Evaluating the Effect of Alzheimer's Disease-Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy.

OBJECTIVES: To evaluate the effect of Alzheimer's disease (AD) -related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). METHODS: Data from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained from the 4-R-Tauopathy Neuroimaging Initiative 1 and 2, the Alzheimer's Disease Neuroimaging Initiative, and a local cohort from the Toronto Western Hospital. Patients with CBS and PSP were divided into AD-positive (CBS/PSP-AD) and AD-negative (CBS/PSP-noAD) groups based on fluid biomarkers and amyloid PET scans. Cognitive, motor, and depression scores; AD fluid biomarkers (cerebrospinal p-tau, t-tau, and amyloid-beta, and plasma ptau-217); and neuroimaging data (amyloid PET, MRI and fMRI) were collected. Clinical features, whole-brain gray matter volume and functional networks connectivity were compared across groups. RESULTS: Data were analyzed from 87 CBS/PSP-noAD and 23 CBS/PSP-AD, 18 AD, and 30 healthy controls. CBS/PSP-noAD showed worse performance in comparison to CBS/PSP-AD in the PSPRS [mean(SD): 34.8(15.8) vs 23.3(11.6)] and the UPDRS scores [mean(SD): 34.2(17.0) vs 21.8(13.3)]. CBS/PSP-AD demonstrated atrophy in AD signature areas and brainstem, while CBS/PSP-noAD patients displayed atrophy in frontal and temporal areas, globus pallidus, and brainstem compared to healthy controls. The default mode network showed greatest disconnection in CBS/PSP-AD compared with CBS/PSP-no AD and controls. The thalamic network connectivity was most affected in CBS/PSP-noAD. INTERPRETATION: AD biomarker positivity may modulate the clinical presentation of CBS/PSP, with evidence of distinctive structural and functional brain changes associated with the AD pathology/co-pathology. ANN NEUROL 2024.

Factors associated with entry to residential care in frail older inpatients.

OBJECTIVE: To examine factors that may influence the risk of discharge to a residential aged care facility (RACF) in a population of frail older inpatients. METHODS: We analysed data from 5846 inpatients aged over 60 years from 27 hospitals in Queensland, Australia, admitted from independent living and referred for geriatric consultation. Patients underwent an interRAI Acute Care Comprehensive Geriatric Assessment by trained nurses. Frailty was assessed using a 52-item frailty index (FI). Risk/protective factors were determined a priori. Logistic regression assessed the relationship between factors and discharge destination, adjusted for FI, age, sex and hospital. Frailty × risk/protective factor interactions were performed. RESULTS: Patients had a mean (SD) age of 79.7 (8.2) years and a mean (SD) FI of 0.44 (0.14). Twenty-nine per cent (n = 1678) of patients were discharged to an RACF. Each 0.1 increment in FI increased the risk of discharge to an RACF by 54% (OR 1.54, 95% CI 1.40-1.68, p < 0.01). Being married or in a de facto relationship had protective effects up to an FI of 0.7, whereas behavioural and psychological symptoms of dementia (BPSD) increased the risk of RACF discharge up to an FI of 0.7. Female sex, faecal incontinence and living alone did not influence the relationship between frailty and discharge destination. CONCLUSIONS: The association between frailty and discharge to RACF has previously been recognised but here we found that risk and protective factors can influence this association. Whether early identification and management of mutable factors can reduce discharge to RACF should be addressed in future studies.

Prevalence of Cognitive and Vestibular Impairment in Seniors Experiencing Falls.

BACKGROUND: Falls are a growing concern in seniors (≥65 yrs). Cognitive impairment (CI) and vestibular impairment (VI) increase fall risk. The aim of this study is to assess the prevalence of CI and VI in seniors experiencing falls. METHODS: Participants (≥65 yrs) with falls were recruited from Falls Prevention Programs (FPPs) and a Memory Clinic (MC). CI was assessed using the Montreal Cognitive Assessment at FPPs. VI was assessed at an MC and FFPs using the Head Impulse- (video + bedside), Headshake-, Dix-Hallpike test, and test of sensory interaction in balance. Questionnaires included Dizziness Handicap Inventory (DHI) and Activities-specific Balance Confidence Scale (ABC). RESULTS: Of 41 participants (29 FPPs, 12 MC); mean age was 80.1 ± 7.1 years, and 58.5% were female. Overall, 82.9% had VI. At FPPs, 76.0% had CI, and 72.3% had CI + VI. Bilateral vestibular hypofunction (BVH) was more common than unilateral vestibular hypofunction (UVH) (70.6% vs. 29.4%); p = 0.016. Dizziness Handicap (DHI) was not different between those with a VI (23.5 ± 23.9) versus without VI [PVI + no impairment] (10.0 ± 15.4); p = 0.160. Balance confidence (ABC) was lowest in VI but not significantly different between those with a VI (63.4 ± 27.3) versus without VI [PVI + no impairment] (85.0 ± 16.5); p = 0.053. CONCLUSIONS: VI and CI are prevalent in seniors experiencing falls. For seniors with history of falls, both cognitive and vestibular functions should be considered in the assessment and subsequent treatment. Screening enables earlier detection, targeted interventions, and prevention, reducing the clinical and financial impact.

