Microglial proliferation and astrocytic protein alterations in the human Huntington's disease cortex.

Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP+ protein expression attributed to the presence of more GFAP+ expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1+ and TMEM119+ microglia with somal enlargement. IBA-1+, TMEM119+, and P2RY12+ reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1+ cells contained either Ki-67 or PCNA, whereas GFAP+ astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.

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.

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.

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.

Globus pallidus degeneration and clinicopathological features of Huntington disease.

OBJECTIVE: Numerous studies have focused on striatal neurodegeneration in Huntington disease (HD). In comparison, the globus pallidus (GP), a main striatal output nucleus, has received less focus in HD research. This study characterizes the pattern of neurodegeneration in 3 subdivisions of the human GP, and its relation to clinical symptomatology. METHODS: Stereology was used to measure regional atrophy, neuronal loss, and soma neuronal atrophy in 3 components of the GP-the external segment (GPe), internal segment (GPi), and ventral pallidum (VP)-in 8 HD cases compared with 7 matched control cases. The findings in the HD patients were compared with HD striatal neuropathological grade, and symptom scores of motor impairment, chorea, cognition, and mood. RESULTS: Relative to controls, in the HD patients the GPe showed a 54% overall volume decline, 60% neuron loss, and 34% reduced soma volume. Similarly, the VP was reduced in volume by 31%, with 48% neuron loss and 64% reduced soma volume. In contrast, the GPi was less affected, with a 38% reduction in overall volume only. The extent of GP neurodegeneration correlated with increasing striatal neuropathological grade. Decreasing GPe and VP volumes were associated with poorer cognition and increasing motor impairments, but not chorea. In contrast, decreasing GPi volumes were associated with decreasing levels of irritability. INTERPRETATION: The HD gene mutation produces variable degrees of GP segment degeneration, highlighting the differential vulnerability of striato-GP target projections. The relationship established between clinical symptom scores and pallidal degeneration provides a novel contribution to understanding the clinicopathological associations in HD. Ann Neurol 2016;80:185-201.

The Simpson's paradox and fMRI: Similarities and differences between functional connectivity measures derived from within-subject and across-subject correlations.

Task-related functional connectivity (fc-MRI) indexes the interaction of brain regions during cognitive tasks. Two general classes of methods exist to investigate fc-MRI: the most widely-used method calculates temporal correlations between voxels/regions within subjects, and then determines if within-subject correlations are reliable across subjects (ws-fcMRI); the other calculates the average (BOLD) signal within voxels/regions and then performs correlations across subjects (as-fcMRI). That is, while both methods rely on correlational techniques, the level at which correlations are calculated is fundamentally different. While conceptually distinct, it is not known how well these two methods of fc-MRI analyses converge on the same findings. The current study addresses this question across a number of analyses. First, using default-mode network regions as seeds, we show that as-fcMRI does not strongly predict ws-fcMRI during episodic simulation tasks. Next, we show that the relationship between as-fcMRI and ws-fcMRI is contingent on whether correlations are calculated between regions from the same functional network (default mode or dorsal attention networks) or between regions from different functional networks. Lastly, we compare seed partial least squares (PLS) - a well-established as-fcMRI method - with a novel version of seed PLS that combines the multivariate approach of PLS analyses and within-subject correlations. The results showed that while many regions exhibited congruent as-fcMRI and ws-fcMRI effects, in some regions the two analyses produced effects in opposite directions. Results are discussed in relation to the Simpson's Paradox, a phenomenon in which across-subject correlations are reversed within individuals present in a sample. Overall, our results suggest that the findings of as-fcMRI do not always map onto those from ws-fcMRI. We end by discussing the advantages associated with using ws-fcMRI to assess the task-related interactions between brain regions.

Symptom heterogeneity in Huntington's disease correlates with neuronal degeneration in the cerebral cortex.

BACKGROUND: Huntington's disease (HD) is characterised by variable symptoms and neuropathology of the basal ganglia and cortex. Previously, we have shown that the pattern of pyramidal cell loss in 8 different cortical regions correlates with the phenotypic variability in HD. In the primary motor and anterior cingulate cortices, the pattern of interneuron degeneration correlates with pyramidal cell death and variable HD symptom profiles. OBJECTIVES: This study aimed to examine the pattern of interneuron degeneration in 3 further regions of the HD cortex (primary sensory, superior frontal, superior parietal cortices) to determine whether HD neuropathogenesis was characterised by a general fundamental pattern of cortical interneuron loss, and explore the relationship between cortical interneuron loss with previously determined pyramidal cell loss and clinical heterogeneity. METHODS: Stereological counting was used to quantify 3 sub-populations of calcium-binding protein containing interneurons in 3 cortical human brain regions of 14 HD and 13 control cases as used in our previous studies (Nana et al., 2014; Kim et al., 2014). The HD cases were grouped according to their predominant symptom profile ("motor", "mood", "mixed"). RESULTS: The present results demonstrated a heterogeneous loss of interneurons across the 3 cortical regions which, when compared with our previous studies, mirrored the pattern of pyramidal cell loss in the same cortical areas. Most interestingly, the pattern of neuronal loss in these regions correlated with the variable HD symptom profiles. CONCLUSION: The overall findings in our present and previous cortical studies establish a clear correlative pattern of variable cortical neuronal degeneration in HD pathogenesis, which mirrors the heterogeneity of HD symptom phenotypes.

