Early Stage AD Research Articles

A multi-slice attention fusion and multi-view personalized fusion lightweight network for Alzheimer’s disease diagnosis

ObjectiveAlzheimer’s disease (AD) is a type of neurological illness that significantly impacts individuals’ daily lives. In the intelligent diagnosis of AD, 3D networks require larger computational resources and storage space for training the models, leading to increased model complexity and training time. On the other hand, 2D slices analysis may overlook the 3D structural information of MRI and can result in information loss.ApproachWe propose a multi-slice attention fusion and multi-view personalized fusion lightweight network for automated AD diagnosis. It incorporates a multi-branch lightweight backbone to extract features from sagittal, axial, and coronal view of MRI, respectively. In addition, we introduce a novel multi-slice attention fusion module, which utilizes a combination of global and local channel attention mechanism to ensure consistent classification across multiple slices. Additionally, a multi-view personalized fusion module is tailored to assign appropriate weights to the three views, taking into account the varying significance of each view in achieving accurate classification results. To enhance the performance of the multi-view personalized fusion module, we utilize a label consistency loss to guide the model’s learning process. This encourages the acquisition of more consistent and stable representations across all three views.Main resultsThe suggested strategy is efficient in lowering the number of parameters and FLOPs, with only 3.75M and 4.45G respectively, and accuracy improved by 10.5% to 14% in three tasks. Moreover, in the classification tasks of AD vs. CN, AD vs. MCI and MCI vs. CN, the accuracy of the proposed method is 95.63%, 86.88% and 85.00%, respectively, which is superior to the existing methods.ConclusionsThe results show that the proposed approach not only excels in resource utilization, but also significantly outperforms the four comparison methods in terms of accuracy and sensitivity, particularly in detecting early-stage AD lesions. It can precisely capture and accurately identify subtle brain lesions, providing crucial technical support for early intervention and treatment.

BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aβ + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aβ + older adults in early-stage sporadic AD. Aβ + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8years, covarying for CSF Aβ42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. Aβ + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aβ-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Shifting From Active to Passive Monitoring of Alzheimer Disease: The State of the Research.

Most research using digital technologies builds on existing methods for staff-administered evaluation, requiring a large investment of time, effort, and resources. Widespread use of personal mobile devices provides opportunities for continuous health monitoring without active participant engagement. Home-based sensors show promise in evaluating behavioral features in near real time. Digital technologies across these methodologies can detect precise measures of cognition, mood, sleep, gait, speech, motor activity, behavior patterns, and additional features relevant to health. As a neurodegenerative condition with insidious onset, Alzheimer disease and other dementias (AD/D) represent a key target for advances in monitoring disease symptoms. Studies to date evaluating the predictive power of digital measures use inconsistent approaches to characterize these measures. Comparison between different digital collection methods supports the use of passive collection methods in settings in which active participant engagement approaches are not feasible. Additional studies that analyze how digital measures across multiple data streams can together improve prediction of cognitive impairment and early-stage AD are needed. Given the long timeline of progression from normal to diagnosis, digital monitoring will more easily make extended longitudinal follow-up possible. Through the American Heart Association-funded Strategically Focused Research Network, the Boston University investigative team deployed a platform involving a wide range of technologies to address these gaps in research practice. Much more research is needed to thoroughly evaluate limitations of passive monitoring. Multidisciplinary collaborations are needed to establish legal and ethical frameworks for ensuring passive monitoring can be conducted at scale while protecting privacy and security, especially in vulnerable populations.

Pathology-specific patterns of cerebellar atrophy in neurodegenerative disorders.