White matter hyperintensities and neuropsychiatric symptoms in mild cognitive impairment and Alzheimer's disease.

Neuropsychiatric symptoms (NPS), such as apathy, irritability and depression, are frequently encountered in patients with Alzheimer's disease (AD). Focal grey matter atrophy has been linked to NPS development. Cerebrovascular disease is common among AD patients and can be detected on MRI as white matter hyperintensities (WMH). In this longitudinal study, the relative contribution of WMH burden and GM atrophy to NPS was evaluated in a cohort of mild cognitive impairment (MCI), AD and normal controls. This study included 121 AD, 315 MCI and 225 normal control subjects from the Alzheimer's Disease Neuroimaging Initiative. NPS were assessed using the Neuropsychiatric Inventory and grouped into hyperactivity, psychosis, affective and apathy subsyndromes. WMH were measured using an automatic segmentation technique and mean deformation-based morphometry (DBM) was used to measure atrophy of grey matter regions. Linear mixed-effects models found focal grey matter atrophy and WMH volume both contributed significantly to NPS subsyndromes in MCI and AD subjects, however, WMH burden played a greater role. This study could provide a better understanding of the pathophysiology of NPS in AD and support the monitoring and control of vascular risk factors.

PET Tau Imaging and Motor Impairments Differ Between Corticobasal Syndrome and Progressive Supranuclear Palsy With and Without Alzheimer's Disease Biomarkers.

Introduction: Frontotemporal lobar degeneration (FTLD)-related syndrome includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). PSP is usually caused by a tauopathy but can have associated Alzheimer's disease (AD) while CBS can be caused by tauopathy, transactive response DNA binding protein 43 kDa, or AD pathology. Our aim was to compare the parkinsonian syndromes presenting without AD biomarkers (CBS/PSP-non-AD) to parkinsonian syndromes with AD biomarkers (CBS/PSP-AD). Materials and Methods: Twenty-four patients [11 males, 13 females; age (68.46 ± 7.23)] were recruited for this study. The whole cohort was divided into parkinsonian syndromes without AD biomarkers [N = 17; diagnoses (6 CBS, 11 PSP)] and parkinsonian syndromes with AD biomarkers [N = 7; diagnoses (6 CBS-AD, 1 PSP-AD)]. Anatomical MRI and PET imaging with tau ligand [18F]-AV1451 tracer was completed. Cerebrospinal fluid analysis or [18F]-AV1451 PET imaging was used to assess for the presence of AD biomarkers. Progressive supranuclear palsy rating scale (PSPRS) and unified Parkinson's disease rating scale (UPDRS) motor exam were implemented to assess for motor disturbances. Language and cognitive testing were completed. Results: The CBS/PSP-non-AD group [age (70.18 ± 6.65)] was significantly older (p = 0.028) than the CBS/PSP-AD group [age (64.29 ± 7.32)]. There were no differences between the groups in terms of gender, education, years of disease duration, and disease severity as measured with the Clinical Dementia Rating scale. The CBS/PSP-non-AD group had significantly lower PET Tau Standard Volume Uptake Ratio (SUVR) values compared to the CBS/PSP-AD group in multiple frontal and temporal areas, and inferior parietal (all p < 0.03). The CBS/PSP-non-AD group had significantly higher scores compared to the CBS/PSP-AD group on PSPRS (p = 0.004) and UPDRS motor exam (p = 0.045). The CBS/PSP-non-AD group had higher volumes of inferior parietal, precuneus, and hippocampus (all p < 0.02), but lower volume of midbrain (p = 0.02), compared to the CBS/PSP-AD group. Discussion: The CBS/PSP-non-AD group had higher motor disturbances compared to the CBS/PSP-AD group; however, both groups performed similarly on neuropsychological measures. The AD biomarker group had increased global uptake of PET Tau SUVR and lower volumes in AD-specific areas. These results show that the presenting phenotype of CBS and PSP syndromes and the distribution of injury are strongly affected by the presence of AD biomarkers.

