bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebrospinal fluid amyloid status and affective symptoms in mild cognitive impairment
Authors: Wiels Wietse , Nous Amber , Engelborghs Sebastiaan
Published: December 2020

Background

Affective and cognitive symptoms are common in old age, and frequently overlap in clinical practice. Mild cognitive impairment (MCI), for example, is a risk state for later dementia where neuropsychiatric symptoms such as depression and anxiety are common. The exact nature of this overlap remains unclear ‐ affective symptoms may be both causative of cognitive issues, they may be related to an underlying neurodegenerative disease, or may stem from common risk factors. Biomarkers of brain diseases such as Alzheimer’s can help determine the etiology of MCI and aid in predicting the risk of progression to dementia.

Aims

To determine whether CSF‐based amyloid positive and amyloid negative individuals with MCI differ in the nature and prevalence of affective symptoms.

Method

An existing database of 476 individuals with MCI will be used. All subjects underwent extensive cognitive and behavioural assessment at baseline and follow‐up (up to 7 years). Behaviour was assessed covering a period of 2 weeks prior to inclusion and at each follow‐up visit using a battery of behavioural assessment scales: Middelheim Frontality Score (MFS), Behave‐AD, Cohen‐Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia and Geriatric Depression Scale (30 items). In a significant subgroup of these patients, the standard AD CSF biomarkers (Aβ, T‐tau, P‐tau181) have been analysed. We will evaluate whether subgroups with differing amyloid status (i.e. normal vs. abnormal CSF biomarkers) are significantly different in the nature and prevalence of affective symptoms as determined by several scales (Behave‐AD, Geriatric Depression Scale, Cornell Scale for Depression in Dementia).

Results

We will compare prevalence, nature and severity of affective symptoms between subgroups of MCI patients (amyloid positive versus amyloid negative; AD CSF biomarker profile suggestive for AD versus not suggestive for AD). Presence and severity of affective symptoms will be related to (rate of) cognitive decline using neuropsychological data (e.g. yearly decline of total MMSE score).

Conclusion

We expect to find more (severe) affective symptoms in MCI due to AD (as compared to MCI not due to AD) and to find an association between these symptoms and rate of cognitive decline. The results will be presented at AAIC 2020 in Amsterdam.
Integration of large‐scale molecular networks and exomic data can identify Alzheimer's disease genes
Authors: Lagiesetty Yashwanth , Bourquard Thomas , Lichtarge Olivier
Published: December 2020

Background

We introduce a new approach to identify gene variants linked to common complex diseases. This method combines whole exome sequencing and large‐scale molecular network analysis. For proof of principle, we studied the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Alzheimer’s Disease Sequencing Project (ADSP) cohorts. In each, we evaluated the coding variants of 16,087 genes in the context of their ∼6,471,000 gene‐gene interactions, and prioritized genes that sorted cases from controls.

Method

The deleterious functional effect of every coding variant was quantified based on an Evolutionary Action (EA) model for the impact of similar variants across evolutionary history. For each gene, this impact was averaged over every individual from the ADNI (or the ADSP) cohort, and this average was used to modulate the edge weights of the STRING network of protein‐protein interactions. This process was carried out in cases and separately in controls, to yield two modified copies of the original STRING network, one representing the mutational perturbation from individuals affected with Alzheimer’s and, the other, representing those found in healthy individuals. We systematically compared these two graphs in order to identify, region by region and gene by gene, which parts of the network was significantly mutationally perturbed.

Result

Among the 100 top‐ranked in ADSP and, separately, in ADNI, a quarter are identical. This overlap indicates a robustness surpassing Genome‐wide association studies. One such gene, for example, is TOMM40, which is known to be relevant to AD. More broadly, these top‐ranked genes also significantly overlap, are significantly enriched for, or significantly diffuse to known gold standard AD genes and AD‐related diseases and pathways. These criteria for success show the top‐ranked genes are not random and are relevant to AD.

Conclusion

This approach to integrate sequencing data with network information promises to be a useful new tool to elucidate disease genes in AD and other complex, common diseases.
Phenotypes associated with MAPT duplications
Authors: Wallon David , Bonnevalle Antoine , Rovelet‐Lecrux Anne , Lagarde Julien , Sarazin Marie , Bottlaender Michel , Sellal François , Jonveaux Therese , Heitz Camille , Magnin Eloi , Ber Isabelle Le , Epelbaum Stéphane , Quillard‐Muraine Muriel , Chastan Mathieu , Hannequin Didier , Boluda Susana , Rousseau Stéphane , Richard Anne‐Claire , Quenez Olivier , Charbonnier Camille , Duyckaerts Charles , Campion Dominique , Nicolas Gaël
Published: December 2020

Background

Duplication of the 17q21.3 region, leading to increased MAPT expression, causes a rare atypical early‐onset dementia (EOD) mimicking Alzheimer’s Disease (AD) clinical presentation. Since our initial report in 2016, the same duplication has been identified in additional patients including 2 progressive supranuclear palsy (PSP) patients. It remains unclear whether MAPT duplication‐associated phenotypes are purely cognitive and if clinical and neuroimaging data are suggestive of a pure tauopathy or an amyloid plus tau underlying pathology.

