bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross‐omics studies of the role of apolipoprotein E in Alzheimer’s disease and dementia: Searching common pathways in patients, populations and cellular models
Authors: van Duijn Cornelia M. , Ahmad Shahzad , Sáez María Eugenia , Bennett Keiryn , Socorro Alfredo Cabrera , Bakker Margot H.M. , Ramirez Alfredo , Ruiz Agustín , Hankemeier Thomas
Published: December 2020

Background

Genetic and transcriptomic studies in patients and cellular models are converging on a key role for lipids and the immune system. ADAPTED aimed to develop a comprehensive atlas of changes in metabolic and protein pathways in the blood and brain and determine whether these are driven by the apolipoprotein E gene (APOE). We conducted cross‐omics studies in human populations and integrated the findings with that of isogenic APOE ε2/ε2, APOE ε3/ε3, and APOE ε4/ε4 cell lines.

Method

Human studies were embedded in the Rotterdam Study and prospective studies of patients with mild cognitive impairment (MCI) in memory clinics of Fundació ACE and the Central Institute of Mental Health (Mannheim). State‐of‐the‐art RNA‐sequencing, proteomics and metabolomics were used to characterize changes in blood and cerebrospinal fluid (CSF). Metabolomics included comprehensive analysis of cholesterol subfractions, signalling lipids including lysophosphatic acids (LPA), amino acids and proteins using NMR and LC‐MS/MS. Proteomics studies are based on high‐multiplex immunoassays and LC‐MS/MS.

Results

In blood, we identified a broad spectrum of metabolites associated with risk of AD, including HDL‐subfractions, DHA, amino acids and glycoproteins. We found systemic changes in the levels of metabolites in circulation are driven by APOE in concert with other genes implicated in AD. In blood, we found a weak correlation between LPA levels and risk of AD. However, LPA levels in CSF strongly associated with amyloid, phosphorylated and total tau, with APOE driving the profiles. LPA 16:0 and 16:1 CSF levels were associated with MCI to AD conversion. Our proteomic studies show a large number of proteins associated with amyloid, phosphorylated and total tau levels in CSF of MCI patients. However, in blood we also discovered two proteins associated with future risk of dementia: CDH6 and Hagh. Integrating the findings with RNA sequence data in iPSC based cellular models showed that CDH6 is differentially expressed across APOE genotypes in isogenic neurons but not in macrophages.

Conclusions

We show a wide range of metabolic and proteomic changes that may be relevant for the development and course of AD. The findings show the potential of cross omics‐research connecting findings in human populations and cellular models.
Hypersynchronization, a common feature along the AD process
Authors: Maestú Fernando ,   Center for Biomedical Technology
Published: December 2020

Background

In the last decade there are more and more literature indicating that subjects at different stages of Alzheimer´s Disease (AD) continuum, have a disrupted organization of their anatomo‐functional networks. Neurophysiological findings with MEG have indicated an increased brain synchrony between different brain regions across different stages of the disease. In this talk we will concentrate on these neurophysiological findings in humans comparing magnetoencephalography (MEG) findings with clinical and current biomarkers

Method

In a series of studies using magnetoencephalography, we have recorded resting state activity in patients with Mild Cognitive Impairment (MCI), Subjective Cognitive Decline (SCD) and in healthy subjects at preclinical stage or at risk for developing dementia. We used functional connectivity in the source space to assess how the brain oscillatory activity synchronize across brain regions. MEG findings will be compared with clinical stages, amyloid‐PET, cerebrospinal fluid (p‐tau), or brain atrophy.

Result

MCI patients and SCD participants showed an increased functional connectivity values in anterior regions of the brain in the alpha band. This was in combination with a posterior hyposynchronization which was slightly higher in MCI patients compared to SCD. MCI patients who did convert to dementia showed hypersynchronization between anterior cingulate cortex and posterior regions in the alpha band. A second MEG scan on MCI converters (when they were at the dementia stage) showed a decrease in brain synchrony in a similar region, indicating that hypersynchrony accelerate the process of network dysfunction (the “X Model”). These profiles of brain synchrony were evaluated in comparison with biomarkers. MCI patients with elevated p‐tau in the CSF showed again increased synchronization between anterior cingulate and the medial temporal lobe. Healthy subjects (no memory complaints, no brain atrophy, no hypometabolism) with a positive amyloid PET showed as well increased brain synchrony. Finally, young relatives of AD patients showed increased phase synchrony in similar brain regions than that found in MCI patients in the alpha band.

Conclusion

All these findings together indicate that hypersynchronization of the brain networks could be an excellent non‐invasive biomarker for tracking the disease and evaluate interventions.
Subjective cognitive impairment differs by racial/ethnic groups and sociodemographic factors: The Multi‐Ethnic Study of Atherosclerosis and Alzheimer’s Disease (MESA‐MIND)
Authors: Hughes Timothy M. , Winkey Khadijah , Sachs Bonnie C. , Fitzpatrick Annette L. , Craft Suzanne , Baker Laura D. , Heckbert Susan , Jacobs David R. , Rapp Stephen R. , Hayden Kathleen M. , Caban‐Holt Allison M.
Published: December 2020

Background

Subjective cognitive decline (SCD) is associated with objective cognitive decline, incident cognitive impairment, and AD pathology in mostly white populations. Little data are available to describe SCD and objective cognitive impairment in diverse populations.

