Diagnosis Of Probable Alzheimer's Disease Research Articles

Quetiapine Oral Solution in Alzheimer's Disease: Efficacy and Dosage Insights from a Real-World Retrospective Study.

Neuropsychiatric symptoms (NPS) are distressing for patients with dementia, often accelerating functional decline and nursing home placement. Medications such as quetiapine are used to alleviate NPS, but their side effects require cautious use. Liquid formulations such as quetiapine oral suspension suit specific populations; however, real-world data on their use in patients with dementia are limited. The purpose of this retrospective, naturalistic study was to provide preliminary data on the effects of treatment with quetiapine oral suspension on behavioral and psychiatric disturbances in Alzheimer's disease (AD) outpatients in Taiwan. Between January 2022 and June 2023, data were collected from outpatients with a diagnosis of probable AD who received treatment with Qting® (quetiapine oral solution 25 mg/ml). Primary outcome measures were changes in Neuropsychiatric Inventory (NPI) total score and its sub-items from baseline to the endpoint. We recruited 66 AD patients with a mean age of 72.1±7.6 years, most of whom were female (69.7%). Twenty-three patients had data on neuropsychological test and NPI scores before and after quetiapine treatment. There was no significant change in global cognitive function from baseline to the endpoint. A significant reduction in NPI total score after quetiapine treatment was noted, while the effect on NPI sub-items was limited. The average maintenance dose was 1.5±0.6 ml. We demonstrated our clinical experience of the use of quetiapine oral solution in AD patients with NPS. Our results showed that quetiapine oral solution treatment significantly improved these symptoms at a relatively low dose.

A comparative study of Amyloid positive and negative individuals with “Alzheimer Syndrome”

AbstractBackgroundOutside academic centres, the diagnosis of probable Alzheimer’s Disease remains a clinical diagnosis supported by basic blood work and structural brain imaging. It has already been documented, approximately 1/3rd of individuals meeting clinical criteria for probable AD, do not show underlying amyloidopathy on PET or cerebrospinal fluid. Thus, the clinical “Alzheimer Syndrome” encompasses individuals with abnormal amyloid (Amyloid positive: A+), as well as “amyloid negative” individuals lacking amyloidopathy. Finding ways to distinguish these subgroups clinically will become increasingly important as anti‐amyloid therapies become more available. It is not yet clear if these two groups have any clinical or imaging features that might distinguish them. Our objective was to find out if there are any clinical or imaging pointers towards amyloid biomarker status.MethodsA retrospective chart review of 23 patients screened for anti‐amyloid clinical trials was performed, of whom 13 were (A+) and 10 were (A‐). The following information was collected from the chart review‐ demography, medical history, clinical presentation, course of disease and rate of progression, neuropsychological test scores, blood work, brain scans, and any other relevant investigations. Relevant data were subjected to appropriate statistical analysis.ResultsThis is an ongoing study and the results are derived from interim analysis. Comparison of the (A+) and (A‐) groups revealed no statistically significant difference in terms of age, sex, amnestic presentation and cognitive decline rate. We did not find evidence (in this small group) that (A‐) subjects had a greater vascular load ‐ no difference in Hachinski score or Fazekas score. The only statistically significant difference between the groups was found in their NPI scores, with the A+ group showing a higher score (2.92 versus 0.80, p = 0.008).ConclusionAmyloid positive individuals are more likely to have neuropsychiatric manifestations during the course of their cognitive decline than their Amyloid negative counterpart. Work is ongoing to delineate biological and biomarker differences that account for the cortical dementia (Alzheimer Syndrome) in Amyloid negative subjects. Delineating differences in clinical presentation may prove useful in specifying which of these individuals are actually Amyloid positive. Confirmation in a larger group of subjects will be necessary.