Vestibular Exercises as a Fall Prevention Strategy in Patients with Cognitive Impairment.

Vestibular impairment (VI) and cognitive impairment (CI) are risk factors for senior falls. We tested the feasibility of a self-directed 12-week vestibular rehabilitation (VR) program in Memory Clinic patients (65 years+) with a fall, CI and VI. We assessed recruitment, exercise adherence and ability to complete questionnaires/assessments. Twelve patients with CI and falls were screened and 8/12 (75% - prevalence) had VI. All patients completed the screening tests/questionnaires (100% - completeness); 7/8 patients were recruited (87.5% - recruitment); 1/7 (85.7% - attrition) patient attended follow-up. VI is prevalent in patients with CI experiencing falls but traditional VR is not feasible, so a novel delivery of VR must be explored.

Les exercices de réadaptation vestibulaire comme stratégie de prévention des chutes chez des patients atteints de troubles cognitifs. Les troubles vestibulaires (TV) et les troubles cognitifs (TC) sont des facteurs de risque de chute chez les personnes âgées. À cet égard, nous avons évalué le caractère réalisable d'un programme autonome de réadaptation vestibulaire de 12 semaines offert, dans une clinique de la mémoire, à des patients âgés de 65 ans et plus ayant chuté au moins une fois et qui sont atteints de TV et de TC. Nous nous sommes ainsi penchés sur leur recrutement, leur adhésion aux exercices du programme et leur capacité à compléter des questionnaires d'évaluation. Douze patients aux prises avec des TC ont été examinés. De ce nombre, huit d'entre eux (75 %) étaient aussi atteints de TV. Tous ces patients ont complété des tests de dépistage ainsi que des questionnaires, lesquels ont été remplis dans 100 % des cas. Au total, sept patients sur huit ont été recrutés, soit 87,5 %, tandis qu'un seul, ce qui représente un taux d'attrition de 85,7 %, s'est présenté lors d'un suivi. Même si les TV affectent les patients atteints de TC, un programme de réadaptation vestibulaire n'est pas réellement réalisable dans ce contexte, de sorte qu'un nouveau programme devrait être exploré.

Association Between Social Cognition Changes and Resting State Functional Connectivity in Frontotemporal Dementia, Alzheimer's Disease, Parkinson's Disease, and Healthy Controls.

OBJECTIVE: To determine the relationship between alterations in resting state functional connectivity and social cognition dysfunction among patients with frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and healthy controls (HC). METHODS: Fifty-seven participants (FTD = 10, AD = 18, PD = 19, and HC = 10) underwent structural and functional imaging and completed the Awareness of Social Inference Test-Emotion Evaluation Test (TASIT-EET), Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scale, Revised Self-Monitoring Scale (RSMS), Interpersonal Reactivity Index (IRI), and Social Norms Questionnaire (SNQ). A multi-variate pattern analysis (MVPA) was carried out to determine activation differences between the groups. The clusters from the MVPA were used as seeds for the ROI-to-voxel analysis. Relationship between social cognition deficits and uncinate integrity was also investigated. RESULTS: BOLD signal activation differed among the four groups of AD, PD, FTD, and HC in the left inferior temporal gyrus-anterior division [L-ITG (ant)], right central opercular cortex (R-COp), right supramarginal gyrus, posterior division (R-SMG, post), right angular gyrus (R-AG), and R-ITG. The BOLD co-activation of the L-ITG (ant) with bilateral frontal pole (FP) and paracingulate gyrus was positively associated with IRI-perspective taking (PT) (r = 0.38, p = 0.007), SNQ total (r = 0.37, p = 0.009), and TASIT-EET (r = 0.47, p < 0.001). CONCLUSION: Patients with neurodegenerative diseases showed alterations in connectivity in brain regions important for social cognition compared with HCs. Functional connectivity correlated with performance on social cognition tasks and alterations could be responsible for some of the social cognition deficits observed in all neurodegenerative diseases.

The relationship between brain atrophy and cognitive-behavioural symptoms in retired Canadian football players with multiple concussions.

Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance in the former athletes. Deformation-based morphometry confirmed smaller bilateral hippocampal volume that was associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age.

Emotion Detection Deficits and Decreased Empathy in Patients with Alzheimer's Disease and Parkinson's Disease Affect Caregiver Mood and Burden.

