Central autonomic network dysfunction and plasma Alzheimer's disease biomarkers in older adults.

BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimer's Disease.

While challenging, identifying individuals displaying resilience to Alzheimer's disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.

Alzheimer's disease ferroptotic associations with oxidative damage and neuronal loss.

The role of reactive iron in Alzheimer's Disease (AD) remains unresolved. Little is known of how AD may alter iron transport, glutathione-mediated oxidative repair, and their associations with ApoE alleles. Postmortem brain intravascular blood was minimized by washing minced brain (n=24/group). HNE from iron-associated lipid peroxidation increased in AD prefrontal cortex by 50% for whole tissue and in subcellular lipid rafts, where Aß-peptides are produced. HNE correlated with iron storage ferritin light chain (FTL; r=0.35); both were higher in ApoE4. Iron chelation by DFO in EFAD mice decreased HNE consistent with ferroptosis. Neuronal and synaptic loss in AD was inversely correlated to FTL (r=-0.55). AD decreased levels of ferroptosis suppressor protein 1, glutamate cysteine ligase modulator subunit (GCLM), and lipid raft glutathione peroxidase 4 (GPx4), mitigators of ferroptosis. These findings provide a mechanistic framework for iron-associated neurodegeneration during AD by impaired lipid peroxidation repair mechanisms involving glutathione.

Beyond amyloid: Immune, cerebrovascular, and metabolic contributions to Alzheimer disease in people with Down syndrome.

People with Down syndrome (DS) have increased risk of Alzheimer disease (AD), presumably conferred through genetic predispositions arising from trisomy 21. These predispositions necessarily include triplication of the amyloid precursor protein (APP), but also other Ch21 genes that confer risk directly or through interactions with genes on other chromosomes. We discuss evidence that multiple genes on chromosome 21 are associated with metabolic dysfunction in DS. The resulting dysregulated pathways involve the immune system, leading to chronic inflammation; the cerebrovascular system, leading to disruption of the blood brain barrier (BBB); and cellular energy metabolism, promoting increased oxidative stress. In combination, these disruptions may produce a precarious biological milieu that, in the presence of accumulating amyloid, drives the pathophysiological cascade of AD in people with DS. Critically, mechanistic drivers of this dysfunction may be targetable in future clinical trials of pharmaceutical and/or lifestyle interventions.

Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aß in Down Syndrome and Sporadic Alzheimer's Disease.

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-ß (Aß) overproduction and earlier onset of Aß deposits compared to patients with sporadic late-onset Alzheimer's disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aß pathology in living people with DS and AD, but its relationship with heterogeneous Aß forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro 3H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aß40 and Aß42 forms and N-terminus truncated and pyroglutamate-modified AßNpE3-40 and AßNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43-63 years and 17 late-onset AD cases aged 62-99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aß40 and AßNpE3-40, while the two groups did not differ by Aß42 and AßNpE3-42 levels. This resulted in lower ratios of Aß42/Aß40 and AßNpE3-42/AßNpE3-40 in the DS group compared to the AD group. Correlations of Aß42/Aß40 and AßNpE3-42/AßNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aß levels were lower than unmodified Aß levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aß forms relative to both unmodified Aß forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by 3H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AßNpE3-40 and unmodified Aß40 forms. Despite the distinct molecular profile of Aß forms and greater vascular amyloidosis in DS cases, cortical 3H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aß plaques in individuals with DS.

Opportunities, barriers, and recommendations in down syndrome research.

BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.

mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia.

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Aß generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Aß and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS.

Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism.

Down Syndrome (DS) is the most common genetic form of intellectual disability that leads in the majority of cases to development of early-onset Alzheimer-like dementia (AD). The neuropathology of DS has several common features with AD including alteration of redox homeostasis, mitochondrial deficits, and inflammation among others. Interestingly, some of the genes encoded by chromosome 21 are responsible of increased oxidative stress (OS) conditions that are further exacerbated by decreased antioxidant defense. Previous studies from our groups showed that accumulation of oxidative damage is an early event in DS neurodegeneration and that oxidative modifications of selected proteins affects the integrity of the protein degradative systems, antioxidant response, neuronal integrity and energy metabolism. In particular, the current review elaborates recent findings demonstrating the accumulation of oxidative damage in DS and we focus attention on specific deregulation of iron metabolism, which affects both the central nervous system and the periphery. Iron dysmetabolism is a well-recognized factor that contributes to neurodegeneration; thus we opine that better understanding how and to what extent the concerted loss of iron dyshomeostasis and increased OS occur in DS could provide novel insights for the development of therapeutic strategies for the treatment of Alzheimer-like dementia.

Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype.

Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.

Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease.

Down syndrome (DS) is the most common genetic cause of intellectual disability and is primarily caused by the triplication of chromosome 21. The overexpression of amyloid precursor protein gene may be sufficient to drive Alzheimer's disease (AD) neuropathology that is observed in virtually all individuals with DS by the age of 40 years. There is relatively little information about inflammation in the DS brain and how the genetics of DS may alter inflammatory responses and modify the course of AD pathogenesis in this disorder. Using the macrophage classification system of M1, M2a, M2b, and M2c inflammatory phenotypes, we have shown that the early stages of AD are associated with a bias toward an M1 or M2a phenotype. In later stages of AD, markers of M1, M2a and M2c are elevated. We now report the inflammatory phenotype in a DS autopsy series to compare this with the progression in sporadic AD. Tissue from young DS cases (under 40 years of age, pre-AD) show a bias toward M1 and M2b states with little M2a or M2c observed. Older DS cases (over 40 with AD pathology) show a distinct bias toward an M2b phenotype. Importantly, this is distinct from sporadic AD where the M2b phenotype has been rarely, if ever observed in postmortem studies. Stimulated by immune complex activation of microglial cells and toll-like receptor activation, the M2b phenotype represents a unique neuroinflammatory state in diseased brain and may have significant implications for therapeutic intervention for persons with DS.

Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer's disease brain and correlates with neurofibrillary tangle pathology.

Recent genome wide association studies have implicated bridging integrator 1 (BIN1) as a late-onset Alzheimer's disease (AD) susceptibility gene. There are at least 15 different known isoforms of BIN1, with many being expressed in the brain including the longest isoform (iso1), which is brain-specific and localizes to axon initial segments and nodes of Ranvier. It is currently unknown what role BIN1 plays in AD. We analyzed BIN1 protein expression from a large number (n = 71) of AD cases and controls from five different brain regions (hippocampus, inferior parietal cortex, inferior temporal cortex, frontal cortex (BA9), and superior and middle temporal gyri). We found that the amount of the largest isoform of BIN1 was significantly reduced in the AD brain compared to age-matched controls, and smaller BIN1 isoforms were significantly increased. Further, BIN1 was significantly correlated with the amount of neurofibrillary tangle (NFT) pathology but not with either diffuse or neuritic plaques, or with the amount of amyloid-ß peptide. BIN1 is known to be abnormally expressed in another human disease, myotonic dystrophy, which also features prominent NFT pathology. These data suggest that BIN1 is likely involved in AD as a modulator of NFT pathology, and that this role may extend to other human diseases that feature tau pathology.

Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain.

Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aß) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR deregulation results in decreased autophagy, inhibition of IRS1 and GSK3ß activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.

Autoimmune manifestations in the 3xTg-AD model of Alzheimer's disease.

BACKGROUND: Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. OBJECTIVE: The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. METHODS: A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. RESULTS: Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory dise6ase, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired "cognitive" flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-ß or tau pathology. CONCLUSION: The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD.

A combination cocktail improves spatial attention in a canine model of human aging and Alzheimer's disease.

