bluuebunny/crossref_metadata_2025 huggingface dataset:
Compact MoCA: A shortened alternative for MCI screening among healthy aging individuals
Authors: Muadmanee Wisawin , Hiransuthikul Akarin , Chunharas Chaipat , Thongkam Achitpol , Petchlorlian Aisawan , Praditpornsilpa Kearkiat
Published: December 2021

Background

The increasing number of elderlies highlights the important of clinical screening for cognitive impairment in healthcare setting. Montreal Cognitive Assessment (MoCA) is a widely used tool for mild cognitive impairment (MCI) screening, particularly among resource‐limited settings. Although originally claims to be a time‐saving tool of approximately 10 minutes, it takes much longer in real‐world settings, which consequently led to lack of MCI screening in many busy clinic settings. In order to shorten the duration for testing, we aimed to determine the performance of a compact MoCA which excludes domain(s) that does not correlate well with the total score.

Method

Data of Thai healthy adults aged ≥60 years from a prospective cohort conducted in King Chulalongkorn Memorial Hospital, a tertiary care center in Bangkok, Thailand was included. MoCA was used to assess cognitive performance. Cognitive domain that showed poor correlation to the total score was excluded to build a compact MoCA in order to shorten the time of assessment. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) were used to evaluate the performance of the compact MoCA.

Result

A total of 2,799 participants who completed MoCA were enrolled. Correlation analysis showed that naming and orientation had the lowest degree of correlation to the total MoCA score (coefficients of 0.355 and 0.364, respectively) and delayed recall had the highest degree of correlation (coefficients of 0.609). After excluding naming, MoCA showed 100% sensitivity and 96.05% at a cut‐off score of 25. After excluding orientation, MoCA showed 100% sensitivity and 97.60% specificity at a cut‐off score of 19. After excluding both naming and orientation, MoCA showed 100% sensitivity and 93.4% specificity at a cutoff score 16. AUROC of MoCA after excluding naming, orientation, and both naming and orientation was 0.996, 0.998 and 0.994, respectively.

Conclusion

The compact MoCA which excludes either naming or orientation showed great performance with 100% sensitivity and >95% specificity, suggesting a possible alternative method to shorten the duration for MCI screening while maintaining the quality of the test. An on‐going MCI screening using an electronic MoCA is on‐going to precisely assess time use per each domain.
Statistical data harmonization for neuropsychological test battery conversion
Authors: Wilkins‐Reeves Steven , Chen Yen‐Chi , Chan Kwun Chuen Gary
Published: December 2021

Background

A current problem scientists and clinicians face when studying cognitive impairment is how to harmonize scores across neuropsychological tests evaluating the same cognitive domains in a longitudinal analysis. Prior point conversion methods typically do not allow quantification of uncertainty and may be based on strong distributional assumptions. Our framework was motivated by an interest in assessing the uncertainty when converting scores.

Method

We established new statistical methodology for converting C1 and C2 neuropsychological batteries of the National Alzheimer’s Coordinating Center Uniform Data Set collected by the NIA Alzheimer’s Disease Research Centers Program. We adapted methodology from the measurement error and latent variable statistical modeling techniques and proposed an algorithm to give point and interval conversions. We developed parametric and non‐parametric models to achieve this task, allowing one to control for important traits such as age, education level and sex at birth. Additionally, we developed variational inference and functional Expectation Maximization algorithms to fit these models and implemented them in R. This method was compared to existing methodology using Z‐score conversions or quantile matching.

Result

We assessed our model by converting C1 scores (e.g. Mini‐Mental State Examination) to C2 scores (e.g. Montreal Cognitive Assessment). We trained our method on 18092 cognitively normal individuals with either a C1 or C2 score observed. The method was validated on a set 420 individuals with both scores observed using the Hellinger and Total Variation probability metrics to compare conversion distributions. Both methods outperformed prior methods in describing intrinsic variability (Table 1), which is the difference of scores from subsequent visits. Additionally, the non‐parametric model outperformed the others in matching the extrinsic variability, which is the difference of scores for individuals with multiple same day tests used to verify a model is capturing the conversion uncertainty (Table 1; Figures 1,2,3).