Method

We report in this study clinical and paraclinical data from 10 MAPT duplication carriers, including 8 with a clinical EOD presentation and two recently identified during the screening of a series of PSP cases. All clinical data were collected as well as family history, neuropsychological assessment, 3D‐structural MRI (n = 7 patients), fluorodesoxyglucose‐PET (n = 5), DaTSCAN SPECT (n = 2), Amyloid‐PET (n = 3) and Tau‐PET (n = 2). Six patients had AD cerebrospinal fluid (CSF) biomarkers measured. Results were interpreted following Amyloid/Tau/Neurodegeneration (A/T/N) classification.

Result

Among the 10 patients, 6 had a positive family history of EOD, with cosegregation in one family. In one of the 4 sporadic patients, we could demonstrate that the duplication occurred de novo. Mean age of onset was 50.4 years [37‐58]. Eight presented a pure cognitive decline with an initial episodic amnesic syndrome. A behavioral dysexecutive syndrome was found in 5 patients (50%). Two patients were diagnosed as PSP but no or minor extrapyramidal signs were found among the 8 cognitive patients, despite 2 DaTSCANS showing presynaptic dopaminergic denervation. MRI of 6 cases (86%) showed hippocampal and temporoparietal bilateral atrophy. All CSF biomarkers were T+ and N+. Amyloid CSF biomarkers were abnormal in 3/6, suggestive of A+, however all three had negative amyloid‐PET. Interestingly, both Tau‐PET imaging showed strong deposits of Tau pathology within mesiotemporal regions and mild frontal cortex uptake in one patient (Figure). The neuropathology of two patients is currently being examined and will be presented.

Conclusion

This largest series of MAPT duplications carriers shows a heterogeneous expression with clinical and neuroimaging data suggesting mixed cortical and subcortical impairment with diverse clinical consequences. We will confront these data to the results of the neuropathological examinations.
Early‐onset Alzheimer’s disease is related to differential spatial patterns of tau pathology and cognitive impairment
Authors: Verfaillie Sander C.J. , Visser Denise , Wolters Emma E. , Coomans Emma M. , Timmers Tessa , Tuncel Hayel , Boellaard Ronald , Golla Sandeep S.V. , Windhorst Albert D. , Scheltens Philip , van Der Flier Wiesje , Ossenkoppele Rik , Van Berckel Bart N.M.
Published: December 2020

Background

Early‐onset Alzheimer’s disease (AD) dementia is characterized by a heterogeneous cognitive profile consisting of language and visuo‐spatial impairment. Spatial patterns of tau pathology measured with [18F]flortaucipir may help to explain the heterogeneity within early‐onset AD.

Method

Seventy‐one patients with Alzheimer’s disease dementia patients (n=28 early‐onset age=58, MMSE=22; n=43 late‐onset age=71, MMSE=23), of whom 6 patients with posterior cortical atrophy, 2 behavioral of AD (bvAD). All patients had available 130 minutes [18F]flortaucipir PET scans and extensive neuropsychological assessment. We generated parametric images and non‐displaceable binding potentials (BPnd) were extracted using receptor parametric mapping in the following brain regions; frontal, occipital, parietal, medial and lateral temporal cortex. We performed principal component analyses to reduce 12 cognitive tests into latent variables which reflect (uncorrelated) cognitive functions. ANOVA and linear regressions were performed to investigate between [18F]flortaucipir group differences and associations with cognition functions.

Result

Early‐onset AD dementia patients showed increased [18F]flortaucipir BPnd in occipital, parietal and frontal cortex (all p<0.001) compared to late‐onset AD. Across all AD patients, adjusted for education, sex and age, frontal [18F]flortaucipir BPnd was associated with attention (p=0.003), occipital [18F]flortaucipir BPnd with visual scanning and memory (both p=0.01), parietal [18F]flortaucipir BPnd with attention and visual scanning (p=0.002 and p=0.02 respectively). Lateral temporal [18F]flortaucipir BPnd was associated with attention (p=0.006) and medial temporal [18F]flortaucipir BPnd with memory (p=0.01). Interaction effects were found for occipital and parietal [18F]flortaucipir BPnd and visual scanning for early‐onset AD, and parietal [18F]flortaucipir BPnd and attention for late‐onset. Frontal [18F]flortaucipir BPnd was associated with visual scanning in late‐onset AD. In an exploratory analysis, we found higher [18F]flortaucipir BPnd in parieto‐occipital cortices in PCA compared early‐ and late‐onset AD (both p<0.001).

Conclusion

Differential spatial patterns of tau pathology were found depending on age‐of‐onset. Tau pathology may help to explain the clinical phenotype of early and late‐onset AD.
Memory assessment in illiterate patients: The diagnostic value of the TNI 93
Authors: Foucard Cendrine , Palisson Juliette , Bereaux Chloé , Dumurgier Julien , Paquet Claire , Degos Bertrand , Amar Elodie Bouaziz , Maillet Didier , Belin Catherine , Garcin Béatrice
Published: December 2020

Background

Assessment of cognitive functioning in illiterate patients is challenging because only few validated tests are available. The “test des neuf images ‐93” (TNI‐93) is a short test (5 to 10 minutes) based on nine black and white drawings, that was developed to assess episodic memory in this specific population (Maillet, 2016). Subjects are asked to learn the nine pictures using the principle of encoding specificity. It has been shown that the TNI‐93 is a suitable test to detect dementia in the elderly low educated population, but it remains unknown whether it is specifically altered in Alzheimer’s disease (AD). The objective of the present study was to examine the diagnostic value of the TNI 93 and its sub‐scores for the screening and diagnosis of biologically confirmed AD in patients explored for cognitive impairment.

Method

We retrospectively collected data of all patients seen in the memory center of Avicenne Hospital between January 2009 and November 2019 who underwent lumbar puncture, brain imaging, and neuropsychological assessment including the TNI 93. We classified patients into two groups: AD/ Non‐AD (NAD) according to the criteria AT(N) proposed by the working group "National Institute on Aging ‐ Alzheimer's Association”(Jack, 2018). We then compared scores at the TNI‐93 between AD and NAD patients.

Result

Among the 113 patients included, 52 presented with AD. Age (mean: 67.5 ± 10.1), gender (49.6% women), and education (mean: 9.2 ± 5.5 years) did not differ between both groups. On the TNI‐93, AD patients were significantly more impaired than NAD patients in immediate recall [mean AD: 5.5; mean NAD: 7; p=0.003], free recall [mean AD: 3.51; mean NAD: 4.78; p=0.018] and total recall [mean AD: 5.53; mean NAD: 6.93; p = 0.031]. In the AD group, there were more intrusions both during encoding (mean AD: 1.23; mean NAD: 0,67; p= 0.056) and restitution (mean AD: 1.22, mean NAD: 0.34; p=0.007).

Conclusion

The TNI 93 seems an interesting tool to discriminate between Alzheimer's disease and other causes of cognitive impairment notably in low educated population.
Detecting mild cognitive impairment by quantifying oculometric features during variable cognitive workload: The novel rapid Oculo‐Cognitive Addition Test
Authors: Hagen Kate , Pradhan Gaurav , Cevette Michael , Stepanek Jan
Published: December 2020

Background

The need exists for a device that can rapidly and accurately assess mild cognitive impairment (MCI). Because the link between oculometrics and cognition is well‐documented, the Oculo‐Cognitive Addition Test (OCAT) was developed which tracks users’ eye movements as they complete a simple mental addition test.

Method

OCAT consisted of 12 trials of summing three consecutive single‐digit numbers, shown separately on three consecutive screens (Figure 1). The first, second, and third screen in each trial corresponded to low, medium, and high cognitive workload. Using an infinity‐loop pattern of 24 symmetrical positions, eye movements were captured systematically in horizontal, vertical, and diagonal directions (Figure 2).

MCI was simulated by exposing subjects to 5 minutes of hypoxic gas mixture (8% O2 + balance N2). 20 subjects completed OCAT in baseline (i.e. normal room air), hypoxic, and post‐baseline (i.e. 20 minutes of room air) conditions. Raw scan‐paths were collected with an eye‐tracking device. Oculometrics pertaining to fixations and saccades were extracted. Statistical significance was assessed using repeated measures ANOVA. Effect size and clinical significance was evaluated using computed Cohen’s d.

Result

OCAT completion time significantly increased from baseline to hypoxia, which corresponded to a significant decrease in cerebral oxygenation from baseline to hypoxia (Figure 3). From baseline to hypoxia, saccadic latency significantly increased while saccadic velocity significantly decreased in the diagonal direction, however, results in the horizontal and vertical directions were not significant (Figure 4). Fixation time significantly increased from baseline to hypoxia in medium and high cognitive workload, but did not significantly change in low cognitive workload (Figure 5). From baseline to hypoxia, fixation size did not significantly change in any cognitive workload, however, the fluctuation in fixation size significantly increased in medium cognitive workload. From baseline to hypoxia, fixation area significantly increased in low and high cognitive workload, but did not significantly change in medium cognitive workload.

Conclusion

OCAT can detect subtle changes in oculometrics that correlate with MCI. This study provides rationale for providing varying degrees of cognitive load to elucidate subtle changes in oculometrics that may otherwise go undetected in neurocognitive tests that do not increase cognitive load.
FDG‐PET subtypes of Alzheimer’s disease and their association with distinct biomarker profiles and clinical trajectories
Authors: Levin Fedor , Ferreira Daniel , Lange Catharina , Dyrba Martin , Westman Eric , Buchert Ralph , Teipel Stefan J. , Grothe Michel J.
Published: December 2020

Background

PET with the glucose analog FDG is a sensitive marker of neuronal dysfunction/degeneration. The aim of this study was to identify distinct metabolic subtypes in prodromal and dementia stages of AD by a data‐driven exploration of FDG‐PET and to compare the subtypes with respect to molecular biomarkers and clinical trajectory.

Method

First, we used hierarchical clustering of voxel‐wise FDG‐PET from 177 biomarker‐confirmed AD dementia patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to identify distinct subtypes of hypometabolism in AD. The AD subtypes were then characterized with respect to clinical and molecular biomarker characteristics. Subsequently, we classified FDG‐PET scans of 217 amyloid‐positive MCI patients (‘prodromal AD’) according to the subtypes identified in AD patients, and examined their prognostic value for predicting domain‐specific cognitive decline and conversion to dementia over a follow‐up interval of up to 72 months.

Result

Four main AD subtypes characterized by differential hypometabolism patterns were identified (Fig. 1): (i) “AD‐typical” (48.6%), showing a classic posterior temporo‐parietal hypometabolic pattern with intermediate cognitive decline and biomarker characteristics, (ii) “minimal limbic” (24.9%), showing least impaired cognitive performance but comparable amyloid and tau biomarker profiles, (iii) “limbic‐frontal” (19.8%), characterized by old age and most severe hippocampal atrophy, and (iv) a “frontal” subtype (6.8%), characterized by younger age, more severe executive dysfunction, and least severe hippocampal atrophy. The subtypes observed in the prodromal AD sample demonstrated similar characteristics as in the AD dementia sample, and further showed differential courses of cognitive decline and progression to dementia. Specifically, the “AD‐typical” and the “limbic‐frontal” subtypes demonstrated a higher risk of progressing to AD dementia, as well as a faster decline of memory and executive function performance compared to the “minimal limbic” subtype.

