Probable Alzheimer's Disease Dementia Research Articles

Real-world performance of plasma p-tau181 in a heterogeneous memory clinic cohort.

In light of clinical trials and disease-modifying therapies, an early identification of patients at-risk of developing Alzheimer's disease (AD) is crucial. Blood-based biomarkers have shown promising results regarding the in vivo detection of the earliest neuropathological changes in AD. Herein, we investigated the ability of plasma p-tau181 to act as a prescreening marker for amyloid positivity in a heterogeneous memory clinic-based cohort. In this retrospective cross-sectional study, we included a total of 115 patients along the clinical AD continuum (mild cognitive impairment [MCI] due to AD, n = 62, probable AD dementia, n = 53). Based on their biomarker status, they were stratified into an amyloid-positive (Aβ+, n = 88) or amyloid-negative cohort (Aβ-, n = 27). Plasma and CSF p-tau181 concentrations were quantified using an ultrasensitive single-molecule array (SIMOA©). Furthermore, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong's test for correlated AUC curves. The median (interquartile range [IQR]) concentration of plasma p-tau181 was significantly higher in Aβ+ patients (3.6 pg/mL [2.5-4.6]), compared with Aβ- patients (1.7 pg/mL [1.2-1.9], p < 0.001). Regarding the distinction between Aβ+ and Aβ- patients and the prediction of amyloid positivity, a high diagnostic accuracy for plasma p-tau181 with an AUC of 0.89 (95% CI = 0.82-0.95) was calculated. Adding the risk factors, age and APOE4, to the model did not significantly improve its performance. Our findings demonstrate that plasma p-tau181 could be a noninvasive and feasible prescreening marker for amyloid positivity in a heterogeneous clinical AD cohort and therefore help in identifying those who would benefit from more invasive assessment of amyloid pathology.

Combining neuropsychological assessment and structural neuroimaging to identify early Alzheimer's disease in a memory clinic cohort.

The current study examined the contributions of comprehensive neuropsychological assessment and volumetric assessment of selected mesial temporal subregions on structural magnetic resonance imaging (MRI) to identify patients with amnestic mild cognitive impairment (aMCI) and mild probable Alzheimer's disease (AD) dementia in a memory clinic cohort. Comprehensive neuropsychological assessment and automated entorhinal, transentorhinal, and hippocampal volume measurements were conducted in 40 healthy controls, 38 patients with subjective memory symptoms, 16 patients with aMCI, 16 patients with mild probable AD dementia. Multinomial logistic regression was used to compare the neuropsychological and MRI measures. Combining the neuropsychological and MRI measures improved group membership prediction over the MRI measures alone but did not improve group membership prediction over the neuropsychological measures alone. Comprehensive neuropsychological assessment was an important tool to evaluate cognitive impairment. The mesial temporal volumetric MRI measures contributed no diagnostic value over and above the determinations made through neuropsychological assessment.

Association of Blood-Based DNA Methylation Markers With Late-Onset Alzheimer Disease: A Potential Diagnostic Approach.

There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls. A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with "probable AD dementia" following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex. The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at NXN, ABCA7, and HOXA3 genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89-0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and APOE ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, HOXA3 DNA methylation levels showed consistent association with AD. These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD. Research Ethics Committee of the University Hospital of Navarre (PI17/02218).

A - 180 Anosognosia across the Spectrum of Alzheimer's Pathology and Validation of a New Measure.

Two studies were performed to validate a brief, new method for assessing informant-patient discrepancies to quantify cognitive insight, and to compare it to an empirically supported model - the Cognitive Awareness Model (CAM). Study 1 included 31 (52% male; Mage = 69.42) patients from an outpatient neuropsychological assessment clinic. Seven patients were diagnosed with probable Alzheimer's dementia (PAD), 15 mild cognitive impairment (MCI), and 9 no diagnosis (i.e., healthy controls; HC). The Cognitive Coding Form (CCF) was compared with several measures to assess convergent and discriminant validity. Study 2 entailed archival data extraction of 240 patients (80 HC, 80 MCI, and 80 PAD; 53.3% female; Mage = 72.8) to examine the ability of the CCF to predict various cognitive domains, including executive functioning (Trail-Making Test Form B). In study 1, the 8-item CCF demonstrated good convergent and discriminant validity with established measures. Study 2 identified that both patient-reported cognitive concerns and, to a greater degree, CCF informant-patient discrepancy scores, can distinguish HCs from those with MCI and PAD. Further, a regression indicated that depression (Geriatric Depression Scale; 5.5%; β= -0.38, p < 0.001) and TMT-B (13%; β= -0.43, p < 0.001), together accounted for 18.5% of the variance in insight (R2 = 0.19, F(2,219) = 26.10, p < 0.001), supporting the CAM. In addition to establishing an efficient measure of insight with high clinical utility (the CCF), these studies inform the literature on the role of insight in predicting performance in those with Alzheimer's pathology.