Method

The Multi‐Ethnic Study of Atherosclerosis (MESA) began cognitive testing, including the Cognitive Abilities Screening Instrument (CASI), in 2010‐12 among four racial/ethnic groups: 38% white, 28% African‐American, 22% Hispanic, and 12% Chinese Americans across six field centers. MESA‐MIND and ancillary studies added repeated CASI by in‐person exam (2016‐2018) and the 12‐item Cognitive Change Index (CCI‐12) during the 2018 annual follow‐up call. Statistical analyses using the CCI‐12 item sum and two published thresholds (CCI‐12≥16 and CCI‐12≥23) established the point prevalence for SCD across racial/ethnic groups. Socio‐demographic factors were examined using multivariable logistic regression. Spearman correlations and general linear models related 5‐year subjective change (CCI‐12) and objective change in cognitive performance (change in CASI) over the same time period.

Result

CCI‐12 data were available on 3,676 MESA participants (aged 60‐95) across all racial/ethnic groups and sites. Table 1 presents demographics, CCI‐12 scores, and CASI scores. The prevalence of SCD (CCI‐12≥16) across racial/ethnic groups ranged between 52% to 72%. There was a lower prevalence in African‐American and white and a higher prevalence in Chinese and Hispanic participants. In adjusted models, various socio‐demographic factors were significantly associated with a higher odds of reporting SCD (CCI‐12≥16), including: older age, female gender, Chinese language preference, diabetes, smoking, birth in the Western US or Mexico, and lacking health insurance coverage. African‐American ethnicity, higher education, and income greater than $75,000 were each associated with a lower reporting of SCD. CCI‐12 was weakly and inversely correlated with antecedent cognitive performance (2010‐12, n=3,200, Rho=‐0.16, p<0.01) and cognitive decline (n=1,800, Rho=‐0.06, p=0.01) over 6 years of follow‐up. In stratified analyses, associations between CCI‐12 and objective cognitive decline were observed in white participants only.

Conclusion

In a large regionally and ethnically diverse cohort of older adults, SCD defined by subjective memory concerns on the CCI‐12 significantly differed by race/ethnicity and indicators of socioeconomic status, suggesting that cultural and institutional biases may influence reporting SCD in diverse populations.
Differences in the characteristics, neuropsychiatric comorbidities, and psychometric features of subjective cognitive decline in Hispanics versus non‐Hispanic whites
Authors: Faustin Arline , Masurkar Arjun V.
Published: December 2020

Background

Subjective cognitive decline (SCD) is thought to be a prodromal stage of Alzheimer’s disease (AD), yet has been primarily studied in non‐Hispanic whites. This study aimed to understand the differences in SCD presentation between Hispanics (of any race) and non‐Hispanic whites.

Method

A cross‐sectional analysis was performed on participants seen at the NYU Alzheimer’s Disease Center with subjective cognitive decline and who identified as Hispanic (of any race, n=52) and non‐Hispanic white (n=265). Demographics, SCD characteristics, mood/behavioral symptoms, and performance on psychometrics tests were analyzed, with statistical analysis by t‐test, ANOVA, or Fisher’s exact test where appropriate.

Result

Hispanic participants with SCD were younger (64.3 vs. 68.2, p=0.0008) and had less education (14.3 vs. 17.6, p<0.0001). The Cognitive Change Index (CCI), a measure of SCD, did not distinguish the two groups (total CCI score nor amnestic and non‐amnestic subgroups). In contrast, on the Brief Cognitive Rating Scale (BCRS), another SCD metric, Hispanic participants showed increased severity in concentration (2.62 vs. 1.93), praxis (2.60 vs. 2.13) and calculation (2.96 vs. 2.10), all p<0.001. Study partner observations on the Neuropsychiatric Inventory‐Questionnaire (NPIQ) revealed an increased prevalence of depression (27% vs. 14%, p<0.001) and appetite changes (10% vs. 0%, p<0.0001) in Hispanic SCD participants. When self‐rated via the Geriatric Depression Scale, there were also notable differences in the quality of depression, with increased prevalence in Hispanics of dropping activities (33% vs. 6%), emptiness (19% vs. 3%), boredom (19% vs. 3%), fear (27% vs. 6%), preference to stay home (31% vs. 8%), and helplessness (15% vs. 4%), all p<0.01. On psychometric testing there were no differences in MoCA or MMSE scores. However, Hispanic participants showed lower performance on the Digit Symbol Substitution Test (DSST) (39.2 vs. 56.1, p<0.0001), which can be influenced by mood and has previously shown to be a marker of decline in SCD.

Conclusion

These findings support that the characteristics, neuropsychiatric comorbidities, and psychometric features of SCD are notably different between Hispanics and non‐Hispanic whites. In particular, depression in Hispanics warrants further study as a particularly significant variable in determining SCD conversion to AD.
“I just glove up and do what has to be done”: A mixed‐methods exploration of dementia care challenges and care management strategies
Authors: Leggett Amanda N , Connell Cathleen M , Gitlin Laura N , Kales Helen C
Published: December 2020

Background

Most family caregivers for persons living with dementia (PLwD) don’t receive training for their role and therefore adopt a variety of care management strategies, some of which may be harmful. The current study utilizes a mixed‐methods design to integrate family caregiver’s qualitative and quantitative descriptions of recent care challenges (e.g. cognitive, functional, and behavioral symptoms of dementia), and the strategies utilized to manage these symptoms.

Method

Participants included 100 primary family caregivers for PLwD who were 74% female, 18% non‐White, and on average 64 years old. Participants were interviewed qualitatively about their management of a recent care challenge and with the Caregiver Assessment of Function and Upset, Neuropsychiatric Symptom Inventory, Dementia Severity Rating Scale, and Dementia Management Strategies Scale (subscales: criticism, active management, encouragement). Care challenges and care management strategies are compared across qualitative analysis and T‐tests.

