Clinical Diagnosis Of Alzheimer's Disease Research Articles

Computational Insight into the Binding Profile of the Second-Generation PET Tracer PI2620 with Tau Fibrils

Abnormal deposition of hyperphosphorylated tau as neurofibrillary tangles (NFTs) is an important pathological hallmark of Alzheimer's disease (AD) and of other neurodegenerative disorders. A noninvasive positron emission tomography (PET) tracer that quantifies neurofibrillary tangles in vivo can enhance the clinical diagnosis of AD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the tau fibril in the brain. In this paper, we study the binding profile of fibrillar tau aggregates with a PET tracer PI2620, which is a new second generation tau PET tracer that is presently experimentally and clinically studied. The target structure for the tau fibril is based on cryo-electron microscopy (cryo-EM) structure. A multiscale simulation workflow including molecular docking, molecular dynamics simulation, metadynamics simulation, and free energy calculations was implemented. We find that PI2620 can bind to eight surface binding sites, three core binding sites, and one entry site. The binding at the core sites and entry site is found to be much more favorable than that on the surface sites due to stronger hydrophobic interactions and less solvent exposure. Furthermore, the entry site which is formed by the terminal β-sheets of the fibril is found to have the highest binding affinity to PI2620. Importantly, the binding capacity at the entry site can be much higher than that at other core sites, due to its easy accessibility. Therefore, the entry site is believed to be the major binding site for PI2620. A previous computational study on tracers with tau fibrils reports a maximum of four binding sites. Through use of methods that allow us to locate "cryptic binding sites", we report here additional core sites available for binding and we address the limitation of using the cryo-EM structure alone for structure-based tracer design. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of tau, a knowledge that in turn can be used to guide the development of compounds with higher affinity and selectivity for tau using structure-based design strategies.

Role of Fluid Biomarkers and PET Imaging in Early Diagnosis and its Clinical Implication in the Management of Alzheimer's Disease.

Clinical diagnosis of Alzheimer’s disease (AD) is based on symptoms; however, the challenge is to diagnose AD at the preclinical stage with the application of biomarkers and initiate early treatment (still not widely available). Currently, cerebrospinal fluid (CSF) amyloid-β 42 (Aβ42) and tau are used in the clinical diagnosis of AD; nevertheless, blood biomarkers (Aβ42 and tau) are less predictive. Amyloid-positron emission tomography (PET) imaging is an advancement in technology that uses approved radioactive diagnostic agents (florbetapir, flutemetamol, or florbetaben) to estimate Aβ neuritic plaque density in adults with cognitive impairment evaluated for AD and other causes of cognitive decline. There is no cure for AD to date—the disease progression cannot be stopped or reversed; approved pharmacological agents (donepezil, galantamine, and rivastigmine; memantine) provide symptomatic treatment. However, the disease-modifying therapies are promising; aducanumab and CAD106 are in phase III trials for the early stages of AD. In conclusion, core CSF biomarkers reflect pathophysiology of AD in the early and late stages; the application of approved radiotracers have potential in amyloid-PET brain imaging to detect early AD.

18F] FBB cortical uptake is not related to the age of onset of Alzheimer's disease.

To investigate the relationships between amyloid burden in brain and the age of onset of Alzheimer's disease. We examined 60 patients with clinical diagnosis of Alzheimer's disease. Of them, 22 were early-onset of Alzheimer's disease and 38 were late-onset of Alzheimer's disease. All of them underwent a brain PET scan 90 minutes after the injection of 4-[(E)-2-[4-[2-[2-(2-fluoranylethoxy)ethoxy]ethoxy]phenyl]ethenyl]-N-methylaniline ([F] FBB); 300 ± 10 MBq). Relationships between amyloid burden in brain and age of onset of Alzheimer's disease were assessed by means of statistical parametric mapping version 12. There were no significant differences [F] FBB uptake between early-onset of Alzheimer's disease and late-onset of Alzheimer's disease patients. In our study group, the age of onset is not related to brain amyloid burden in Alzheimer's disease patients.

Whole-Blood Levels of MicroRNA-9 Are Decreased in Patients With Late-Onset Alzheimer Disease.