Conclusion

Our framework provides a statistically grounded approach to convert scores with uncertainty, a significant step towards understanding cognitive progression in settings where different neuropsychological batteries are used over time. This work establishes groundwork for future study including detection of Mild Cognitive Impairment when multiple testing batteries are used during an individual’s lifetime.
Quantifying patterns of pathology: A characterization of the 3D spatial distribution of tau tangles and amyloid plaques in Alzheimer’s disease using multi‐modal image registration with a scattering transform
Authors: Stouffer Kaitlin M , Wang Zhenzhen , Xu Eileen , Lee Karl S , Lee Paige , Mori Susumu , Troncoso Juan C , Saito Atsushi , Albert Marilyn S. , Miller Michael I , Tward Daniel J
Published: December 2021

Background

Volumetric measures of MRI scans have consistently shown medial temporal lobe (MTL) atrophy in individuals across the spectrum of AD. However, these measures are not considered to be specific for AD, partly because a direct link to tau and amyloid pathology has not been demonstrated (Jack et. al, 2018). To address this limitation, we developed multi‐modal image registration and analysis tools to integrate neuropathological data from 2D histology images with 3D postmortem MRI images in the same brain region, in order to quantify the density of tangles and plaques.

Methods

We imaged tissue excised from the MTL at 0.125 mm resolution with an 11T MR scanner (fig 1a) and manually segmented it into subregions (fig 1b). We sliced the tissue into 10um thick sections, 1mm apart, and digitally imaged them with a light microscope after staining for amyloid (6E10) or tau (PHF‐1) (fig 1c). Locations of tangles and plaques on histology were estimated with a deep convolutional neural network (UNET) trained on a smaller set of annotated data (fig 1d). To align histology images with the MRI images, we first computed scattering transforms of histology to capture high resolution textural information (fig 1e). This was then used to find both optimal spatial and intensity profile transformations between the two imaging modalities (fig 1f). We rigidly aligned MRI images to the Mai Paxinos atlas for interpretability.

Results

We localized tau tangles and amyloid plaques from histology sections of a person with severe AD, and in corresponding 3D MRI images of the brain tissue from the same individual. We quantified density of particles per region. Initial findings demonstrated the highest amount of tau in the entorhinal cortex, subiculum, and CA1 (fig 2) compared to other subregions in the MTL, consistent with Braak staging. No obvious differential distribution of amyloid was observed.

Conclusion

Our detailed localization of tangles and plaques in 3D offers the opportunity to study spatial distribution of pathology within brain regions among patients that span the spectrum of disease, which will foster more robust comparison with MRI atrophy, and potentially shed new light on the progression of AD.
Greater COVID‐19 impact for underrepresented racial and ethnic minority groups: A survey study on the Wisconsin Alzheimer’s Disease Research Center participants
Authors: Ma Yue , Spalitta Alice , Wahoske Michelle L , Blazel Hanna , Chappell Richard J , Chin Nathaniel A , Johnson Sterling C , Asthana Sanjay , Gleason Carey E , Carlsson Cynthia M
Published: December 2021

Background

The COVID‐19 pandemic has posed substantial impact on people’s life and wellbeing, especially for the aging population who are at greater risk. This study compared the difference in the impact between older adults from underrepresented racial/ethnic groups (URGs) versus non‐URGs.

Method

The National Alzheimer’s Coordinating Center COVID‐19 Impact Survey was self‐reported by 221 participants aged 49‐99 years from the Wisconsin Alzheimer’s Disease Research Center clinical core between August and December, 2020. 43 participants who reported “Black or African American” or “American Indian or Alaska Native” in primary or secondary race or reported “Yes” to Hispanic” ethnicity were classified as URGs. The remaining 178 participants who reported only “White” or “Asian” in the primary and secondary races and “No” to “Hispanic” ethnicity were classified as non‐URGs. The survey inquired on (1) COVID‐19 symptoms, testing, diagnosis, and hospitalization; (2) worrying, social isolation, and disruption on everyday life associated with the pandemic; (3) related cognitive, psychiatric, and behavioral changes; and (4) change of willingness in research participation. Group differences on survey responses were tested using Fisher’s exact test, non‐parametric Kruskal‐Wallis test, and binary or ordinal logistic regressions.

Result

No significant group difference was found in sex, age, and clinical diagnosis. However, URG participants had lower education and higher Clinical Dementia Rating (CDR) scores (Table 1). URGs were approximately doubled non‐URGs in the percentages of experiencing COVID‐19 symptoms, having a positive diagnosis, and reporting “very much” or “extremely” worrying about getting COVID‐19 and changing willingness to participate in clinical research. Controlling for sex, age, education, and CDR score, URGs were more likely to be tested for COVID‐19 (Odds Ratio = 2.37), have significantly reduced income (OR=4.74), experience change in memory or thinking (OR=2.97), and report a greater total number of psychiatric or behavioral changes (OR=2.04). However, URGs felt less isolated from family or friends (OR=0.55).

Conclusion

URGs had greater medical, psychological, and economical consequences than non‐URGs, which implied racial/ethnic disparities associated with the pandemic. Future research is needed to identify inequities in the social determinants and understand their association with disparities, which would help inform policies and strategies to achieve health equity.
The effect of sad mood on subjective appraisal of memory performance in older people with and without subjective memory complaints: An experimental study
Authors: Farmer Hilary Faithfull , Bahar‐Fuchs Alex , Bryant Christina
Published: December 2021

Background

Subjective memory complaints (SMC) have been identified as a possible precursor to cognitive decline and may indicate a need for an early intervention for at‐risk older adults. However, it is well‐established that low mood is associated with SMC, leading to claims that memory concerns in older people may often reflect primarily psychological symptoms. This study aimed to determine the effect of low mood on subjective memory appraisal in older adults.

Method

We used a film‐based mood induction procedure (MIP) to test the effect of sad vs. neutral mood on subjective appraisal of memory performance in an experimental 2X2 between‐subjects design. Participants were 98 cognitively unimpaired older people (n=45 with SMC), randomised to the sad MIP (n=56) or the neutral MIP (n=42). All participants completed measures of trait SMC and ruminative self‐focused attention (RSFA) as well as perceived performance and metacognitive experience (ME) following the MIP and completion of a face‐name and a maze‐learning task.

Result

Participants in the sad MIP condition (M=42.75, SD=30.97) reported significantly greater sadness than those in the neutral condition following the manipulation (M=11.57, SD=18.44). The association between objective and subjective memory performance was stronger for cued recall on the face‐name task (r=.61, p=.001) and was weaker free recall on the face‐name task (r=.26, p=0.016) as well on the maze‐learning task (r=‐.16, p=.200). Contrary to expectation, there was no significant effect of mood condition on perceived performance on Face‐Name learning task (MD=‐2.43, p=498), but sad mood was associated with better perceived performance on the maze‐learning task (MD=13.34, p=.015). Results also indicated that RSFA and ME were implicated as mechanisms in subjective memory performance appraisal.

Conclusion

Findings indicate that SMC is a complex multifaceted phenomenon which may be underpinned by maladaptive self‐regulation and attentional systems, suggesting that psychological interventions may be appropriate for many older adults with SMC.
Longitudinal tau accumulation in cognitively normal older adults is associated with baseline age, pathology, and activation
Authors: Adams Jenna N. , Harrison Theresa M. , Maass Anne , Baker Suzanne L. , Jagust William J.
Published: December 2021

Background

Predictors of longitudinal tau accumulation have not yet been fully characterized, but are critical for understanding progression from normal aging to Alzheimer’s disease (AD). We investigated whether baseline AD pathology, demographic risk factors, and activation during a memory task predicted longitudinal tau deposition in cognitively normal older adults (OA).

Method

Tau pathology was measured with [18F] Flortaucipir (FTP) at ≥2 time points (44 2TPs; 24 3TPs; 2 4TPs; 2.5±1.1 years follow‐up) in 70 OA (mean age 77 years, 59% female). FTP scans were processed with a longitudinal pipeline using an eroded white matter reference region. Linear mixed models were used to calculate FTP slope in entorhinal cortex (EC), inferior temporal gyrus (IT), and a MetaROI composed of AD‐vulnerable temporal regions. Aβ was measured with global PiB DVR. A subset of 37 OA received baseline fMRI while performing a memory task, and task activation (all images vs. perceptual baseline contrast) was calculated for EC and hippocampus.

Result

There was significant group‐level tau accumulation in EC, IT, and MetaROI across the full sample, and within Aβ+ and Aβ‐ groups (one‐sample t‐tests, all ps<0.001; Figure 1). Older age at baseline was specifically associated with increased FTP slope in EC (Figure 2A). Higher baseline PiB DVR was associated with increased FTP slope in EC, IT, and MetaROI (Figure 2B). ApoE ε4+ was associated with greater FTP slope in IT and MetaROI, but not EC (Figure 2C). Multiple regression models including age, sex, ApoE, and baseline EC FTP and PiB DVR showed a significant interaction between baseline EC FTP and PiB DVR, and an independent effect of ApoE ε4+, in predicting FTP slope in IT and MetaROI (predictor ps<0.01). In the subset with fMRI data, greater task activation in EC and hippocampus was associated with increased EC FTP slope (Figure 3).

Conclusion

Age was a specific risk factor for tau accumulation in EC, while baseline Aβ and ApoE ε4+ were related to tau accumulation in neocortical regions. Positive associations between activation and tau change within EC support theories of activity‐related tau accumulation. Our findings help elucidate potential underlying causes of tau accumulation in aging.
Prevalence of mild behavioral impairment subdomains: A meta‐analysis
Authors: Pan Yining , Shea Yat Fung , Ismail Zahinoor , Li Victor OK , Lam Jacqueline CK
Published: December 2021

Background

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of neuropsychiatric symptoms. Our previous meta‐analysis showed that the pooled prevalence of MBI among cognitively normal (CN), subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) subjects are 17%, 35.8% and 45.5% respectively. The main aim of this study is to calculate the pooled prevalence of MBI subdomains.

Method

A search of the literature on MBI in MCI, CN, and SCI and CN but at risk (CN‐AR) subjects published between 1 January 2003 and 14 January 2021 was conducted. Meta‐analysis using a random effects model was performed to determine the pooled estimate of the prevalence of MBI subdomains. Meta‐regression was performed to identify factors contributing to the variance of prevalence rate.

Result

Nine studies conducted among 11568 subjects (9259 CN, 1057 SCI & 1252 MCI) with retrievable subdomain data underwent meta‐analysis, revealing pooled prevalence of affective dysregulation (AFD), impulse dyscontrol (IDS), decreased motivation (DMT), social inappropriateness (SIP) and abnormal perception/ thought (APT) of 31.2% (95% CI 24.6‐38.5%), 27.9% (95% CI 22.2‐34.6%), 11.5% (95% CI 7‐g18.5%), 7.4% (95% CI 4.1‐12.9%), and 3.4% (95% CI 1.7‐6.7%) respectively. Although all subdomains demonstrate ordinal increase in pooled prevalence from CN, SCI and MCI subgroups, meta‐regression demonstrated no significant difference in subdomains prevalence among cognitive subgroups. The pooled prevalence of AFD and IDS are greater than that of SIP and APT among all cognitive subgroups. Among MCI subjects, racial group (Asian vs. Caucasians) could account for variance between the studies in prevalence of IDS (coefficient 1.5908, 95% CI 0.7850‐2.3966, R2 analogue 0.63, p<0.001).

Conclusion

AFD and IDS are two most prevalent MBI subdomains and remain the same with cognitive deterioration. This finding is potentially relevant to clinical practice.
Novel oddity detection task differentiates early Alzheimer’s disease and major depression
Authors: Frei Marlen , Berres Manfred , Kivisaari Sasa L , Monsch Andreas U. , Kressig Reto W. , Krumm Sabine
Published: December 2021

Background

The differentiation between early Alzheimer’s disease (AD) and Major depression (MD) is a common clinical challenge. AD‐related neurofibrillary tau‐pathology starts in the perirhinal cortex (PRC) whereas little to no neurodegeneration is found in MD. Thus, testing PRC functioning could help distinguishing these pathologies. The PRC is involved, amongst others, in visual discrimination of complex objects. We assessed the ability of a novel visual oddity detection task to differentiate adults in early stages of AD from those with MD and healthy controls (HCs).

Method

Participants had to choose the odd figure out of six highly ambiguous, simultaneously presented Kanji‐like stimuli. The sample included 28 patients in early stages of AD (8 amnestic mild cognitive impairment, 20 Alzheimer's dementia, 14 female, age = 75.74±6.72 years, education = 13.51±3.13 years, MMSE = 26.29±1.94), 26 patients with MD (14 female, age = 61.88±10.82 years, education = 13.31±3.04 years, MMSE = 28.77±1.27), and 25 HCs (11 female, age = 68.98±10.74 years, education = 14.26±3.91 years, MMSE = 29.01±1.04). As proof of concept, only AD patients showed distinct PRC thinning adjusted for age and total intracranial volume (HC vs. AD: t = ‐3.355, p = .001; HC vs. MD: t = ‐.596, p = .553). Logistic regressions were performed using demographically adjusted z‐scores of task performance.

Result

Incorrect responses predicted group membership of AD vs. MD patients (odds ratio [OR] = 0.45, 95% confidence interval [CI; 0.22, 0.77], p = .011), as well as AD patients vs. HCs (OR = 0.45, 95% CI [0.22, 0.79], p = .012). Furthermore, correct responses predicted group membership of AD patients vs. HCs (OR = 0.35, 95% CI [0.16, 0.66], p = .004), but not between AD patients vs. MD (p = .11). Omitted responses did not have a distinct effect (AD vs. MD: p =.36; AD vs. HC: p = .051).

Conclusion

A novel oddity detection task differentiated patients in early stages of AD from MD patients and HCs. Although further validation is needed, these findings indicate that the task detects early cognitive impairment related to AD and may support differential diagnosis.
Is it possible to implement standard neuropsychological assessment in European memory clinics? An EADC‐ISTAART survey
Authors: Grazia Alice , Monsch Andreas U. , Cappa Stefano , Teipel Stefan J. , Frölich Lutz , Winblad Bengt , Welsh‐Bohmer Kathleen A. , Boccardi Marina
Published: December 2021

Background

Neuropsychological assessment of mild cognitive impairment (MCI), a gateway for the biomarker‐based diagnosis, should follow a standard operating procedure to enhance the reliability of clinical diagnosis across centers and decrease costs to both patients and health‐care systems. A previous consensus adapted the NACC UDS‐3 for use in European memory clinics (cUDS). Here, we assess its implementability.

Method

Clinicians from the European Alzheimer’s Disease Consortium (EADC) memory clinics answered an online semi‐structured survey investigating center practices, potential hurdles and facilitators to implement the cUDS. We performed descriptive statistics and content analysis of explanatory comments to investigate the nature and frequency of perceived hurdles and facilitators.

Result

Fifty out of the 69 EADC memory clinics (72%) answered from 17 countries: 7 Northern, 22 Western, 4 Eastern and 17 from Southern Europe, with heterogeneous national participation (range: 1‐8 centers per country) (Figure).

Centers have a variable yearly patient flow (range: 100‐2500), use heterogeneous definitions of MCI and cognitive batteries, and offer variable proportions of neurology (86%), psychology (80%), psychiatry (64%) and geriatrics (62%) services.

Thirty‐three centers (66%) expressed propensity to implement the cUDS. Six of the twelve cUDS tests are already frequently used: e.g, the fluency tests are used in 87‐100% of the assessments. Up to 9 of the 12 tests have local norms in different countries, although not systematically. Hurdles for the 17 EADC responders (34%) not inclined to implement the cUDS are organizational‐logistical (7/13 providing explanations) relative to time‐management issues and need for clinicians training, cultural barriers and resistances to change ongoing practices (6/13). Among the latter, availability of previous local harmonization (Germany, Netherlands, Spain, Switzerland and United Kingdom) appears the strongest motive, followed by a preference for patient‐tailored assessment. Economic factors did not seem to hinder implementation, 90% of the centers not in favor having 61‐100% refund for cognitive assessment.