Result

The most common type of qualitatively reported care challenge was BPSD (45%) followed by symptoms of cognitive decline (18%). Quantitatively caregivers reported the most stressful ADL to be toileting and BPSD as aggression. Caregivers providing ADL/IADL care (r=.34, p<.01) and with PLwDs with more severe cognitive symptoms (r=.30, p<.01) had significantly higher use of active management care strategies, relative to caregivers not assisting with those tasks. In contrast, caregivers providing care for PLwDs with greater BPSD burden (r=.34, p<.001) and particularly challenging symptoms of aggression (t=‐.4.0, p<.001), agitation (t=‐3.4, p<.001), irritability (t=‐.2.4, p<.05) and hallucinations (t=‐2.3, p<.05) reported more use of criticism as a management strategy.

Conclusion

Mixed‐methods assessment of care challenges provides a more nuanced understanding of how caregivers manage care stressors. Active management or other straightforward assistive approaches may be required when the severity of dementia increases, yet critical strategies seem to emerge with greater severity of BPSD. Encouragement strategies, on the other hand, were independent of any care challenges and may be used to support the PLwD, not address an underlying symptom. As criticism tends to be associated with more negative care outcomes (burden, potentially harmful behavior), intervention approaches may help caregivers identify more adaptive responses to prepare for stressful challenges such as BPSD.
Defining the role of the Alzheimer disease risk factor CD2AP in brain vascular function
Authors: Vandal Milene , Gunn Colin , Bourassa Philippe , Institoris Adam , Shin Steven Seungjae , Jiang Yulan , Tremblay Cyntia , Belzil Camille , Bennett David A. , Gordon Grant , Calon Frederic , Nguyen Minh Dang
Published: December 2020

Background

Brain hypoperfusion is the earliest change observed in Alzheimer’s Disease (AD) brains. Degeneration of the brain vasculature, that includes cerebral amyloid pathology, white matter hyperintensities and cortical infracts, isomnipresent in AD, and predicts the progression of cognitive decline in AD patients. CD2‐associated protein (CD2AP) functions as scaffolding protein for cytoskeletal remodeling, membrane trafficking during clathrin‐mediated receptor endocytosis and cell‐cell interactions. Interestingly, polymorphisms in CD2AP constitute one of the top 10 genetic predisposition factor to AD. Since CD2AP is enriched in brain endothelial cells (BECs) that form the brain microvessels, we reason that the protein plays a key role in BECs and therefore, defects in CD2AP may contribute to cerebrovascular dysfunction observed in AD.

Method

We use a multidisciplinary approach (culture of primary BECs and cerebral arteries, two‐photon brain imaging of awake active mice and analysis of isolated brain microvessels from human AD volunteers) to investigate the role of CD2AP in BECs and brain vascular function.

Result

We found that 1) CD2AP regulates the Apolipoprotein E receptor 2 (ApoER2) in BECs, 2) the CD2AP/ApoER2 axis is key for brain vascular function in vitro and in vivo and 3) human AD volunteers have altered the levels of CD2AP and this alteration is associated with cognitive dysfunction.

Conclusion

We propose that the deregulation of the ApoER2/CD2AP axis contributes to the vascular defects observed in AD.
Age‐related resident memory CD8 T cells link amyloid to NFTs and neurodegeneration in mice and are modulated in AD and MCI blood
Authors: Wheeler Christopher J. , Panwar Akanksha , Rentsendorj Altan , Cordner Ryan , Yeager Nicole , Jin Lee‐Way , Koronyo Yosef , Koronyo‐Hamaoui Maya , Black Keith L. , Van Dam Debby , De Deyn Peter Paul , Yamamoto Vicky , Trujillo Kristina
Published: December 2020

Background

While autosomal dominant mutations that promote amyloid deposition guarantee rare genetically‐determined Alzheimer’s disease (AD), discrete factors promoting more prominent sporadic AD have not been identified. Evidence from mice, and more recently from a patient resistant to autosomal dominant AD, suggests that an age‐sensitive factor missing from mice links amyloid deposition to NFTs and neurodegeneration in AD, and is critical for AD development. We previously engineered mice that possess human‐like predominance of an age‐related resident memory CD8 T cell population (hiTRM mice), and exhibit antigen‐specific CD8 T cell accumulation in brain, as well as sporadic amyloid deposition linked to NFT‐like structures and neurodegeneration.

Method

We used CD8 T cell antigen specificity within the hiTRM model to generate pHLA reagents that identify analogous antigen‐specific memory CD8 T cells in humans, and used them to quantify their levels in blood and/or brain of HLA‐A2+, normal aging, MCI with or without AD biomarkers (AD‐associated and non‐associated MCI, respectively), and confirmed late‐onset AD cohorts. Cognitive performance was also assessed using the MoCA test in sub‐cohorts of MCI patients.

Result

We show that antigen‐specific hiTRM analogues were increased in perivascular and cortical regions of human AD relative to normal aging brain (13 vs. 3%; P < 0.01), but decreased in blood of AD‐associated MCI and late‐onset AD patients (1.3 and 0.7%, respectively; 3.4% in normal controls; P < 0.00009), and correlated with cognitive impairment in MCI (r = 0.828; P < 0.005). Receiver operating characteristic (ROC) analysis of levels of these analogues in blood revealed area under the curve (AOC) of 0.715, 0.803, and 0.862 for non‐associated, AD‐associated, and AD, respectively.

