pathology in frontotemporal dementia (FTD) and Alzheimer’s disease (AD) remain elusive. Experimental studies in AD demonstrate that tau cleavage by active caspase-6 contributes to tau pathology since cleaved tau may be toxic and prone to self-aggregation. Yet, the role of caspase-cleaved tau in promoting toxicity and cell death is unclear. Here, we generated two neoepitope monoclonal antibodies against caspase-6 tau and evaluated tau cleavage in postmortem human brains, iPSC-induced cortical neurons with the FTD-causing V337M MAPT mutation, and isogenic wild-type MAPT controls. Our results demonstrate a time-dependent accumulation of caspase-cleaved tau and increased neurotoxicity in the mutant iNs that is reversed by caspase-6 inhibition. Caspases could be viable therapeutic targets against tau pathology in tauopathies.

Diffusion tractography MRI can infer changes in network connectivity in patients with traumatic brain injury (TBI), but pathological substrates of disconnected tracts have not been well-defined due to a lack of high-resolution imaging with histopathological validation. We developed an ex vivo MRI protocol to analyze tract terminations at 750 μm resolution, followed by histopathologic evaluation of white matter pathology, and applied these methods to a 60-year-old man who died 26 days after TBI. Analysis of 74 cerebral hemispheric white matter regions revealed a heterogeneous distribution of tract disruptions. Associated histopathology identified variable white matter injury with patchy deposition of amyloid precursor protein and loss of neurofilament-positive axonal processes, myelin dissolution, astrogliosis, microgliosis, and perivascular hemosiderin-laden macrophages. Multiple linear regression revealed that tract disruption strongly correlated with neurofilament loss. Ex vivo diffusion MRI can detect tract disruptions in the human brain that reflect axonal injury.

Background: Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Tau proteolysis by caspases, including caspase-6, represents an understudied PTM that may increase neurotoxicity and tau self-aggregation. Methods: To elucidate the presence and temporal course of caspase activation, tau cleavage, and neuronal death, we generated two novel epitope (neoepitope) monoclonal antibodies (mAbs) against caspase-6 tau proteolytic sites. We evaluated tau cleavage and response to apoptotic stress in cortical neurons derived from induced pluripotent stem cells (iPSCs) with frontotemporal dementia (FTD)-causing V337M MAPT mutation. We tested the neuroprotective effect of caspase inhibitors in the induced neurons. We also demonstrated the presence of the tau neoepitopes in postmortem brains from an individual with FTD (V337M MAPT) and an individual with AD, compared to a healthy control. Results: FTLD V337M MAPT and AD postmortem brains showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau and phosphorylated (p)-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by inhibition of effector caspases.Conclusions: Culturing iPSC-derived neurons for three months exposes age-related tau pathologies, including caspase-mediated cleavage, that are also observed in human postmortem brains with abnormal tau deposition. Neoepitope antibodies to caspase-cleaved tau may serve as biomarkers of tau pathology. Furthermore, caspases could be viable therapeutic targets for tau pathogenesis in FTLD and other tauopathies.

Introduction Neurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD. Methods In a well-characterized clinicopathological cohort of AD patients (n = 13), we quantified neuronal synchrony within alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination. Results Abnormal synchrony in alpha, but not in delta-theta, significantly predicted the NFT density at post mortem neuropathological examination. Discussion Reduced alpha synchrony is a sensitive neurophysiological index associated with pathological tau, and a potential network biomarker for clinical trials, to gauge the extent of network dysfunction and the degree of rescue in treatments targeting tau pathways in AD.

AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer’s disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in healthy controls, AD, and primary tauopathies.ResultsCasp-6 activation was strongest in AD, followed by Pick’s disease (PiD), but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD than in 4R tauopathies, and disproportionally higher when normalizing by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD lacked p-tau aggregates.ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD, and possibly PiD, but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that not all neurons that are vulnerable to tau pathology are detected by a conventional p-tau Ser 202 antibody and that AD has distinct mechanisms of tangle formation. Therapeutic strategies against tr-tau pathology could be necessary to modulate tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD supports the investigation of biofluid biomarkers against N-terminus tr-tau, which could detect AD and differentiate it from 4R tauopathies at a single patient level.3 - sentence summaryTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation, but the relationship between aCasp-6, tr-tau, and hyperphosphorylated tau (p-tau) accumulation in Alzheimer’s disease (AD) and other tauopathies remains unclear. We generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6 and used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in brains from healthy controls, AD, and primary tauopathies. We detected relatively high Casp-6 activation in AD, followed by Pick’s disease (PiD). aCasp-6 was almost absent in 4-repeat (4R) tauopathies, suggesting that early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy in AD, and possibly PiD, but is unlikely to benefit 4R tauopathies.