Phonological and Semantic Fluency in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Semantic and Phonological fluency (SF and PF) are routinely evaluated in patients with Alzheimer's disease (AD). There are disagreements in the literature regarding which fluency task is more affected while developing AD. Most studies focus on SF assessment, given its connection with the temporoparietal amnesic system. PF is less reported, it is related to working memory, which is also impaired in probable and diagnosed AD. Differentiating between performance on these tasks might be informative in early AD diagnosis, providing an accurate linguistic profile. Compare SF and PF performance in healthy volunteers, volunteers with probable AD, and patients with AD diagnosis, considering the heterogeneity of age, gender, and educational level variables. A total of 8 studies were included for meta-analysis, reaching a sample size of 1,270 individuals (568 patients diagnosed with AD, 340 with probable AD diagnosis, and 362 healthy volunteers). The three groups consistently performed better on SF than PF. When progressing to a diagnosis of AD, we observed a significant difference in SF and PF performance across our 3 groups of interest (p = 0.04). The age variable explained a proportion of this difference in task performance across the groups, and as age increases, both tasks equally worsen. The performance of SF and PF might play a differential role in early AD diagnosis. These tasks rely on partially different neural bases of language processing. They are thus worth exploring independently in diagnosing normal aging and its transition to pathological stages, including probable and diagnosed AD.

Using fsQCA to Illuminate Person Attributes of Music Engagement in Alzheimer's Disease

Preserved engagement with music in Alzheimer's disease (AD) is noteworthy given that such persons lack interest and engagement in the activities of daily life. Because music engagement is associated with increased well-being, illuminating personal attributes that facilitate music engagement is an important step towards utilizing music as a therapeutic tool. Here, we use Fuzzy Set Qualitative Comparative Analysis, a systematic approach to case study series analysis, to explore the role of personal attributes such as musical semantic memories, music perceptual abilities, and overall cognitive status in facilitating music engagement in 15 individuals with a diagnosis of probable AD. Nine different solution terms revealed many different pathways to preserved music engagement in AD. Solutions demonstrated the equifinality of music engagement and the usefulness of the qualitative comparative analysis approach. This article is meant to provide both concrete evidence for the role of different person attributes in music engagement in AD and an illustration of the application of qualitative comparative analysis. We discuss our results using the Comprehensive Process Model as a framework and provide suggestions on how to incorporate qualitative comparative analysis in the research workflow.

Efficacy, Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: A 12‐Week, Randomized, Double‐Blind, Placebo‐Controlled Trial

AbstractBackgroundAgitation is a prevalent clinical manifestation of Alzheimer’s dementia, and is one of the most stressful aspects of care in patients affected by the disease. However, currently, there are no FDA‐approved pharmacological treatments for agitation in this patient population. Following two prior clinical trials of brexpiprazole in this patient population, the aim of this study was to confirm the efficacy, safety and tolerability of brexpiprazole in patients with agitation in Alzheimer’s dementia.MethodsThis was a 12‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐arm study (NCT03548584). Eligible patients were aged 55–90 years, in a care facility or community‐based setting, had a diagnosis of probable Alzheimer’s disease, and met criteria for agitation as defined by the International Psychogeriatric Association (IPA). Patients were randomized 2:1 to brexpiprazole or placebo; within the brexpiprazole arm, patients were further randomized 1:2 to fixed‐dose 2 mg/day or 3 mg/day. Stable background medications for the treatment of Alzheimer’s disease were permitted. The primary endpoint was change from baseline to Week 12 in Cohen–Mansfield Agitation Inventory (CMAI) Total score. The key secondary endpoint was change from baseline to Week 12 in Clinical Global Impression − Severity of illness (CGI‐S) score, as related to agitation. Safety was also assessed.ResultsA total of 345 patients were randomized to brexpiprazole or placebo. On the primary endpoint, the mean change from baseline to Week 12 in CMAI Total score was statistically significantly greater in the brexpiprazole group (2 mg/day or 3 mg/day) versus the placebo group (p = 0.0026). Statistically significant separation between the brexpiprazole and placebo groups was also observed on the key secondary endpoint of change from baseline to Week 12 in CGI‐S score (p = 0.0055). Aside from headache (6.6%), no other treatment‐emergent adverse events occurred with an incidence ≥5% in the brexpiprazole group.ConclusionIn this Phase 3 study of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole was associated with a statistically significantly greater reduction in agitation, and improvement in clinical global impression of agitation, compared with placebo, supporting the findings of two prior clinical trials. Brexpiprazole was generally well tolerated, and no new safety signals were observed.

