Neurobiology of delusions in Alzheimer’s disease

Alzheimer’s disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric sequelae, including psychotic symptoms such as delusions and hallucinations. Strong evidence supports the need to study delusions separate from hallucinations. Integrating the epidemiology, clinical correlates, and neuropathological and genetic literature for delusions in AD allows us to speculate on etiology and mechanisms. Plaque and tangle deposition in individuals with susceptible alleles of serotonergic, muscarinic, nicotinic, or Apoε4 genes appears to result in disruption of cortical circuitry, culminating in delusions. While delusions in AD correspond to a phenotype distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities. Persecutory delusions may occur earlier in the illness and have a more significant genetic component than misidentification delusions, which are associated with increased cognitive impairment and advanced dementia. Clearly distinguishing between these two syndromes is essential to making progress in the area of delusions in AD.peer-reviewe

Hipermemória, sinestesia, savants: Luria e Borges revisitados

In this paper, we investigated two subjects with superior memory, or hyper memory: Solomon Shereshevsky, who was followed clinically for years by A. R. Luria, and Funes the Memorious, a fictional character created by J. L. Borges. The subjects possessed hyper memory, synaesthesia and symptoms of what we now call autistic spectrum disorder (ASD). We will discuss interactions of these characteristics and their possible role in hyper memory. Our study suggests that the hyper memory in our synaesthetes may have been due to their ASD-savant syndrome characteristics. However, this talent was markedly diminished by their severe deficit in categorization, abstraction and metaphorical functions. As investigated by previous studies, we suggest that there is altered connectivity between the medial temporal lobe and its connections to the prefrontal cingulate and amygdala, either due to lack of specific neurons or to a more general neuronal dysfunction.Neste artigo, investigamos dois sujeitos com memória superior ou hipermemória: Solomon Shereshevsky, que foi seguido clinicamente por anos por A. R. Luria, e Funes o memorioso, um personagem fictício criado por J. L. Borges. Os sujeitos possuem hipermemória, sinestesia e sintomas do que hoje chamamos de transtorno do espectro autista (TEA). Vamos discutir interações dessas características e seu possível papel na memória hiper. Nosso estudo sugere que a hipermemória em nossos sujeitos sinestésicos pode ser devido às suas características de síndrome do DSA-savant. No entanto, esse talento foi acentuadamente diminuído pelo profundo déficit de categorização, abstração e funções metafóricas. Conforme investigado por estudos anteriores, sugerimos que há conectividade alterada entre o lobo temporal medial e suas conexões com o cingulado e a amígdala pré-frontal, devido à falta de neurônios específicos ou a uma disfunção neuronal mais geral.Fil: Fornazzari, Luis. University of Toronto; CanadáFil: Leggieri, Melissa. University of Toronto; CanadáFil: Schweizer, Tom A.. University of Toronto; CanadáFil: Arizaga, Raúl Luciano. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fischer, Corinne E.. University of Toronto; Canad

Music Intervention Approaches for Alzheimer’s Disease: A Review of the Literature

Music interventions have been widely adopted as a potential non-pharmacological therapy for patients with Alzheimer’s disease (AD) to treat cognitive and/or behavioral symptoms of the disease. In spite of the prevalence of such therapies, evidence for their effectiveness report mixed results in the literature. The purpose of this narrative review is to investigate the effectiveness of various intervention strategies (music therapy vs. music listening techniques) and music type used in the intervention (individualized vs. non-individualized music) on cognitive and behavioral outcomes for persons with AD. Databases were searched for studies using either active music therapy or music listening techniques over the last 10 years. These studies were in English, included persons with AD dementia, and whose protocol gathered pre- and post-intervention outcome measures. We initially identified 206 papers which were then reduced to 167 after removing duplicates. Further review yielded 13 papers which were extensively reviewed, resulting in a final sample of six papers. Our analysis of these papers suggested that, regardless of the music intervention approach, individualized music regimens provided the best outcomes for the patient. Furthermore, music listening may act as a relaxation technique and therefore provide a long-term impact for the patient, while active music therapy may acts to engage participants through social interaction and provide acute benefits. Our findings suggest that music techniques can be utilized in various ways to improve behavior and cognition

The Neural Correlates of the Clock-Drawing Test in Healthy Aging

Importance: The clock-drawing test (CDT) is an important neurocognitive assessment tool, widely used as a screening test for dementia. Behavioral performance on the test has been studied extensively, but there is scant literature on the underlying neural correlates.Purpose: To administer the CDT naturalistically to a healthy older aging population in an MRI environment, and characterize the brain activity associated with test completion.Main Outcome and Measure: Blood-oxygen-level dependent (BOLD) functional MRI was conducted as participants completed the CDT using novel tablet technology. Brain activity during CDT performance was contrasted to rest periods of visual fixation. Performance on the CDT was evaluated using a standardized scoring system (Rouleau score) and time to test completion. To assess convergent validity, performance during fMRI was compared to performance on a standard paper version of the task, administered in a psychometric testing room.Results: Study findings are reported for 33 cognitively healthy older participants aged 52–85. Activation was observed in the bilateral frontal, occipital and parietal lobes as well as the supplementary motor area and precentral gyri. Increased age was significantly correlated with Rouleau scores on the clock number drawing (R2) component (rho = -0.55, p < 0.001); the clock hand drawing (R3) component (rho = -0.50, p < 0.005); and the total clock (rho = -0.62, p < 0.001). Increased age was also associated with decreased activity in the bilateral parietal and occipital lobes as well as the right temporal lobe and right motor areas.Conclusion and Relevance: This imaging study characterizes the brain activity underlying performance of the CDT in a healthy older aging population using the most naturalistic version of the task to date. The results suggest that the functions of the occipital and parietal lobe are significantly altered by the normal aging process, which may lead to performance decrements