Conclusion

Despite barriers, our preliminary data denote propensity to standardize neuropsychological assessment. The involved centers of excellence may be not fully representative, especially relative to non‐academic contexts. Next steps may require to collect more detailed information, also from non‐academic clinics, and identify specific country and context requirements.
Assessment of retinal microvascular alterations in individuals with amnestic and non‐amnestic mild cognitive impairment using optical coherence tomography angiography
Authors: Akrobetu Dennis , Robbins Cason B. , Stinnett Sandra , Soundararajan Srinath , Liu Andy , Johnson Kim , Grewal Dilraj S. , Fekrat Sharon
Published: December 2021

Background

Individuals with mild cognitive impairment (MCI) can be categorized into amnestic and non‐amnestic subgroups based on the absence or presence of intact working memory. Patients with amnestic MCI have increased likelihood of progressing to Alzheimer’s disease (AD); however, identification of predictive biomarkers distinguishing amnestic and non‐amnestic MCI remains ambiguous. This prospective, cross‐sectional study utilizes optical coherence tomography angiography (OCT‐A) to assess how retinal microvascular density and structure might differ among amnestic and non‐amnestic MCI patients.

Method

One hundred and twelve eyes of 59 amnestic MCI participants, 32 eyes of 17 non‐amnestic MCI participants, and 111 eyes of 56 cognitively healthy controls were included in our study. All participants were imaged using the Zeiss Cirrus HD‐5000 AngioPlex. OCT‐A vessel density (VD) and perfusion density (PD) in Early Treatment Diabetic Retinopathy Study (ETDRS) 3mm and 6mm circles and rings were assessed. Retinal thickness parameters on OCT including retinal nerve fiber layer thickness (RNFL), ganglion cell‐inner plexiform layer (GC‐IPL), and central subfield thickness (CST) were also analyzed. Generalized estimating equations accounting for correlation between two eyes of the same subject were utilized for statistical analysis.

Result

Assessment of PD in the 3x3mm inner ETDRS ring revealed a significant decrease in amnestic MCI when compared to non‐amnestic MCI (0.29 ± 0.03 vs 0.34 ± 0.09, p = 0.025), and was significantly lower in amnestic MCI when compared to healthy controls (0.29 ± 0.03 vs 0.39 ± 0.02, p < 0.001), after adjustment for age and sex. Vessel density, subfoveal choroidal thickness, and other retinal thickness parameters (GC‐IPL, RNFL, CST) showed no statistically significant difference among or between diagnostic groups.

Conclusion

After adjusting for age and sex, OCT‐A perfusion density significantly differed among controls, non‐amnestic MCI, and amnestic MCI. Other retinal parameters did not differ between groups after adjusting for covariates. Non‐invasive retinal imaging deserves further study as a potential biomarker for diagnosing and classifying subtypes of MCI.
Duration of life in the three common variants of primary progressive aphasia: A retrospective study in a tertiary memory clinic
Authors: Tastevin Maud , Lavoie Monica , Sablonnière Justine De La , Laforce Robert
Published: December 2021

Background

Primary progressive aphasias (PPAs) are a group of neurodegenerative disorders characterized by an insidious and progressive language impairment. Clinical expression and underlying pathology remain highly heterogeneous. To date, there is a lack of knowledge on the natural history of each of the three main variants, particularly mortality. Moreover, advanced stages and end of life issues are rarely discussed with caregivers and families at diagnosis. In turn, this can cause additional psychological distress.We studied the natural history of the three main variants of PPA. More specifically, we focused on mortality and end of life issues in an attempt to better prepare patients and their families.

Method

We retrospectively studied all deceased patients with a diagnosis of PPA that had been followed at our tertiary memory clinic over the past twenty years (n=83). Clinical data included age of onset of symptoms, duration of illness, age at death and specific cause of death.