Associations of cerebellar atrophy with specific neuropathologies in Alzheimer's disease and related dementias (ADRD) have not been systematically analyzed. This study examined cerebellar gray matter volume across major pathological subtypes of ADRD. Cerebellar gray matter volume was examined using voxel-based morphometry in 309 autopsy-proven ADRD cases and 80 healthy controls. ADRD subtypes included AD, mixed Lewy body disease and AD (LBD-AD), and frontotemporal lobar degeneration (FTLD). Clinical function was assessed using the Clinical Dementia Rating (CDR) scale. Distinct patterns of cerebellar atrophy were observed in all ADRD subtypes. Significant cerebellar gray matter changes appeared in the early stages of most subtypes and the very early stages of AD, LBD-AD, FTLD-TDP type A, and progressive supranuclear palsy. Cortical atrophy positively predicted cerebellar atrophy across all subtypes. Our findings establish pathology-specific profiles of cerebellar atrophy in ADRD and propose cerebellar neuroimaging as a non-invasive biomarker for differential diagnosis and disease monitoring. Cerebellar atrophy was examined in 309 patients with autopsy-proven neurodegeneration. Distinct patterns of cerebellar atrophy are found in all pathological subtypes of Alzheimer's disease and related dementias (ADRD). Cerebellar atrophy is seen in early-stage (Clinical Dementia Rating [CDR] ≤1) AD, Lewy body dementia (LBD), frontotemporal lobar degeneration with tau-positive inclusion (FTLD-tau), and FTLD-transactive response DNA binding protein (FTLD-TDP). Cortical atrophy positively predicts cerebellar atrophy across all neuropathologies.

Understanding barriers to and facilitators of clinician-patient conversations about brain health and cognitive concerns in primary care: a systematic review and practical considerations for the clinician

BackgroundPrimary care clinicians (PCCs) are typically the first practitioners to detect cognitive impairment in their patients, including those with Alzheimer’s disease or related dementias (ADRD). However, conversations around cognitive changes can be challenging for patients, family members, and clinicians to initiate, with all groups reporting barriers to open dialogue. With the expanding array of evidence-based interventions for ADRD, from multidomain care management to novel biotherapeutics for early-stage AD, incorporating conversations about brain health into routine healthcare should become a standard of care. We conducted a systematic review to identify barriers to and facilitators of brain health conversations in primary care settings.MethodsWe systematically searched PubMed, Scopus, Web of Science, and the Cochrane Library for qualitative or quantitative studies conducted in the US between January 2000 and October 2022 that evaluated perceptions of cognition and provider-patient brain health conversations prior to formal screening for, or diagnosis of, mild cognitive impairment or ADRD. We assessed the quality of the included studies using the Mixed Methods Appraisal Tool.ResultsIn total, 5547 unique abstracts were screened and 22 articles describing 19 studies were included. The studies explored perceptions of cognition among laypersons or clinicians, or provider-patient interactions in the context of a patient’s cognitive concerns. We identified 4 main themes: (1) PCCs are hesitant to discuss brain health and cognitive concerns; (2) patients are hesitant to raise cognitive concerns; (3) evidence to guide clinicians in developing treatment plans that address cognitive decline is often poorly communicated; and (4) social and cultural context influence perceptions of brain health and cognition, and therefore affect clinical engagement.ConclusionsEarly conversations about brain health between PCCs and their patients are rare, and effective tools, processes, and strategies are needed to make these vital conversations routine.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer’s mouse model

BackgroundAlzheimer’s disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined.MethodsCircuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression.ResultsWe identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons.ConclusionWe report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.

Accelerating diversity in Alzheimer's disease research by partnering with a community advisory board.

Community advisory boards (CABs) and researcher partnerships present a promising opportunity to accelerate enrollment of underrepresented groups (URGs). We outline the framework for how the CAB and researchers at the Indiana Alzheimer's Disease Research Center (IADRC) partnered to accelerate URG participation in AD neuroimaging research. CAB and the IADRC researchers partnered to increase the CAB's impact on URG study enrollment through community and research interactions. Community interactions included the CAB collaboratively building a network of URG focused community organizations and collaborating with those URG-focused organizations to host IADRC outreach and recruitment events. Research interactions included direct impact (CAB members referring themselves or close contacts as participants) and strategic impact, mainly by the CAB working with researchers to develop and refine URG focused outreach and recruitment strategies for IADRC and affiliated studies to increase URG representation. We created a database infrastructure to measure how these interactions impacted URG study enrollment. Out of the 354 URG research referrals made to the IADRC between October 2019 and December 2022, 267 referrals were directly referred by the CAB (N = 36) or from community events in which CAB members organized and/or volunteered at (N = 231). Out of these 267 referrals, 34 were enrolled in IADRC and 2 were enrolled in Indiana University Longitudinal Early Onset AD Study (IU LEADS). Of note, both studies require the prospective participants to be willing to do MRI and PET scans. As of December 2022, 30 out of the 34 enrolled participants have received a consensus diagnosis; the majority were cognitively normal (64.7%), with the remainder having mild cognitive impairment (17.6%) or early-stage AD (2.9%). The IADRC CAB-researcher partnership had a measurable impact on the enrollment of African American/Black adults in AD neuroimaging studies. Future studies will need to test whether this conceptual model works for other sites and for other URGs.