IMPORTANCE: Sleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena. OBJECTIVES: To examine the correlation between the number of important subcortical wake-promoting neurons and clinical sleep phenotypes in patients with Alzheimer disease (AD) or progressive supranuclear palsy (PSP). DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study enrolled 33 patients with AD, 20 patients with PSP, and 32 healthy individuals from the Memory and Aging Center of the University of California, San Francisco, between August 22, 2008, and December 31, 2020. Participants received electroencephalographic and polysomnographic sleep assessments. Postmortem neuronal analyses of brainstem hypothalamic wake-promoting neurons were performed and were included in the clinicopathological correlation analysis. No eligible participants were excluded from the study. EXPOSURES: Electroencephalographic and polysomnographic assessment of sleep and postmortem immunohistological stereological analysis of 3 wake-promoting nuclei (noradrenergic locus coeruleus [LC], orexinergic lateral hypothalamic area [LHA], and histaminergic tuberomammillary nucleus [TMN]). MAIN OUTCOMES AND MEASURES: Nocturnal sleep variables, including total sleep time, sleep maintenance, rapid eye movement (REM) latency, and time spent in REM sleep and stages 1, 2, and 3 of non-REM (NREM1, NREM2, and NREM3, respectively) sleep, and wake after sleep onset. Neurotransmitter, tau, and total neuronal counts of LC, LHA, and TMN. RESULTS: Among 19 patients included in the clinicopathological correlation analysis, the mean (SD) age at death was 70.53 (7.75) years; 10 patients (52.6%) were female; and all patients were White. After adjusting for primary diagnosis, age, sex, and time between sleep analyses and death, greater numbers of LHA and TMN neurons were correlated with decreased homeostatic sleep drive, as observed by less total sleep time (LHA: r = −0.63; P = .009; TMN: r = −0.62; P = .008), lower sleep maintenance (LHA: r = −0.85; P

Study ObjectivesThe lateral hypothalamic area (LHA) is one of the key regions orchestrating sleep and wake control. It is the site of wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons, which share a close anatomical and functional relation. The aim of the study was to investigate the degeneration of MCH neurons in Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP), and relate the new findings to our previously reported pattern of degeneration of wake-promoting orexinergic neuronsMethodsPost-mortem human brain tissue of subjects with AD, PSP and controls was examined using unbiased stereology. Double immunohistochemistry with MCH- and tau-antibodies on formalin-fixed, celloidin embedded tissue was performed.ResultsThere was no difference in the total number of MCH neurons between AD, PSP and controls, but a significant loss of non-MCH neurons in AD patients (p=0.019). The proportion of MCH neurons was significantly higher in AD (p=0.0047). No such a difference was found in PSP. In PSP, but not AD, the proportion of tau+ MCH neurons was lower than the proportion of tau+ non-MCH neurons (p=0.002). When comparing AD to PSP, the proportion of tau+MCH neurons was higher in AD (pConclusionsMCH neurons are more vulnerable to AD than PSP pathology. High burden of tau-inclusions, but comparably milder loss of MCH neurons in AD, together with previously reported orexinergic neuronal loss may lead to a hyperexcitability of the MCH system in AD, contributing to wake-sleep disorders in AD. Further experimental research is needed to understand why MCH neurons are more resistant to tau-toxicity compared to orexinergic neurons.STATEMENT OF SIGNIFICANCEThis is the first study to investigate the involvement of melanin-concentrating hormone (MCH) neurons in patients with Alzheimer’s disease and progressive supranuclear palsy. MCH neurons are key regulators of sleep and metabolic functions, and one of the major neuronal populations of the lateral hypothalamic area (LHA), but still underexplored in humans. Uncovering the pathology of this neuronal population in neurodegenerative disorders will improve our understanding of the complex neurobiology of the LHA and the interaction between MCH and orexinergic neurons. This new knowledge may open new strategies for treatment interventions. Further, this study represents a fundament for future research on MCH neurons and the LHA in tauopathies.

Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, has been viewed as a relatively pure form of AD with a more homogenous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with EOAD (median age of onset = 55 years, 44 females) and 48 with late-onset AD (LOAD) (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of AD. Prevalence and stage of Lewy body disease (LBD), limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease (AGD), hippocampal sclerosis (HS), cerebral amyloid angiopathy (CAA), vascular brain injury (VBI) and aging-related tau astrogliopathy (ARTAG) were compared between the two cohorts. We found at least one non-AD pathological diagnosis in 98% of patients with EOAD (versus 100% of LOAD), and the number of comorbid diagnoses per patient was lower in EOAD than in LOAD (median=2 versus 3, Mann-Whitney Z=3.00, p=0.002). LBD and CAA were common in both EOAD and LOAD (CAA: 86% versus 79%, Fisher exact p=0.33; LBD: 49% versus 42%, p=0.48, respectively), although amygdala-predominant LBD was more commonly found in EOAD than LOAD (22% versus 6%, p=0.02). In contrast, LATE (35% versus 8%, p

Sleep and wakefulness control in the mammalian brain requires the coordination of various discrete interconnected neurons. According to the most conventional sleep model, wake-promoting neurons (WPNs) and sleep-promoting neurons (SPNs) compete for network dominance, creating a systematic “switch” that results in either the sleep or awake state. WPNs and SPNs are ubiquitous in the brainstem and diencephalon, areas that together contain less than 1% of the neurons in the human brain. Interestingly, many of these WPNs and SPNs co-express and co-release various types of the neurotransmitters that often have opposing modulatory effects on the network. Co-transmission is often beneficial to structures with limited numbers of neurons because it provides increasing computational capability and flexibility. Moreover, co-transmission allows subcortical structures to bi-directionally control postsynaptic neurons, thus helping to orchestrate several complex physiological functions such as sleep. Here, we present an in-depth review of co-transmission in hypothalamic WPNs and SPNs and discuss its functional significance in the sleep-wake network.

Typical Alzheimer disease (AD) features an amnestic syndrome that reflects the progression of pathology through specific neural networks. However, a subset of patients exhibits atypical onset with prominent language, behavioral, or visuospatial deficits that are not explained by current neuropathological staging schemes. Astrogliopathy featuring tau inclusions with thorn-shaped and granular fuzzy morphologies is common in the aging brain and collectively known as aging-related tau astrogliopathy (ARTAG). Prior studies have identified tau-positive thorn-shaped astrocytes in the white matter that associate with a primary progressive aphasia phenotype in an AD cohort. However, a possible contribution of ARTAG copathology to AD clinical heterogeneity has yet to be systematically examined. To investigate whether ARTAG pathology contributes to atypical presentations, we mapped the presence and density of ARTAG subtypes throughout cortical and subcortical regions in a well-characterized cohort of AD cases enriched for atypical presentations. In our cohort, ARTAG pathology is frequent and correlates with older age and higher Braak stage. ARTAG subtypes exhibit distinct distribution patterns with subpial and subependymal deposition occurring in the amygdala, while white and grey matter astrocytic deposition are distributed throughout cortical regions. However, ARTAG pathology is equally prevalent in cases with typical and atypical clinical presentations.

ObjectivesAlzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations.MethodsWe mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing.ResultsWM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high–WM-TSA (n = 9) and low–WM-TSA (n = 74) pathology signature. The high–WM-TSA group scored significantly worse in language but not in other cognitive domains.ConclusionsThe negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.

The clinical spectrum of Alzheimer’s disease (AD) extends well beyond the classic amnestic–predominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (p = 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (p = 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with worsening visuospatial dysfunction. In addition, unbiased hierarchical clustering based on regional NFT densities identified three groups characterized by a low overall NFT burden, high overall burden, and cortical-predominant burden, respectively, which were found to differ in sex ratio, age, disease duration, and clinical presentation. In comparison, the typical, hippocampal sparing, and limbic-predominant subtypes derived from a previously proposed algorithm did not reproduce the same degree of clinical relevance in this sample. Overall, our results suggest domain-specific functional consequences of regional NFT accumulation. Mapping these consequences presents an opportunity to increase understanding of the neuropathological framework underlying atypical clinical manifestations.