Psychometrics of the patient-reported outcomes measurement information system measures in hemophilia:the applicability of the pediatric item banks

Background: The use of patient-reported outcomes measures (PROMs) is important in hemophilia care, as it facilitates communication between patients and clinicians and promotes patient-centered care. Currently, a variety of PROMs with insufficient psychometric properties are used. Patient-reported outcomes measurement information system (PROMIS) measures, including Computer Adaptive Tests, were designed to measure generically and more efficiently and, therefore, are an alternative for the existing PROMs. Objectives: To assess the feasibility, measurement properties, and outcomes of 8 PROMIS pediatric measures for boys with hemophilia. Methods: In this multicenter study, boys with hemophilia completed 8 PROMIS measures and 2 legacy instruments. Feasibility was determined by the number of completed items and floor or ceiling effects (percentage of participants that achieved the lowest or highest possible score). Reliability was assessed as the percentage of scores with a SE ≤ 4.5. Construct validity was evaluated by comparing the PROMIS measures with the legacy instruments. Mean PROMIS T-scores were calculated and compared with the Dutch general population. Results: In total, 77 boys with hemophilia participated. Reliability was good for almost all PROMIS measures and legacy instruments. The total number of completed items varied from 49 to 90 for the PROMIS pediatric measures, while the legacy instruments contained 117 to 130 items. Floor and ceiling effects were observed in both the PROMIS measures (0-39.5%) and legacy instruments (0-66.7%), but were higher for the legacy instruments. Conclusions: The PROMIS pediatric measures are feasible to use for boys with hemophilia. With the use of the PROMIS measures in clinical care and research, a step toward worldwide standardization of PROM administration can be taken.</p

Determining the association of medical co-morbidity with subjective and objective cognitive performance in an inner city memory disorders clinic: a retrospective chart review

<p>Abstract</p> <p>Background</p> <p>Medical co-morbidity may be associated with impaired cognitive function based on prior studies. However, no studies to date have determined to what extent this association is linked to medical illness or other factors that may be linked to medical illness (such as education, income levels, depression or subjective memory loss). The present study examined how medical co-morbidity, socioeconomic status (defined as residential SES), education and depression are associated with subjective and objective memory function in a sample of patients recruited from a university affiliated Memory Disorders Clinic located in a large Canadian inner city teaching hospital.</p> <p>Methods</p> <p>Data was collected from 85 consecutive referrals to an Inner City Memory Disorders Clinic including socio-demographic characteristics, cognitive status and medical co-morbidity. Descriptive and correlational analyses were conducted.</p> <p>Results</p> <p>Impaired objective cognitive function correlated significantly with increased medical co-morbidity and partially with education but not with residential SES or depression. Elevated memory complaints correlated significantly with depression, inversely with residential SES and not at all with medical co-morbidity or education.</p> <p>Conclusions</p> <p>Increased medical co-morbidity is significantly associated with impaired cognitive performance but not with subjective memory complaints in an Inner City Memory Clinic sample.</p

Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer’s disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson’s disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit\u27s Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?. Methods/Design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer\u27s disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson\u27s disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. Results: We found three components in the ZBI. The first was “overall burden” and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = −0.566, basic ADLs r = −0.43), (2) moderately related to cognition (MoCA r = −0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions

Exploratory Assessment of K-means Clustering to Classify 18F-Flutemetamol Brain PET as Positive or Negative

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.Rationale: We evaluated K-means clustering to classify amyloid brain PETs as positive or negative. Patients and Methods: Sixty-six participants (31 men, 35 women; age range, 52–81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 demen- tia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson–Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID soft- ware (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/ nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpreta- tion based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data. Results: Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal partici- pants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson–Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%. Conclusions: K-means clustering may be a powerful algorithm for classifying amyloid brain PET.This is a multisite project of the Toronto Dementia Research Alli- ance (www.tdra.utoronto.ca) partly funded by Brain Canada, The Edward Foundation, the Canadian Institutes of Health Research (FDN 159910), the LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, and the Dr Sandra Black Cen- tre for Brain Resilience and Recovery. M.F. received support from the Saul A. Silverman Family Foundation as a Canada Interna- tional Scientific Exchange Program and the Morris Kerzner Memo- rial Fund. We gratefully acknowledge GE Healthcare and the CAMH Brain Health Imaging Centre for manufacturing and sup- plying the ligand. We are also grateful to GE Healthcare for provid- ing the software to calculate the brain region of interest SUV ratios. The study protocol, Brain Eye Amyloid Memory study (BEAM), is registered at https://clinicaltrials.gov/ct2/show/NCT02524405? term=beam+sandra+black&rank=1

Structural Brain Magnetic Resonance Imaging to Rule out Comorbid Pathology in the Assessment of Alzheimer\u27s Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials over the Past 10 Years

Background/Objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer\u27s disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Results: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity