Differential spatial working memory-related functional network reconfiguration in young and older adults.

Functional brain networks have preserved architectures in rest and task; nevertheless, previous work consistently demonstrated task-related brain functional reorganization. Efficient rest-to-task functional network reconfiguration is associated with better cognition in young adults. However, aging and cognitive load effects, as well as contributions of intra- and internetwork reconfiguration, remain unclear. We assessed age-related and load-dependent effects on global and network-specific functional reconfiguration between rest and a spatial working memory (SWM) task in young and older adults, then investigated associations between functional reconfiguration and SWM across loads and age groups. Overall, global and network-level functional reconfiguration between rest and task increased with age and load. Importantly, more efficient functional reconfiguration associated with better performance across age groups. However, older adults relied more on internetwork reconfiguration of higher cognitive and task-relevant networks. These reflect the consistent importance of efficient network updating despite recruitment of additional functional networks to offset reduction in neural resources and a change in brain functional topology in older adults. Our findings generalize the association between efficient functional reconfiguration and cognition to aging and demonstrate distinct brain functional reconfiguration patterns associated with SWM in aging, highlighting the importance of combining rest and task measures to study aging cognition.

Brain networks identified by functional connectivity (FC) have preserved architectures from rest to task and across task demands. Higher similarity, implying more efficient network reconfiguration, was associated with better cognition and task performance in young adults. To examine how it may be influenced by aging, we compared whole-brain and network-level FC similarities between resting-state and spatial working memory fMRI in young and older adults. At whole-brain level and higher order cognitive networks, older adults evidenced less efficient network reconfiguration from rest to task than young adults. Importantly, more efficient reconfiguration was associated with better accuracy. This relationship relied more on internetwork connections in older adults. Despite reduced neural resources compared to young, maintaining efficient network updating still contributes to better cognition at older age.

Plasma Neurofilament Light Relates to Divergent Default and Salience Network Connectivity in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia.

Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) show differential vulnerability to large-scale brain functional networks. Plasma neurofilament light (NfL), a promising biomarker of neurodegeneration, has been linked in AD patients to glucose metabolism changes in AD-related regions. However, it is unknown whether plasma NfL would be similarly associated with disease-specific functional connectivity changes in AD and bvFTD. Objective: Our study examined the associations between plasma NfL and functional connectivity of the default mode and salience networks in patients with AD and bvFTD. Methods: Plasma NfL and neuroimaging data from patients with bvFTD (n = 16) and AD or mild cognitive impairment (n = 38; AD + MCI) were analyzed. Seed-based functional connectivity maps of key regions within the default mode and salience networks were obtained and associated with plasma NfL in these patients. RESULTS: We demonstrated divergent associations between NfL and functional connectivity in AD + MCI and bvFTD patients. Specifically, AD + MCI patients showed lower default mode network functional connectivity with higher plasma NfL, while bvFTD patients showed lower salience network functional connectivity with higher plasma NfL. Further, lower NfL-related default mode network connectivity in AD + MCI patients was associated with lower Montreal Cognitive Assessment scores and higher Clinical Dementia Rating sum-of-boxes scores, although NfL-related salience network connectivity in bvFTD patients was not associated with Neuropsychiatric Inventory Questionnaire scores. CONCLUSIONS: Our findings indicate that plasma NfL is differentially associated with brain functional connectivity changes in AD and bvFTD.

Predictors of post stroke cognitive impairment: VITATOPS cognition substudy.

INTRODUCTION: Post stroke cognitive impairment (PSCI) is a common complication of ischemic stroke. PSCI can involve different depending on clinical and stroke related characteristics. The aim of this study is to determine the factors associated with impairments in specific cognitive domains. METHODS: The Vitamins to Prevent Stroke (VITATOPS) trial is a large, multinational randomised controlled trial. In this substudy, consecutive patients admitted for ischaemic stroke or transient ischaemic attack (TIA) at a tertiary hospital in Singapore were included. PSCI was defined as impairment of any of the six cognitive subgroups - visuoconstruction, attention, verbal memory, language, visual memory and visuomotor function - that were assessed annually for up to five years. Univariate and multivariate Cox proportional hazard models were used to determine factors associated with impairments in each of these cognitive domains. RESULTS: A total of 736 patients were included in this study, of which 173 (23.5 %) developed cognitive impairment. Out of the six cognitive domains, the greatest proportion of patients had an impairment in visuoconstruction (26.4 %) followed by attention (19.8 %), verbal memory (18.3 %), language (17.5 %), visual memory (17.3 %) and visuomotor function (14.8 %). Patients with posterior circulation cerebral infarction (POCI) as the index stroke subtype had higher rates of cognitive impairment. Further subgroup analyses show that Indian race and advanced age were predictive of language impairment, whilst fewer years of education and POCI were predictive of verbal memory impairment. POCI was predictive of visual memory impairment, and advanced age and POCI were predictive of visuomotor function impairment. CONCLUSION: We identified visuoconstruction and attention domains to be the most affected in our Asian cohort of PSCI. Advanced age, lower levels of education, posterior circulation strokes and concomitant comorbidities such as peripheral artery disease are independent predictors of PSCI.