BackgroundNeurofibrillary tangle (NFT) pathology in Alzheimer’s disease (AD) follows a stereotypic progression well-characterized by Braak staging. However, some AD cases show deviations from the Braak staging scheme. In this study, we tested the hypothesis that these variations in the regional distribution of tau pathology are linked to heterogeneity in the clinical phenotypes of AD.MethodsWe included a clinicopathological cohort of ninety-four AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E (APOE) genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z-score. We assessed NFT density and distribution from thioflavin S fluorescent microscopy throughout four neocortical and two hippocampal regions. A mathematical algorithm classifying AD cases into typical, hippocampal sparing (HpSp), and limbic predominant (LP) subtypes based on regional NFT burden was compared to unbiased hierarchical clustering for cases with Braak stage > IV.ResultsPatients diagnosed with logopenic primary progressive aphasia showed significantly higher NFT density in the superior temporal gyrus relative to patients diagnosed with Alzheimer-type dementia (p = 0.0091), while patients with corticobasal syndrome showed significantly higher NFT density in the primary motor cortex (p = 0.0205). Hierarchical clustering identified three discrete clusters of patients characterized respectively by low overall NFT burden (n = 18), high overall burden (n = 30), and cortical-predominant burden (n = 24). A regionally specific effect was observed for visuospatial ability; higher NFT density in the angular gyrus (β = - 0.0921, p = 0.0099) and in the CA1 sector of the hippocampus (β = −0.0735, p = 0.0380) was significantly associated with more severe visuospatial dysfunction, modulated by age of death.ConclusionsOur results suggest domain-specific functional consequences of regional NFT accumulation. In particular, we observed focal aggregation of NFT density in clinically relevant regions among different clinical AD variants. Continued work to map the regionally specific clinical consequences of tau accumulation presents an opportunity to increase understanding of disease mechanisms underlying atypical clinical manifestations.

Introduction Sleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear. Methods We performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls. Results The three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. Discussion WPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP.

Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of Sao Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

The brainstem nuclei of the reticular formation (RF) are critical for regulating homeostasis, behavior, and cognition. RF degenerates in tauopathies including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Although the burden of phopho-tau inclusion is high across these diseases, suggesting a similar vulnerability pattern, a distinct RF-associated clinical phenotype in these diseases indicates the opposite. To compare patterns of RF selective vulnerability to tauopathies, we analyzed 5 RF nuclei in tissue from 14 AD, 14 CBD, 10 PSP, and 3 control cases. Multidimensional quantitative analysis unraveled discernable differences on how these nuclei are vulnerable to AD, CBD, and PSP. For instance, PSP and CBD accrued more tau inclusions than AD in locus coeruleus, suggesting a lower vulnerability to AD. However, locus coeruleus neuronal loss in AD was so extreme that few neurons remained to develop aggregates. Likewise, tau burden in gigantocellular nucleus was low in AD and high in PSP, but few GABAergic neurons were present in AD. This challenges the hypothesis that gigantocellular nucleus neuronal loss underlies REM behavioral disorders because REM behavioral disorders rarely manifests in AD. This study provides foundation for characterizing the clinical consequences of RF degeneration in tauopathies and guiding customized treatment.

Background: Beliefs about cancer risk and experience of early detection and treatment can impact on willingness to engage with these initiatives. This study describes changes in perceptions of cancer mortality, early detection and treatment among adult New Zealanders (NZ) between two cross-sectional studies conducted in 2001 and 2014/5. Methods: Data was collected via telephone interviews conducted by trained interviewers in 2001 (231 females and 207 males, 64% response rate) and 2014/5 (588 females and 476 males, 64% response rate). Participants were asked to identify the most common three causes of cancer mortality among women and then men. They were also asked to note their agreement or otherwise with statements about early detection and treatment of cancer. Results: There was an increase in proportions of men who correctly identified prostate cancer as one of the top three causes of cancer mortality among men, and also an increase among women who correctly identified bowel cancer as one of the top three. Most participants agreed that there were benefits from early detection for cancer outcomes. Over time, there was a significant decline in proportions which felt that most cancer treatment is “so terrible it is worse than death” and that alternative therapy has an “equal or better chance of curing cancer.” Conclusion: Internationally, there is little information available about changes in cancer perceptions over time, these findings suggest some changes in perceptions of treatment and awareness of types of cancer with the highest mortality in NZ, which should support timely engagement with early detection and treatment services.

Objective: Cancer risk reduction messages are a part of cancer control efforts around the world. The complex reality is that risk factors differ for different types of cancer, making clear communication of desired behavioural changes more difficult. This study aims to describe awareness of risk factors for breast, bowel, cervical, prostate and lung cancer and cutaneous melanoma among New Zealanders in 2014/15 and identify changes in awareness since 2001. Methods: Two national telephone surveys, the first (CAANZ01) conducted in 2001, included 438 adults (231 females and 207 males, 64% response rate). The second, conducted in 2014/15 (CAANZ15), included 1064 adults (588 females and 476 males, 64% response rate). Results: In 2014/5, most participants could identify evidence-based risk factors for lung cancer and melanoma. In contrast, many participants were unable to name any risk factors (evidence-based or otherwise) for bowel (34.8%), breast (48.8%), cervical (53.9%) and prostate cancer (60.9%). Between 2001 and 2014/5 there were increases in the proportion of individuals identifying sunbeds as increasing melanoma risk, and alcohol consumption and family history as increasing risk for bowel and breast cancer. Conclusions: Effective communication of risk information for specific cancers remains a challenge for cancer control. Although some positive changes in awareness over the 14 year period were observed, there remains substantial room for progressing awareness of evidence-based risk factors.

