Exploring training, involvement and confidence: a study of healthcare professionals in decision-making capacity assessments.

AIM: To explore the training, involvement and confidence of healthcare professionals involved in decision-making capacity (DMC) assessments, and to compare any differences between those conducting and those involved in, but not conducting DMC assessments. METHOD: A 10-minute anonymous, online survey was conducted with both closed and open questions. A total of 78 participants completed the survey. RESULTS: Training was lacking in quantity and adequacy. Only 14.1% received formal training during and post their qualification and only 38.5% reported the right amount of training. Just over 55% reported having the right amount of involvement, with 18% having too much and 27% having not enough involvement. A significantly higher response was given for having too much involvement by those conducting DMC assessments (p=0.006), while those not conducting felt they do not have enough involvement (p<0.001). Only 25.6% (n=20) were very confident in being able to explain DMC to a patient. CONCLUSIONS: Healthcare professionals working in this area urgently require support in the form of formal training and defined roles. Given what can be at stake for an individual undergoing a DMC assessment, it is imperative that improvements are made to upskill the workforce and utilise expertise of all healthcare professionals.

Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer's disease (DEBBIE-AD): a prospective observational multicohort study protocol.

INTRODUCTION: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). METHODS AND ANALYSIS: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. ETHICS AND DISSEMINATION: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Neural substrates of specific and general autobiographical memory retrieval in younger and older adults.

Healthy aging is associated with a shift away from the retrieval of specific episodic autobiographical memories (AMs), towards more general and semanticized memories. Younger adults modulate activity in the default mode network according to the episodic specificity of AM retrieval. However, little is known about whether aging disrupts this neural modulation. In the current study we examine age-related changes in the modulation of whole-brain networks in response to three tasks falling along a gradient of episodic specificity. Younger and older adults retrieved specific (unique) AMs, general (routine) AMs, and semantic (general knowledge) memories. We found that both younger and older adults modulated default mode regions in response to varying episodic specificity. In addition, younger adults upregulated activity in several default mode regions with increasing episodic specificity, while older adults either did not modulate these regions, or downregulated activity in these regions. In contrast, older adults upregulated activity in the left temporal pole for tasks with higher episodic specificity. These brain activation patterns converge with prior findings that specific AMs are diminished in episodic richness with age, but are supplemented with conceptual and general information. Age-related reductions in the modulation of default mode regions might contribute to the shift away from episodic retrieval and towards semantic retrieval, resulting in reduced episodic specificity of personal memories.

Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability.

Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA's suppression of disease-associated repeat expansions, which may extend to other DNA processes.

Microglial and Astrocytic Responses in the Human Midcingulate Cortex in Huntington's Disease.

OBJECTIVE: Patients with Huntington's disease can present with variable difficulties of motor functioning, mood, and cognition. Neurodegeneration occurs in the anterior cingulate cortex of some patients with Huntington's disease and is linked to the presentation of mood symptomatology. Neuroinflammation, perpetrated by activated microglia and astrocytes, has been reported in Huntington's disease and may contribute to disease progression and presentation. This study sought to quantify the density of mutant huntingtin protein and neuroinflammatory glial changes in the midcingulate cortex of postmortem patients with Huntington's disease and determine if either correlates with the presentation of mood, motor, or mixed symptomatology. METHODS: Free-floating immunohistochemistry quantified 1C2 immunolabeling density as an indicative marker of mutant huntingtin protein, and protein and morphological markers of astrocyte (EAAT2, Cx43, and GFAP), and microglial (Iba1 and HLA-DP/DQ/DR) activation. Relationships among the level of microglial activation, mutant huntingtin burden, and case characteristics were explored using correlative analysis. RESULTS: We report alterations in activated microglia number and morphology in the midcingulate cortex of Huntington's disease cases with predominant mood symptomatology. An increased proportion of activated microglia was observed in the midcingulate of all Huntington's disease cases and positively correlated with 1C2 burden. Alterations in the astrocytic glutamate transporter EAAT2 were observed in the midcingulate cortex of patients associated with mood symptoms. INTERPRETATION: This study presents pathological changes in microglia and astrocytes in the midcingulate cortex in Huntington's disease, which coincide with mood symptom presentation. These findings further the understanding of neuroinflammation in Huntington's disease, a necessary step for developing inflammation-targeted therapeutics. ANN NEUROL 2023;94:895-910.