Content development of the VISION-Cog: a novel tool to assess cognitive impairment in visually impaired older adults in Singapore.

OBJECTIVES: Current cognitive screening and diagnostic instruments rely on visually dependent tasks and are, therefore, not suitable to assess cognitive impairment (CI) in visually impaired older adults. We describe the content development of the VISually Independent test battery Of NeuroCOGnition (VISION-Cog)-a new diagnostic tool to evaluate CI in visually impaired older Singaporean adults. DESIGN: The content development phase consisted of two iterative stages: a neuropsychological consultation and literature review (stage 1) and an expert-panel discussion (stage 2). In stage 1, we investigated currently available neuropsychological test batteries for CI to inform constructions of our preliminary test battery. We then deliberated this battery during a consensus meeting using the Modified Nominal Group technique (stage 2) to decide, via agreement of five experts, the content of a pilot neuropsychological battery for the visually impaired. SETTING: Singapore Eye Research Institute. PARTICIPANTS: Stakeholders included researchers, psychologists, neurologists, neuro-ophthalmologists, geriatricians and psychiatrists. OUTCOME MEASURE: pilot VISION-Cog. RESULTS: The two-stage process resulted in a pilot VISION-Cog consisting of nine vision-independent neuropsychological tests, including the modified spatial memory test, list learning, list recall and list recognition, adapted token test, semantic fluency, modified spatial analysis, verbal subtests of the frontal battery assessment, digit symbol, digit span forwards, and digit span backwards. These tests encompassed five cognitive domains-memory and learning, language, executive function, complex attention, and perceptual-motor abilities. The expert panel suggested improvements to the clarity of test instructions and culturally relevant test content. These suggestions were incorporated and iteratively pilot-tested by the study team until no further issues emerged. CONCLUSIONS: We have developed a five-domain and nine-test VISION-Cog pilot instrument capable of replacing vision-dependent diagnostic batteries in aiding the clinician-based diagnosis of CI in visually impaired older adults. Subsequent phases will examine the VISION-Cog's feasibility, comprehensibility and acceptability; and evaluate its diagnostic performance.

Feasibility, comprehensibility and acceptability of the VISION-Cog, a novel tool to assess cognitive impairment in visually impaired older adults: a cross-sectional pilot study in Singapore.

OBJECTIVES: We pilot-tested the VISually Independent test battery Of NeuroCOGnition (VISION-Cog) to determine its feasibility, comprehensibility and acceptability in evaluating cognitive impairment (CI) in visually impaired older Asian adults. DESIGN: The VISION-Cog was iteratively fine-tuned through pilot studies and expert-panel discussion. In the first pilot study (Stage 1), we recruited 15 visually impaired and cognitively normal participants aged ≥60 years to examine the pilot VISION-Cog's feasibility (length of time to administer), comprehensibility (clarity of instructions) and acceptability (participant burden). We then presented the pilot results to the expert panel (Stage 2) who decided via agreement on a revised version of the VISION-Cog. Subsequently, we conducted a second pilot study (Stage 3) on another four participants to ascertain improvement in feasibility, comprehensibility and acceptability of the revised version. SETTING: Singapore Eye Research Institute. PARTICIPANTS: Nineteen Asian adults aged ≥60 years with visual impairment (defined as near visual acuity worse than N8) were recruited. OUTCOME MEASURE: Revised VISION-Cog. RESULT: The VISION-Cog was deemed feasible, taking approximately 60 min to complete on average. All participants agreed that the test instructions were clear, and the battery did not cause undue discomfort or frustration. The data collector rated all tests as very user-friendly (score of 5/5). Minor modifications to the pilot VISION-Cog were suggested by the panel to improve its safety, clarity of instructions and content validity, which were incorporated and iteratively tested in the second pilot study until no further issues emerged. CONCLUSIONS: Using an iterative mixed-methods process, we have developed a feasible, comprehensible and acceptable 5-domain and 9-item visually independent VISION-Cog test battery suitable to assist CI diagnosis in older adults with visual impairment. We will assess its diagnostic potential against clinician-based assessment of CI in subsequent phases.