Do strategic processes contribute to the specificity of future simulation in depression?

OBJECTIVES: The tendency to generate overgeneral past or future events is characteristic of individuals with a history of depression. Although much research has investigated the contribution of rumination and avoidance to the reduced specificity of past events, comparatively little research has examined (1) whether the specificity of future events is differentially reduced in depression and (2) the role of executive functions in this phenomenon. Our study aimed to redress this imbalance. METHODS: Participants with either current or past experience of depressive symptoms ('depressive group'; N = 24) and matched controls ('control group'; N = 24) completed tests of avoidance, rumination, and executive functions. A modified Autobiographical Memory Test was administered to assess the specificity of past and future events. RESULTS: The depressive group were more ruminative and avoidant than controls, but did not exhibit deficits in executive function. Although overall the depressive group generated significantly fewer specific events than controls, this reduction was driven by a significant group difference in future event specificity. Strategic retrieval processes were correlated with both past and future specificity, and predictive of the future specificity, whereas avoidance and rumination were not. CONCLUSIONS: Our findings demonstrate that future simulation appears to be particularly vulnerable to disruption in individuals with current or past experience of depressive symptoms, consistent with the notion that future simulation is more cognitively demanding than autobiographical memory retrieval. Moreover, our findings suggest that even subtle changes in executive functions such as strategic processes may impact the ability to imagine specific future events. PRACTITIONER POINTS: Future simulation may be particularly vulnerable to executive dysfunction in individuals with current/previous depressive symptoms, with evidence of a differential reduction in the specificity of future events. Strategic retrieval abilities were associated with the degree of future event specificity whereas levels of rumination and avoidance were not. Given that the ability to generate specific simulations of the future is associated with enhanced psychological wellbeing, problem solving and coping behaviours, understanding how to increase the specificity of future simulations in depression is an important direction for future research and clinical practice. Interventions focusing on improving the ability to engage strategic processes may be a fruitful avenue for increasing the ability to imagine specific future events in depression. The autobiographical event tasks have somewhat limited ecological validity as they do not account for the many social and environmental cues present in everyday life; the development of more clinically-relevant tasks may be of benefit to this area of study.

Cortical interneuron loss and symptom heterogeneity in Huntington disease.

OBJECTIVE: The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons. METHODS: We undertook a double-blind study using stereological cell counting methods to quantify the 3 major types of γ-aminobutyric acidergic interneurons (calbindin-D28k, calretinin, parvalbumin) in 13 HD cases of variable motor/mood symptomatology and 15 matched control cases in the primary motor and anterior cingulate cortices. RESULTS: In the primary motor cortex, there was a significant loss (57% reduction) of only calbindin interneurons (p=0.022) in HD cases dominated by motor symptoms, but no significant interneuron loss in cases with a dominant mood phenotype. In contrast, the anterior cingulate cortex showed a major significant loss in all 3 interneuron populations, with 71% loss of calbindin (p=0.001), 60% loss of calretinin (p=0.001), and 80% loss of parvalbumin interneurons (p=0.005) in HD cases with major mood disorder, and no interneuron loss was observed in cases with major motor dysfunction. INTERPRETATION: These findings suggest that region-specific degeneration of cortical interneurons is a key component in understanding the neural basis of symptom heterogeneity in HD.

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.

Striatal parvalbuminergic neurons are lost in Huntington's disease: implications for dystonia.