Diagnosing and Treating Alzheimer Disease During the Early Stage

Recent advances in technology can lead to earlier detection of Alzheimer disease (AD) in patients and therefore opportunities for early diagnosis and treatment. In addition, novel agents can slow disease progression and improve symptoms. However, clinicians are not providing a diagnosis to over half of individuals who meet criteria for dementia. Early detection and intervention are crucial to slow symptom progression, and these advances provide a window of opportunity to diagnose the disease early and even prevent it from becoming symptomatic. Clinicians need education on early recognition of AD and on sharing the diagnosis of AD with patients and families as well as guidance for providing patients and families with information on next steps and facilitating early treatment initiation for AD. Partnering with clinicians in the primary care setting and providing them with the necessary tools can change the trajectory of the disease for patients and caregivers.

Differences in structural MRI and diffusion tensor imaging underlie visuomotor performance declines in older adults with an increased risk for Alzheimer's disease.

Visuomotor impairments have been demonstrated in preclinical AD in individuals with a positive family history of dementia and APOE e4 carriers. Previous behavioral findings have also reported sex-differences in performance of visuomotor tasks involving a visual feedback reversal. The current study investigated the relationship between grey and white matter changes and non-standard visuomotor performance, as well as the effects of APOE status, family history of dementia, and sex on these brain-behavior relationships. Older adults (n = 49) with no cognitive impairments completed non-standard visuomotor tasks involving a visual feedback reversal, plane-change, or combination of the two. Participants with a family history of dementia or who were APOE e4 carriers were considered at an increased risk for AD. T1-weighted anatomical scans were used to quantify grey matter volume and thickness, and diffusion tensor imaging measures were used to quantify white matter integrity. In APOE e4 carriers, grey and white matter structural measures were associated with visuomotor performance. Regression analyses showed that visuomotor deficits were predicted by lower grey matter thickness and volume in areas of the medial temporal lobe previously implicated in visuomotor control (entorhinal and parahippocampal cortices). This finding was replicated in the diffusion data, where regression analyses revealed that lower white matter integrity (lower FA, higher MD, higher RD, higher AxD) was a significant predictor of worse visuomotor performance in the forceps minor, forceps major, cingulum, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and uncinate fasciculus (UF). Some of these tracts overlap with those important for visuomotor integration, namely the forceps minor, forceps major, SLF, IFOF, and ILF. These findings suggest that measuring the dysfunction of brain networks underlying visuomotor control in early-stage AD may provide a novel behavioral target for dementia risk detection that is easily accessible, non-invasive, and cost-effective. The results also provide insight into the structural differences in inferior parietal lobule that may underlie previously reported sex-differences in performance of the visual feedback reversal task.

Influence of cerebral blood flow on volumetric loss related to Alzheimer's disease.