Conclusion

Data‐driven clustering of FDG‐PET identified distinct hypometabolic subtypes in AD that were readily detectable at prodromal disease stages and associated with differential clinical courses and biomarker characteristics. The convergence of these hypometabolic subtypes with previously described MRI‐derived atrophy subtypes remains to be determined.
Impact of modulating gut bacteria using antibiotic, probiotic, and prebiotic interventions in the APPNL‐G‐F mouse model of Alzheimer disease
Authors: Kaur Harpreet , Nagamoto‐Combs Kumi , Combs Colin K.
Published: December 2020

Background

Alzheimer's disease (AD) is a multifactorial, neurodegenerative disorder and several factors are known to contribute to its etiology. Evidence suggests that AD may be associated with a dysbiosis of the intestinal microbiota but whether is it is a cause, or an effect is yet to be understood.

Method

In order to understand the effect of gut bacteria on the pathophysiology of AD, we used two approaches to manipulate gut bacteria in mice; probiotic and antibiotic therapies. Female wild type control C57BL/6 mice were compared to a mouse line that has the human Aβ sequence knocked into the mouse APP gene along with three disease causing mutations (AppNL‐G‐F
). The animals at 2.5 months of age were randomly divided into five groups and three groups were treated with a cocktail of non‐absorbable antibiotics (ABX) in drinking water and two groups were given water only for 10 days. Following ABX treatment, animals were either given normal diet, a probiotic (VSL#3) containing diet, or a diet containing both probiotic and prebiotic for 2 months. Upon completion, learning and memory was assessed along with brain Aβ and cytokines levels. GFAP and Iba‐1 immunohistochemistry was performed on brain sections.

Result

AppNL‐G‐F
mice showed a significant deficit in memory performance compared to controls. An increase in pro‐inflammatory cytokines and Aβ along with increased GFAP and Iba‐1 immunoreactivity was observed in AppNL‐G‐F
brains. No change was observed in intestinal permeability across all groups. Two months of probiotic supplementation improved memory and decreased plaque load in AppNL‐G‐F
mice. Consistent with this, probiotic feeding attenuated GFAP and Iba‐1 immunoreactivity in AppNL‐G‐F
brains. On other hand, antibiotic treatment alone or in combination with probiotic/prebiotics appeared to increase microgliosis and astrogliosis in AppNL‐G‐F
brains.

Conclusion

These results demonstrate that transiently depleting gut bacteria with antibiotic treatment has a long‐term effect on worsening AD‐associated parameters in AppNL‐G‐F
brains. On the other hand, modulating gut bacteria using probiotic feeding decreases plaque load and gliosis. This data suggests that gut microbiota modulate host brains and probiotics might be useful as supplementary therapy in AD.
Assessing functional disability in individuals with MCI and dementia
Authors: Umucu Emre , Wyman Mary F , Lee Beatrice , Zuelsdorff Megan , Lambrou Nickolas H , Johnson Adrienne L , Bouges Shenikqua , James Taryn T , Salazar Hector , Simó Carola A Ferrer , Carter Fabu P , Asthana Sanjay , Gleason Carey E
Published: December 2020

Background

Mild cognitive impairment (MCI) and dementia are among the most disabling conditions. Patients with MCI and dementia may experience difficulties in executing instrumental activities of daily living (IADL), resulting in distress for patients and families. Measuring and understanding abilities to execute IADL is important to understand how MCI and dementia impacts patients’ functioning. We explored the factor structure of the Functional Activities Questionnaire as a measure of functional disability in a sample with MCI and dementia.

Methods

Participants were 198 enrollees in the Wisconsin ADRC who had MCI, and dementia. Not applicable responses were counted as missing data, resulting in 98 participants in main analyses. The majority of participants were male (61.1%) and Caucasian (88.4%). Average age at baseline was 73.76 (SD=8.90). We conducted the following analysis: exploratory factor analysis (EFA), reliability analysis, correlation analysis, and Mann‐Whitney U test.

Results

The Kaiser–Meyer–Olkin (KMO) measure of sampling adequacy was .89, and the Barlett’s test of sphericity was significant, χ
2(45,N=98)=717.24, p<.001, indicating suitability for factor analysis. Kaiser–Guttman’s criterion and Cattell’s scree test both indicated a single‐factor measurement structure, accounting for 64% of the total variance. The Cronbach’s alpha was found to be .94 for the FAQ. Functional disability was positively correlated with neuropsychiatric symptoms (r=.43, p<.001), CDR global score (r=.79, p<.001), and lack of independence (r=.66, p<.001). A Mann‐Whitney U test showed that individuals with dementia had significantly higher levels of functional disability than those with MCI (U=214.00, p<.001).