Recent evidence suggests changes in circulating microRNA levels may be promising biomarkers for the clinical diagnosis of Alzheimer disease (AD). We hypothesized that whole-blood microRNAs may be useful to identify individuals with established AD. For this purpose, a sample of community-dwelling women (≥55 years old) carrying the ApoE ∊4 allele were clinically evaluated using the American Psychiatric Association/Diagnostic and Statistical Manual of Mental Disorders, Fourth edition and the Alzheimer Disease Assessment Scale-Cognitive Subscale criteria to diagnose probable AD, and the Clinical Dementia Rating scale to stage the dementia. A set of 25 mature microRNAs was rationally selected for evaluation based on experimental evidence of interaction with genes linked to the late-onset AD neuropathology. Whole-blood concentrations were determined by quantitative real-time polymerase chain reaction. Compared to patients without dementia, a median 3-fold decrease in miR-9 levels was found among patients with AD (P = .001). Our findings support blood-borne miR-9 as a candidate biomarker for probable AD, embodied by evidence from the literature of its implication in amyloidogenesis.

Development of AD-Like Pathology in Skeletal Muscle.

Effective therapeutic strategy against Alzheimer's disease (AD) requires early detection of AD; however, clinical diagnosis of Alzheimer's disease (AD) is not precise and a definitive diagnosis of AD is only possible via postmortem examination for AD pathological hallmarks including senile plaques composed of Aβ and neuro fibrillary tangles composed of phosphorylated tau. Although a variety of biomarker has been developed and used in clinical setting, none of them robustly predicts subsequent clinical course of AD. Thus, it is essential to identify new biomarkers that may facilitate the diagnosis of early stages of AD, prediction of subsequent clinical course, and development of new therapeutic strategies. Given that pathological hallmarks of AD including Aβaccumulation and the presence of phosphorylated tau are also detected in peripheral tissues, AD is considered a systemic disease. Without the protection of blood-brain barrier, systemic factors can affect peripheral tissues much earlier than neurons in brain. Here, we will discuss the development of AD-like pathology in skeletal muscle and the potential use of skeletal muscle biopsy (examination for Aβaccumulation and phosphorylated tau) as a biomarker for AD.

Racial Disparity in Cerebrospinal Fluid Amyloid and Tau Biomarkers and Associated Cutoffs for Mild Cognitive Impairment

Prior evidence suggests that racial differences exist in tau biomarkers in mild cognitive impairment (MCI) and Alzheimer disease (AD). Whether this reported disparity is associated with a differential level of neurodegeneration and disease stage or with underlying mechanisms separate from amyloid or tau is unclear. To compare cerebrospinal fluid (CSF) biomarkers in African American and white individuals with normal cognition and MCI, to estimate race-based cutoffs for these biomarkers that maximize diagnostic discrimination between normal cognition and MCI, and to study the association of demographic characteristics, cognitive performance, and common vascular risk factors with these differences. This case-control study conducted from March 1, 2016, through January 31, 2019, included participants in the Brain Stress Hypertension and Aging Research Program cohort undergoing baseline assessment. Participants were 50 years or older and recruited from the Atlanta, Georgia, area. Self-reported race and cognitive status categorized using modified Petersen criteria and clinical consensus diagnosis. Levels of β-amyloid 1-42 (Aβ1-42), tau, and phosphorylated tau 181 (pTau181), the ratio of tau or pTau181 to Aβ1-42, and hippocampal volume on magnetic resonance imaging of the brain. Data from 362 study participants were analyzed (mean [SD] age, 65.6 [7.9] years), of whom 152 (42.0%) were African American, 230 (63.5%) were women, and 189 (52.2%) had MCI. After adjustment for demographic characteristics and cognitive performance, lower mean (SE) levels were observed in African American vs white individuals with MCI for tau (52.40 [5.90] vs 78.98 [5.02] pg/mL; P = .001) and pTau181 (15.42 [2.06] vs 25.24 [1.75] pg/mL; P = .001) and a lower pTau181 to Aβ1-42 ratio (0.07 [0.02] vs 0.14 [0.01]; P = .003). There were no racial differences in the normal cognition group or in hippocampal volumes in the MCI group. Cutoffs for CSF biomarkers were higher for Aβ1-42 in African American relative to white individuals (208 [95% CI, 126-321] vs 197 [95% CI, 183-245] pg/mL) and lower for tau (51 [95% CI, 31-59] vs 59 [95% CI, 56-92] pg/mL) and pTau181 (12 [95% CI, 12-19] vs 20 [95% CI, 12-27] pg/mL) levels. Cutoffs for the pTau181 to Aβ1-42 ratio were 0.05 (95% CI, 0.03-0.12) for African American participants and 0.05 (95% CI, 0.05-0.13) for white participants. This study found that African American individuals had lower levels of tau-based biomarkers that were not likely explained by the degree of disease stage or neurodegeneration reflected by hippocampal volumes. This study suggests that race is an important factor when interpreting CSF biomarkers, especially in the clinical diagnosis of prodromal AD. It appears that using the pTau181 to Aβ1-42 ratio may ameliorate these differences.