Verify the correlation between atrophy and CBF in patients with MCI and mild phase ADD, to demonstrate whether changes in CBF can be considered as vascular biomarkers in the diagnosis of the DA continuum. 11 healthy volunteers, 16 MCI and 15 mild ADD were evaluated. Images of the brain were acquired, including CBF measured with Arterial Spin Labeling (ASL). When comparing MCI with control, a reduction in normalized CBF was observed in left posterior cingulate (estimated difference -0.38; p=0.02), right posterior cingulate (estimated difference -0.45; p=0.02) and right precuneus (estimated difference -0.28; p <0.01); also increase in normalized CBF in right upper temporal pole (estimated difference 0.22; p=0.03). It was also observed that in MCI, the smaller the gray matter volume, the smaller the CBF in the left posterior cingulate; as well as the greater the cerebrospinal fluid volume, consequent to the encephalic volumetric reduction associated with atrophy, the greater the CBF in the right superior temporal pole. When comparing controls, MCI and mild AD, in relation to the other variables, no other correlations were observed between CBF and atrophy. In patients with MCI, the reduction of CBF in the left posterior cingulate correlated with gray matter atrophy, as well as the increase of CBF in the right upper temporal pole correlated with an increase in cerebrospinal fluid consequent to the encephalic volumetric reduction associated with atrophy, demonstrating the influence of CBF in AD related brain atrophy. These findings position CBF as a possible vascular biomarker for early-stage AD diagnoses.

Sex Differences in Mild Cognitive Impairment Risk by APOE Genotype

AbstractBackgroundMale sex is suggested as a risk factor for mild cognitive impairment (MCI), but this association may be influenced by the female verbal memory advantage, and the use of verbal memory tests has been shown to delay MCI diagnosis in women. Moreover, this association may vary by apolipoprotein E (APOE) genotype. The National Alzheimer’s Coordinating Center (NACC) uniform data set (UDS) contains demographic data and annual standardized neuropsychological (with memory being assessed primarily with verbal tests) and clinical diagnostic data obtained by 41 NIA‐funded Alzheimer’s Disease Centers across the U.S. This large database is a rich resource for evaluating sex effects on MCI/Dementia diagnosis by APOE genotype.MethodWe restricted to NACC enrollees above 60 years old, with available APOE genotype, cognitively normal at their initial UDS visit, had at least one follow‐up visit, and without a documented dominantly inherited Alzheimer mutation, leaving 10,461 participants (35.3% men, 77.0% non‐Hispanic White). Cox proportional hazards models of time to incident MCI/dementia controlling for sex, baseline age, years of education, baseline Mini‐Mental Status Exam (MMSE), and interaction terms as indicated were fit separately to APOE E3/E3 homozygotes and E3/E4 heterozygotes. Small sample size precluded analyses of other APOE genotypes. Secondary analyses restricting to non‐Hispanic White participants were also examined.ResultAmong APOE E3/E3 homozygotes, male sex is a risk factor for clinically diagnosed MCI/dementia (Hazard ratio (HR) = 1.27, p &lt; 0.001) independent of age at enrollment. Among APOE E3/E4 heterozygotes, male sex is a risk factor at the lower range of age (age 60–75), while female sex is a risk factor at the higher range (interaction p = 0.006). Similar findings were obtained when restricting to the non‐Hispanic White participants.ConclusionThe higher risk of MCI/dementia in men in the NACC cohort may reflect previously‐reported sex differences in verbal memory performance at early stage AD pathogenesis and the use of verbal memory diagnostic tests more sensitive in men early in the disease.

Gaze tracking patterns on different types of traffic risk in early-stage Alzheimer’s disease

Many fatal accidents are caused by the driver’s inability, upon the occurrence of sudden events, to detect hazards in time, an ability that is based on the driver’s eye movement patterns, the detection of involved persons, events, objects, as well as the length of time spent on noticing same. This study intends to compare risk perception and decision-making in high-risk traffic situations between individuals with AD and controls by exploring gaze tracking and hazard detection patterns. The study included 16 individuals with early-stage AD and 26 controls. During the experiment, participants underwent several vision and cognitive tests and watched twelve videos of high-risk traffic situations while their eye movement patterns were being recorded by the eye tracking device, in order to understand how cognitive abilities affect eye movement patterns during high-risk traffic situations. The results revealed poorer cognitive abilities and diminished risk perception in individuals with AD compared with the controls and thus an inability to predict potential accidents. In terms of high-risk traffic situations involving pedestrians, traffic violations by others and view-blocking events, a significant difference in gaze patterns was found between individuals with AD and healthy seniors. The contribution of this study is in elaborating the effect of different traffic event type and specific cognitive abilities on traffic risk-detection in individuals with AD. The results of this study may aid in the formulation of driver licensing policies and the design of traffic scenarios; they also elucidate the driving behaviors of individuals with AD.