Conclusion

The FAQ was found to be a unidimensional, reliable, and valid measure of functional disability. Participants with higher scores on the FAQ endorsed greater levels of neuropsychiatric symptoms, symptoms of cognitive impairment, and dependence to others. As expected, those with dementia had higher levels of functional disability/limitations. Future research may examine whether functional disability/limitations predicts incident MCI or dementia in cognitively normal individuals.
An analysis of driving characteristics and awareness by older adult mild cognitive impairment drivers
Authors: Suzuki Mio
Published: December 2020

Background

In Japan, the Traffic Act was revised that Alzheimer drivers prohibited to drive. However, there is no clear relationship between dementia and driving skills. So in this study, we conducted a driving experiment for dementia, mild cognitive impairment, and normal drivers over 65 years old, and compared their driving skills and their awareness.

Method

I observed driving characteristics on a training course, a car driving school. At first, I analyzed the relationship among scores of screening tests, their driving customs and driving behavior. Secondly, I also observed 7 MCI drivers’ driving behavior on open roads with driving recorders, and compared the driving behavior between at the driving school and the open roads.

Result

Driving behavior of intersections or parking were not different significantly, but the one of lane change and obstacle avoidance on midblocks was different between MCI and normal drivers significantly. On the other hand, the almost all older adult drivers couldn’t behave safely at intersections. Moreover, the surrounding environment, for example, families or friends, affected to the will to continue driving for MCI drivers.

Conclusion

Both of MCI or non‐MCI drivers are needed to check their driving skill. And support system should be developed for communication on driving (turn signals, etc.).
Assessment of a novel tau propagation pathway from layer II medial entorhinal cortical neurons to CA1 pyramidal neurons as an early BRAAK stage mouse model
Authors: Delpech Jean Christophe , Pathak Dhruba , Kalava Srinidhi V. , Iwahara Naotoshi , Varghese Merina , Hof Patrick R. , Medalla Maria , Ikezu Seiko , Luebke Jennfier , Ikezu Tsuneya
Published: December 2020

Background

Tau pathology correlates with cognitive impairment and is thought to propagate along neuroanatomical pathways. Tau accumulation is first observed in layer II of the entorhinal cortex (ECII), and then in CA1/2 of the hippocampus. The mechanism and nature of this propagation remains unclear and at present, no animal model recapitulates predominant tau propagation from ECII to CA1. Wolframin‐1‐immunoreactive (Wfs1+) neurons in the mouse ECII project to CA1 pyramidal neurons directly, or indirectly via interneurons in the S. lacunosum‐moleculare. We hypothesized that ECII Wfs1+ neurons mediate tau propagation to the CA1 pyramidal cells, making our model relevant for mimicking early stages of tau pathology in Alzheimer’s disease (AD).

Method

To specifically express mutant tau in Wfs1+ neurons, Wfs1‐Cre mice at 4‐6 months of age were injected with Cre‐inducible AAV2/6‐Flex‐P301Ltau expressing human P301L tau mutant or AAV2/6‐Flex‐Tdtomato in ECII, and euthanized at 4 weeks post‐injection for immunohistochemistry, electrophysiology and electron microscopy. To label and trace ECII‐CA1 connections, AAV9‐hSyn‐FLEX‐TVA‐P2A‐GFP‐2A‐oG and EnvA‐G‐deleted Rabies‐mCherry were injected into the CA1 pyramidal cells. The functional effects of tau on these connections were assessed by the multielectrode array to evaluate light‐evoked CA1 neuronal firing responses after the optogenetic stimulation of Wfs1+ ECII axons and also by measuring chemogenetic activation of CA1 pyramidal cells.

Result

Wfs1‐Cre mice injected in ECII with AAV2/6‐Flex‐P301Ltau exhibited significant human tau+ cells in the CA1 but not dentate gyrus at 4 weeks post‐injection. Monosynaptic tracing and electron microscopy revealed a direct synaptic connection between ECII Wfs1+ axons and CA1 pyramidal dendrites, and confirmed the presence of human tau in the pre‐ and post‐synaptic elements. Whole cell patch clamp recordings of CA1 pyramidal cells demonstrated reduction in measures of excitability. Optogenetic stimulation of Wfs1+ axons in the hippocampus coupled with multielectrode array‐recordings revealed a reduction in CA1 neuronal firing to light stimulation after AAV2/6‐Flex‐P301Ltau injection. Chemogenetic activation of CA1 neurons showed a reduction in c‐fos+ cells in CA1 after AAV2/6‐Flex‐P301Ltau injection compared to AAV2/6‐Flex‐Tdtomato controls.

Conclusion

Expression of P301Ltau in Wfs1+ neurons in the ECII induces the spread of human tau specifically to CA1 pyramidal neurons, which as a consequence exhibit several measures of neurophysiological impairment.
An ethnomusicologist's perspective: A potential experimental model to revive long‐term memories of the Alzheimer's patient through individualized music and the amygdala pathway
Authors: Pillay Jayendran
Published: December 2020

Background

Since a significant symptom of Alzheimer's is memory loss caused through the aggregation of beta‐amyloid, the ethnomusicologist is in a unique position to potentially recover some long‐term memories by developing the personalized music history one patient at a time. The idea is to bypass the amyloid aggregates, accessing the amygdala, therefore using the patient's emotions to recover their memories through their own music and their associative strengths. A song or a strain of music can transport anybody in the world with the functional hearing ability to a place in time retrieving those memories. Instead of sedating a patient, their own music may be better. My case study involved one individual diagnosed with dementia. Being familiar with the patient for a few decades, I pieced together her music history which I treated as a part of her medical history since the music memory resides in the brain. Her cognition and joy increased significantly over the year, according to her and her family. I videotaped some sessions. More research is needed to establish whether my method of individualized music history and memory recollection increases the quality of life of the patient or not. For further research, I propose inviting an ethnomusicologist to build a music profile of a number of Alzheimer's patients the neurologists are treating at a clinic. The music profile will include a playlist of songs or instrumental music that transports the patient to particular memories. The sound database could also include non‐musical sounds that generate memories e.g. the sounds of a drill, a barking dog, etc.. To access the patients’ memories the ethnomusicologist would need to do extensive interviews with the patients, family members, and friends, and look at their music collections. The process of building a music profile of the Alzheimer’s patient for treatment by a neurologist can, therefore, be done globally where the ethnomusicologist teams up with the medical staff.
Three types of white matter hyperintensities have different effects on depression and cognitive function in patients with CADASIL
Authors: Park Joon Hyuk , Lee Jungseok , Yang Hyun‐Ju , Lee Subin , Kim Ki Woong
Published: December 2020

