We aimed to investigate factors associated with self- and carer-rated quality of life (QoL) and caregiver burden related to very mild to severe clinical Alzheimer disease (AD).
One hundred ...patient-carer dyads were recruited, and assessments of relevant outcomes were performed, including sociodemographic characteristics, QoL, activities of daily living (ADL), cognitive performance, behavioural and psychological symptoms of dementia (BPSD), caregiver burden, and health resource utilisation.
There was a strong correlation between carer- and self-rated QoL, with patients consistently rating their QoL higher than caregivers. Duration of illness did not affect the QoL ratings. There was an inverse association between both self- and carer-rated QoL with age, age at symptom onset, impairment of ADL, time spent on assisting the patient, and depression. Both self- and carer-rated QoL ratings were higher if the caregiver was a spouse vs a child. Carer-rated QoL was inversely associated with severity of dementia, BPSD, caregiver burden, and requirement to supervise the patient. The variables age at symptom onset, ADL, and living together with the primary caregiver explained 34.50% of the variance in self-rated QoL, whereas age at symptom onset, ADL, and BPSD explained 48.20% of the variance in carer-rated QoL. For caregiver burden, 26% of the variance was explained by the variables ADL, living together with the primary caregiver, and agitation.
Our study highlights the need for a stronger focus on QoL in clinical AD research by providing further pieces of evidence on the key determinants, including the important aspect of caregiver burden.
The objective of this study was to assess cerebrospinal fluid (CSF) β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity in relation to Alzheimer's disease (AD) and to correlate ...the enzyme activity with protein markers of APP metabolism and axonal degeneration.
BACE1 activity and protein concentrations were measured and analyzed in 342 participants of the Alzheimer's Disease Neuroimaging Initiative, including 99 normal control, 75 stable mild cognitive impairment (MCI), 87 progressive MCI, and 79 AD dementia cases. All statistical analyses were Bonferroni corrected for multiple comparisons.
No significant differences between controls and any of the three patient groups were detected for BACE1 activity and soluble APPβ (sAPPβ) concentrations in CSF. Significant correlations with BACE1 activity were found for CSF APPβ and total tau in all four groups and for CSF phosphorylated tau181 in all groups but the progressive MCI group. There were no correlations for CSF amyloid β (Aβ)1-42 or for plasma Aβ1-42 and Aβ1-40.
The consistent correlation between BACE1 activity and sAPPβ supports their role as biomarkers of target engagement in clinical trials on BACE1 inhibition.
The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a ...large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies.
This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24-25 November 2017, Munich, Germany) and the Alzheimer's Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer's disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models.
There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.
Although the clinical course of Alzheimer disease (AD) is gradual, it is useful for a number of reasons to distinguish between different levels of severity. The Clinical Dementia Rating (CDR) has ...demonstrated high validity and reliability for this purpose, but it requires a considerable amount of data to be collected both from the patient and from an informant. In the present study, the authors mapped Mini-Mental State Examination (MMSE) scores onto CDR categories to determine how well the MMSE performs as a surrogate of the CDR as a timesaving method of staging dementia.
Eight hundred sixty-three probands, including 524 patients with probable AD, 92 patients with questionable dementia, and 247 with memory complaints but no objective cognitive impairment, were included. Cutoff scores were identified on one-half of the sample using a receiver operating characteristic analysis. The cutoff values were then applied to the other half of the sample, and the agreement between MMSE score ranges and CDR stages was determined by calculating Cohen's kappa.
The MMSE discriminated well between CDR stages 0.5, 1, 2, and 3 but performed poorly in the separation between CDR stages zero and 0.5. The MMSE ranges were 30 for no, 26–29 for questionable, 21–25 for mild, 11–20 for moderate, and 0–10 for severe dementia. Substantial agreement between the two instruments was obtained for the categories mild (κ = 0.62, p <0.001, N = 115), moderate (κ = 0.69, p <0.001, N = 114), and severe dementia (κ = 0.76, p <0.001, N = 39), whereas the agreement was moderate for no (κ = 0.44, p <0.001, N = 120) and only fair for questionable dementia (κ = 0.28, p <0.001, N = 42).
The MMSE can be used as a surrogate measure for the CDR for the staging of dementia in AD.
The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale for use in Mild Cognitive Impairment (MCI), the ADCS-ADL-MCI, is an evaluation scale with information provided by an ...informant/caregiver to describe the functional impairment of patients with MCI. As the ADCS-ADL-MCI has yet to undergo a full psychometric evaluation, this study aimed to evaluate the measurement properties of the ADCS-ADL-MCI in subjects with amnestic MCI.