N-terminal mutant huntingtin deposition correlates with CAG repeat length and symptom onset, but not neuronal loss in Huntington's disease.

Huntington's disease (HD) is caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (Htt) protein, with mutant Htt protein subsequently forming aggregates within the brain. Mutant Htt is a current target for novel therapeutic strategies for HD, however, the lack of translation from preclinical research to disease-modifying treatments highlights the need to improve our understanding of the role of Htt protein in the human brain. This study aims to undertake an immunohistochemical screen of 12 candidate antibodies against various sequences along the Htt protein to characterize Htt distribution and expression in post-mortem human brain tissue microarrays (TMAs). Immunohistochemistry was performed on middle temporal gyrus TMAs comprising of up to 28 HD and 27 age-matched control cases, using 12 antibodies specific to various sequences along the Htt protein. From this study, six antibodies directed to the Htt N-terminus successfully immunolabeled human brain tissue. Htt aggregates and Htt protein expression levels for the six successful antibodies were subsequently quantified with a customized automated image analysis pipeline on the TMAs. A 2.5-12 fold increase in the number of Htt aggregates were detected in HD cases using antibodies MAB5374, MW1, and EPR5526, despite no change in overall Htt protein expression compared to control cases, suggesting a redistribution of Htt into aggregates in HD. MAB5374, MW1, and EPR5526 Htt aggregate numbers were positively correlated with CAG repeat length, and negatively correlated with the age of symptom onset in HD. However, the number of Htt aggregates did not correlate with the degree of striatal degeneration or the degree of cortical neuron loss. Together, these results suggest that longer CAG repeat lengths correlate with Htt aggregation in the HD human brain, and greater Htt cortical aggregate deposition is associated with an earlier age of symptom onset in HD. This study also reinforces that antibodies MAB5492, MW8, and 2B7 which have been utilized to characterize Htt in animal models of HD do not specifically immunolabel Htt aggregates in HD human brain tissue exclusively, thereby highlighting the need for validated means of Htt detection to support drug development for HD.

Reproducibility and repeatability of magnetic resonance imaging in dementia.

PURPOSE: Individualised predictive models of cognitive decline require disease-monitoring markers that are repeatable. For wide-spread adoption, such markers also need to be reproducible at different locations. This study assessed the repeatability and reproducibility of MRI markers derived from a dementia protocol. METHODS: Six participants were scanned at three different sites with a 3T MRI scanner. The protocol employed: T1-weighted (T1w) imaging, resting state functional MRI (rsfMRI), arterial spin labelling (ASL), diffusion-weighted imaging (DWI), T2-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted (T2w) imaging, and susceptibility weighted imaging (SWI). Participants were scanned repeatedly, up to six times over a maximum period of five years. One participant was also scanned a further three times on sequential days on one scanner. Fifteen derived metrics were computed from the seven different modalities. RESULTS: Reproducibility (coefficient of variation; CoV, across sites) was best for T1w derived grey matter, white matter and hippocampal volume (CoV < 1.5%), compared to rsfMRI and SWI derived metrics (CoV, 19% and 21%). For a given metric, long-term repeatability (CoV across time) was comparable to reproducibility, with short-term repeatability considerably better. CONCLUSIONS: Reproducibility and repeatability were assessed for a suite of markers calculated from a dementia MRI protocol. In general, structural markers were less variable than functional MRI markers. Variability over time on the same scanner was comparable to variability measured across different scanners. Overall, the results support the viability of multi-site longitudinal studies for monitoring cognitive decline.

A test of the unified model of vision and attention: Effects of parietal-occipital damage on visual orienting.