Follow-up Comparisons of Two Plasma Biomarkers of Alzheimer's Disease, Neurofilament Light Chain, and Oligomeric Aβ: A Pilot Study.

Recent evidence suggests that blood-based biomarkers might be useful for Alzheimer's disease (AD). Among them, we intend to investigate whether neurofilament light (NfL) and multimer detection system-oligomeric Aβ (MDS-OAβ) values can be useful in screening, predicting, and monitoring disease progression and how the relationship between NfL and MDS-OAβ values changes. Eighty participants with probable AD dementia, 50 with mild cognitive impairment (MCI), and 19 with subjective cognitive decline (SCD) underwent baseline and follow-up evaluations of the Mini-Mental Status Examination (MMSE) and both plasma biomarkers. Baseline MDS-OAß (p = 0.016) and NfL (p = 0.002) plasma concentrations differed significantly among groups, but only NfL correlated with baseline MMSE scores (r = -0.278, p = 0.001). In follow-up, neither correlated with MMSE changes overall. However, in SCD and MCI participants (n = 32), baseline MDS-OAß correlated with follow-up MMSE scores (r = 0.532, p = 0.041). Linear regression revealed a relationship between baseline MDS-OAβ and follow-up MMSE scores. In SCD and MCI participants, plasma NfL changes correlated with MMSE changes (r = 0.564, p = 0.028). This study shows that only in participants with SCD and MCI, not including AD dementia, can MDS-OAß predict the longitudinal cognitive decline measured by follow-up MMSE. Changes of NfL, not MDS-OAß, parallel the changes of MMSE. Further studies with larger samples and longer durations could strengthen these results..

Automated Classification of Cognitive Decline and Probable Alzheimer's Dementia Across Multiple Speech and Language Domains.

Decline in language has emerged as a new potential biomarker for the early detection of Alzheimer's disease (AD). It remains unclear how sensitive language measures are across different tasks, language domains, and languages, and to what extent changes can be reliably detected in early stages such as subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Using a scene construction task for speech elicitation in a new Spanish/Catalan speaking cohort (N = 119), we automatically extracted features across seven domains, three acoustic (spectral, cepstral, and voice quality), one prosodic, and three from text (morpholexical, semantic, and syntactic). They were forwarded to a random forest classifier to evaluate the discriminability of participants with probable AD dementia, amnestic and nonamnestic MCI, SCD, and cognitively healthy controls. Repeated-measures analyses of variance and paired-samples Wilcoxon signed-ranks test were used to assess whether and how performance differs significantly across groups and linguistic domains. The performance scores of the machine learning classifier were generally satisfactorily high, with the highest scores over .9. Model performance was significantly different for linguistic domains (p < .001), and speech versus text (p = .043), with speech features outperforming textual features, and voice quality performing best. High diagnostic classification accuracies were seen even within both cognitively healthy (controls vs. SCD) and MCI (amnestic and nonamnestic) groups. Speech-based machine learning is powerful in detecting cognitive decline and probable AD dementia across a range of different feature domains, though important differences exist between these domains as well. https://doi.org/10.23641/asha.23699733.

The effects of low-dose radiation therapy in patients with mild-to-moderate Alzheimer's dementia: an interim analysis of a pilot study.