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.

USING NEURAL NETWORK TO UNCOVER CELL TYPES THROUGH SNRNA SEQUENCING

The advent of single-nucleus RNA-sequencing (snRNAseq) has allowed for the exploration of genetic signatures of the numerous cells in the brain. In particular, snRNAseq data can provide new insights into how many neurodegenerative diseases, such as Alzheimer’s Disease, alter cells in the brain. One major challenge with analyzing snRNAseq data is the lack of a systematic way to classify the various cell types across different datasets. To address this challenge, we developed a general classifier (“DeepSeq”) that uses state-of-the-art deep learning approaches. We trained our model on multiple snRNAseq datasets derived from post-mortem brain tissue in individuals with and without clinical diagnosis of Alzheimer’s Disease from the ROSMAP cohorts. The two snRNAseq datasets contained 70,064 nuclei and 170,275 nuclei. The two studies employed different clustering techniques, and identified 44 and 18 putative cell types. To map these disparate cluster identities across datasets, we extracted the most relevant genes and trained two separate networks, one on each dataset. We then validated each classifier separately on the holdout cells. The resulting classifier accuracy were 87% and 94%. To map clusters across datasets, we then applied each classifier to the other dataset. Both classifiers yielded mappings that reflected the overall biology, correctly categorizing the nuclei into broad and fine cell type classes. Although validation on additional datasets would expand the generality of this approach, our results show that DeepSeq is an easily implementable classification tool that can assign identity to nuclei in new snRNAseq datasets without the need for preprocessing or cross-batch alignment.

Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: from biological biomarkers to clinical syndromes

BackgroundAccording to the 2018 NIA-AA research framework, Alzheimer’s disease (AD) is not defined by the clinical consequences of the disease, but by its underlying pathology, measured by biomarkers. Evidence of both amyloid-β (Aβ) and phosphorylated tau protein (p-tau) deposition—assessed interchangeably with amyloid-positron emission tomography (PET) and/or cerebrospinal fluid (CSF) analysis—is needed to diagnose AD in a living person. Our aim was to test the new NIA-AA research framework in a large cohort of cognitively impaired patients to evaluate correspondence between the clinical syndromes and the underlying pathologic process testified by biomarkers.MethodsWe retrospectively analysed 628 subjects referred to our centre in suspicion of dementia, who underwent CSF analysis, together with neuropsychological assessment and neuroimaging, and were diagnosed with different neurodegenerative dementias according to current criteria, or as cognitively unimpaired. Subjects were classified considering CSF biomarkers, and the prevalence of normal, AD-continuum and non-AD profiles in each clinical syndrome was calculated. The positivity threshold of each CSF biomarker was first assessed by receiver operating characteristic analysis, using Aβ-positive/negative status as determined by amyloid-PET visual reads. The agreement between CSF and amyloid-PET data was also evaluated.ResultsAmong patients with a clinical diagnosis of AD, 94.1% were in the AD-continuum, whereas 5.5% were classified as non-AD and 0.4% were normal. The AD-continuum profile was found also in 26.2% of frontotemporal dementia, 48.6% of Lewy body dementia, 25% of atypical parkinsonism and 44.7% of vascular dementia. Biomarkers’ profile did not differ in amnestic and not amnestic mild cognitive impairment. CSF Aβ levels and amyloid-PET tracer binding negatively correlated, and the concordance between the two Aβ biomarkers was 89%.ConclusionsThe examination of the 2018 NIA-AA research framework in our clinical setting revealed a good, but incomplete, correspondence between the clinical syndromes and the underlying pathologic process measured by CSF biomarkers. The AD-continuum profile resulted to be a sensitive, but non-specific biomarker with regard to the clinical AD diagnosis. CSF and PET Aβ biomarkers were found to be not perfectly interchangeable to quantify the Aβ burden, possibly because they measure different aspects of AD pathology.