Visual orienting was studied in a patient (FM) with parietal-occipital damage due to oligodendroglioma and associated surgery, and in eighteen control participants. The ability of FM and control participants to shift attention in response to spatial landmark cues, and in response to cues that recruit endogenous orienting via encoding of cue identity, were assessed. According to the unified model of vision and attention (Lambert, A. et al., Journal of Experimental Psychology: Human Perception & Performance, 44, 412-432) FM should find it difficult to orient attention in response to spatial landmarks due to impaired functioning of the dorsal visual stream; but shifting attention in response to cue identity, encoded via the ventral visual stream, should be spared. Consistent with these predictions, FM was unable to shift attention in the landmark cueing task, but shifted attention effectively in response to identity cues; and her visual orienting performance differed reliably from controls. These findings complement our earlier observation of preserved orienting towards landmark cues in a patient with bilateral damage to the ventral visual stream, and add to a growing body of evidence in support of the unified model of vision and attention.

Exploring Cognitively Loaded Physical Activity Compared With Control to Improve Global Cognitive Function in Older Community-Dwelling Adults With Mild Cognitive Impairment: Systematic Review With Meta-Analysis.

OBJECTIVE: A systematic review with a meta-analysis explored effects of cognitively loaded physical activity interventions on global cognition in community-dwelling older adults (≥65 years of age) experiencing mild cognitive impairment (MCI), compared to any control. METHODS: A literature search was conducted in 4 databases (MEDLINE [OvidSP], PubMed, CINAHL, and the Cochrane Central Register of Controlled Trials [Wiley]) from inception until January 30, 2018. The meta-analysis was conducted with Review Manager 5.3. RESULTS: Six randomized controlled trials (RCTs) with 547 participants were identified. The interventions ranged from 4 to 52 weeks. Baseline and initial follow-up assessments were used. The primary pooled analysis of all RCTs demonstrated a nonsignificant trivial effect (standardized mean difference [SMD] 0.07, 95% confidence interval [CI] -0.44 to 0.58) favoring the intervention. In pooled subanalysis of 4 RCTs (n = 405) using the same global cognition measure (Mini-Mental State Examination) and duration of intervention >12 weeks, the intervention group achieved a small but significant improvement for global cognition (SMD 0.45, 95% CI 0.14 to 0.75). CONCLUSION: When all the RCTs were pooled, the effect of cognitively loaded physical activity intervention on global cognitive function in older adults with MCI remained unclear. The subgroup analysis provides translation evidence for future RCT study designs.

Modifiable Risk Factors and Change in Cognition of Maori and Non-Maori in Advanced Age: LiLACS NZ.

OBJECTIVE: This study investigated whether previously identified modifiable risk factors for dementia were associated with cognitive change in Maori (indigenous people of New Zealand) and non-Maori octogenarians of LiLACS NZ (Life and Living in Advanced Age; a Cohort Study in New Zealand), a longitudinal study. METHOD: Multivariable repeated-measure mixed effect regression models were used to assess the association between modifiable risk factors and sociodemographic variables at baseline, and cognitive change over 6 years, with p values of <.05 regarded as statistically significant. RESULTS: Modifiable factors associated with cognitive change differed between ethnic groups. Depression was a negative factor in Maori only, secondary education in non-Maori was protective, and obesity predicted better cognition over time for Maori. Diabetes was associated with decreased cognition for both Maori and non-Maori. CONCLUSION: Our results begin to address gaps in the literature and increase understanding of disparities in dementia risk by ethnicity. These findings have implications for evaluating the type and application of culturally appropriate methods to improve cognition.

Spatial variation of perfusion MRI reflects cognitive decline in mild cognitive impairment and early dementia.

Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer's dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the view that vascular health contributes to cognitive decline associated with Alzheimer's disease.

Discontinuity in the Subjective Experience of Self Among People with Mild-To-Moderate Dementia Is Associated with Poorer Psychological Health: Findings from the IDEAL Cohort.