Conclusion

Our results identify antigen‐specific memory CD8 T cells, a factor critically linking amyloidopathy to NFTs and which dominantly promote the development of AD‐like neurodegeneration in mice, as unique blood‐based biomarkers that accurately track the AD continuum in patients. As such, these cells may play a similar role in AD pathoetiology in mice and sporadic human AD. These cells thus represent novel biometric and therapeutic candidates for sporadic AD.
Red blood cell α‐synuclein heteroaggregates can discriminate healthy controls from cognitively impaired subjects of the AD‐LBD spectrum
Authors: Giampietri Linda , Daniele Simona , Piccarducci Rebecca , Palermo Giovanni , Manca Maria Laura , Nicoletti Valentina , Giorgi Filippo Sean , Frosini Daniela , Petrozzi Lucia , Gerfo Annalisa Lo , Pietrobono Deborah , Cavallini Chiara , Franzoni Ferdinando , Trincavelli Maria Letizia , Bonuccelli Ubaldo , Siciliano Gabriele , Tognoni Gloria , Ceravolo Roberto , Baldacci Filippo , Martini Claudia
Published: December 2020

Background

α‐synuclein’s (α‐syn) pathological accumulation is involved in the development of Lewy body dementias (LBDs), namely Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). Several autoptic series have nonetheless documented pathologic α‐syn deposits up to 30% cases of otherwise confirmed Alzheimers’s disease (AD) brains. A considerable body of evidence supports the mutual pathological interaction between α‐syn and AD’s hallmark altered proteins, namely beta‐amyloid and tau, both in AD and LBDs. Aim of this study was to explore the diagnostic potential of red blood cells (RBCs) levels of α‐syn, beta‐amyloid 1‐42 (Aβ1‐42), total‐tau (t‐tau), and their heteromers in subjects with LBDs, AD, and healthy controls (HCs).

Method

Total α‐syn, Aβ1‐42, t‐tau, α‐syn/Aβ1‐42, α‐syn/tau concentrations in RBCs were determined by means of an “in‐house” immunoenzimatic assay, and confronted in AD subjects (either AD Dementia or Prodromal‐AD, N=51), LDB subjects (either DLB or PDD, N=27), and HCs (N=60). Then, the diagnostic potential of each significant biomarker was examined calculating the area under the receiver operating characteristic curve (AUROC).

Result

Compared to HCs, both AD and LBD subjects had significantly lower levels of t‐tau (4.25±4.99 and 3.19±5.13 ng/mg respectively, vs 8.43±11.52 ng/mg of HC) and α‐syn (16.46±15.85 and 15.31±18.30 ng/mg respectively, vs 39.62±57.19 ng/mg of HC) concentrations, as well α‐syn/tau heterodimers (1.04±1.54 and 0.86±0.10 ng/mg respectively, vs 2.36±1.87 ng/mg of HC), while only AD subjects showed significantly reduced levels of α‐syn/Aβ1‐42 (1.91±1.91 ng/mg vs 3.80±3.32 ng/mg in HC). Regarding t‐tau diagnostic accuracy, it turned out to be fair in differentiating LBD patients from HCs, and just poor in discriminating AD from HCs. Notably, RBCs α‐syn/tau heterodimers were able to discriminate LBD and AD subjects from HC with good and fair accuracy respectively. Similarly, α‐syn/Aβ1‐42 heterodimers concentrations were found to have fair accuracy in discriminating between AD and HCs (Table 1).

Conclusion

RBC α‐syn heteromers concentrations were able to discriminate HCs from AD and LBD patients, though provided no help in the differential diagnosis of LBD vs AD. The interest for these data goes beyond eventual clinical implications, supporting new perspectives on the interaction of the different pathologies in these neurodegenerative diseases.
A novel type of amyloid‐beta plaques identified in early‐onset AD
Authors: Boon Baayla D.C. , Bulk Marjolein , Jonker Allert J. , Popovic Marko , Walter Jochen , Kumar Sathish , Natte Remco , van der Weerd Louise , Bouwman Femke , Van de Berg Wilma D.J. , Hoozemans Jeroen J.M. , Rozemuller Annemieke J.M.
Published: December 2020

Background

The clinical presentation of Alzheimer’s disease (AD) including age at onset, is remarkably heterogeneous. In previous research, we showed that inflammation is differently distributed between typical and atypical AD (Boon et al., 2018). In addition, distinct Aβ deposits in AD pathology are recognized. These deposits are called plaques when located in brain parenchyma or cerebral amyloid angiopathy (CAA) when located in the cerebral vessels. Recently, we described a novel Aβ plaque‐type, referred to as ‘the coarse‐grained plaque’. In this study, we evaluate its clinical relevance and perform in‐depth morphological characterization.

Method

The coarse‐grained plaque’s presence was investigated in the frontal cortex of Aβ‐pathology‐positive cases (N=74), including non‐demented controls (n=15), early‐onset (EO)AD (n=38), and late‐onset (LO)AD (n=21), using a semi‐quantitative approach. Main plaque characteristics were compared to other well‐defined Aβ deposits; the classic cored plaque, the cotton wool plaque, and CAA. In‐depth characterization was done by studying the coarse‐grained plaque’s Aβ isoform (Aβ40, Aβ42, AβN3pE, and pSer8Aβ) composition, neuroinflammatory component, and vascular association using immunohistochemistry and 3D confocal laser scanning microscopy imaging.

Result

The plaque was only observed in cases with clinical symptoms, it was more prominent in EOAD (95%) than in LOAD (66%) and was associated with a homozygous ApoE4 status (Figure 1). The coarse‐grained plaque showed a multi‐cored Aβ morphology and was seen in the proximity of CAA‐affected sulci. Its predominant Aβ40 composition was distinct from other plaques, but showed similarities to that of CAA (Figure 2A). 3D imaging revealed a unique hollow Aβ40‐shell structure (Figure 2B) with microglia in Aβ‐devoid holes (Figure 3). Furthermore, the plaque’s immunoreactivity for the CAA‐Type 1 specific marker norrin suggests – although having a different morphology ‐ a close etiological relation with CAA.