Accuracy of the Brazilian version of the Prefrontal Symptoms Inventory (PSI-16) in the neuropsychological assessment of patients diagnosed with Alzheimer's disease

The aim of the present study was to ascertain the accuracy of the Prefrontal Symptoms Inventory (PSI-16) for patients with probable Alzheimer, as well as to compare it with the Mini Mental State Examination (MMSE) and the Frontal Assessment Battery (FAB). The study included 159 elderly people, aged over 60 years, 50 with a diagnosis of probable Alzheimer and 109 without the pathology. In the total sample, the cut-off point of the PSI-16 was > 19 points, with sensitivity and specificity moderate. Accuracy in the group with a ³ 8 years of education was superior in all instruments. The AUCs of PSI-16 and MMSE remained similar, the SE of all instruments increased, and the SP obtained a decline, considering the elderly over 70 years old. PSI-16 is a self-report instrument suitable for tracking behavioral problems related to the prefrontal cortex, with little impact from age and education level.

Effect of Age, Cognitive Impairment Severity, and Duration of Disease on Efficacy of Masupirdine in Moderate Alzheimer's Disease Patients: A Post Hoc Analysis of a Phase-2 Randomized Placebo Controlled Study Results

Alzheimer's disease (AD) is an age-related progressive neurodegenerative brain disorder with cognitive symptoms as a hallmark phenotype of the disease. Masupirdine, a pure serotonin 6 (5-HT6) receptor antagonist is being developed for the treatment of cognitive deficits in AD. The objective of the current study is the post hoc analysis of a multicenter, randomized, double-blind, parallel group, 26-week, placebo-controlled phase-2 study (NCT02580305) that evaluated the effects of masupirdine on cognition in patients with moderate AD. Methods: Masupirdine phase 2 study included AD patients of 50 to 85 years age, mini-mental state examination (MMSE) score of 12 to 20 and diagnosis of probable AD at least 1 year prior to the screening visit. The impact of age, cognitive impairment severity, and duration of disease since diagnosis on efficacy of masupirdine as assessed by 11-item version of the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog 11) was evaluated. Treatment effects were assessed by Cohen’s d effect size. Results: Cohen’s d effect size for change in ADAS-Cog 11 scores from baseline to week 26 ranged between ~0.2 and 0.4 for the subgroup of population with age ≤ 70 years, MMSE range of 18 to 20, and duration of disease over 4 years (since diagnosis). Conclusions: Considering the linear relationship between age and cognitive decline, masupirdine effects across the subgroups could be attributed to “slowing of cognitive decline”. The study provides important findings for design of future clinical trials. Further research is warranted to confirm the potential beneficial effects of masupirdine on cognition in AD patients.

Performance of Plasma Amyloid β, Total Tau, and Neurofilament Light Chain in the Identification of Probable Alzheimer's Disease in South China.

Background: Alzheimer's disease (AD) is the most common type of dementia and has no effective treatment to date. It is essential to develop a minimally invasive blood-based biomarker as a tool for screening the general population, but the efficacy remains controversial. This cross-sectional study aimed to evaluate the ability of plasma biomarkers, including amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL), to detect probable AD in the South Chinese population.Methods: A total of 277 patients with a clinical diagnosis of probable AD and 153 healthy controls with normal cognitive function (CN) were enrolled in this study. The levels of plasma Aβ42, Aβ40, t-tau, and NfL were detected using ultra-sensitive immune-based assays (SIMOA). Lumbar puncture was conducted in 89 patients with AD to detect Aβ42, Aβ40, t-tau, and phosphorylated (p)-tau levels in the cerebrospinal fluid (CSF) and to evaluate the consistency between plasma and CSF biomarkers through correlation analysis. Finally, the diagnostic value of plasma biomarkers was further assessed by constructing a receiver operating characteristic (ROC) curve.Results: After adjusting for age, sex, and the apolipoprotein E (APOE) alleles, compared to the CN group, the plasma t-tau, and NfL were significantly increased in the AD group (p < 0.01, Bonferroni correction). Correlation analysis showed that only the plasma t-tau level was positively correlated with the CSF t-tau levels (r = 0.319, p = 0.003). The diagnostic model combining plasma t-tau and NfL levels, and age, sex, and APOE alleles, showed the best performance for the identification of probable AD [area under the curve (AUC) = 0.89, sensitivity = 82.31%, specificity = 83.66%].Conclusion: Blood biomarkers can effectively distinguish patients with probable AD from controls and may be a non-invasive and efficient method for AD pre-screening.