BACKGROUND: The onset and progression of dementia can result in changes in the subjective experience of self, impacting on psychological health. OBJECTIVE: We aimed to explore the extent to which people with mild-to-moderate dementia experience discontinuity in the subjective experience of self, and the factors associated with this experience for people with dementia and their family caregivers. METHODS: We used data from the baseline assessment of the IDEAL cohort. Discontinuity in the subjective experience of self was assessed by asking participants about their agreement with the statement 'I feel I am the same person that I have always been'. Participants were divided into those who did and did not experience discontinuity, and the two groups were compared in terms of demographic and disease-related characteristics, psychological well-being, measures of 'living well', and caregiver stress. RESULTS: Responses to the continuity question were available for 1,465 participants with dementia, of whom 312 (21%) reported experiencing discontinuity. The discontinuity group experienced significantly poorer psychological well-being and had significantly lower scores on measures of 'living well'. There was no clear association with demographic or disease-related characteristics, but some indication of increased caregiver stress. CONCLUSION: A significant proportion of people with mild-to-moderate dementia describe experiencing discontinuity in the subjective sense of self, and this is associated with poorer psychological health and reduced ability to 'live well' with the condition. Sensitively asking individuals with dementia about the subjective experience of self may offer a simple means of identifying individuals who are at increased risk of poor well-being.

[Formula: see text] Cognitive and social/emotional influences on adaptive functioning in children with FASD: Clinical and cultural considerations.

Fetal Alcohol Spectrum Disorder (FASD) is one of the leading causes of intellectual disability and learning difficulties around the world. Children with FASD often have extremely low adaptive behavior due to the severity of brain impairment, however there is limited understanding as to the important predictors of adaptive behavior. In a study of 39 children with FASD and 29 comparison children, we found that social cognition (specifically recognizing emotions) was the only significant independent predictor of teacher-rated adaptive functioning even after including IQ, executive functioning, and adverse childhood experiences into the model. In this current study, Maori (Indigenous people of Aotearoa New Zealand) were overrepresented; therefore, the research was supported by a strong partnership with Te Wahanga Hauora Maori (Maori Health Service). Aotearoa New Zealand's colonized history is recognized and findings are discussed with regard to both the psychological literature and a Te Ao Maori worldview.

New avenue for the geriatric depression scale: Rasch transformation enhances reliability of assessment.

BACKGROUND: Depression is a common problem in older adults. The 15-item Geriatric Depression Scale (GDS-15) is a widely used psychometric tool for measuring depression in the elderly, but its psychometric properties have not been yet rigorously investigated. The aim was to evaluate psychometric properties of the GDS-15 and improve precision of the instrument by applying Rasch analysis and deriving conversion tables for transformation of raw scores into interval level data. METHODS: The data was extracted from the prospective cohort Sydney Memory and Ageing Study of initially not demented individuals aged 70 years and older. The GDS-15 items scores of 212 participants (47.2% males) were analysed using the dichotomous Rasch model. RESULTS: Initially poor reliability of the GDS-15, Person Separation Index (PSI) = 0.68, was improved by combining locally dependent items into seven super-items. These modifications improved reliability of the GDS-15 (PSI = 0.78) and resulted in the best Rasch model fit (χ2(28)=37.72, p = =0.104), strict unidimensionality and scale invariance across personal factors such as gender, diagnostic and language background. LIMITATIONS: Presence of participants with cognitive impairment may be a potential limitation. CONCLUSIONS: Reliability and psychometric characteristics of the GDS-15 were improved by minor modifications and now satisfy expectations of the unidimensional Rasch model. By using Rasch transformation tables published here psychiatrists, psychologists and researchers can transform GDS raw scores into interval-level data, which improves reliability of the GDS-15 without the need to modify its original response format. These findings increase accuracy of clinical psychometric assessments, leading to more precise diagnosis of depression in the elderly.

Community Knowledge and Awareness of Stroke in New Zealand.

INTRODUCTION: Community knowledge and stroke awareness is crucial for primary prevention of stroke and timely access to stroke treatments including acute reperfusion therapies. We conducted a national telephone survey to quantify the level of community stroke awareness. METHODS: A random sample of 400 adults in New Zealand (NZ), stratified by the 4 main ethnic groups, was surveyed. Eligible participants answered stroke awareness questions using both unprompted (open-ended) and prompted questions (using a list). Proportional odds logistic regression models were used to identify factors associated with stroke awareness. RESULTS: Only 1.5% of participants named stroke as a major cause of death. The stroke signs and symptoms most frequently identified from a list were sudden speech difficulty (94%) and sudden 1-sided weakness (92%). Without prompting, 78% of participants correctly identified at least 1 risk factor, 62% identified at least 2, and 35% identified 3 or more. When prompted with the list, scores increased 10-fold compared with unprompted responses. Ethnic disparities were observed, with Pacific peoples having the lowest level of awareness among the 4 ethnic groups. Higher education level, higher income, and personal experience of stroke were predictive of greater awareness (P ≤ .05). CONCLUSIONS: Stroke was not recognized as a major cause of death. Although identification of stroke risk factors was high with prompting, awareness was low without prompting, particularly among those with lower education and income. Nationwide, culturally tailored public awareness campaigns are necessary to improve knowledge of stroke risk factors, recognition of stroke in the community and appropriate actions to take in cases of suspected stroke.