Although dystonia represents a major source of motor disability in Huntington's disease (HD), its pathophysiology remains unknown. Because recent animal studies indicate that loss of parvalbuminergic (PARV+) striatal interneurons can cause dystonia, we investigated if loss of PARV+ striatal interneurons occurs during human HD progression, and thus might contribute to dystonia in HD. We used immunolabeling to detect PARV+ interneurons in fixed sections, and corrected for disease-related striatal atrophy by expressing PARV+ interneuron counts in ratio to interneurons co-containing somatostatin and neuropeptide Y (whose numbers are unaffected in HD). At all symptomatic HD grades, PARV+ interneurons were reduced to less than 26% of normal abundance in rostral caudate. In putamen rostral to the level of globus pallidus, loss of PARV+ interneurons was more gradual, not dropping off to less than 20% of control until grade 2. Loss of PARV+ interneurons was even more gradual in motor putamen at globus pallidus levels, with no loss at grade 1, and steady grade-wise decline thereafter. A large decrease in striatal PARV+ interneurons, thus, occurs in HD with advancing disease grade, with regional variation in the loss per grade. Given the findings of animal studies and the grade-wise loss of PARV+ striatal interneurons in motor striatum in parallel with the grade-wise appearance and worsening of dystonia, our results raise the possibility that loss of PARV+ striatal interneurons is a contributor to dystonia in HD.

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.

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.

Cognitive and behavioural deficits associated with the orbitomedial prefrontal cortex in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis, a progressive disease affecting motor neurons, may variably affect cognition and behaviour. We tested the hypothesis that functions associated with orbitomedial prefrontal cortex are affected by evaluating the behavioural and cognitive performance of 18 participants with amyotrophic lateral sclerosis without dementia and 18 healthy, matched controls. We measured Theory of Mind (Faux Pas Task), emotional prosody recognition (Aprosodia Battery), reversal of behaviour in response to changes in reward (Probabilistic Reversal Learning Task), decision making without risk (Holiday Apartment Task) and aberrant behaviour (Neuropsychiatric Inventory). We also assessed dorsolateral prefrontal function, using verbal and written fluency and planning (One-touch Stockings of Cambridge), to determine whether impairments in tasks sensitive to these two prefrontal regions co-occur. The patient group was significantly impaired at identifying social faux pas, recognizing emotions and decision-making, indicating mild, but consistent impairment on most measures sensitive to orbitomedial prefrontal cortex. Significant levels of aberrant behaviour were present in 50% of patients. Patients were also impaired on verbal fluency and planning. Individual subject analyses involved computing classical dissociations between tasks sensitive to different prefrontal regions. These revealed heterogeneous patterns of impaired and spared cognitive abilities: 33% of participants had classical dissociations involving orbitomedial prefrontal tasks, 17% had classical dissociations involving dorsolateral prefrontal tasks, 22% had classical dissociations between tasks of both regions, and 28% had no classical dissociations. These data indicate subtle changes in behaviour, emotional processing, decision-making and altered social awareness, associated with orbitomedial prefrontal cortex, may be present in a significant proportion of individuals with amyotrophic lateral sclerosis without dementia, some with no signs of dysfunction in tasks sensitive to other regions of prefrontal cortex. This demonstration of variability in cognitive integrity supports previous research indicating amyotrophic lateral sclerosis is a heterogeneous disease.

Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington's disease.

Huntington's disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntington's disease correlates with the variable compartmental pattern of GABAA receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntington's disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntington's disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntington's disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntington's disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntington's disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate cortex.

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.

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.

Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery.

BACKGROUND AND PURPOSE: Improvements in cardiac surgery mortality and morbidity have focused interest on the neurological injury such as stroke and cognitive decline that may accompany an otherwise successful operation. We aimed to investigate (1) the rate of stroke, new ischemic change on MRI, and cognitive impairment after cardiac valve surgery; and (2) the controversial relationship between perioperative cerebral ischemia and cognitive decline. METHODS: Forty patients (26 men; mean [SD] age 62.1 [13.7] years) undergoing intracardiac surgery (7 also with coronary artery bypass grafting) were studied. Neurological, neuropsychological, and MRI examinations were performed 24 hours before surgery and 5 days (MRI and neurology) and 6 weeks (neuropsychology and neurology) after surgery. Cognitive decline from baseline was determined using the Reliable Change Index. RESULTS: Two of 40 (5%) patients had perioperative strokes and 22 of 35 (63%) tested had cognitive decline in at least one measure (range, 1 to 4). Sixteen of 37 participants (43%) with postoperative imaging had new ischemic lesions (range, 1 to 17 lesions) with appearances consistent with cerebral embolization. Cognitive decline was seen in all patients with, and 35% of those without, postoperative ischemic lesions (P<0.001), and there was an association between the number of abnormal cognitive tests and ischemic burden (P<0.001). CONCLUSIONS: We have provided a reliable estimate of the rate of stroke, postoperative ischemia, and cognitive impairment at 6 weeks after cardiac valve surgery. Cognitive impairment is associated with perioperative ischemia and is more severe with greater ischemic load.