Towards an Automatic Speech-Based Diagnostic Test for Alzheimer’s Disease

Automatic Speech Recognition (ASR) is widely used in many applications and tools. Smartphones, video games, and cars are a few examples where people use ASR routinely and often daily. A less commonly used, but potentially very important arena for using ASR, is the health domain. For some people, the impact on life could be enormous. The goal of this work is to develop an easy-to-use, non-invasive, inexpensive speech-based diagnostic test for dementia that can easily be applied in a clinician’s office or even at home. While considerable work has been published along these lines, increasing dramatically recently, it is primarily of theoretical value and not yet practical to apply. A large gap exists between current scientific understanding, and the creation of a diagnostic test for dementia. The aim of this paper is to bridge this gap between theory and practice by engineering a practical test. Experimental evidence suggests that strong discrimination between subjects with a diagnosis of probable Alzheimer’s vs. matched normal controls can be achieved with a combination of acoustic features from speech, linguistic features extracted from a transcription of the speech, and results of a mini mental state exam. A fully automatic speech recognition system tuned for the speech-to-text aspect of this application, including automatic punctuation, is also described.

Discontinuation Rate of Newly Prescribed Donepezil in Alzheimer's Disease Patients in Asia.

Background and PurposeThe rate of donepezil discontinuation and the underlying reasons for discontinuation in Asian patients with Alzheimer's disease (AD) are currently unknown. We aimed to determine the treatment discontinuation rates in AD patients who had newly been prescribed donepezil in routine clinical practice in Asia.MethodsThis 1-year observational study involved 38 institutions in seven Asian countries, and it evaluated 398 participants aged 50–90 years with a diagnosis of probable AD and on newly prescribed donepezil monotherapy. The primary endpoint was the rate of donepezil discontinuation over 1 year. Secondary endpoints included the reason for discontinuation, treatment duration, changes in cognitive function over the 1-year study period, and compliance as assessed using a clinician rating scale (CRS) and visual analog scale (VAS).ResultsDonepezil was discontinued in 83 (20.9%) patients, most commonly due to an adverse event (43.4%). The mean treatment duration was 103.67 days in patients who discontinued. Among patients whose cognitive function was assessed at baseline and 1 year, there were no significant changes in scores on the Mini-Mental State Examination, Montreal Cognitive Assessment, and Trail-Making Test–Black and White scores, whereas the Clinical Dementia Rating score increased significantly (p<0.001). Treatment compliance at 1 year was 96.8% (306/316) on the CRS and 92.6±14.1% (mean±standard deviation) on the VAS.ConclusionsIn patients on newly prescribed donepezil, the primary reason for discontinuation was an adverse event. Cognitive assessments revealed no significant worsening at 1 year, indicating that continuous donepezil treatment contributes to the maintenance of cognitive function.

Anatomical and functional changes in the retina in patients with Alzheimer's disease and mild cognitive impairment.