Diagnostic accuracy of a global cognitive screen for Maori and non-Maori octogenarians.

INTRODUCTION: We assessed the sensitivity and specificity of the Modified Mini-Mental State Examination (3MS) in predicting dementia and cognitive impairment in Maori (indigenous people of New Zealand) and non-Maori octogenarians. METHODS: A subsample of participants from Life and Living in Advanced Age: a Cohort Study in New Zealand were recruited to determine the 3MS diagnostic accuracy compared with the reference standard. RESULTS: Seventy-three participants (44% Maori) completed the 3MS and reference standard assessments. The 3MS demonstrated strong diagnostic accuracy to detect dementia with areas under the curve of 0.87 for Maori and 0.9 for non-Maori. Our cutoffs displayed ethnic variability and are approximately 5 points greater than those commonly applied. Cognitive impairment yielded low accuracy, and discriminatory power was not established. DISCUSSION: Cutoffs that are not age or ethnically appropriate may compromise the accuracy of cognitive screens. Consequently, older age and indigeneity increase the risk of mislabeled cognitive status.

Specificity of Future Thinking in Depression: A Meta-Analysis.

Reduced specificity of autobiographical memory has been well established in depression, but whether this overgenerality extends to future thinking has not been the focus of a meta-analysis. Following a preregistered protocol, we searched six electronic databases, Google Scholar, and personal libraries and contacted authors in the field for studies matching search terms related to depression, future thinking, and specificity. We reduced an initial 7,332 results to 46 included studies, with 89 effect sizes and 4,813 total participants. Random-effects meta-analytic modeling revealed a small but robust correlation between reduced future specificity and higher levels of depression (r = -.13, p < .001). Of the 11 moderator variables examined, the most striking effects were related to the emotional valence of future thinking (p < .001) and the sex of participants (p = .025). Namely, depression was linked to reduced specificity for positive (but not negative or neutral) future thinking, and the relationship was stronger in samples with a higher proportion of males. This meta-analysis contributes to our understanding of how prospection is altered in depression and dysphoria and, by revealing areas where current evidence is inconclusive, highlights key avenues for future research.

Cerebellar degeneration correlates with motor symptoms in Huntington disease.

OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by variable motor and behavioral symptoms attributed to major neuropathology of mainly the basal ganglia and cerebral cortex. The role of the cerebellum, a brain region involved in the coordination of movements, in HD neuropathology has been controversial. This study utilizes postmortem human brain tissue to investigate whether Purkinje cell degeneration in the neocerebellum is present in HD, and how this relates to disease symptom profiles. METHODS: Unbiased stereological counting methods were used to quantify the total number of Purkinje cells in 15 HD cases and 8 neurologically normal control cases. Based on their predominant symptoms, the HD cases were categorized into 2 groups: "motor" or "mood." RESULTS: The results demonstrated a significant 43% loss of Purkinje cells in HD cases with predominantly motor symptoms, and no cell loss in cases showing a major mood phenotype. There was no significant correlation between Purkinje cell loss and striatal neuropathological grade, postmortem delay, CAG repeat in the IT15 gene, or age at death. INTERPRETATION: This study shows a compelling relationship between Purkinje cell loss in the HD neocerebellum and the HD motor symptom phenotype, which, together with our previous human brain studies on the same HD cases, provides novel perspectives interrelating and correlating the variable cerebellar, basal ganglia, and neocortical neuropathology with the variability of motor/mood symptom profiles in the human HD brain. ANN NEUROL 2019;85:396-405.