Clinical characteristics of pathological confirmed prodromal dementia with Lewy bodies.

INTRODUCTION: Misdiagnosis rate of Dementia with Lewy Bodies (DLB) remains high despite being second most common cause of neurodegenerative dementia. To date, understanding of clinical profile of pathologically confirmed prodromal DLB remains limited. The main objective of this study was to describe and compare it with pathologically confirmed Alzheimer's disease (AD). METHODS: We accessed the National Alzheimer's Coordinating Center database from 2005 to December 2022 data freeze and included 111 and 501 prodromal DLB and AD patients respectively. First visit data was analyzed. RESULTS: Clinician-determined memory impairment is common in prodromal DLB (>70%) but associated with higher risk for AD diagnosis (OR 0.355, p = 0.0003). DLB had a higher proportion of non-amnestic mild cognitive impairment (MCI) diagnoses but statistically insignificance in differentiating the two. Inattention (OR 2.273, p = 0.0015), and neuropsychiatric features, such as visual hallucinations (OR 11.98, p < 0.0001), depressed mood (OR1.709, p = 0.0292), apathy (1.824, p = 0.0345), and night/REM sleep behaviors, are associated with DLB diagnosis. Hallucinations are infrequent (7-11%). Motor symptoms, particularly gait disorders (OR 4.570, p < 0.001), falls (OR3.939, p = 0.0003), tremors (OR2.237, p = 0.0154), slowness (OR3.573, p < 0.0001), and parkinsonism signs (OR2.443, p < 0.0001), are common. 32% showed no parkinsonism during initial presentation. Neuropsychological examination revealed less impaired memory and language but impaired executive function in DLB. CONCLUSION: In clinical practice, it is important to note that memory symptoms although being higher risk associated with AD diagnosis, are prominent in prodromal DLB. Psychosis is infrequent, and non-amnestic MCI is not necessarily associated with higher risk of DLB diagnosis. A careful clinical approach is key to improve the diagnosis of prodromal DLB.

Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition.

BACKGROUND: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. OBJECTIVE: To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD). METHODS: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. RESULTS: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. CONCLUSION: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

C9orf72 expansions are the most common cause of genetic frontotemporal dementia in a Southeast Asian cohort.

OBJECTIVE: Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative disorders, including behavioural variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent variant PPA (nfvPPA). While a strong genetic component is implicated in FTD, genetic FTD in Asia is less frequently reported. We aimed to investigate the frequency of Southeast Asian FTD patients harbouring known genetic FTD variants. METHODS: A total of 60 FTD-spectrum patients (25 familial and 35 sporadic) from Singapore and the Philippines were included. All underwent next-generation sequencing and repeat-primed PCR for C9orf72 expansion testing. Neurofilament light chain (NfL) levels were measured in a subset of patients. RESULTS: Overall, 26.6% (16/60 cases) carried pathogenic or likely pathogenic variants in a FTD-related gene, including: MAPT Gln351Arg (n = 1); GRN Cys92Ter (n = 1), Ser301Ter (n = 2), c.462 + 1G > C (n = 1); C9orf72 expansion (35-70 repeats; n = 8); TREM2 Arg47Cys (n = 1); and OPTN frameshift insertion (n = 2). Genetic mutations accounted for 48% (12/25) of patients with familial FTD, and 11.4% (4/35) of patients with sporadic FTD. C9orf72 repeat expansions were the most common genetic mutation (13.3%, 8/60), followed by GRN (6.7%, 4/60) variants. Within mutation carriers, plasma NfL was highest in a C9orf72 expansion carrier, and CSF NfL was highest in a GRN splice variant carrier. INTERPRETATION: In our cohort, genetic mutations are present in one-quarter of FTD-spectrum cases, and up to half of those with family history. Our findings highlight the importance of wider implementation of genetic testing in FTD patients from Southeast Asia.

B-vitamin supplementation on mitigating post-stroke cognition and neuropsychiatric sequelae: A randomized controlled trial.