We aimed to determine whether low-dose radiotherapy (LDRT) is effective in patients with Alzheimer disease (AD). We included patients according to the following criteria: probable Alzheimer's dementia according to the New Diagnostic Criteria for Alzheimer's Disease; confirmation of amyloid plaque deposits on baseline amyloid positron emission tomography (PET); a Korean Mini-Mental State Examination 2nd edition (K-MMSE-2) score of 13-26; and a Global Clinical Dementia Rating (CDR) score of 0.5-2 points. LDRT was performed six times at 0.5 Gy each. Post-treatment cognitive function tests and PET-CT examinations were performed to evaluate efficacy. The medication for AD treatment was maintained throughout the study period. At 6 months after LDRT, neurological improvement was seen in 20% of patients. Patient #2 showed improvement in all domains of the Seoul Neuropsychological Screening Battery II (SNSB-II). Moreover, the K-MMSE-2 and Geriatric Depression Score-Short Form scores improved from 20 to 23 and from 8 to 2, respectively. For patient #3, the CDR score (sum of box score) improved from 1 (4.0) to 1 (3.5) at 3 months follow-up. Moreover, the Z scores for language and related functions, memory, and frontal executive function improved to -2.56, -1.86, and -1.32, respectively at the 6-month follow-up. Two patients complained of mild nausea and mild hair loss during LDRT, which improved after treatment. One of the five patients with AD treated with LDRT experienced a temporary improvement in SNSB-II. LDRT is tolerable in patients with AD. We are currently under follow-up and will conduct cognitive function tests after 12 months after LDRT. A large-scale randomized controlled trial with a longer follow-up period is warranted to determine the effect of LDRT on patients with AD.

Cognitive phenotypes in probable mild Alzheimer’s disease

AbstractBackgroundNew technologies have helped the biological diagnosis of Alzheimer’s disease to make it more accurate over the years. However, establishing prognosis for each case is still a significant challenge, as there are different cognitive profiles in the same diagnosis. Also, there is no well‐defined standard for a cognitive profile that predicts future functionality impairment. In this sense, a better understanding of cognitive phenotypes can help establishing prognosis of Alzheimer’s dementia. Our aim with this study was to identify the main cognitive profiles of patients with amnestic variant of probable Alzheimer’s dementia at a mild presentation (CDR 1) with the amnestic variant. We verified the performance of these cognitive profiles applying the neuropsychological assessment.MethodThe study comprised 141 participants with probable Alzheimer dementia, recruited from a Reference Center for the Elderly in Brazil. We conducted a complete neuropsychological assessment evaluating the following domains: memory, executive functions, language, simple attention/processing speed, and visuospatial abilities. Initially, the data were transformed in z‐scores, considering age and education, according to references for the cultural adaptations and validations for the Brazilian population. We use the K‐Nearest Neighbors (K = 3) to solve the missing data problem. After preparing the base for cluster analysis, we performed the ward’s hierarchical method and the Euclidean distance to measure similarity. Finally, we performed comparisons of the groups using the Kruskal‐Wallis tests.ResultData analysis suggested existence of five cognitive subgroups (Figure 1). Bye general comparison, performed by the Kruskal‐Wallis test, we found the groups were different in the neuropsychological assessment instruments (p&lt;0.001). Cognitive phenotypes varied about impaired and/or preserved ability, as well as impairment severity (Figure 2). The cognitive phenotypes were different considering educational level (Figure 3). We observed accentuated global impairment cognitive phenotype in a lower level of formal education group, and less accentuated impairment profiles in a higher formal education.ConclusionIn conclusion, we identified five Cognitive phenotypes which had differences in severity of cognitive symptoms, and impaired abilities. These Cognitive phenotypes were based on different degrees of severity in visuospatial ability, simple attention/processing speed, and planning and had different education level.

Lower semantic fluency scores and a phonemic-over-semantic advantage predict abnormal CSF P-tau181 levels in Aβ + patients within the Alzheimer's disease clinical spectrum.