Measurement properties, including item-level analysis, internal consistency reliability, test-retest reliability, construct validity (convergent/discriminant, known-groups validity), and responsiveness were evaluated using data from the ADCS ADC-008 trial, a 36-month, multicenter, placebo-controlled study in 769 subjects with amnestic MCI (defined by clinical criteria and a global clinical dementia rating, CDR, score of 0.5). Due to most subjects' mild condition at baseline and resulting low variance in scores, psychometric properties were assessed using both baseline and 36-month data.
Ceiling effects were not apparent at the total score level, with 3% of the cohort reaching the maximum score of 53, despite most subjects having a relatively high score at baseline (mean score = 46.0 standard deviation = 4.8). Item-total correlations were overall weak at baseline, most likely due to low variability in responses; however, at month 36, good item homogeneity was found. Cronbach's alpha values ranged from acceptable (0.64 at baseline) to good (0.87 at month 36), indicating overall very good internal consistency reliability. Further, moderate to good test-retest reliability was found (intraclass correlation coefficients ranging from 0.62-0.73). The analyses also largely supported convergent/discriminant validity, especially at month 36. Finally, the ADCS-ADL-MCI discriminated well between groups showing good known-groups validity, and was responsive in patients who indicated a longitudinal change in other instruments.
This study provides a comprehensive psychometric evaluation of the ADCS-ADL-MCI. Findings suggest that the ADCS-ADL-MCI is a reliable, valid and responsive measure capable of capturing functional abilities in patients with amnestic MCI.
ClinicalTrials.gov Identifier: NCT00000173.
The neural basis of reserve capacity in Alzheimer's disease is yet to be fully determined. Franzmeier et al. show that greater left frontal hub connectivity within the fronto-parietal control network ...is associated with greater resilience of cognitive performance during the early stages of autosomal dominant and sporadic Alzheimer's disease.
Abstract
Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.
The main objective of the study was to validate the findings of previous cerebrospinal fluid (CSF) proteomic studies for the differentiation between Alzheimer’s disease (AD) dementia and ...physiological ageing. The most consistently significant proteins in the separation between AD dementia versus normal controls using CSF proteomics were identified in the literature. The classification performance of the four pre-selected proteins was explored in 92 controls, 149 patients with mild cognitive impairment (MCI), and 69 patients with AD dementia. Heart-type fatty acid binding protein (hFABP) and vascular endothelial growth factor (VEGF) CSF concentrations distinguished between healthy controls and patients with AD dementia with a sensitivity and specificity of 57 and 35 %, and 76 and 84 %, respectively. The optimal classification was achieved by a combination of the two additional CSF biomarker candidates in conjunction with the three established markers Amyloid-β (Aβ)
1–42
, total-Tau (tTau), and phosphorylated-Tau (pTau)
181
, which resulted in a sensitivity of 83 % and a specificity of 86 %. hFABP also predicted the progression from MCI to AD dementia. The present study provides evidence in support of hFABP and VEGF in CSF as AD biomarker candidates to be used in combination with the established markers Aβ
1–42
, tTau, and pTau
181
.
Early post-operative delirium is a common perioperative complication in the post anesthesia care unit. To date it is unknown if a specific anesthetic regime can affect the incidence of delirium after ...surgery. Our objective was to examine the effect of volatile anesthetics on post-operative delirium.
Single Center Observational Study.
Post Anesthesia Care Units at a German tertiary medical center.
30,075 patients receiving general anesthesia for surgery.
Delirium was assessed with the Nursing Delirium Screening Scale at the end of the recovery period. Subgroup-specific effects of volatile anesthetics on post-operative delirium were estimated using generalized-linear-model trees with inverse probability of treatment weighting. We further assessed the age-specific effect of volatiles using logistic regression models.
Out of 30,075 records, 956 patients (3.2%) developed delirium in the post anesthesia care unit. On average, patients who developed delirium were older than patients without delirium. We found volatile anesthetics to increase the risk (Odds exp. (B) for delirium in the elderly 1.8-fold compared to total intravenous anesthesia. Odds increases with unplanned surgery 3.0-fold. In the very old (87 years or older), the increase in delirium is 6.2-fold. This result was confirmed with internal validation and in a logistic regression model.
Our exploratory study indicates that early postoperative delirium is associated with the use of volatile anesthetics especially in the sub-cohort of patients aged 75 years and above. Further studies should include both volatile and intravenous anesthetics to find the ideal anesthetic in elderly patients.
•Early post-operative delirium is a common perioperative complication.•Though many risk factors are known, the ideal anesthetic regime is unknown.•In a big data approach, the association of volatiles with delirium was examined.•Use of volatile anesthetics in the very old is associated with delirium.
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