Modulation of Brain Activity and Functional Connectivity by Acupuncture Combined With Donepezil on Mild-to-Moderate Alzheimer's Disease: A Neuroimaging Pilot Study.

BackgroundFunctional brain imaging changes have been proven as potential pathophysiological targets in early-stage AD. Current longitudinal neuroimaging studies of AD treated by acupuncture, which is one of the growingly acknowledged non-pharmacological interventions, have neither adopted comprehensive acupuncture protocols, nor explored the changes after a complete treatment duration. Thus, the mechanisms of acupuncture effects remain not fully investigated.ObjectiveThis study aimed to investigate the changes in spontaneous brain activity and functional connectivity and provide evidence for central mechanism of a 12-week acupuncture program on mild-to-moderate AD.MethodsA total of forty-four patients with mild-to-moderate AD and twenty-two age- and education-level-matched healthy subjects were enrolled in this study. The forty-four patients with AD received a 12-week intervention of either acupuncture combined with Donepezil (the treatment group) or Donepezil alone (the control group). The two groups received two functional magnetic resonance imaging (fMRI) scans before and after treatment. The healthy subject group underwent no intervention, and only one fMRI scan was performed after enrollment. The fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) were applied to analyze the imaging data. The correlations between the imaging indicators and the changed score of Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-cog) were also explored.ResultsAfter the 12-week intervention, compared to those in the control group, patients with AD in the treatment group scored significantly lower on ADAS-cog value. Moreover, compared to healthy subjects, the areas where the fALFF value decreased in patients with AD were mainly located in the right inferior temporal gyrus, middle/inferior frontal gyrus, middle occipital gyrus, left precuneus, and bilateral superior temporal gyrus. Compared with the control group, the right precuneus demonstrated the greatest changed value of fALFF after the intervention in the treatment group. The difference in ADAS-cog after interventions was positively correlated with the difference in fALFF value in the left temporal lobe. Right precuneus-based FC analysis showed that the altered FC by the treatment group compared to the control group was mainly located in the bilateral middle temporal gyrus.ConclusionThe study revealed the key role of precuneus in the effect of the combination of acupuncture and Donepezil on mild-to-moderate AD for cognitive function, as well as its connection with middle temporal gyrus, which provided a potential treating target for AD.Trial Registration Number:NCT03810794 (http://www.clinicaltrials.gov).

The effect of Alzheimer’s disease risk factors on brain aging in normal Chineses: Cognitive aging and cognitive reserve

Aging has been recognized as a major driving force of the Alzheimer’s disease’s (AD) progression, however, the relationship between brain aging and AD is still unclear. There is also a lack of studies investigating the influence of AD risk factors on brain aging in cognitively normal people. Here, the “Brain Age Gap Estimation” (BrainAGE) framework was applied to investigate the effects of AD risk factors on individual brain aging. Across a total of 165 cognitively normal elderly subjects, although no significant difference was observed in the BrainAGE scores among the three groups, AD risk dose (i.e., the number of AD risk factors) is tend to associated with an increased BrainAGE scores (high-risk > middle risk > low risk). Female exhibited more advanced brain aging (P = 0.004), and higher education years were associated with preserved brain aging (P < 0.001). APOE-ɛ4 (P = 0.846) and family history (FH) of dementia (P = 0.209) did not increase BrainAGE scores. When comparing 52 aMCI patients with 38 cognitively normal controls from ADNI dataset, aMCI patients showed significantly increased BrainAGE scores. BrainAGE scores were negatively correlated with CSF Aβ42 levels in the aMCI group (r = −0.275, P = 0.048). With an accuracy of 68.9%, BrainAGE outperformed APOE-ɛ4 and hippocampus gray matter volume (GMV) in predicting aMCI. In conclusion, AD is independently associated with structural changes in the brain that reflect advanced aging. Potentially, BrainAGE combined with APOE-ɛ4 and hippocampus GMV could be used as a pre-screening tool in early-stage AD.