Organisations seeking to establish themselves as leading cancer information sources for the public need to understand patterns and motivators for information seeking. This study describes cancer information seeking among New Zealanders through a national cross-sectional survey conducted in 2014/15 with a population-based sample of adults (18 years and over). Participants were asked if they had sought information about cancer during the past 12 months, the type of information they sought, what prompted them to look for information and ways of getting information they found helpful. Telephone interviews were completed by 1064 participants (588 females, 476 males, 64% response rate). Of these, 33.8% of females and 23.3% of males (total, 29.2%) had searched for information about cancer over the past year. A search was most frequently prompted by a cancer diagnosis of a family member or friend (43.3%), a desire to educate themselves (17.5%), experience of potential symptoms or a positive screening test (9.4%), family history of cancer (8.9%) or the respondent's own cancer diagnosis (7.7%). Across the cancer control spectrum, the information sought was most commonly about treatment and survival (20.2%), symptoms/early detection (17.2%) or risk factors (14.2%), although many were general or non-specific queries (50.0%). The internet was most commonly identified as a helpful source of information (71.7%), followed by health professionals (35.8%), and reading material (e.g. books, pamphlets) (14.7%).This study provides a snapshot of cancer information seeking in New Zealand, providing valuable knowledge to help shape resource delivery to better meet the diverse needs of information seekers and address potential unmet needs, where information seeking is less prevalent.

Population cancer awareness is of interest worldwide, as efforts are made to reduce cancer incidence via changes in risk and protective behaviours. To date, few studies have described changes in awareness over time, despite significant investment in raising awareness about various cancer types and risk behaviours. This paper describes the Cancer Awareness in Aotearoa New Zealand (CAANZ) survey, a cross-sectional telephone survey of adult New Zealanders conducted in 2014/2015 (CAANZ15, n = 1064) and its comparison with a similar 2001 study (CAANZ01, n = 438). Both aimed to describe current cancer awareness among a national sample of New Zealand (NZ) adults, with additional aims for CAANZ15 being to explore emerging issues in information provision and supportive care. Follow-up studies are challenged by changes in communication technologies and, in turn, potential issues in sampling. However, given the value of information about changing awareness, pragmatic steps were taken in CAANZ15 to maximise the response rate and comparability of the surveys. A response rate of 64 % was achieved for both samples. When compared to the adult NZ population, the CAANZ15 sample tended to be older, of higher socioeconomic status and under-representative of people with Pacific, Asian or, to a lesser extent, Māori (the indigenous population of NZ) ethnicity. To compensate for possible disproportionate age-by-ethnicity (Māori/non-Māori) groups in the sample, poststratification weighting was adopted. While caution will need to be exercised in drawing conclusions from comparisons made between these two cohorts, the dearth of such studies means that insights gained should be useful for guiding reflection on future cancer control directions and the generation of new hypotheses.

Behaviour change, specifically that which decreases cancer risk, is an essential element of cancer control. Little information is available about how awareness of risk factors may be changing over time. This study describes the awareness of cancer risk behaviours among adult New Zealanders in two cross-sectional studies conducted in 2001 and 2014/5.Telephone interviews were conducted in 2001 (n = 436) and 2014/5 (n = 1064). Participants were asked to recall things they can do to reduce their risk of cancer. They were then presented with a list of potential risk behaviours and asked if these could increase or decrease cancer risk.Most New Zealand adults could identify at least one action they could take to reduce their risk of cancer. However, when asked to provide specific examples, less than a third (in the 2014/5 sample) recalled key cancer risk reduction behaviours such as adequate sun protection, physical activity, healthy weight, limiting alcohol and a diet high in fruit. There had been some promising changes since the 2001 survey, however, with significant increases in awareness that adequate sun protection, avoiding sunbeds/solaria, healthy weight, limiting red meat and alcohol, and diets high in fruit and vegetables decrease the risk of developing cancer.