Background: Changes in social cognition occur in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and can be caused by several factors, including emotion recognition deficits and neuropsychiatric symptoms (NPS). The aims of this study were to investigate: (1) group differences on emotion detection between patients diagnosed with AD or PD and their respective caregivers; (2) the association of emotion detection with empathetic ability and NPS in individuals with AD or PD; (3) caregivers' depression and perceived burden in relation to patients' ability to detect emotions, empathize with others, presence of NPS; and (4) caregiver's awareness of emotion detection deficits in patients with AD or Parkinson. Methods: In this study, patients with probable AD (N = 25) or PD (N = 17), and their caregivers (N = 42), performed an emotion detection task (The Awareness of Social Inference Test-Emotion Evaluation Test, TASIT-EET). Patients underwent cognitive assessment, using the Behavioral Neurology Assessment (BNA). In addition, caregivers completed questionnaires to measure empathy (Interpersonal Reactivity Index, IRI) and NPS (Neuropsychiatric Inventory, NPI) in patients and self-reported on depression (Geriatric Depression Scale, GDS) and burden (Zarit Burden Interview, ZBI). Caregivers were also interviewed to measure dementia severity (Clinical Dementia Rating (CDR) Scale) in patients. Results: The results suggest that individuals with AD and PD are significantly worse at recognizing emotions than their caregivers. Moreover, caregivers failed to recognize patients' emotion recognition deficits and this was associated with increased caregiver burden and depression. Patients' emotion recognition deficits, decreased empathy and NPS were also related to caregiver burden and depression. Conclusions: Changes in emotion detection and empathy in individuals with AD and PD has implications for caregiver burden and depression and may be amenable to interventions with both patients and caregivers.

Motor Function in Former Professional Football Players with History of Multiple Concussions.

The objective of this study was to assess the incidence of motor impairment in former professional Canadian Football League (ex-CFL) players with multiple concussions. We investigated motor symptoms and signs in 45 ex-CFL players with multiple concussions and 25 age- and education-matched healthy controls with no history of concussion. Neurological assessment included items from the SCAT3 (Sport Concussion Assessment Tool 3) and the Unified Parkinson's Disease Rating Scale part III (UPDRS-Part III). A performance-based measurement of manual motor function was undertaken using the Grooved Pegboard test. Cognition was measured with patient-reported outcomes for memory, executive and behavioral symptoms as well as performance-based measures of memory and executive function. Symptoms of anxiety and depression were measured using the Personality Assessment Inventory. There was no significant difference between the ex-CFL players and controls on the UPDRS-Part III scores, and neither group reported clinically significant motor complaints. Ex-CFL players did not perform differently from control subjects on the Grooved Pegboard test. In contrast, with regard to cognitive and mood testing, players were more symptomatic: The ex-CFL players reported significantly more memory (77.8% vs. 16%, respectively, p < 0.001), executive (53.3% vs. 8%, respectively, p < 0.001), and behavioral symptoms (66.7% vs. 20%, respectively, p < 0.001). No significant differences were found when comparing ex-CFL players and controls in performance on memory and executive tests. In summary, in a group of retired CFL players who self-reported declines in memory, executive and behavioral symptoms, no motor symptoms were reported and no motor signs were detected.

Performance comparison of 10 different classification techniques in segmenting white matter hyperintensities in aging.