Conclusion

The coarse‐grained plaque is a clinically relevant Aβ deposit as it occurs only in clinical AD and is more frequent in early‐onset cases. The plaque is strongly associated with neuroinflammatory and vascular changes. Differences in presence of coarse‐grained plaque among AD subtypes, contributes to the compiling evidence that also pathophysiology in AD is heterogeneous.
Differentiating among stages of cognitive impairment: Comparisons of versions two and three of the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) neuropsychological test battery
Authors: Dodge Hiroko H , Goldstein Felicia C , Wakim Nicky I , Gefen Tamar , Teylan Merilee , Kukull Walter A , Barnes Lisa L , Giordani Bruno , Hughes Timothy M , Kramer Joel H , Loewenstein David A , Marson Daniel C , Mungas Dan M , Sachs Bonnie , Salmon David P. , Steenland Kyle , Parker Monica W , Welsh‐Bohmer Kathleen A , Morris John C , Weintraub Sandra ,   National Alzheimer's Coordinating Center
Published: December 2020

Background

National Institute on Aging (NIA)‐funded Alzheimer’s Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS was implemented in 2015 and included several changes to its neuropsychological battery, replacing the previous version [Version 2 (V2)]. The current study compares the V3 and V2 neuropsychological batteries with respect to their ability to distinguish among categories of cognitive impairment captured by the Clinical Dementia Rating (CDR) global scores representing either no cognitive impairment (CDR=0), questionable or mild cognitive impairment (CDR=0.5) or mild stage of dementia (CDR=1.0).

Method

Data from the NACC UDS V2 and V3 neuropsychological batteries were examined. There were 16,935 unique subjects from V2 and 5022 unique subjects from V3 aged 60 years and older with CDR global score ≤ 1. To reduce the influence of practice effects, only data from their first assessment was used. To control for inequalities in sample sizes between V2 and V3, we identified an approximately equal number of subjects from V2 within each CDR group. Receiver Operating Characteristics Area under Curve (ROC‐AUC) in differentiating stages of cognitive impairment were compared and optimal cut‐points based on Youden’s J scores were calculated.

Result

ROC‐AUCs from all of the V3 neuropsychological tests were comparable in their ability to differentiate CDR global scores with the corresponding tests in V2, despite the fact that V3 participants included more subjects at earlier stage of CDR 0.5. UDS V3 composite scores yielded similar ROC‐AUCs to the best performing individual test within each domain, while the Montreal Cognitive Assessment (MoCA) total score yielded higher ROC‐AUCs than any individual MoCA index scores. Racial differences in differentiating between CDR=0 and CDR=0.5 were also found.

Conclusion

A nonproprietary suite of neuropsychological tests in UDS V3 provided similar discriminative ability to tests in UDS V2 to distinguish categories of cognitive impairment. Optimal cut‐points calculated in this study will be useful for clinical diagnosis.
Amyloid (a), tau (t) and voxel‐based morphometry (n) correlates of visual memory performance
Authors: Arias Jaime Fernandez , Pascoal Tharick A. , Benedet Andréa Lessa , Therriault Joseph , Kang Min Su , Savard Melissa , Mathotaarachchi Sulantha , Lussier Firoza Z. , Tissot Cecile , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

The Aggie Figures Learning Test (AFLT) is a memory test that was designed to be a visual analogue of the Rey Auditory Verbal Learning Test (RAVLT). Previous studies have found associations between tau and amyloid PET and brain volume and RAVLT scores. However, to date, no study has explored the associations between these markers and AFLT scores. We aimed at exploring such associations.

Methods

Structural MRI, amyloid PET ([18F]‐NAV4694) and tau PET ([18F]‐MK6240) were acquired for 161 individuals. We conducted analyses on two sub‐samples. Demographic data is shown on Tables 1 and 2. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non‐linearly registered to the ADNI template using Dartel and smoothed with an 8mm FWHM gaussian kernel. Voxel‐wise linear regression models were applied, using VoxelStats, with AFLT sub‐scores as dependent variables and either tau and amyloid binding or Voxel‐Based Morphometry as predictors. We corrected for sex, Apoe genotype, age and years of education.

Results

We found negative associations between tau binding and AFLT total (trials 1‐5) and AFLT delayed recall (DR) scores in the MTL and temporo‐occipital cortices, as well as in some of their WM tracts. These associations were stronger for the total scores and, in both cases, in the right hemisphere. For the amyloid biomarker, associations with AFLT total and AFLT DR scores were negative in right ventromedial PFC, right posterior thalamus and basal ganglia. In this case, strongest associations are reported between amyloid burden and AFLT DR scores. Finally, we found positive associations between AFLT total and DR scores and VBM in the fusiform gyrus bilaterally.

Conclusions

Results resemble previously reported findings on associations between RAVLT and tau, amyloid and brain volume estimates. Our findings are also in line with initial reporting of patients with right hemisphere damage having difficulties with AFLT tasks (Madjan, et al. 1996). In addition, relationships with tau tend to be more posterior, while relationships with amyloid were shown to be more anterior. Further analyses based on diagnostic categories are needed to explore how these associations change with pathology.
Dynamic network connectivity alteration predicts cognitive decline in Alzheimer’s disease spectrum
Authors: Wang Qing , He Cancan , Xie Ming Chun
Published: December 2020

Background

Brian network integrity plays a pivotal role in the regulation of high‐order cognitive function and emotion for human brain. Disrupted functional coupling within‐ and between resting‐state networks (RSNs) are selectively vulnerable for neurodegenerative disease, such as Alzheimer’s disease. However, dynamic network alteration and its molecular pathological basis following the disease course in the AD spectrum still remain unclear. Currently, we integrated a new method combination of large‐scale network analysis and canonical correlation analysis (CCA) to explore dynamic spatiotemporal patterns within‐ and between RSNs and their significance in the AD spectrum.