Retrospective Medical Record Research: Reflections of A Unsponsored Researcher

This article is a reflective narrative by the author following the successful completion of a doctoral thesis involving the analysis of primary care data. The aim of the study was to identify patterns in signs and symptoms preceding a clinical diagnosis of Alzheimer’s Disease (AD). Here, we discuss the challenges of conducting research using the patient medical health records as a non-sponsored researcher. The narrative explores the experiences of undertaking practice recruitment, issues that arose around access to data and the requirement for stakeholder commitment, with proposals for other similar projects that attempt to undertake research using patients’ data. The Gibbs reflective cycle was adopted in this narrative. This model encourages a clear description of events, analysis of personal feelings, evaluation of the experience, conclusions as to the options that were considered and actions to take if faced with the same study methods (involving primary care practitioners and/or the review of patient records). It also allows a structured reflection while simultaneously discussing the barriers and facilitators to undertaking a retrospective medical record research. The researcher also proposes some recommendation(s) to overcoming barriers to recruitment in primary care.

Picture Recognition Errors in the Differential Diagnosis of Alzheimer’s Disease

Abstract. This article explores the possibility of differentiating between patients suffering from Alzheimer’s disease (AD) and patients with other kinds of dementia by focusing on false alarms (FAs) on a picture recognition task (PRT). In Study 1, we compared AD and non-AD patients on the PRT and found that FAs discriminate well between these groups. Study 2 served to improve the discriminatory power of the FA score on the picture recognition task by adding associated pairs. Here, too, the FA score differentiated well between AD and non-AD patients, though the discriminatory power did not improve. The findings suggest that AD patients show a liberal response bias. Taken together, these studies suggest that FAs in picture recognition are of major importance for the clinical diagnosis of AD.

The Pathology of Rapid Cognitive Decline in Clinically Diagnosed Alzheimer's Disease.

Background:Variable rate of cognitive decline among individuals with Alzheimer’s disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus.Objective:To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD.Methods:Neuropsychology test and autopsy data was pulled from the National Alzheimer’s Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all others were NCD.Results:Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97], p < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p = 0.007), TMT Part B (187[86.1] versus 159[79.0], p = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p = 0.04), and the BNT (21.5[7.05] versus 23.6[5.09], p = 0.04). RCD had more thyroid disease (30% versus 16%, p = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p = 0.01). RCD had more severe cerebral amyloid angiopathy (1.62[1.0] versus 1.13[1.0], p = 0.002), more neocortical Lewy bodies (20% versus 10%, p = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p = 0.04). A model combining select variables was significant above chance (χ2 = 25.8, p = 0.002), but not to clinical utility (AUC < 0.70; 95% CI).Conclusion:Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function.

An Amyloid-β Targeting Chemical Exchange Saturation Transfer Probe for In Vivo Detection of Alzheimer's Disease.

A reliable and reproducible detection of Aβ deposits would be beneficial for the early diagnosis of Alzheimer's disease (AD). In the present study, the feasibility of applying chemical exchange saturation transfer (CEST) for Aβ deposit detection using angiopep-2 as a probe was evaluated, and it was demonstrated that CEST could detect angiopep-2 and Aβ-angiopep-2 aggregates in vitro. Furthermore, APP/PS1 mice injected with angiopep-2 exhibited a significantly higher in vivo CEST effect when compared with controls. The distribution of Aβ deposits detected by CEST imaging was consistent with the histological staining results. The present study is the first to report a reliable exogenous CEST probe to noninvasively evaluate Aβ deposits in APP/PS1 mice. Furthermore, these results demonstrate the potential for clinical AD diagnosis and Aβ-targeted drug therapy assessment using CEST imaging with the angiopep-2 probe.