INTRODUCTION: White matter hyperintensities (WMHs) are areas of abnormal signal on magnetic resonance images (MRIs) that characterize various types of histopathological lesions. The load and location of WMHs are important clinical measures that may indicate the presence of small vessel disease in aging and Alzheimer's disease (AD) patients. Manually segmenting WMHs is time consuming and prone to inter-rater and intra-rater variabilities. Automated tools that can accurately and robustly detect these lesions can be used to measure the vascular burden in individuals with AD or the elderly population in general. Many WMH segmentation techniques use a classifier in combination with a set of intensity and location features to segment WMHs, however, the optimal choice of classifier is unknown. METHODS: We compare 10 different linear and nonlinear classification techniques to identify WMHs from MRI data. Each classifier is trained and optimized based on a set of features obtained from co-registered MR images containing spatial location and intensity information. We further assess the performance of the classifiers using different combinations of MRI contrast information. The performances of the different classifiers were compared on three heterogeneous multi-site datasets, including images acquired with different scanners and different scan-parameters. These included data from the ADC study from University of California Davis, the NACC database and the ADNI study. The classifiers (naïve Bayes, logistic regression, decision trees, random forests, support vector machines, k-nearest neighbors, bagging, and boosting) were evaluated using a variety of voxel-wise and volumetric similarity measures such as Dice Kappa similarity index (SI), Intra-Class Correlation (ICC), and sensitivity as well as computational burden and processing times. These investigations enable meaningful comparisons between the performances of different classifiers to determine the most suitable classifiers for segmentation of WMHs. In the spirit of open-source science, we also make available a fully automated tool for segmentation of WMHs with pre-trained classifiers for all these techniques. RESULTS: Random Forests yielded the best performance among all classifiers with mean Dice Kappa (SI) of 0.66±0.17 and ICC=0.99 for the ADC dataset (using T1w, T2w, PD, and FLAIR scans), SI=0.72±0.10, ICC=0.93 for the NACC dataset (using T1w and FLAIR scans), SI=0.66±0.23, ICC=0.94 for ADNI1 dataset (using T1w, T2w, and PD scans) and SI=0.72±0.19, ICC=0.96 for ADNI2/GO dataset (using T1w and FLAIR scans). Not using the T2w/PD information did not change the performance of the Random Forest classifier (SI=0.66±0.17, ICC=0.99). However, not using FLAIR information in the ADC dataset significantly decreased the Dice Kappa, but the volumetric correlation did not drastically change (SI=0.47±0.21, ICC=0.95). CONCLUSION: Our investigations showed that with appropriate features, most off-the-shelf classifiers are able to accurately detect WMHs in presence of FLAIR scan information, while Random Forests had the best performance across all datasets. However, we observed that the performances of most linear classifiers and some nonlinear classifiers drastically decline in absence of FLAIR information, with Random Forest still retaining the best performance.

Validation of a Regression Technique for Segmentation of White Matter Hyperintensities in Alzheimer's Disease.

Segmentation and volumetric quantification of white matter hyperintensities (WMHs) is essential in assessment and monitoring of the vascular burden in aging and Alzheimer's disease (AD), especially when considering their effect on cognition. Manually segmenting WMHs in large cohorts is technically unfeasible due to time and accuracy concerns. Automated tools that can detect WMHs robustly and with high accuracy are needed. Here, we present and validate a fully automatic technique for segmentation and volumetric quantification of WMHs in aging and AD. The proposed technique combines intensity and location features frommultiplemagnetic resonance imaging contrasts and manually labeled training data with a linear classifier to perform fast and robust segmentations. It provides both a continuous subject specific WMH map reflecting different levels of tissue damage and binary segmentations. Themethodwas used to detectWMHs in 80 elderly/AD brains (ADC data set) as well as 40 healthy subjects at risk of AD (PREVENT-AD data set). Robustness across different scanners was validated using ten subjects from ADNI2/GO study. Voxel-wise and volumetric agreements were evaluated using Dice similarity index (SI) and intra-class correlation (ICC), yielding ICC=0.96 , SI = 0.62±0.16 for ADC data set and ICC=0.78 , SI=0.51±0.15 for PREVENT-AD data set. The proposed method was robust in the independent sample yielding SI=0.64±0.17 with ICC=0.93 for ADNI2/GO subjects. The proposed method provides fast, accurate, and robust segmentations on previously unseen data from different models of scanners, making it ideal to study WMHs in large scale multi-site studies.

C9orf72 and ATXN2 repeat expansions coexist in a family with ataxia, dementia, and parkinsonism.

BACKGROUND: Intermediate interrupted ataxin 2 (ATXN2) alleles (27-33 CAG-repeats) increase the risk for amyotrophic lateral sclerosis and are reported as modifiers in chromosome 9 open reading frame 72 (C9orf72) carriers, rendering susceptibility to amyotrophic lateral sclerosis rather than frontotemporal lobar degeneration. The clinical presentation of C9orf72 patients with pathogenic ATXN2 alleles (≥35 CAG-repeats) is unknown. METHODS: Blood samples were collected from a family affected by ataxia, dementia, and parkinsonism, but not amyotrophic lateral sclerosis. Mutation analyses of the proband included C9orf72 and 14 ataxia genes, followed by segregation analyses in family members. RESULTS: Both affected siblings carry an uninterrupted 37-repeat expansion in ATXN2 and a methylated G4 C2 -repeat allele in C9orf72 that is typical of large pathogenic expansions. CONCLUSIONS: The CAG-expansion in ATXN2 likely caused the ataxia, whereas the dementia may be linked to both C9orf72 and ATXN2 repeat expansions. The pathological uninterrupted ATXN2 repeat may not have the same modifying effect as intermediate interrupted alleles. © 2016 International Parkinson and Movement Disorder Society.