Background
As an outcome measure in Alzheimer’s disease (AD) clinical trials, the integrated Alzheimer’s Disease Rating Scale (iADRS) assesses the impact of cognitive loss on the ability to perform ...daily activities. The iADRS integrates items from the ADAS‐Cog13 and the ADCS‐iADL, providing a measure of global AD severity. The present work evaluated integration of cognitive and functional items within the iADRS using RMT, a psychometric approach that models individual items and responses on to a single measurement continuum representing a latent construct (i.e., disease severity).
Method
RMT was performed using RUMM2030 using data from the Phase 2, placebo‐controlled TRAILBLAZER‐ALZ study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD. Data from 245 participants were pooled across treatment arms and timepoints (7 timepoints over 18 months).
Result
The iADRS person separation index (PSI) was 0.89, indicating good reliability and ability to differentiate between levels of impairment. Results also indicated good item‐person targeting, with items covering the range of disease severity (mean = ‐1.27, SE = 0.67). The hierarchy of items along the iADRS measurement continuum (Figure 1) reflected observed patterns of clinical decline. Delayed episodic memory impairments preceded broader impairments in immediate memory and memory‐dependent iADLs, including talking about recent experiences (reading, television); more widespread deficits in iADL functioning (telephone use, meal preparation) emerged next, followed by multi‐domain cognitive impairments in orientation and language. While cognition (specifically memory) was impaired earlier than function, cognitive and functional items demonstrated similar rates of decline along the disease severity continuum.
Conclusion
Model fit and item placement provide support for integration of cognitive and functional items within the iADRS. Placement of items along a single continuum revealed a mixture of cognitive and functional items sensitive to impairment across the spectrum of mild symptomatic disease, and demonstrated how items work together to provide improved coverage of disease‐related impairments. The findings provide further support for the use of the iADRS in clinical trials as an integrated assessment of global disease progression in early symptomatic AD.
Background
Associations between disease progression (DP) and health outcomes are poorly characterized in mild cognitive impairment (MCI) and mild AD (MILD). To address this, we examined the impact of ...DP on incremental changes in independent functioning over 18 months; baseline factors associated with DP were also explored.
Methods
Participants included amyloid‐positive participants assigned to placebo in EXPEDITION‐1/2/3 (solanezumab) and AMARANTH (lanabecestat) studies. DP defined as worsening ³5 (MCI1) or ³9 (MILD2) points on the Integrated Alzheimer’s Disease Rating Scale (iADRS). Endpoints included proportions of participants requiring home supervision (³1 hour) or unable to leave home independently (score <3) and change in total care partner time. Machine learning methods using penalized logistic regression and random forest identified factors associated with DP. Least squares mean change (LSMC) was estimated from mixed‐model repeated measures.
Results
Of 1884 participants (274 MCI, 1610 MILD), 56% of MCI and 63% of MILD participants met DP criteria over 18 months.
Baseline AD medication use, greater care partner time, worse functional activities questionnaire (FAQ) score and CDR‐SB, higher iADRS, and lower BMI and MMSE increased odds of DP for MILD (Figure 1) but not for MCI.
Proportion of participants with DP requiring home supervision (p<0.001; MILD only) and not leaving home independently (p<0.05; MCI&MILD) increased significantly at each post‐baseline visit over 18 months (Figure 2). DP in MILD only had significantly higher proportions of participants who could not be left home alone or travel outside of home independently vs no DP (p<0.05).
In those with DP, total care partner time increased significantly from baseline to 18 months (LSMC: 46.0±12.5 hours/month for MCI and 73.2±5.5 for MILD) (Figure 3). For DP vs no DP, increased care partner time at 18 months was significantly higher for MILD (LSMC difference, 66.0±9.3 hours/month; p<0.001) but not for MCI.
Conclusions
Early symptomatic AD participants who progressed over 18 months had reduced independence and required more care partner time. Treatments that slow DP may preserve independence and reduce overall health care burden.
References
1. Wessels AM, et al. J Prev Alzheimers Dis. 2015;2:227‐241
2. Wessels AM, et al. J Alzheimers Dis. 2022;88:577‐588.
Individuals with type 1 diabetes have mild performance deficits on a range of neuropsychological tests compared with nondiabetic control subjects. The mechanisms underlying this cognitive ...deterioration are still poorly understood, but chronic hyperglycemia is now emerging as a potential determinant, possibly through microvascular changes in the brain. In 24 type 1 diabetic patients, we tested at euglycemia and at acute hypoglycemia whether the presence of proliferative diabetic retinopathy, as a marker of microvascular disease, adversely affects the ability of the brain to respond to standardized hypoglycemia, using functional magnetic resonance imaging with a cognitive task. Patients with retinopathy, compared with patients without, showed less deactivation (hence, an increased response) in the anterior cingulate and the orbital frontal gyrus during hypoglycemia compared with euglycemia (P < 0.05). Task performance and reaction time were not significantly different for either group. We conclude that microvascular damage in the brain of patients with retinopathy caused this increased brain response to compensate for functional loss.