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.

Clinical diagnoses among individuals with primary age-related tauopathy versus Alzheimer's neuropathology

Primary age-related tauopathy (PART) is increasingly recognized as a pathologic entity distinct from Alzheimer's disease (AD). Given that the diagnosis of PART is an autopsy diagnosis, it is unclear how PART is perceived in clinical practice. Thus, we investigated the presumptive primary and contributing diagnoses in individuals who had cognitive impairment while alive and who met neuropathologic criteria for PART at autopsy. We also compared these clinical diagnoses for people with PART to those with AD neuropathology (ADNP). We used data on 1354 participants from the National Alzheimer's Coordinating Center, restricting to those with no neuritic plaques (PART) or moderate/frequent neuritic plaques (ADNP); clinical visit within two years of autopsy; and mild cognitive impairment (MCI) or dementia at last visit. To assess if PART participants were less likely to receive a clinical diagnosis of AD at their last visit prior to autopsy, we used logistic regression, controlling for age, sex, education, and APOE ε4 status. There were 161 PART individuals (n = 49 MCI; n = 112 dementia) and 1193 individuals with ADNP (n = 75 MCI; n = 1118 dementia). Primary clinical diagnosis of AD was more common in those with ADNP (MCI: 69%; demented: 86%) than PART (MCI: 57%; demented: 52%). In the adjusted analysis, primary and contributing clinical diagnoses of AD remained less likely in PART vs. ADNP participants with dementia (OR: 0.22, 95% CI: 0.13–0.38). This study suggests that clinicians recognize a distinction in the clinical presentation between PART and ADNP, diagnosing AD less frequently in those with PART. Nonetheless, clinical AD was diagnosed greater than 50% of the time in PART participants with MCI or dementia. Ante-mortem criteria for diagnosis of PART need to be established, as PART is a neuropathological entity that is distinct from AD and has its own clinical and cognitive outcomes.

CEREBRAL HEMODYNAMIC CHANGES DURING MODERATE INTENSITY EXERCISE IN OLDER ADULTS WITH HIGH AND NORMAL RESTING PULSATILITY INDEX

A large body of recent evidence shows a substantial overlap exists among abnormality in the pulsatility index (PI) and cognitive decline. PI can be quantified using transcranial Doppler (TCD) measurement of cerebral blood flow velocities (CBFV) in the middle cerebral artery (MCA). PI of the MCA is postulated to reflect the vascular resistance in the arteries distal from the location of acoustic insonation. Higher PI indicates increased arterial rigidity and decreased arterial compliance and it is associated with a clinical diagnosis of Alzheimer disease. Physical exercise is suggested to have a beneficial effect on cognition in older adults. The study aimed to compare cerebral hemodynamic changes during exercise in older adults with normal and high resting PI. We enrolled eighty-one cognitively normal elderly subjects aged from 65 to 86 years old with a Clinical Dementia Rating (CDR) score of 0. TCD envelope, end-tidal carbon dioxide (PETCO2) and beat-to-beat mean arterial blood pressure (MAP) were recorded during moderate intensity exercise. The pulsatility index (PI) for each cardiac cycle during rest was calculated and averaged. The participants were divided into two groups based on the resting PI value: Fifty participants with normal resting PI, and thirty-one with high resting PI. The threshold for normal resting PI was age-adjusted using a formula adapted from the Rotterdam study 0.97 + (0.01*(Participant age - 65)). Percentage change from rest to exercise in TCD parameters, PETCO2, and MAP between the two groups were compared. Both groups showed a significant increase in mean CBFV, PETCO2, and MAP (P=0.01). Participants with normal resting PI showed a significant increase in PI during exercise. No change in PI during exercise was observed in those with high resting PI. This was mainly driven by a significant increase in diastolic velocity (Vd).