Method

We analyzed data from the Alzheimer’s Disease Neuroimaging Initiative 1, GO and 2 datasets. A total of 160participants (59 cognitively normal (CN) participants, 49 patients with early mild cognitive impairment (EMCI), 28 patients with late mild cognitive impairment (LMCI) and 24 AD patients) completed fMRI scan, 3T MRI brain scan, CSF biomarkers and genes which strongly tied to AD risk detection and cognitive function assessment (MMSE and ADAS‐Cog scores). We studied group differences in within‐ and between RSNs. For cognitive function, genes and biomarkers, we did canonical correlation analysis between gene scores, cognitive scores , the biomarker levels and network variables across disease spectrum.

Result

We identified that all RSNs represented the increase connectivity within networks by enhancing inner cohesive ability, while seven out of ten RSNs were characterized by the decreased connectivity between networks, which indicates weaken connector ability among networks from the early stage to dementia. This dichotomous mode presenting large‐scale dynamic network abnormality was significantly correlated with the levels of molecular biomarkers (amyloid‐β, Tau, p‐Tau), cognitive performance, as well as accumulating effects of AD‐related ten genetic risk factors. This study implicated that spatiotemporal pattern of large‐scale network connectivity failure was not cascading, but represented a bouncing mode with the progression of cognitive decline. Taken together, we identified the determinants of the spread of disrupted network incoherence, molecular correlates, and summative effects of genetic variants on the RSNs.

Conclusion

These findings provide novel insights for better understanding the mechanism underlying large‐scale network disruption linking molecular biomarkers and phenotypic variations in the AD spectrum.
Modifiable risk factor possession patterns of dementia in elderly with mild cognitive impairment: A 4‐year longitudinal study
Authors: Katayama Osamu , Lee Sangyoon , Bae Seongryu , Makino Keitaro , Shinkai Yohei , Chiba Ippei , Harada Kenji , Shimada Hiroyuki
Published: December 2020

Background

We clarified modifiable risk factor patterns of dementia in elderly patients with mild cognitive impairment (MCI) and determined the relationship between retention patterns and reversion from MCI over a 4‐year follow‐up.

Method

Participants were 5104 older adults who completed the National Center for Geriatrics and Gerontology‐Study of Geriatric Syndromes (NCGG‐SGS) examinations in August 2011–February 2012; 3095 (60.6%) completed the second‐wave cognitive examination in August 2015–August 2016. Among the longitudinal data, missing values were imputed for 789 community‐dwelling people who were aged ≥65 years (mean age, 72.0±5.4 years; 368 men and 421 women) with MCI and classified them as “reverters” and “nonreverters.” Longitudinal analysis was performed after missing values resulting from dropout were imputed. Nine modifiable risk factors at baseline—namely, less education, hearing loss, hypertension, obesity, smoking, depression, physical inactivity, social isolation, and diabetes—were classified in latent class analysis. In subsequent binomial logistic regression analysis, reversion status was the dependent variable (the nonreverters served as a reference group) and cluster membership the independent variable.

Result

Of the 461 participants for whom data were not imputed, 234 (50.8%) reverted from MCI to normal cognitive status. Reversion rate among the 789 participants for whom we imputed data was 30.9%. The modifiable risk factors among participants with MCI were classified into five patterns: low‐risk, psychosocial, health behavior, educational, and smoking factors. According to logistic regression analysis, people with low‐risk factors were more likely to revert from MCI to normal cognitive status than were patients with the other factors (P<.05).

Conclusion

We formulated five patterns of modifiable risk factors among elderly people with MCI. Participants with low‐risk factors were more likely to recover from MCI than participants with the other factors. These results may provide useful information for designing interventions to prevent cognitive decline and dementia in individuals with MCI.
AD biomarker stability for stored CSF based on immunoassay results
Authors: Vandijck Manu , Bastard Nathalie Le , Persson Staffan , Zetterberg Henrik , Blennow Kaj , Kostanjevecki Vesna
Published: December 2020

Background

Diagnosis of Alzheimer’s Disease (AD) is currently more often based on a clinical assessment combined with biomarker data. For AD, four core cerebrospinal fluid (CSF) biomarkers have been identified and levels are determined on measurements with various immunoassays (INNOTEST, Lumipulse, Elecsys, etc.). Each assay has its own concept (technology, antibodies, protocol) and performance characteristics.

The Alzheimer’s Association Quality Control (AA‐QC) program lead by the University of Gothenburg aims to monitor the inter‐laboratory variation for immunoassays for CSF biomarkers using a set of CSF samples (2 round specific & 1 longitudinal), periodically measured at participating sites.

Biomarker levels over time of the longitudinal QC CSF sample (2016QC‐L) on the different immunoassays can be interpreted to assess long‐term stability. This is relevant given that CSF samples are often stored in a biorepository as part of a study cohort for future assessment of (new) biomarkers.

Method

In the AA‐QC program, immunoassays for the different AD CSF core biomarkers (Aβ1‐42, Aβ1‐40, total‐Tau, and pTau181) from different suppliers are tested three times per year with 2016QC‐L. The average result per immunoassay for this sample since round 22 (October 2016) till round 31 (October 2019) were analyzed, considering round 22 as start of storage.