Type 1 diabetes mellitus (T1DM) is associated with cerebral compromise, typically found in patients with microangiopathy. Associations between subclinical macroangiopathy and the brain, whether or ...not in the presence of microangiopathy, have not been fully explored in T1DM. We hypothesized that subclinical macroangiopathy in adult T1DM may affect the brain and interacts with microangiopathy.
In 51 asymptomatic T1DM patients with, 53 without proliferative retinopathy and 51 controls, right common carotid artery ultrasound was used to assess intima media thickness (cIMT) and distensibility (cD). Neuropsychological tests for cognitive functions, and magnetic resonance imagining for white matter integrity and functional connectivity, i.e. neuronal communication, were used.
After correction for confounders, cIMT was borderline significantly increased in all T1DM patients (P = 0.071), whereas cD was not statistically significantly altered (P = 0.45). Patients with proliferative retinopathy showed the largest increase in cIMT and decrease in cD. In all participants, after adjustment for confounders, increased cIMT was related to decreased white matter integrity (β = -0.198 P = 0.041) and decreased functional connectivity in visual areas (β = -0.195 P = 0.046). For cognition, there was a significant interaction between cIMT and the presence of proliferative retinopathy after adjustment for confounding factors (all P < 0.05). Increased cIMT was associated with lower general cognitive ability (β = -0.334; P = 0.018), information processing speed (β = -0.361; P = 0.010) and attention (β = -0.394; P = 0.005) scores in patients without, but not in patients with proliferative retinopathy.
These findings suggest that subclinical macroangiopathy may be a factor in the development of diabetes-related cognitive changes in uncomplicated T1DM, whereas in patients with advanced T1DM, proliferative retinopathy may rather be the driving force of cerebral compromise.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Compared with biofluid‐biomarkers, tau‐PET shows stronger association with cognitive impairment (Ossenkoppele,R‐2021) and decline, and better detects Alzheimer’s disease (AD) pathology ...(Coomans,EM‐2022; Smith,R‐2022). Conventionally, tau‐cognition relationship has been evaluated between global cortical tau‐PET and composite cognitive scores. However, tau‐PET binding patterns are heterogenous, with regional binding showing strong correlations with domain‐specific cognitive performance and decline. The goal of this study was to evaluate domain‐specific patterns of tau‐PET at baseline and in change‐from‐baseline (CFB) in symptomatic AD patients.
Method
Amyloid‐positive participants (n = 172) with a clinical diagnosis of mild‐cognitive‐impairment (n = 97) or dementia due to AD (n = 76) and amyloid‐negative healthy‐controls (n = 68) underwent a 18Flortaucipir tau‐PET and neuropsychological testing (AV1451‐A05:NCT02016560) at baseline and 18months. Observed cognitive scores in impaired patients were normalized to age‐adjusted outcomes in healthy‐controls at baseline and 18months (Ossenkoppele,R‐2015). These scores were subsequently averaged within the episodic‐memory, semantic‐memory, language, visuospatial, and executive function cognitive domains (Malpetti,M‐2022). Standardized uptake value ratio (SUVr) in automated‐anatomical‐labelling regions (Tzourio‐Mazoyer,M‐2002) and AD‐specific region (MUBADA; Devous,M‐2017) was calculated in reference to cerebellum‐crus. The CFB (18months‐baseline) in SUVr and domain‐specific sub‐scores were calculated for all participants. Correlations between global SUVr versus composite cognitive score and regional SUVr versus domain‐specific scores at baseline and CFB were calculated.
Result
Differential cross‐sectional tau‐PET patterns showed significant negative associations with domain‐specific cognitive performance (Fig.1A). When evaluated longitudinally, higher global CFB in tau‐PET SUVr showed no‐to‐modest correlation with cognitive decline (Fig.2: ADAS‐Cog11 = 0.012, FAQ = ‐0.015, MMSE = ‐0.210, CDR‐SB = 0.014), however, heterogeneous associations were observed at the regional‐ and voxel‐level (Fig.1B,Fig.3), ranging from maximum of r = ‐0.45 (p<0.001; frontal‐inferior and visuospatial) to minimum of r = ‐0.002 (p<0.1; lingual and episodic). Increase in tau‐PET signal was associated with greater cognitive decline (i.e. visuospatial function: predominantly frontal; executive function: parietal and prefrontal; semantic‐memory: superior temporal region). An extensive and asymmetric tau‐PET pattern (L>R) in frontal and occipital regions was related to language.
Conclusion
We found associations between patterns of tau accumulation and domain‐specific cognitive decline in MCI and AD dementia. After validations using larger datasets, these relationships can supplement widely used associations between global tau‐PET and composite cognitive scores and, therefore, enhance tau PET‐guided and patient‐centered staging, prognosis, and response assessment.
Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe ...characteristics of dosing history in participants with depression receiving once daily escitalopram. Participants were randomly assigned to interpersonal psychotherapy (IPT) or pharmacotherapy. Participants assigned to IPT who did not evidence a response or remission had escitalopram added to their treatment. Adherence to pharmacotherapy was assessed using an electronically monitored pill cap (MEMS). Fifty-four participants on escitalopram alone and 32 on escitalopram+IPT were monitored. After 200 days, 71.7% of the participants in the escitalopram group and 54.8% of those in the escitalopram+IPT group were still engaged with the dosing regimen. Of those engaged in the dosing regimen, 17.9% (average over 210 days) of the participants did not take their medication (nonexecution). In 69% of the days participants took the correct dosage required. On average, participants had three drug holidays and the mean length of a holiday was 7 days per patient. No difference in adherence patterns was observed between patients receiving escitalopram alone vs. IPT+escitalopram. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimen are the most common facets of poor adherence in this study population.
Abstract
Background
Sex‐based differences in pathophysiology and clinical presentation of Alzheimer’s Disease (AD) have been reported. These differences could impact trial eligibility. This analysis ...of screening data assesses the most common reasons for exclusion within sex.
Method
Phase 2/3 AMARANTH (NCT02245737) enrolled early AD (MCI due to AD, mild AD dementia) with MMSE 20‐30 and RBANS DMI ≤85. Phase 3 DAYBREAK‐ALZ (NCT02783573) enrolled mild AD with MMSE 20‐26. For MCI, NIA‐AA criteria were met, with CDR of 0.5 and memory box score ≥0.5. For mild AD, NIA‐AA criteria were met, with CDR of 0.5 or 1 and memory box score ≥0.5. Both studies enrolled participants 55‐85 years‐of‐age with proof of amyloid (PET scan or cerebrospinal fluid). Excluded participants meeting prespecified criteria were permitted ≤2 rescreens. Reasons for exclusion and patients randomized are presented by sex. The top three reasons for exclusion are compared by female and male subsets. In AMARANTH, participants could fail >1 criterion. For DAYBREAK‐ALZ, MMSE exclusion is further divided into MMSE score subsets (<20 or >26, when available). Statistical comparisons are made using Pearson’s Chi‐Square and not adjusted for multiplicity.
Result
For both studies, proportions of females represented in reasons for exclusion and randomization are similar (AMARANTH: 52% vs. 53%; DAYBREAK‐ALZ: 57% vs. 59%). In AMARANTH, MMSE score not within range was more commonly reported and lack of presence of amyloid was less commonly reported in the female subset than the male subset (17.8% vs 13.5% (p<0.001) and 22.4% vs 24.5% (p<0.05) of reasons, respectively). In DAYBREAK‐ALZ, proportions of reasons for exclusion in sex subsets were similar. However, MMSE score <20 was more common and MMSE score >26 less common as a reason for exclusion in the female subset compared to the male subset (females vs. males: score <20: 24.6% vs 18.3%, score >26: 12.8% vs 19.7%; p<0.001 for each).
Conclusion
These results suggest females presenting for screening may have more advanced disease. Possible reasons include late referral of females due to advanced verbal memory skills delaying recognition of disease, social circumstances, faster disease progression of females identified from clinical trial site databases, or differences in educational attainment.
Background
Sex‐based differences in pathophysiology and clinical presentation of Alzheimer’s Disease (AD) have been reported. These differences could impact trial eligibility. This analysis of ...screening data assesses the most common reasons for exclusion within sex.
Method
Phase 2/3 AMARANTH (NCT02245737) enrolled early AD (MCI due to AD, mild AD dementia) with MMSE 20‐30 and RBANS DMI ≤85. Phase 3 DAYBREAK‐ALZ (NCT02783573) enrolled mild AD with MMSE 20‐26. For MCI, NIA‐AA criteria were met, with CDR of 0.5 and memory box score ≥0.5. For mild AD, NIA‐AA criteria were met, with CDR of 0.5 or 1 and memory box score ≥0.5. Both studies enrolled participants 55‐85 years‐of‐age with proof of amyloid (PET scan or cerebrospinal fluid). Excluded participants meeting prespecified criteria were permitted ≤2 rescreens. Reasons for exclusion and patients randomized are presented by sex. The top three reasons for exclusion are compared by female and male subsets. In AMARANTH, participants could fail >1 criterion. For DAYBREAK‐ALZ, MMSE exclusion is further divided into MMSE score subsets (<20 or >26, when available). Statistical comparisons are made using Pearson’s Chi‐Square and not adjusted for multiplicity.
Result
For both studies, proportions of females represented in reasons for exclusion and randomization are similar (AMARANTH: 52% vs. 53%; DAYBREAK‐ALZ: 57% vs. 59%). In AMARANTH, MMSE score not within range was more commonly reported and lack of presence of amyloid was less commonly reported in the female subset than the male subset (17.8% vs 13.5% (p<0.001) and 22.4% vs 24.5% (p<0.05) of reasons, respectively). In DAYBREAK‐ALZ, proportions of reasons for exclusion in sex subsets were similar. However, MMSE score <20 was more common and MMSE score >26 less common as a reason for exclusion in the female subset compared to the male subset (females vs. males: score <20: 24.6% vs 18.3%, score >26: 12.8% vs 19.7%; p<0.001 for each).
Conclusion
These results suggest females presenting for screening may have more advanced disease. Possible reasons include late referral of females due to advanced verbal memory skills delaying recognition of disease, social circumstances, faster disease progression of females identified from clinical trial site databases, or differences in educational attainment.
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