The present study aimed to determine whether patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD), semantic verbal fluency (SVF), and the semantic-phonemic discrepancy (SPD) could predict abnormal cerebrospinal fluid (CSF) phosphorylated tau (P-tau181) and total tau (T-tau) levels. Phonemic verbal fluency (PVF) and SVF scores of N = 116 Aβ-positive patients with either MCI due to AD (N = 39) or probable AD dementia (ADD; N = 77) were retrospectively collected. The SPD was computed by subtracting PVF scores from SVF ones (positive and negative values corresponding to a semantic and phonemic advantage, respectively). Patients were cognitively phenotyped via a thorough test battery and profiled according to the amyloidosis/tauopathy/neurodegeneration (ATN) framework via CSF analyses. Two separate sets of logistic regressions were run to predict normal vs. abnormal P-tau181 and T-tau levels by encompassing as predictors SVF + PVF and SPD and covarying for demographic, disease-related features, and cognitive profile. Lower SVF, but not PVF, scores, as well as a greater phonemic advantage (i.e., negative SPD values), predicted abnormal CSF P-tau181 levels (p ≤ .01). Moreover, lower SVF scores were selectively predictive of abnormal CSF T-tau levels too (p = .016), while the SPD was not. SVF and the SPD are able to predict tauopathy across the AD spectrum, thus supporting their status of valid, and sufficiently specific, cognitive markers of AD.

Cerebral vasomotor reactivity across the continuum of subjective cognitive impairment, amnestic mild cognitive impairment and probable Alzheimer's dementia: A transcranial Doppler and PET/MRI study

Cerebrovascular dysfunction has been suggested as a physiomarker of Alzheimer's disease (AD)-associated neuronal degeneration, but the underlying mechanisms are still debated. Herein cerebral vasomotor reactivity (VMR, breath-hold index: BHI), metabolic activity (lobar SUVs, FDG PET MRI), amyloid load (Centiloid score, Flutemetamol PET MRI), hemispheric cortical thickness, white matter lesion load and cerebral blood flow (ASL) were studied in 43 consecutive subjects (mean age: 64 years, female 13), diagnosed with subjective cognitive impairment (SCI, n = 10), amnestic mild cognitive impairment (aMCI, n = 15), and probable Alzheimer's dementia (AD, n = 18). BHI was significantly reduced in AD and aMCI patients compared to SCI subjects. A highly significant inverse correlation was found between BHI and the centiloid score (r = −0.648, p < 0.001). There was moderate positive correlation between BHI and frontal, temporal and parietal FDG SUV and ASL values, and a borderline negative correlation with age and white matter lesion volume. The link between amyloid burden and VMR was independent and strong in linear regression models where all these parameters were included (β from –0.580 to –0.476, p < 0.001). In conclusion, our study confirms the negative association of cerebral amyloid accumulation and vasomotor reactivity in Alzheimer's disease with the most direct data to date in humans.

The Relationship Between Muscle Strength and Cognitive Performance Across Alzheimer's Disease Clinical Continuum.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline, mostly prominent in the domain of memory, but also associated with other cognitive deficits and non-cognitive symptoms. Reduced muscle strength is common in AD. However, the current understanding of its relationship with cognitive decline is limited. This study investigates the relationship between muscle strength and cognition in patients with AD and mild cognitive impairment (MCI). We enrolled 148 consecutive subjects, including 74 patients with probable AD dementia, 37 MCI, and 37 controls. Participants underwent neuropsychological evaluation focused on attention, working memory, declarative memory and learning. Muscle strength and muscle mass were measured through hand dynamometer and bio-electrical impedance analysis, respectively. Patients with AD dementia were divided with respect to the severity of cognitive impairment into mild and moderate-to-severe patients. Moderate-to-severe patients with AD presented lower handgrip strength than MCI and controls. No differences were observed in muscle mass. In MCI and AD dementia, handgrip strength was associated with overall cognitive functioning, attentional and memory performance. The routine implementation of handgrip strength assessment in the clinical work-up of patients with MCI and AD could potentially represent a simple method to monitor functional and cognitive decline along the disease course.

Probing gut-brain links in Alzheimer's disease with rifaximin.

Gut‐microbiome‐inflammation interactions have been linked to neurodegeneration in Alzheimer's disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut‐specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open‐label trial, we treated 10 subjects with mild to moderate probable AD dementia (Mini‐Mental Status Examination (MMSE) = 17 ± 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament‐light levels (P < .004) and a significant increase in fecal phylum Firmicutes microbiota. Serum phosphorylated tau (pTau)181 and glial fibrillary acidic protein (GFAP) levels were reduced (effect sizes of −0.41 and −0.48, respectively) but did not reach statistical significance. In addition, there was a nonsignificant downward trend in serum cytokine interleukin (IL)‐6 and IL‐13 levels. Cognition was unchanged. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo‐controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.