SnoRNAs in plasma extracellular vesicles of AD patients are differentially associated with APOE genotype

AbstractBackgroundStandardized disease specific PET patterns correctly classify 95% of AD MCI patients. The cost of PET, however, is still prohibitive as a widespread AD diagnostic test. Diagnostic tests using CSF have also been established to measure the levels of Aβ and hyperphosphorylated tau for early diagnosis of AD or to monitor the effects of therapeutics and progression of the disease. CSF biomarkers show a good agreement with amyloid imaging and a combination of CSF Aβ42/Aβ40 increases the agreement between markers of amyloid pathology. Plasma extracellular vesicles (EVs) and their cargo present an opportunity to isolate and profile molecules associated with human pathological conditions. We have recently found small nucleolar non‐coding RNAs (snoRNAs) of box C/D (SNORDs), transcribed from imprinted chromosomal domains SNURF‐SNRPN at human chromosomal region 15q11q13 and DLK1‐DIO3 at region 14q32, highly enriched in plasma EVs of AD patients compared to non‐demented individuals.MethodDuring the discovery phase of the study, using RNA‐seq we profiled four major classes of ncRNAs in EVs isolated from early stage AD patients and control non‐demented individuals: miRNAs, snoRNAs, tRNAs and piRNAs. We verified the results by Digital Droplet PCR in plasma samples of independent group of AD and control plasma samples.ResultWe report a significant enrichment of SNORDs in AD samples compared to controls. Through verification assays we confirmed these results and identified SNORD115s &amp; SNORD116s with the highest discriminatory power to differentiate AD samples against Controls.ConclusionThe results of our study present evidence that AD is associated with changes in enrichment of SNORDs, transcribed from imprinted genomic loci, in plasma EVs and provide a rationale to further explore validity of snoRNAs as plasma biomarkers for AD.

In vivo alterations of mitochondrial activity and amyloidosis in early-stage senescence-accelerated mice: a positron emission tomography study

PurposeWhile marked reductions in neural activity and mitochondrial function have been reported in Alzheimer’s disease (AD), the degree of mitochondrial activity in mild cognitive impairment (MCI) or early-stage AD remains unexplored. Here, we used positron emission tomography (PET) to examine the direct relationship between mitochondrial activity (18F-BCPP-EF) and β-amyloid (Aβ) deposition (11C-PiB) in the same brains of senescence-accelerated mouse prone 10 (SAMP10) mice, an Aβ-developing neuroinflammatory animal model showing accelerated senescence with deterioration in cognitive functioning similar to that in MCI.MethodsFive- to 25-week-old SAMP10 and control SAMR1 mice, were used in the experiments. PET was used to measure the binding levels (standard uptake value ratios; SUVRs) of [18F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (18F-BCPP-EF) for mitochondrial complex 1 availability, and 11C-PiB for Aβ deposition, in the same animals, and immunohistochemistry for ATPB (an ATP synthase on the mitochondrial inner membrane) was also performed, to determine changes in mitochondrial activity in relation to amyloid burden during the early stage of cognitive impairment.ResultsThe SUVR of 18F-BCPP-EF was significantly lower and that of 11C-PiB was higher in the 15-week-old SAMP10 mice than in the control and 5-week-old SAMP10 mice. The two parameters were found to negatively correlate with each other. The immunohistochemical analysis demonstrated temporal upregulation of ATPB levels at 15-week-old, but decreased at 25 week-old SAMP10 mice.ConclusionThe present results provide in vivo evidence of a decrease in mitochondrial energy production and elevated amyloidosis at an early stage in SAMP10 mice. The inverse correlation between these two phenomena suggests a concurrent change in neuronal energy failure by Aβ-induced elevation of neuroinflammatory responses. Comparison of PET data with histological findings suggests that temporal increase of ATPB level may not be neurofunctionally implicated during neuropathological processes, including Aβ pathology, in an animal model of early-phase AD spectrum disorder.

Power Spectral Changes of Quantitative EEG in the Subjective Cognitive Decline: Comparison of Community Normal Control Groups.