Result

For all four CSF biomarkers, the coefficient of variation (CV) per immunoassay obtained over all round averages was below 10% (except one). The CVs ranged from 2% to 10% for Aβ1‐42, 1% to 8% for Aβ1‐40, 1% to 17% for total‐Tau, and 1% to 9% for pTau181, indicating relatively stable concentration assignment over time, despite the use of different batches. For each biomarker, no consistent trend in analyte concentration over all immunoassays in function of time was observed.

Conclusion

For the CSF sample analyzed, AD core biomarkers are stable over the follow‐up period of 36 months. The results of the different immunoassays all show a comparable behavior of the analyte concentration over time. These results from Clinical Chemistry practice confirm the long‐term stability of the core CSF biomarkers, lending further support for their use in clinical research studies and therapy monitoring in clinical trials, where stored samples are often analyzed in batch at end‐of‐study.
A case of amyotrophic lateral sclerosis with frontotemporal dementia manifested as naming and sentence comprehension disorder
Authors: Zhang Yuan , Yang Bo , Chen Qidong , Shi Jiong , Xu Jun
Published: December 2020

Background

Approximately half of the patients with motor neuron disease (MND) will develop frontotemporal dysfunction. Most of case reports showed a strong association between amyotrophic lateral sclerosis (ALS) and behavioral variant frontotemporal dementia (bvFTD) and mostly presented as FTD at the onset, while the relationship between ALS and primary progressive aphasia (PPA) has not been fully understood.

Method

A patient suspected to be ALS‐PPA admitted to Beijing Tiantan Hospital, Capital Medical University in January 2020. We want to describe this case to summarize its clinical characteristics.

Result

The patient is 70 years old,female, illiteracy and with severe hearing impairment. She developed bulbar paralysis manifestations like hoarseness, dysarthria and dysphagia without obvious mental, character and behavior changes in the course of the disease.Both upper limbs tendon reflex was hyperactive and lower limbs tendon reflex was decreased. Sucking reflex existed. Neuropsychological test suggested dementia, impaired naming and sentence comprehension. Electromyography suggested neurogenic changes around the upper and lower extremities. Magnetic resonance imaging showed symmetrical anomaly signal of bilateral basal ganglia, where manifested as low metabolism on PETCT. Amyloid β (1‐42) was elevated, the total protein Tau was reduced and the phosphorylated tau protein was normal in cerebrospinal fluid.

Conclusion

ALS‐PPA is a relatively rare disease. Sometimes maybe genetic and pathological examinations are required for diagnosis.
Power and functional connectivity of alpha oscillations in mild cognitive impairment: A systematic review and meta‐analysis
Authors: Lejko Nena , Larabi Daouia I , Herrmann Christoph S , Aleman André , Ćurčić‐Blake Branislava
Published: December 2020

Background

Alzheimer’s disease (AD) is sometimes preceded by a less severe decline in cognitive abilities called mild cognitive impairment (MCI). Having affordable and non‐invasive biomarkers of MCI would ease diagnosis, improve prognosis, and open up possibilities to delay the transition to AD. One potential biomarker is alpha oscillations measured with electroencephalography (EEG) that have been found to differ between cognitively intact older adults (OA) and people with AD. To find whether these changes can already be detected in MCI, we reviewed studies that compared alpha power and functional connectivity in people with MCI and OA, in people with MCI and people with AD, and in people with MCI who progress to AD and those who do not.

Method

We searched for records published until 24 January 2020 using search terms “mild cognitive impairment” AND (eeg OR oscillations). 65 studies were included in the review. We conducted four random effects meta‐analyses. We compared resting state power in people with MCI and OA in the full alpha band (∼ 8‐12 Hz; k=5; n=198 MCI, 258 OA), in lower alpha frequencies (∼ 8‐10 Hz; k=5; n=196 MCI, 203 OA), and in upper alpha frequencies (∼ 10‐12 Hz; k=5; n=131 MCI, OA 139). We also compared resting state power in the full alpha band in people with AD and people with MCI (k=6; n=481 AD, 499 MCI).

Result

In the full alpha band, resting state power was lower in people with AD than in people with MCI (ES=‐0.30, 95% CI=‐0.51, ‐0.10, p=0.003), and in people with MCI than in OA (ES=‐1.49, 95% CI=‐2.69, ‐0.29, p=0.02). Reviewing the literature showed that resting state alpha power is lower in people with MCI who eventually progress to AD than in those who do not. During task performance, alpha activity changed less in people with MCI than in OA. Studies that compared functional connectivity between the three groups reported inconsistent results.

Conclusion

Lower resting state alpha power, that has been found in people with AD can, though to a lesser degree, also be detected in people with MCI, especially those who are on a trajectory towards AD.
The Mini Linguistic State Examination (MLSE): A standardised tool to classify and monitor primary progressive aphasia
Authors: Patel Nikil , Peterson Katie A. , Ralph Matthew L. , Rowe James B. , Patterson Karalyn , Cappa Stefano , Ingram Ruth , Garrard Peter
Published: December 2020

Background

Language assessment is critical in the diagnosis of patients with neurodegenerative diseases, in particular those presenting with progressive speech and language impairment such as the primary progressive aphasias (PPA). Current diagnostic criteria identify three main variants of PPA based on clinical and neuroimaging features: semantic variant PPA ‐ characterised by dramatically reduced ability to understand the meaning of words and objects; nonfluent variant PPA – featuring problems with the grammatical and phonetic aspects of language production; and logopenic variant PPA – characterised by a striking inability to repeat spoken sentences. Most currently utilised assessments of the heterogeneous language profiles of PPA are time‐consuming and not readily comparable across languages. Improved tools to screen, diagnose, and monitor these conditions will be essential to progress in the characterisation and treatments for brain diseases underlying PPAs. The aim of the current project is to develop and fully validate English and Italian versions of an abbreviated language assessment instrument, the Mini Linguistic State Examination (MLSE), which will be able to detect the differing patterns of linguistic deficit that characterise the three variants of PPA with complete equivalence between English and Italian versions.