91-Year-Old Man With Recurrent Falls

A 91-year-old man with probable Alzheimer dementia (Functional Assessment Staging Tool stage 6B, with no recent cognitive testing), major depressive disorder, insomnia, repeated falls, atrial fibrillation not on anticoagulation, hypertension, chronic kidney disease, urinary retention requiring self-catheterization, bilateral cataracts, osteoarthritis of the hips and lumbar spine, and constipation was seen in a memory-care unit after recent hospitalization for left hip fracture sustained in a ground-level fall.

Editors' Note: Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment

The key to possible prevention of cognitive impairment in patients with Alzheimer disease (AD) lies in preclinical detection using serologic, radiographic, and other novel biomarkers. In the prospective observational cohort study of cognitively unimpaired adults, adults with mild cognitive impairment, and adults with probable AD dementia by Therriault and colleagues, they report that 1 in 12 cognitively unimpaired adults had biologic evidence of Alzheimer pathology using amyloid PET and tau PET imaging. In this study, 7.88% of cognitively unimpaired adults had abnormalities in both imaging modalities, which would be consistent with biologically defined AD. Dr. Garnier-Crussard and Krolak-Salmon acknowledge that Alzheimer pathology is not unusual among unimpaired adults and further suggest that additional factors (e.g., comorbid conditions and exposures) may be contributing to the clinical features of the disease. Ongoing studies exploring preclinical biomarkers may one day elucidate which mechanism (or mechanisms) are responsible for later cognitive impairment in at-risk individuals. Furthermore, such a panel of biomarkers may become useful in the personalization of disease-modifying therapy for such patients. The key to possible prevention of cognitive impairment in patients with Alzheimer disease (AD) lies in preclinical detection using serologic, radiographic, and other novel biomarkers. In the prospective observational cohort study of cognitively unimpaired adults, adults with mild cognitive impairment, and adults with probable AD dementia by Therriault and colleagues, they report that 1 in 12 cognitively unimpaired adults had biologic evidence of Alzheimer pathology using amyloid PET and tau PET imaging. In this study, 7.88% of cognitively unimpaired adults had abnormalities in both imaging modalities, which would be consistent with biologically defined AD. Dr. Garnier-Crussard and Krolak-Salmon acknowledge that Alzheimer pathology is not unusual among unimpaired adults and further suggest that additional factors (e.g., comorbid conditions and exposures) may be contributing to the clinical features of the disease. Ongoing studies exploring preclinical biomarkers may one day elucidate which mechanism (or mechanisms) are responsible for later cognitive impairment in at-risk individuals. Furthermore, such a panel of biomarkers may become useful in the personalization of disease-modifying therapy for such patients.

Cerebral microbleeds and hemodynamic changes in individuals with cognitive impairment

Background &amp; Objective: Cerebral microbleeds (CMBs) are considered key markers of small vessel pathology linking mechanisms relating to ischemic and amyloid related vascular damage in Alzheimer disease (AD). We aim to investigate the differences of hemodynamic markers between patients with and without CMBs who presented with cognitive decline using transcranial Doppler (TCD) ultrasonography. Methods: We consecutively enrolled patients who were diagnosed with mild cognitive impairment (MCI) and probable AD dementia from May 2011 to December 2012. Using TCD ultrasonography, cerebrovascular reactivity (CVR) was evaluated with hyperventilation (HV) and breath-holding (BH) tests in addition to mean flow velocity (MFV) and pulsatility index (PI) of the middle cerebral artery. The number and location of CMBs were visually analyzed by two independent neurologists. Results: A total of 134 patients (probable AD, n=81; MCI, n=53) were enrolled in this study. Among them, 28 (20.9%) patients had CMBs; 18 (64.3%) lobar CMBs, 7 (25.0%) non-lobar CMBs. Patients with CMBs showed reduced MFV, higher resistance index value, and lower CVR compared with patients without CMBs after adjusting for age, vascular risk factors, and white matter hyperintensity. Multiple regression models showed that PI was dependent on age and presence of CMBs in frontal and parietal areas. CVR was closely associated with WMH severity and presence of CMBs in temporal. Conclusions: Our study showed that patients with CMBs had higher microvascular resistance and decreased cerebrovascular autoregulation compared to those without.

Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations.

Background and ObjectivesTo investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid–positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum.MethodsIn this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up).ResultsWe included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = −0.18 to −0.11, false discovery rate [FDR]–adjusted p < 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = −0.32 to 0.36, all FDR-adjusted p > 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = −0.13 to 0.44, all FDR-adjusted p > 0.05).DiscussionNPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.

Pilot evaluation of a consumer wearable device to assess sleep in a clinical polysomnography trial of suvorexant for treating insomnia in patients with Alzheimer's disease.

The orexin receptor antagonist suvorexant was previously reported to significantly improve total sleep time (TST), by 28min per night versus placebo after 4weeks, in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer's disease and insomnia. The study included an exploratory evaluation of a consumer-grade wearable "watch" device for assessing sleep that we report on here. Participants who met diagnostic criteria for both probable Alzheimer's disease dementia and insomnia were randomized to suvorexant 10-20mg (N=142) or placebo (N=143) in a double-blind, 4-week trial. Patients were provided with a consumer-grade wearable watch device (Garmin vívosmart® HR) to be worn continuously. Overnight sleep laboratory PSG was performed on three nights: screening, baseline and Night 29 (last dose). Watch treatment effects were assessed by change-from-baseline in watch TST at Week 4 (average TST per night). We also analysed Night 29 data only, with watch data restricted to the PSG recording time. In the 193 participants included in the Week 4 watch analysis (suvorexant=97, placebo=96), the suvorexant-placebo difference in watch TST was 4min (p=.622). In patients with usable data for both assessments at the baseline and Night 29 PSG (suvorexant=57, placebo=50), the watch overestimated TST compared to PSG (e.g., placebo baseline=412min for watch and 265min for PSG) and underestimated change-from-baseline treatment effects: the suvorexant-placebo difference was 20min for watch TST (p=.405) and 35min for PSG TST (p=.057). These findings show that the watch was less sensitive than PSG for evaluating treatment effects on TST.

CSF neurofilament light may predict progression from amnestic mild cognitive impairment to Alzheimer's disease dementia

Neurofilament light (NfL) is a promising biomarker of neurodegeneration in Alzheimer's disease (AD). In this study, cerebrospinal fluid (CSF) NfL was measured in a 24-month longitudinal cohort consisting of control (n = 52), amnestic mild cognitive impairment (aMCI) (n = 55), and probable AD dementia (n = 28) individuals. The cohort was reevaluated after 6-10 years. Baseline CSF NfL was significantly elevated in aMCI and probable AD dementia groups compared to controls (p < 0.0001). CSF NfL was significantly lower in stable aMCI patients compared to aMCI patients who converted to probable AD dementia within the 24-month period (p = 0.004). Substituting T-tau for NfL in the core AD biomarkers model (Aβ42/P-tau/T-tau) did not improve ability to separate control and AD, or stable and converter aMCI patients. Our results support that elevated CSF NfL could predict progression in aMCI patients, but its utility cannot improve the core AD biomarkers.

Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment.

ObjectiveTo assess the frequency of biologically defined Alzheimer disease (AD) in relation to age, sex, APOE ε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET.MethodsWe assessed cognitively unimpaired (CU) elderly (n = 166), patients with amnestic mild cognitive impairment (n = 77), and patients with probable AD dementia (n = 62) who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [18F]AZD4694 and tau-PET with [18F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles was assessed using logistic regressions with odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe clinical diagnosis of probable AD dementia demonstrated good agreement with biologically defined AD (positive predictive value 85.2%). A total of 7.88% of CU were positive for both amyloid-PET and tau-PET. Frequency of biologically defined AD increased with age (OR 1.14; p < 0.0001) and frequency of APOE ε4 allele carriers (single ε4: OR 3.82; p < 0.0001; double ε4: OR 17.55, p < 0.0001).ConclusionWhereas we observed strong, but not complete, agreement between clinically defined probable AD dementia and biomarker positivity for both β-amyloid and tau, we also observed that biologically defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically defined AD and related entities.Classification of EvidenceThis study provides Class I evidence that biologically defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of CU elderly.

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.