Background

White matter hyperintensities (WMH) according to the distance to the ventricle have been associated with different clinical, histopathological, and etiological correlates, which may provide the clues for understanding pathophysiology of many geriatric syndromes associated with WMH. The purpose of this study was to investigate the effects of WMH on depression and cognitive function in patients with CADASIL according to the locations of WMH.

Method

84 subjects with CADASIL, aged 34–86 years, participated in this study. They underwent comprehensive clinical evaluation, including 3T MRI and genotyping of NOTCH3. With new subclassification of WMH (Kim, 2008), WMH were subclassified into juxtaventricular WMH (JVWMH), periventricular WMH (PVWMH), and deep WMH (DWMH) according to the distance to the ventricle. Lesions were segmented by the lesion prediction algorithm (Schmidt, 2017, Chapter 6.1) as implemented in the LST toolbox version 3.0.0 (www.statistical‐modelling.de/lst.html) for SPM. WMH volume was corrected as a ratio of the WMH volume to total intracranial volume.

Result

Using linear regression model after controlling for age, only JVWMH volume was associated with the scores of geriatric depression scale (GDS) (p=0.027) and CES‐D (p=0.041) among 3 types of WMH. There were no association trends between DWMH volume and scores of GDS (p=0.641) and CES‐D (p=0.427). After controlling age, education and sex, JVMMH volume was associated with poor performances in Categorical Verbal Fluency Test (cVFT) (P=0.013), 15‐item Boston Naming Test (sBNT) (P=0.020), Word List Memory Test (WLMT) (P=0.006), Word List Recall Test (WLRT) (P=0.010), Constructional Recall Test (CRT) (P=0.012), and Trail Making Test A and B (TMT‐A and TMT‐B) (p=0.003, p=0.004). PVWMH volume was associated with poor performances with in cVFT (P=0.027) and WLMT (P=0.031). DWMH volume had no associations with the scores of CERAD neuropsychological tests.

Conclusion

JVWMH are closely associated with depression and various domains of cognitive function. However, DWMH have no association with both depression and cognitive decline. 3 Types of WMH have different effects on depression and cognitive function in patients with CADASIL.
Functional connectome vulnerability to Alzheimer’s disease in alcohol use disorder: A preliminary study
Authors: Joseph Jane E , Flanagan Julianne , Nowling Duncan , Vaughan Brandon , Warner Graham , Lohnes Laura , Ross‐Simmons Shaquanda , Mintzer Jacobo , Dean Brian , Lawson Andrew , Back Sudie , Jensen Jens H. , Benitez Andreana
Published: December 2020

Background

Alcohol Use Disorder (AUD) is a risk factor for Alzheimer’s Disease (AD) and other dementias. Despite the emerging association between AUD and AD, there is a paucity of data available from mid‐life age ranges (e.g., 45 to 65 years) to assess AUD‐related risk for AD that might be present early in the disease trajectory.

Method

Functional connectome measures (graph‐theory) were calculated from resting state fMRI scans in 118 healthy controls (HC), 25 subjects with AUD (45‐61 years of age), and 51 subjects with amnestic mild cognitive impairment (aMCI) or AD. Following dimension reduction of 282 network nodes into 10 components using principal components analysis, predictive modeling with best subsets was used to isolate network components that predicted age in HC. Network components that significantly predicted age in HC were further examined to determine whether the AUD group exhibited premature brain aging or showed similar pathologic profiles as AD/aMCI.

Result

Predictive modeling with eigenvector centrality as a predictor of age yielded significant models (p’s < .0001). A network component including occipital and frontal pole nodes was a significant predictor in all models. In the frontal pole, AUD age trajectories showed a baseline shift relative to age‐matched HC subjects (49‐61 years of age), indicating premature brain aging. However, these age trends were not significantly different when Fisher z‐transformations of age trends were compared with a t‐test (p = .5). Nevertheless, the ANOVA revealed a significant main effect of group (AUD, HC, aMCI; p < .0001): average eigenvector centrality of the frontal pole in AUD was significantly lower than in HC (p = 0.0001) and indistinguishable from that of AD/aMCI subjects (p = 1.0), according to Bonferroni post‐hoc tests.