BACKGROUND AND PURPOSE: A third of stroke patients suffer from post-stroke cognitive decline, depressive symptoms, and anxiety symptoms. B-vitamin supplementation provides a possible safe and affordable treatment to mitigate post-stroke neuropsychiatric sequelae via reducing homocysteine levels. Our study aims to examine the effect of B-vitamin supplementation in the prevention of post-stroke cognitive decline, depressive symptoms, and anxiety symptoms. Our secondary aims were to investigate associations between baseline factors and the three outcomes. METHODS: Patients were recruited as part of a Singaporean substudy of a randomized controlled trial that examined the effect of B-vitamin supplementation on recurrent cardiovascular events. Cognitive decline, depressive symptoms, and anxiety symptoms were assessed with neuropsychological assessments and Hospital Anxiety and Depression Scale 6 monthly. Cox regression analyses were performed to determine treatment efficacy. Logistic regression used to examine factors associated with cognitive decline, depressive symptoms, and anxiety symptoms. RESULTS: A total of 707 were included in the analyses. Survival and hazards ratio analysis showed no treatment effect of B-vitamins on cognitive decline, depressive symptoms, and anxiety symptoms. Cognitive decline was only associated with age. Depressive symptoms were associated with large anterior cerebral infarcts and hyperlipidemia. CONCLUSIONS: Our study showed no benefit of supplementation with B-vitamins for post-stroke cognitive decline, depressive symptoms, or anxiety symptoms. Depressive symptoms were associated with larger anterior cerebral infarcts, which may be reflective of the disability associated with larger infarcts.

Clinical Manifestations of Early-Onset Dementia With Lewy Bodies Compared With Late-Onset Dementia With Lewy Bodies and Early-Onset Alzheimer Disease.

Importance: Early-onset dementia, presenting in individuals younger than 65 years, is a diagnosis with significant social and financial implications. The early-onset form of dementia with Lewy bodies (DLB) is poorly understood. Objective: To investigate clinical features that distinguish early-onset DLB (onset and diagnosis at age <65 years) from late-onset DLB (onset at age ≥65 years) and from early-onset Alzheimer disease (AD) dementia. Design, Setting, and Participants: This is a retrospective case-control study on patients with pathologically confirmed DLB or AD enrolled in the National Alzheimer's Coordinating Center database from January 2005 to July 2017. The National Alzheimer's Coordinating Center Uniform Data Set comprised deidentified data collected by Alzheimer disease centers in the United States. Of patients fulfilling criteria for all-cause dementia at enrollment (n = 1152), those who at post mortem received a pathological diagnosis of either AD (n = 848) or Lewy body disease (n = 218) were selected. Excluding 52 patients owing to missing data and 12 diagnosed with Parkinson disease dementia, remaining patients were classified by age of symptom onset into early-onset AD, early-onset DLB, and late-onset DLB subgroups. Data were analyzed from June to December 2018 and from November to December 2021. Exposures: Demographics, cognitive, behavioral, and motor features recorded at first clinic visit and neuropathological characteristics at autopsy were analyzed by disease subgroup. Main Outcomes and Measures: Concordance between initial etiologic diagnosis of dementia and final pathological diagnosis was assessed, as was time to death. Results: A total of 542 individuals were categorized as having early-onset AD (n = 363; mean [SD] age, 53.0 [5.8] years; 208 [57.3%] male), early-onset DLB (n = 32; mean [SD] age, 57.9 [3.2] years; 23 [71.9%] male), and late-onset DLB (n = 147; mean [SD] age, 73.5 [5.5] years; 103 [70.1%] male). Early-onset DLB was clinically misdiagnosed in 16 individuals (50%). Features that predicted a diagnosis of early-onset DLB over early-onset AD included visual hallucinations (15 [46.9%] vs 42 [11.6%]), slowness (23 [71.9%] vs 95 [26.2%]), apathy (23 [71.9%] vs 189 [52.1%]), and motor deterioration that preceded cognitive and behavioral symptoms (7 [21.9%] vs 6 [1.7%]). Late-onset DLB had more amnestic features, but this was accounted for by a higher proportion of neocortical neuritic plaques and diffuse plaques (frequent in 79 [53.7%] vs 8 [25%]) than seen in early-onset DLB. Conclusions and Relevance: This study found that early-onset DLB has clinical features that distinguish it from early-onset AD, whereas features of late-onset DLB are associated with a higher burden of AD copathology.

Assessment of small intestinal bacterial overgrowth in Alzheimer's disease.

There is great interest in crosstalk between the gastrointestinal and immune systems. Small intestinal bacterial overgrowth (SIBO) is a bowel disorder prevalent among patients with Parkinson's disease; SIBO treatment has been shown to modulate neurological inflammation, motor and cognitive outcomes there. However, to date, no link between Alzheimer's dementia and SIBO has been established. This pilot study sought to estimate the prevalence of SIBO in Alzheimer's dementia in the outpatient setting in Singapore General Hospital. It entailed performing a hydrogen breath test and objectively scoring gastrointestinal symptoms and their severity in 48 patients, comparing symptom scores and mean breath test values in those with mild to moderate Alzheimer's against age- and sex-matched controls that did not fulfill DSM-V criteria for probable Alzheimer's. Here, the prevalence of positive breath tests and symptoms of SIBO were no greater among Alzheimer's patients than in controls. This suggests that the gut microbiome changes and increased bowel inflammation seen in previous studies on Alzheimer's patients are likely effected through pathways other than SIBO, and are likely more complex than a mere increase in small bowel bacterial volume. Rather, future research could be directed along the lines of qualitative changes in small bowel microbiota, or pathologies in other parts of the gastrointestinal tract such as the colon or stomach, aspects which are not adequately captured by the hydrogen breath test. Keywords: Alzheimer's disease; dementia; gut-brain axis; small intestinal bacterial overgrowth; microbiome.