Alzheimer's disease (AD) involves multiple pathological processes in the brain, including increased inflammation and oxidative damage, as well as the accumulation of amyloid-ß (Aß) plaques. We hypothesized that a combinatorial therapeutic approach to target these multiple pathways may provide cognitive and neuropathological benefits for AD patients. To test this hypothesis, we used a canine model of human aging and AD. Aged dogs naturally develop learning and memory impairments, human-type Aß deposits, and oxidative damage in the brain. Thus, 9 aged beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechingallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; and (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. After 3 months of treatment, 13 dogs completed a variable distance landmark task used as a measure of spatial attention. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t11 = 4.3, p = 0.001) and were more accurate across all distances (F(1,9) = 20.7, p = 0.001), suggesting an overall improvement in spatial attention. Measures of visual discrimination learning, executive function and spatial memory, and levels of brain and cerebrospinal fluid Aß were unaffected by the cocktail. Our results indicate that this medical food cocktail may be beneficial for improving spatial attention and motivation deficits associated with impaired cognition in aging and AD.

BDNF increases with behavioral enrichment and an antioxidant diet in the aged dog.

The aged canine (dog) is an excellent model for investigating the neurobiological changes that underlie cognitive impairment and neurodegeneration in humans, as canines and humans undergo similar pathological and behavioral changes with aging. Recent evidence indicates that a combination of environmental enrichment and antioxidant-fortified diet can be used to reduce the rate of age-dependent neuropathology and cognitive decline in aged dogs, although the mechanisms underlying these changes have not been established. We examined the hypothesis that an increase in levels of brain-derived neurotrophic factor (BDNF) is one of the factors underlying improvements in learning and memory. Old, cognitively impaired animals that did not receive any treatment showed a significant decrease in BDNF mRNA in the temporal cortex when compared with the young group. Animals receiving either an antioxidant diet or environmental enrichment displayed intermediate levels of BDNF mRNA. However, dogs receiving both an antioxidant diet and environmental enrichment showed increased levels of BDNF mRNA when compared with untreated aged dogs, approaching levels measured in young animals. BDNF receptor TrkB mRNA levels did not differ between groups. BDNF mRNA levels were positively correlated with improved cognitive performance and inversely correlated with cortical Aß((1-42)) and Aß((1-40)) levels. These findings suggest that environmental enrichment and antioxidant diet interact to maintain brain levels of BDNF, which may lead to improved cognitive performance. This is the first demonstration in a higher animal that nonpharmacological changes in lifestyle in advanced age can upregulate BDNF to levels approaching those in the young brain.

Atorvastatin treatment in a dog preclinical model of Alzheimer's disease leads to up-regulation of haem oxygenase-1 and is associated with reduced oxidative stress in brain.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Only acetylcholinesterase inhibitors and the NMDA antagonist memantine are approved for AD treatment. Recent preclinical and epidemiological studies proposed statins as novel therapeutics for AD, but the mechanisms of action are still unknown. Here, we demonstrate that atorvastatin (80 mg/d for 14.5 months) treatment resulted in an up-regulation of the inducible isoform of haem oxygenase (HO-1), an enzyme with significant neuroprotective activity. Atorvastatin selectively increased HO-1 in the parietal cortex but not cerebellum. In contrast, HO-2 was increased in cerebellum but not parietal cortex. No changes were observed in HO-1 or HO-2 in the liver. Significant negative correlations between HO-1 and oxidative stress indices and positive correlations with glutathione levels in parietal cortex were found. HO-1 up-regulation significantly correlated with lower discrimination learning error scores in aged beagles. Reference to therapeutic applications of atorvastatin in AD is discussed.

BACE2 expression increases in human neurodegenerative disease.

ß-Secretase, the rate-limiting enzymatic activity in the production of the amyloid-ß (Aß) peptide, is a major target of Alzheimer's disease (AD) therapeutics. There are two forms of the enzyme: ß-site Aß precursor protein cleaving enzyme (BACE) 1 and BACE2. Although BACE1 increases in late-stage AD, little is known about BACE2. We conducted a detailed examination of BACE2 in patients with preclinical to late-stage AD, including amnestic mild cognitive impairment, and age-matched controls, cases of frontotemporal dementia, and Down's syndrome. BACE2 protein and enzymatic activity increased as early as preclinical AD and were found in neurons and astrocytes. Although the levels of total BACE2 mRNA were unchanged, the mRNA for BACE2 splice form C (missing exon 7) increased in parallel with BACE2 protein and activity. BACE1 and BACE2 were strongly correlated with each other at all levels, suggesting that their regulatory mechanisms may be largely shared. BACE2 was also elevated in frontotemporal dementia but not in Down's syndrome, even in patients with substantial Aß deposition. Thus, expression of both forms of ß-secretase are linked and may play a combined role in human neurologic disease. A better understanding of the normal functions of BACE1 and BACE2, and how these change in different disease states, is essential for the future development of AD therapeutics.