Conclusion

Premature brain aging in AUD may reflect vulnerability to AD‐like neurodegenerative processes that are manifest at the level of large‐scale network connectivity. Some data used in preparation of this abstract were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.
Proteomics identifies CSF biomarker panels reflective of pathological networks in the Alzheimer's disease brain
Authors: Higginbotham Lenora A , Ping Lingyan , Dammer Eric B , Duong Duc , Zhou Maotian , Gearing Marla , Johnson Erik CB , Hajjar Ihab , Lah James J , Levey Allan I , Seyfried Nicholas T
Published: December 2020

Background

The repeated failures of amyloid‐targeting therapies have underscored the need for additional biomarkers of Alzheimer’s disease (AD) that reflect its complex multi‐network dysfunction. Using a network‐based proteomic approach, we previously defined a wide range of protein system alterations in the AD brain. In this study, we integrated these brain networks with proteomic analysis of cerebrospinal fluid (CSF), resulting in the identification of CSF biomarker panels reflective of diverse pathophysiology within the AD brain.

Methods

Using quantitative liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS), we comparatively analyzed the CSF proteomes of 40 samples (20 controls, 20 AD). Differential expression analysis resolved CSF proteins significantly altered in AD. These CSF biomarkers were mapped to proteomic networks derived from 48 postmortem brain tissues comprising control, asymptomatic AD (AsymAD), AD, and other neurodegenerative diseases. Validation was performed in an independent CSF cohort of 96 control, AsymAD, and AD samples using high‐throughput proteomic methods.

Results

We identified >3,500 proteins across the initial 40 CSF samples and >12,000 proteins across the 48 postmortem brain tissues. Co‐expression network analysis of the brain tissues yielded 44 protein modules, nearly half of which correlated significantly to AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain‐linked fluid markers representing a variety of cortical functions. Neuron‐enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial‐enriched myelination and immunity panels were highly increased in both the brain and CSF. Validation of these findings in an independent CSF cohort of control, AsymAD, and AD samples remarkably demonstrated panel alterations in the early, asymptomatic stages of disease. In fact, several panel markers appeared to stratify subpopulations within this preclinical cohort.

Conclusion

These brain‐linked CSF biomarker panels represent a promising step toward a comprehensive physiological tool that could enhance the therapeutic management of AD.
Effect of apolipoprotein‐E Ε4 genotype on amyloid‐β and tau accumulation in Alzheimer’s disease
Authors: Baek Min Seok , Cho Hanna , Lee Jae Hoon , Ryu Young Hoon , Lyoo Chul Hyoung
Published: December 2020

Background

We investigated effects of apolipoprotein E (ApoE) ε4 genotype on Aβ and tau burden and their longitudinal changes in Alzheimer’s disease spectrum.

Method

Among 272 individuals who underwent PET scans (18F‐florbetaben for Aβ and 18F‐flortaucipir for tau), and ApoE genotyping, 187 individuals completed 2‐year follow up PET scans. After correcting for partial‐volume effect, we compared the SUV ratio (SUVR) for Aβ and tau burden between ε4+ and ε4‐ groups. By using a linear mixed‐effect model, we measured the changes in SUVR in ApoE ε4+ and ε4‐ groups.

Result

ε4+ group showed greater baseline Aβ burden in diffuse cortical regions, and greater tau burden in lateral, and medial temporal, cingulate, and insula cortices. An annual accumulation rates of tau was higher in parietal, occipital, lateral and medial temporal cortices in ε4+ group. However, the accumulation of Aβ was not significantly different between ε4+ and ε4‐ groups. In Aβ+ individuals, baseline tau burden was higher in medial temporal cortex, while Aβ burden was conversely greater in ε4‐ group than ε4+ group in the global cortex, sensorimotor, and parietal cortices. Baseline Aβ burden showed decreasing trend and tau burden showed increasing trend associated with the number of ε4 alleles in dose‐dependent manner in Aβ+ individuals.

Conclusion

Progressive tau accumulation occurs in ε4 carriers in AD spectrum especially in medial and lateral temporal cortices. Existence of ε4 may modulate Aβ and tau burden differently based on the amount of existing amyloidosis.
The role of calbindin‐D28k in a mouse model of Down syndrome‐related Alzheimer's disease
Authors: Hamlett Eric D. , Carroll Steven L. , Granholm Ann‐Charlotte
Published: December 2020

Background

Calbindin‐D28k (CB) is a calcium‐binding/buffering protein that plays critical roles in preventing neuronal death as well as maintaining calcium homeostasis. Marked reductions in neuronal CB expression have been previously observed in individuals suffering from Alzheimer’s disease (AD) and recently observed in individuals with Down syndrome (DS) who develop early‐onset AD in the mid‐40s. The Ts65Dn mouse model of DS develops neurodegenerative patterns in the basal forebrain, the locus coeruleus and in the hippocampal perforant path. We hypothesized that neuronal expression of the mouse CB‐homologue, calbindin 1, may also be reduced in Ts65Dn mice and associated with cognitive deficits and neurodegeneration.

Method

Male Ts65Dn mice (n = 24) and euploid control mice (n = 26) were obtained from Jackson Laboratory (Bar Harbor, ME). Mouse cohorts were either 4‐5 months of age (pre‐neurodegeneration) or 8‐10 months of age (post‐neurodegeneration). A behavioral battery was administered to quantify spontaneous activity (SA), novel object recognition(NORT), and spatial memory (WRAM). We performed immunostaining and immunoblotting of the CB‐homologue (calbindin 1) in cortical areas and in the hippocampal formation. performed two‐way ANOVAs to test for differences between the groups (karyotype x treatment), followed by Tukey’s post hoc analyses. Correlations and linear regressions were performed between calbindin 1 and cognitive performance measures. All statistical tests were performed with GraphPad Prism 7.03 (GraphPad Software, La Jolla, CA).