Distinct network topology in Alzheimer's disease and behavioral variant frontotemporal dementia.

BACKGROUND: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social-emotional functional deficits. METHODS: In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. RESULTS: Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. CONCLUSIONS: Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5'-untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long-read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92-138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26-380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID.

NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long-Term Follow-up.

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618.

Nanosilver Targets the Bacterial Cell Envelope: The Link with Generation of Reactive Oxygen Radicals.

The work describes the interactions of nanosilver (NAg) with bacterial cell envelope components at a molecular level and how this associates with the reactive oxygen species (ROS)-mediated toxicity of the nanoparticle. Major structural changes were detected in cell envelope biomolecules as a result of damages in functional moieties, such as the saccharides, amides, and phosphodiesters. NAg exposure disintegrates the glycan backbone in the major cell wall component peptidoglycan, causes complete breakdown of lipoteichoic acid, and disrupts the phosphate-amine and fatty acid groups in phosphatidylethanolamine, a membrane phospholipid. Consistent with the oxidative attacks, we propose that the observed cell envelope damages are inflicted, at least in part, by the reactive oxygen radicals being generated by the nanoparticle during its leaching process, abiotically, without cells. The cell envelope targeting, especially those on the inner membrane phospholipid, is likely to then trigger the rapid generation of lethal levels of cellular superoxide (O2•-) and hydroxyl (OH•) radicals herein seen with a model bacterium. The present study provides a better understanding of the antibacterial mechanisms of NAg, whereby ROS generation could be both the cause and consequence of the toxicity, associated with the initial cell envelope targeting by the nanoparticle.

Frontotemporal dementia and COVID-19: Hypothesis generation and roadmap for future research.

The COVID-19 pandemic has caused tremendous suffering for patients with dementia and their caregivers. We conducted a survey to study the impact of the pandemic on patients with mild frontotemporal dementia (FTD). Our preliminary findings demonstrate that patients with FTD have significant worsening in behavior and social cognition, as well as suffer greater negative consequences from disruption to health-care services compared to patients with AD. The reduced ability to cope with sudden changes to social environments places patients with FTD at increased vulnerability to COVID-19 infection as well as to poorer clinical and social outcomes. Caregivers of FTD patients also demonstrate high burden during crisis situations. A proportion of patients with FTD benefitted from use of web-based interactive platforms. In this article, we outline the priority areas for research as well as a roadmap for future collaborative research to ensure greatest benefit for patients with FTD and their caregivers.

Medial Temporal Atrophy in Amyloid-Negative Amnestic Type Dementia Is Associated with High Cerebral White Matter Hyperintensity.

BACKGROUND: Non-amyloid mechanisms behind neurodegeneration and cognition impairment are unclear. Cerebrovascular disease (CVD) may play an important role in suspected non-Alzheimer's pathophysiology (SNAP), especially in Asia. OBJECTIVE: To examine the association between CVD and medial temporal lobe atrophy (MTA) in amyloid-ß negative patients with mild amnestic type dementia. METHODS: Thirty-six mild dementia patients with complete neuropsychological, cerebrospinal fluid (CSF) biomarker, and neuroimaging information were included. Only patients with clinically significant MTA were recruited. Patients were categorized based on their CSF Aß levels. Neuroimaging and neuropsychological variables were analyzed. RESULTS: Despite comparable MTA between Aß positive and negative patients, Aß-negative patients had significantly greater white matter hyperintensities (WMH; Total Fazekas Rating) than their Aß-positive counterparts (6.42 versus 4.19, p = 0.03). A larger proportion of Aß-negative patients also had severe and confluent WMH. Regression analyses controlling for baseline characteristics yielded consistent results. CONCLUSION: Our findings demonstrate that MTA is associated with greater CVD burden among Aß-negative patients with amnestic type dementia. CVD may be an important mechanism behind hippocampal atrophy. This has implications on clinical management strategies, where measures to reduce CVD may slow neurodegeneration and disease progression.