Good quality white-light transurethral resection of bladder tumours (GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking.

UNLABELLED: Study Type - Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Apart from bladder tumour multiplicity, size, stage, grade and presence of cis, early recurrence following white light TURBT for new bladder tumours is also determined by surgeon experience, completeness of resection and presence or absence of detrusor muscle in the specimen. This study aims to validate surgeon experience and detrusor muscle as independent predictors of early recurrence following apparently complete white light TURBT in new bladder tumours. OBJECTIVE: To validate in patients undergoing first transurethral resection of bladder tumour (TURBT) for non-muscle-invasive bladder cancer (NMIBC), the presence/absence of detrusor muscle (DM) in the specimen and surgeon experience as independent predictors of the quality of TURBT. PATIENTS AND METHODS: Patients with new NMIBC, who had undergone complete first resections were recruited from a prospectively maintained cohort from the 1980s at the Western General Hospital, Edinburgh, UK and a contemporary cohort from the Aberdeen Royal Infirmary, UK. Tumour size, multiplicity, surgeon category, presence or absence of DM in the specimen, grade, stage, findings at first check cystoscopy and early re-TURBT were evaluated. Surgeons were stratified into a senior group (consultant and trainees in year five or six) and a junior group (trainees below year five). Early recurrence, or recurrence rate at the first follow up cystoscopy (RRFFC), was used to measure quality and was defined as finding pathologically confirmed tumour at early re-TURBT or the first check cystoscopy. RESULTS: From a total of 566 patients evaluated from both cohorts, 473 NMIBC specimens were suitable for analysis. Logistic regression multivariate analysis revealed that the absence of DM was associated with a higher RRFFC (odds ratio [OR]= 3.6, 95% CI = 1.7-7.5, P < 0.001). Senior surgeons were more likely to resect DM (OR = 4.9, 95% CI = 2.3-10.7, P < 0.001) Senior surgeons were independently associated with a lower RRFFC (OR = 5.3, 95% CI = 2.1-12.9, P < 0.001). CONCLUSIONS: Detrusor muscle status at the first, apparently complete, TURBT and surgeon's experience independently predict the quality of TURBT. • Documented complete resection by experienced surgeons with DM presence (good quality white-light TURBT) should be considered a benchmark for white-light TURBT in NMIBC.

Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease.

We examined the relationships between normal aging, Alzheimer's disease (AD), and brain levels of sex steroid hormones in men and women. In postmortem brain tissue from neuropathologically normal, postmenopausal women, we found no age-related changes in brain levels of either androgens or estrogens. In comparing women with and without AD at different ages, brain levels of estrogens and androgens were lower in AD cases aged 80 years and older but not significantly different in the 60-79 year age range. In male brains, we observed that normal aging was associated with significant decreases in androgens but not estrogens. Further, in men aged 60-79 years, brain levels of testosterone but not estrogens were lower in cases with mild neuropathological changes as well as those with advanced AD neuropathology. In male cases over age 80, brain levels hormones did not significantly vary by neuropathological status. To begin investigating the relationships between hormone levels and indices of AD neuropathology, we measured brain levels of soluble ß-amyloid (Aß). In male cases with mild neuropathological changes, we found an inverse relationship between brain levels of testosterone and soluble Aß. Collectively, these findings demonstrate sex-specific relationships between normal, age-related depletion of androgens and estrogens in men and women, which may be relevant to development of AD.

Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy.

Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages (ICHs), microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical secondary role in many neurodegenerative diseases, including Alzheimer's disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood-brain barrier (BBB) lesions. The accumulation of amyloid beta (Aß) in the cerebrovascular system is a significant risk factor for ICH and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-Aß immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits but have been plagued by CAA-associated adverse events. Although management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of ß-amyloidosis in the cerebral vasculature.