Result

In the adult hippocampus and in cortical areas, calbindin 1 expression was observed in specific principal neurons and subsets of interneurons for all mice. Ts65Dn mice were found to have significant reductions (15‐30% ) of calbindin 1 at 4 months of age. However, loss of calbindin 1‐positive principal neurons in the CA1 was more prominent at 8‐10 months of age in Ts65Dn mice. Calbindin 1 expression in the hippocampus and parietal cortex (but not frontal cortex) significantly correlated with SA and WRAM. Linear regression confirmed the goodness of fit and non‐deviation from linearity for all correlations.

Conclusion

Early calbindin 1 depletion contributes to neuronal deficits and cognitive dysfunction in the Ts65Dn mouse model of DS mouse models. These results may be highly translatable to DS‐AD, where a similar CB phenotype also occurs.
PSEN1 M139L mutation in a Chinese pedigree with early‐onset familial Alzheimer's disease
Authors: Li Runzhi , Xu Jun , Suen Mengfan
Published: December 2020

Background

presenilin 1(PSEN1) is the most common gene associated with familial Alzheimer's disease. we reported a case with M139L mutation of PSEN1 which was reported as pathogenic mutation in February 2019.

Method

chose an early‐onset Alzheimer's patient (proband) and her family (I‐V generation) as the research object. clinical and imaging data of the proband and her family members were collected. High throughput second generation exon sequencing and sanger method was used to analyze the gene of the proband.

Result

1. Proband clinical characteristic: The proband (IV8) started to progressive memory loss, especially short‐term memory at 38 years old. She can't work because of memory problem. Now she lives on her own, can use mobile phone and APP, drive, remember familiar roads, but cannot shop, take bus to new place, handle own finances. The MMSE score was 27/30, and the MOCA score was 20/30 (delayed recall, time orientation, visuospatial disfunction, calculation) (Figure 1). Brain Magnetic Resonance Imaging suggested hippocampal atrophy (Figure 2). 2. Family phenotypic distribution (Figure 3): The onset age of Alzheimer's disease in this family was early, starting between 38 and 55 years old. The first and prominent clinical manifestations were memory loss, followed by orientation and executive function impairment. Movement disorder appears later or does not appear. It may have mild anxiety or depression. 3. Gene results (Figure 4): a heterozygotic mutation was found in the exon region of the PSEN1 gene: c.415A>T (adenine > thymine), resulting in an amino acid change of p.139l (methionine > leucine).

Conclusion

We reported the early onset familial Alzheimer's disease caused by M139L mutation of PSEN1 in Han Chinese family which was helpful to enrich the clinical phenotypic characteristics of early onset familial Alzheimer's disease associated with PSEN1 mutation.
The relationship between VEGF and cerebral vascular territory glucose metabolism is modified by cardiovascular risk in Alzheimer's disease
Authors: Tubi Meral A , Matsiyevskiy Elizabeth , Hapenney Matthew N , Riedel Brandalyn C , Mack Wendy J , King Kevin , Thompson Paul M , Braskie Meredith N
Published: December 2020

Background

Vascular endothelial growth factor (VEGF) regulates angiogenesis, neurogenesis, and glucose transport. Cardiovascular risk factors promote atherosclerosis and disrupt vascular integrity, possibly interfering with VEGF function. Variability in cardiovascular dysfunction severity may explain an inconsistent neuroprotective effect of VEGF across Alzheimer’s disease (AD) studies. Atherosclerosis in the middle and posterior cerebral arteries is associated with AD. We hypothesize that a higher Framingham Risk Score (FRS), a proxy for atherosclerosis severity, will moderate the association between VEGF and glucose metabolism in brain regions supplied by the MCA and PCA.

Method

In 158 participants (age: 55‐90 years; 39 normal, 80 MCI, 39 AD; 105M/53F) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we evaluated whether CSF VEGF levels were associated with bilateral glucose metabolism (FDG‐PET) in gray matter vascular territories supplied by the anterior (ACA), middle (MCA), and posterior cerebral arteries (PCA), each defined by the vascular territory MNI template (Figure‐1, Figure‐2). We evaluated whether FRS modified the regional relationship between VEGF (Figure‐3) and FDG‐PET across all participants and within each diagnostic group. We used a mixed effects linear regression model (covarying for age, sex, education, APOE4 carrier status, CSF T‐tau, and diagnosis; random effect=site). All p‐values presented are false discovery rate (FDR) corrected at FDR <5%.

Result

Higher VEGF was associated with higher FDG‐PET MCA‐SUVR (β=0.170, p=0.043), nominally associated with higher PCA‐SUVR (β=0.129, p=0.078), and not associated with ACA‐SUVR (β=0.092, p=0.244). In all participants, FRS nominally modified the association between VEGF and ACA‐SUVR (VEGF‐FRS interaction β=‐0.040, p=0.066) and MCA‐SUVR (VEGF‐FRS interaction β=‐0.032, p=0.066). In MCI participants alone, FRS significantly modified the association between VEGF and both ACA‐SUVR (VEGF‐FRS interaction β=‐0.078, p=0.014) and MCA‐SUVR (VEGF‐FRS interaction β=‐0.068, p=0.014).

Conclusion

The region‐specific negative interaction of FRS with CSF VEGF suggests that higher VEGF levels were associated with greater MCA territory glucose metabolism in persons with lower FRS. Greater cardiovascular dysfunction may dampen VEGF’s neuroprotective effects, particularly in MCA‐supplied brain regions and in populations at risk for AD.