How many patients are eligible for disease-modifying treatment in Alzheimer’s disease? A French national observational study over 5 years

ObjectiveWe aimed to study the epidemiology of the prodromal and mild stages of Alzheimer’s disease (AD) patients who are eligible for clinical trials with disease-modifying therapies.SettingsWe analysed two large complementary...

Timing of onset and rate of decline in learning and retention in the pre-dementia phase of Alzheimer's disease.

To examine trajectories of declines in learning and retention during the predementia phase of Alzheimer's disease (AD) using the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT+IR). Learning was defined by the sum of free recall over three test trials. Retention was defined in two ways: by delayed free recall (DFR) and by savings; DFR adjusted for learning. The performances of 217 incident AD cases from the Baltimore Longitudinal Study of Aging (BLSA) were aligned based on the time that AD was first diagnosed. The predementia phase of learning and retention decline was assessed using change point models in which cognitive trajectories are described by a series of linear components with knots delineating times of accelerating decline. Trajectories for both learning and DFR had two change points: the first at 6.58 (95% confidence intervals (CI): 6.56, 6.60) to 7.29 (95% CI: 6.13, 8.46) years before diagnosis followed by gradual decline over the next 4 years, and a second acceleration of decline 1.89 (0.56, 3.24) to 2.93 (95% CI: 1.56, 4.30) years before diagnosis. The change points for DFR were not significantly earlier in the predementia phase than the change points for learning. Savings had one change point, 5.3 (95% CI: 3.56, 7.04) years before diagnosis. Both learning and DFR showed similar profiles of decline in the years prior to the clinical diagnosis of AD. When delayed recall was adjusted for initial learning, the measure was less sensitive to early disease. (JINS, 2019, 25, 699-705).

Fluorescence Chemicals To Detect Insoluble and Soluble Amyloid-β Aggregates.

Misfolded amyloid-β (Aβ) is the key biomarker of Alzheimer's disease (AD), and discoveries of fluorescence chemicals visualizing such Aβ aggregates in the brain have made major contributions in postmortem and antemortem diagnosis of the disorder. Insoluble senile plaques of Aβ in brain tissues are commonly stained with thioflavin and congo red dyes and observed through microscopy, while those in living patient brains are detected via radioisotope-labeled fluorescence chemicals for positron emission tomography. Clinical evidence strongly supports the view that plaques are well-associated with the onset but not with the progression of AD. Plaques could accumulate while cognitive functions of at-risk individuals are still intact, and thus, another biomarker is needed to monitor neurodegeneration. Soluble Aβ oligomers are considered to have strong correlation with neuronal loss and brain atrophy as they are the most neurotoxic forms of misfolded Aβ. However, oligomer-targeting probes encounter several major difficulties in development. There is a significant structural distinction between two Aβ species-plaques are β-sheet-rich while oligomers are unordered-and it is still difficult to isolate and stabilize the oligomeric forms of Aβ. Due to these challenges, soluble oligomer-detecting imaging probes are relatively rare compared to the plaque-targeting chemical probes. This Review describes biochemical and optical characteristics of up-to-date fluorescence chemicals targeting insoluble plaques and soluble oligomers of Aβ. We also highlight the contributions of Aβ fluorescence chemicals to the clinical diagnosis of AD and technical challenges in searching for enhanced imaging probes.

Intrathecal cell therapy with autologous stromal cells increases cerebral glucose metabolism and can offer a new approach to the treatment of Alzheimer's type dementia

Background aimsAfter recent observations that intrathecal administration of autologous bone marrow mesenchymal stromal cells (MSCs) increases cerebral metabolism in patients with severe traumatic brain injury (TBI), we examined this type of cell therapy in Alzheimer's type dementia. MethodsThree patients with clinical diagnosis of Alzheimer's disease received every 3 months 100million autologous MSCs by intrathecal route, until a total dose of 300million. ResultsDuring cell therapy the patients showed arrest in neurological deterioration and two of them manifested clear improvement of previous symptoms. A global increase in cerebral glucose metabolism, measured using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), was observed after every administration of cell therapy. ConclusionsOur present findings suggest that intrathecal administrations of autologous MSCs can be a new strategy for the treatment of Alzheimer's dementia.