PurposeThere is evidence that mild cognitive impairment (MCI) or Alzheimer's disease (AD) is accompanied by alterations in the retina. The current study was performed to investigate structural and functional changes in patients with systemic neurodegenerative disease.MethodsA total of 47 patients with either MCI or AD and 43 healthy age‐ and sex‐matched control subjects were included. Inclusion criteria for MCI were abnormal memory function and a mini‐mental state examination (MMSE) score >26 points, for patients with AD a diagnosis of probable AD of mild to moderate degree and an MMSE score in the range of 20–26. Retinal blood flow was measured using a Doppler optical coherence tomography (OCT) system. Retinal vessel diameter, oxygen saturation and flicker‐induced vasodilatation were measured using a Vessel Analyzer. Retinal nerve fibre layer thickness (RNFLT) was assessed using an OCT system.ResultsGlobal RNFLT was lower in patients compared to healthy controls (93.7 ± 12.8 µm versus 99.1 ± 9.0 µm, p = 0.02). The same was found in regards to retinal arterial blood flow, which was 9.3 ± 2.4 and 12.3 ± 3.2 μl/min in the patient and control groups, respectively (p < 0.001). Mean retinal arterial diameter was reduced in patients (76.0 ± 8.9 µm versus 80.6 ± 8.0 µm, p = 0.03). Arteriovenous difference in oxygen saturation was lower in patients (20.4 ± 5.1% versus 23.5 ± 4.0%, p < 0.01). No difference in the flicker response was observed.ConclusionIn patients with MCI and AD, arteriovenous difference in oxygen saturation, retinal blood flow and arterial vessel diameter was reduced. No difference was found in flicker response between groups. This indicates alterations in retinal oxygen metabolism in patients with neurodegenerative disease.

Validity Evidences of the Prefrontal Symptoms Inventory for the Elderly Brazilian Population

OBJECTIVES:This study aimed to translate the Prefrontal Symptoms Inventory (PSI) (abbreviated version) for the elderly into Brazilian Portuguese, evaluate its psychometric properties, and investigate if the PSI could distinguish between groups with (clinical group) and without (non-clinical group) a diagnosis of probable Alzheimer’s disease (AD).METHODS:The PSI was idiomatically and culturally adapted, and then administered to 256 individuals over 60 years of age who also completed a clinical interview, the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS)-15, and the Frontal Assessment Battery (FAB).RESULTS:The results indicated satisfactory adjustment and adequate reliability (Ω of 0.83 and α=0.80) for the uni-factorial model. The non-clinical group showed significant correlations between the PSI-16, GDS-15, MMSE, and FAB and its six subtests. In the clinical group, there were negative correlations between the PSI-16, MMSE, and the FAB and the conceptual subtest. The groups differed statistically significantly, with the clinical sample showing the highest PSI-16 score. In the non-clinical group, there were significant positive correlations between age and PSI-16, and negative correlations between education and PSI-16.CONCLUSION:The results of this study indicate that the PSI-16 can be used as a valid and reliable screening tool for clinical use in the elderly with and without pathology.

Tau PET imaging with 18F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study.

18F-PI-2620 is a PET tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both 3-repeat and 4-repeat tau isoforms. The purpose of this first-in-humans study was to evaluate the ability of 18F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess the safety and tolerability of this new tau PET tracer. Methods: Participants with a clinical diagnosis of probable AD and healthy controls (HCs) underwent dynamic 18F-PI-2620 PET imaging for 180 min. 18F-PI-2620 binding was assessed visually and quantitatively using distribution volume ratios (DVR) estimated from noninvasive tracer kinetics and SUV ratio (SUVR) measured at different time points after injection, with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC subjects, as well as DVR and SUVR correlations and effect size (Cohen's d) over time. Results:18F-PI-2620 showed peak brain uptake around 5 min after injection and fast washout from nontarget regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD subjects than in HCs. Very low background signal was observed in HCs. 18F-PI-2620 administration was safe and well tolerated. SUVR time-activity curves in most regions and subjects achieved a secular equilibrium after 40 min after injection. A strong correlation (R2 > 0.93) was found between noninvasive DVR and SUVR for all imaging windows starting at more than 30 min after injection. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC subjects demonstrated a high image quality and excellent signal-to-noise ratio of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Noninvasive quantification using DVR and SUVR for 30-min imaging windows between 30 and 90 min after injection-for example, 45-75 min-provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions correlates strongly with neurocognitive performance.

Med Check: Alzheimer’s Therapy; Adhansia XR; Dasotraline for Binge-Eating Disorder; Somryst for Insomnia; Nuplazid

Med Check: Alzheimer’s Therapy; Adhansia XR; Dasotraline for Binge-Eating Disorder; Somryst for Insomnia; Nuplazid

Neuroinflammation and Functional Connectivity in Alzheimer's Disease: Interactive Influences on Cognitive Performance.

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 patients (12 females/16 males) with clinical diagnosis of probable AD or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy controls (8 females/6 males). Source-based “inflammetry” was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were preprocessed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal covariance between neuroinflammation and brain connectivity profiles, in relation to the diagnostic group (patients, controls) and cognitive status.Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, frontal, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganization of brain networks, is proposed as a target for emerging immunotherapeutic strategies aimed at preventing or slowing the emergence of dementia.SIGNIFICANCE STATEMENT Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between neuro inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses, and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

Cox Proportional Hazard Regression for Risk Factors of Alzheimer’s Disease

Background: Alzheimer’s disease is a form of dementia, mainly strikes people in their 60 and 70s. While no one cause has been determined, researchers have identified certain factors which may put people at a higher risk of developing the disease. Iran’s Alzheimer Association has announced that more than 35% of people over 80 years old suffers from this problem across the country. This paper aims to investigate modifiable risk factors of Alzheimer’s disease based on Kaplan-Meier estimator and Cox regression analysis (proportional hazard model) and to find out which factors are related to developing of this disease.&#x0D; Materials &amp; methods: Residents newly admitted to nursing homes with a diagnosis of probable Alzheimer’s disease have been considered. Patients were at least 75 years of age from 9 Medicare/ Medicaid certified nursing homes of Khorasan and Tehran states and we excluded patients with a history of mental retardation, mental illness or any other long-life mental health disorders. This strategy yielded a sample of 115 patients (37 Males and 78 Females) with total death rate of 47%.&#x0D; Results: Our findings demonstrate that Age, Gender, Heritage, Apoplexy, Mental and Physical Activities statistically affect Survival and also Hazard Rate, In contrast, we found no link between survival duration and a history of Addiction and Blood Pressure.&#x0D; Conclusions: These findings have implications for clinical practice and intervention strategies in medical and public health.&#x0D; J MEDICINE JUL 2019; 20 (2) : 72-79

Associations between sleep duration and cognitive impairment in mild cognitive impairment

The prevalence of mild cognitive impairment (MCI) increases among elderly people and is associated with a high risk of dementia. Identifying factors that may contribute to the progress of MCI to dementia is critical. The objective of this study was to examine the association of objective sleep with cognitive performance in MCI patients. A subsample of 271 participants with a diagnosis of probable Alzheimer's disease (AD; N=50) or mild cognitive impairment (MCI; N=121) and 100 persons who were not cognitively impaired (NI) were recruited from a large population-based cohort in the island of Crete, Greece (3140 older adults aged >60years). All participants underwent extensive neuropsychiatric/neuropsychological evaluation and a 3-day 24-hr actigraphy. Objective sleep variables and their association with neuropsychological performance were examined across the three groups, controlling for demographics, body mass index, depression, sleep apnea symptoms and psychotropic medications. Patients with AD had significantly longer 24-hr total sleep time (TST) compared to the MCI and NI groups. Long 24-hr TST was associated with reduced performance on tasks that placed significant demands on attention and processing speed in the MCI group and the AD group. Elderly patients with MCI have similar objective sleep duration to normal controls, whereas AD patients sleep longer. Long sleep duration in patients with multidomain subtypes of MCI is associated with critical non-memory cognitive domains. It appears that within the MCI group those that sleep longer have more severe cognitive impairment.