PurposeThe purpose of this study is to compare and analyze the power spectral changes between subjective cognitive decline (SCD) subjects and normal controls (NC) while checking the preclinical stage of AD in the SCD subjects and to use the derived data for biomarker research that can diagnose early-stage AD in the future.MethodsWe recruited 23 SCD patients and 23 normal control subjects and QEEG analysis including power spectral density (PSD) and source-level analysis were performed. An automated preprocessing procedure and statistical analysis were performed by iSync Brain® (iMediSync Inc., Republic of Korea) (https://isyncbrain.com/) using the international standard 10–20 system (19 electrodes).ResultsAbsolute PSD, there was no statistically significant difference in all of the EEG power measurements of the 19 channels. In the relative PSD analysis, the average delta band power of the SCD group was significantly higher in Fp2, F4, and F8 than NC. Alpha1 band power of the O1 channel was 22.56±16.05 for the SCD group and 33.19±19.05 for the NC (p-value <0.05). Source-level analysis did not show a statistically significant difference.ConclusionSCD subjects showed a partial increase of delta waves in the frontal lobe region and a partial decrease in alpha1, a fast wave in the occipital region, compared to the NC. SCD is considered one of the earliest clinical symptoms of AD and it is predicted to be related to minor nerve damage. We were able to observe the power spectral changes in SCD subjects in this cross-sectional study, a large number of subjects and longitudinal studies are needed to evaluate their predictability for future deterioration such as conversion to MCI.

Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults.

Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aβ), remains unclear. We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aβ. We next examined associations between cytokine levels and neuroimaging biomarkers of Aβ/tau/neurodegeneration. Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aβ (false discovery rate [FDR]=0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aβ (FDR=0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aβ. Immune dysregulation is implicated in early-stage cognitive decline, and greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage AD progression.

Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer\u2019s disease

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer’s disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer’s disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

A Polymorphism Cluster at the 2q12 locus May Predict Response to Piromelatine in Patients with Mild Alzheimer\u2019s Disease

BackgroundPiromelatine is a novel melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptors agonist developed for mild Alzheimer’s disease (AD). In a randomized, placebo-controlled, dose-ranging study (ReCognition) of piromelatine (5, 20, and 50 mg daily for 6 months) in participants with mild dementia due to AD (n=371, age 60–85 years), no statistically significant differences were found between the piromelatine and placebo-treated groups on the primary (i.e., computerized neuropsychological test battery (cNTB)) and secondary outcomes (ADCS-CGIC, ADCS-MCI-ADL, ADAS-cog14, NPI, and Pittsburgh Sleep Quality Index (PSQI)) nor were there safety concerns (https://clinicaltrials.gov/ct2/show/NCT02615002).ObjectivesThis study was aimed at identifying genetic markers predicting piromelatine treatment response using a genome-wide association approach (GWAS).DesignVariant genotyping of a combined whole genome and whole exome sequencing was performed using DNA extracted from lymphocytes from consenting participants. The general case-control allelic test was performed on piromelatine-treated participants, taking “responders” (i.e., >0.125 change from baseline in the cNTB) as cases and “non responders” as controls, using a Cochran-Armitage trend test.Setting58 outpatient clinics in the US.Participants371 participants were randomized in the trial; 107 provided informed consent for genotyping.ResultsThe GWAS sample did not differ from the full study cohort in demographics, baseline characteristics, or response to piromelatine. Six single-nucleotide polymorphisms (SNPs) in chromosome 2q12 (2:107,510,000-107,540,000) were associated with response (p-value < 1×10 −4 each). Post hoc analyses suggested that the carriers of the 2q12 polymorphism cluster (27% of the GWAS sample) improved significantly on the cNTB on piromelatine as compared to placebo but significantly worsened on the ADAS-Cog14 and PSQI. By contrast, “non-carriers” improved significantly with piromelatine compared to placebo on the ADAS-Cog14 (2.91 (N=23) with piromelatine 20 mg vs 1.65 (N=19) with placebo (p=0.03)) and PSQI.ConclusionsThe 2q12 (2:107,510,000-107,540,000) 5–6 SNPs cluster may predict efficacy of piromelatine for mild AD. These findings warrant further investigation in a larger, prospective early-stage AD clinical trial for patients who are non-carriers of the 2q12 polymorphism cluster.