Methods

Participants completed the MLSE test which included tasks of picture naming, word and sentence repetition, word and sentence comprehension, semantic association, reading, writing, and picture description.

Results

Data were used to present contrasting characteristics of the MLSE performance in 61 patients with PPA (20 PNFA, 17 SD, and 24 LPA), and a matched control group (40 controls; aged: 45‐75 years).

Conclusions

The MLSE will provide a much‐needed short clinical tool to classify and monitor PPA. Additionally, the MLSE will be a template for further language‐specific versions.
Early tau phosphorylation as a potential retinal biomarker for AD and other tauopathies
Authors: de Ruyter Frederique Jasmine Hart
Published: December 2020

Background

There is increased interest in in vivo labeling of Alzheimer’s disease (AD) pathology in the retina as a non‐invasive diagnostic approach (Jiang, Wang, Li, Cao, & Li, 2016; Koronyo et al., 2017). While the majority of studies focus on the detection of amyloid beta (Aβ) in the retina, the characterization of tau related pathology is scarce. In this study we assessed the presence of different tau isoforms in the retina in AD as well as other neurodegenerative diseases associated with and without tau pathology.

Method

Post mortem eyes were collected through the Netherlands Brain Bank from donors with AD (n=6), progressive supranuclear palsy (PSP, n=2), frontotemporal lobar degeneration (FTLD; FUS and TDP43) (n=4), Lewy body disease (LBD, n=2), multiple system atrophy (MSA, n=2), Parkinson’s disease (PD, n=6), and non‐neurodegenerative controls (n=10). Superior‐temporal quadrants were cut in 10 µm sections. Sections were immunostained using primary antibodies directed against total tau (HT7), early tau phosphorylation (AT8), 3R and 4R tau isoforms (RD3/RD4) and late tau phosphorylation (pS422). The frontal cortex was used as a positive control.

Result

Total tau (HT7) was observed in non‐demented control and neurodegenerative cases (Figure 1). The presence of 3‐ and 4‐repeat isoforms of tau varied within the inner plexiform layer (IPL) and outer plexiform layer (OPL) with more 3‐repeat tau in the IPL and more 4‐repeat tau in the OPL. Only AD and PSP cases showed positive immunoreactivity for AT8, which was found differently distributed in the IPL and OPL (Figure 2). Tau phosphorylated at Ser422 was negative in all groups.

Conclusion

In control and neurodegenerative cases, high levels of tau are present in the retina, mainly in the plexiform layers. Interestingly, we found different intensities for 3‐ and 4‐repeat tau in the IPL and OPL, implicating differences in tau expression by amacrine and horizontal cells (Chidlow, Wood, Manavis, Finnie, & Casson, 2017). Tau phosphorylated at Ser202/Thr205 clearly differentiates tauopathies from other neurodegenerative disease and non‐demented controls. Depending on the epitope, phosphorylated tau is a potential retinal biomarker for AD and other tauopathies.
Cognitive profiles in amyloid‐PET‐eligible patients: A retrospective study
Authors: Loreto Flavia , Gunning Stephen , Golemme Mara , Watt Hilary , Patel Neva , Win Zarni , Carswell Christopher J. , Perry Richard J. , Malhotra Paresh A.
Published: December 2020

Background

The early cognitive profile of Alzheimer’s Disease (AD) is typically characterised by predominant impairment in episodic memory, reflecting medial temporal lobe dysfunction. However, little is known about the cognitive profile associated with AD pathology in those patients who meet Appropriate Use Criteria (AUC, Johnson et al., 2013) for Amyloid PET Imaging (API). In this group, AD pathology is frequently associated with an atypical clinical course or presentation. Here, we systematically evaluate the cognitive profiles of AUC‐meeting patients in a real‐world clinical setting, combining the information provided by the neuropsychological assessment with the results of Amyloid PET Imaging.

Method

From a larger sample of 396 patients who underwent Amyloid PET at the Imperial Memory Centre between December 2013 and June 2019, we included those individuals who also had at least one formal neuropsychological assessment (minimum of 4 tests) within 18 months of API (n=124). Both these were solely conducted for clinical purposes, and API was requested after multidisciplinary team discussion. Cognitive measures in amyloid positive (Aβ+) and negative (Aβ‐) patients were compared using non‐parametric tests.

Results

Neuropsychological assessment preceded Amyloid PET Imaging in most cases, for both amyloid‐positive (n=51, mean age 67.24±9.32 years, 58.8% female) and amyloid‐negative (n=73, mean age 67.9±9.64 years, 41.1% female) groups. Cognitive performance in the amyloid‐positive group was significantly worse in 6 of the 14 cognitive measures taken into account: visuo‐spatial functioning, executive functioning, working memory, verbal learning, verbal delayed recall, and confrontation naming (Figure 1). Verbal learning, verbal delayed recall and confrontation naming were the most frequently impaired measures in the amyloid‐positive group, with around 50% of patients performing below 2 standard deviations. Notably, self‐reported symptoms of depression were significantly higher in the amyloid‐negative (7.3±4.38) than in the amyloid‐positive group (4.68±3.7) (p=.002) (Figure 2).

Conclusions

In a sample of patients attending a tertiary Behavioural Neurology clinic, neuropsychological evaluation revealed worse performance in positive API across a range of domains, particularly verbal memory and confrontation naming, with higher rates of symptoms of depression being reported more frequently in the amyloid negative group.