Elevated Glutamate and Glutamine Levels in the Cerebrospinal Fluid of Patients With Probable Alzheimer's Disease and Depression

Recent evidence suggests that Alzheimer's disease (AD) and depression share common mechanisms of pathogenesis. In particular, deregulation of glutamate-mediated excitatory signaling may play a role in brain dysfunction in both AD and depression. We have investigated levels of glutamate and its precursor glutamine in the cerebrospinal fluid (CSF) of patients with a diagnosis of probable AD or major depression compared to healthy controls and patients with hydrocephalus. Patients with probable AD or major depression showed significantly increased CSF levels of glutamate and glutamine compared to healthy controls or hydrocephalus patients. Furthermore, CSF glutamate and glutamine levels were inversely correlated to the amyloid tau index, a biomarker for AD. Results suggest that glutamate and glutamine should be further explored as potential CSF biomarkers for AD and depression.

Reappraisal of Aβ40 and Aβ42 Peptides Measurements in Cerebrospinal Fluid of Patients with Alzheimer's Disease.

Cerebrospinal fluid (CSF) biomarkers are currently included in the diagnostic criteria for Alzheimer's disease (AD), in particular, decreased concentrations of amyloid-β peptide 1-42 (Aβ42) in the CSF, coupled with increased levels of tau and phosphorylated tau proteins, are supportive of AD diagnosis. To date, the quantification of Aβ42 levels with antibody-dependent immunoassay shows a marked variability among different laboratories and is also affected by different pre-analytical factors, suggesting that part of Aβ42 peptides might be aggregated and thus undetected by antibodies. To bypass an antibody-dependent measurement, we determined the Aβ40 and Aβ42 levels by immunoblot. We analyzed CSF samples from 35 patients with clinical diagnosis of probable AD and from 15 age-matched normal controls; CSF Aβ levels were determined by two different ELISA kits and by immunoblot analysis. Aβ40 levels measured by ELISA were comparable to those obtained by immunoblot, whereas CSF concentrations of Aβ42 measured by ELISA were significantly lower compared to values obtained by immunoblot quantification. Biochemical analysis, following 1D- and 2D-PAGE analysis, showed that the qualitative composition of Aβ peptides in the CSF is similar in AD and controls but different from that of AD brain tissues. Moreover, sedimentation velocity in sucrose gradient of CSF and brain homogenate from AD demonstrated that Aβ42 in CSF is different from Aβ42 in brain in terms of solubility and aggregation state.

EVALUATION OF [F-18]-PI-2620, A SECOND-GENERATION SELECTIVE TAU TRACER, FOR THE ASSESSMENT OF ALZHEIMER’S AND NON-ALZHEIMER’S TAUOPATHIES

Most first-generation tau tracers bind to the typical 3R/4R tau deposits prevalent in Alzheimer's disease (AD). These first-generation tau tracers have varying degrees of “off-target” binding or lack of selectivity for tau. The new tau tracer, 18F-PI-2620 appears unique in that it binds to all types (3R, 4R and 3R/4R) of tau deposits in vitro. The purpose of the study was to assess the ability of 18F-PI-2620 to detect and measure global and regional tau burden in the brain in healthy older controls, AD and non-AD tauopathies such as Progressive Supranuclear Palsy (PSP) and Frontotemporal Lobar Degeneration (FTLD). Participants with clinical diagnosis of probable AD, PSP, FTLD as well as healthy age-matched controls (HC) and participants classified as suffering mild cognitive impairment (MCI), underwent a 50-70 min static scan with 18F-NAV4694 to establish Aβ-status (Aβ-/Aβ+), and 0-120 min dynamic tau imaging with 18F-PI-2620. Global and regional 18F-PI-2620 binding was assessed using Distribution Volume Ratios (DVR), and with standardized uptake value ratios (SUVR), calculated using the cerebellar cortex as reference region. No tracer retention was observed in Aβ-HC. No “off-target” binding in choroid plexus or basal ganglia was observed in any of the participants scanned. In Aβ+AD patients 18F-PI-2620 binding was significantly higher than in HC, with the highest tracer retention in temporoparietal and posterior cingulate areas (Figure 1A). Tracer presented reversible kinetics and apparent steady state was reached ∼80-90 min after 18F-PI-2620 injection (Figure 1B). There was high agreement between regional DVRCbCtx and SUVRCbCtx. Identical classification into tau-/tau+ resulted from semiquantitative measures and visual inspection of the images