Result

Age at death was similar across all three PPA variants but there was less variability in the non‐fluent variant (nfvPPA) group (M=76.6, SD=6.2) than in the semantic variant (svPPA; M=74.1, SD=8.5) or the logopenic variant (lvPPA; M=76.1, SD=9.1) groups. Age at onset of symptoms was earlier for svPPA participants (M=64.5, SD=8.3) then for the two other variants (lvPPA: M=69.3, SD= 10.7; nfvPPA: M=70.4, SD=6.3). Consequently, duration of the disease (number of years between symptoms’ onset and death) was longer for svPPA participants (M=9.6, SD=3.0) than for nfvPPA and lvPPA participants (respectively M=6.2, SD=2.1 and M=7.0, SD=2.9). Surprisingly, cause of death was unknown for most of the participants. When available (n=15), it included sepsis (n=6), respiratory failure (n=4), neoplasia (n=3) and stroke (n=2), and. There were no differences in causes of death among PPA variants.

Conclusion

Despite similar age of death across PPA variants, disease duration was longer in the svPPA. Causes of death per se were similar among PPAs. Future studies should include more participants with better emphasis on causes of death. Nonetheless, our study provides useful information about the natural history of the common variants of PPA.
Memory improvement effects of Ganoderma mediosinense in mice via its anticholinergic and antioxidant activities
Authors: Singh Varinder , Arora Sandeep , Kaur Ravneet , Shri Richa
Published: December 2021

Background

Species of the genus Ganoderma are valued both for their medicinal as well as nutritional properties. Traditionally, these are employed in neurological disorders. However, G. mediosinense has not been evaluated for anti‐amnesic effects previously. Therefore the present study is aimed to explore the cognitive improvement effects of the G. mediosinense extract (GME) against mouse model of scopolamine induced amnesia.

Method

Animals were orally administered with GME (200, 400 and 800 mg/kg) for 7 consecutive days and amnesia was induced by scopolamine (1 mg/kg, i.p.) after 30 min of treatment. Cognitive functions were determined by employing passive shock avoidance task and novel object recognition test. Brain AChE and lipid peroxidation were determined to have an insight into the associated neuroprotective mechanism of GME.

Result

Treatment with GME showed dose dependent amelioration of cognitive deficit induced by scopolamine in animals. Also, GME reduced the brain AChE activity and oxidative stress.

Conclusion

These results indicated the anti‐amnesic effects of GME via decreasing brain cholinergic and oxidative stress.
Pre‐analytical and clinical validation on the highway to implementation of novel dementia blood tests
Authors: Teunissen Charlotte E.
Published: December 2021

Background

Blood based biomarkers for Alzheimer’s disease and other dementias are now a reality. Results in large well‐defined research cohorts suggest high potential for implementation for diagnosis (pTau, amyloid isoforms, GFAP), prognosis (pTau, GFAP, NfL) or monitoring (pTau, NfL) in clinical practice and treatment development. Implementation of novel blood based biomarkers requires several aspects to be addressed, among which pre‐analytical sample handling, patient heterogeneity and the development of cut‐offs and computer‐assisted tools for interpretation.

Method

To mimic pre‐analytical variations occurring in current practice, systematic experiments were performed and effects on plasma Amyloid beta(42/40), (p)Tau, NfL and GFAP levels were measured using different technologies. To understand patient heterogeneity, these markers are measured in several cohorts of normal aging elderly using Simoa technology. To develop cut‐offs and tools for interpretation, these markers are measured in a retrospective cohort of patients with various dementias. Lastly, prospective analysis of these markers in the memory clinic setting has been started.

Result

The generated knowledge on the most important pre‐analytical factors affecting Amyloidbeta(42/40), (p)Tau, NfL and GFAP levels resulted in the construction of a standardized operating procedure for use in clinical practise and research (Figure). Results in the normal aging population followed longitudinally show that these biomarkers are higher in patients that are proven to be amyloid positive 10 year later. Detailed results of patient biomarker heterogeneity will be presented as well as a decision tool for use in clinical practice. Lastly, pilot data on experience with these novel blood based biomarkers and the decision tools for dementia diagnosis in the memory clinic setting will be presented.

Conclusion

Together, the addressed are important steps towards smooth and widespread implementation of blood based biomarkers in clinical practise.
CSF and blood plasma mass spectrometry measures of Aβ, tau, and NfL species and longitudinal relationship to preclinical and clinical staging of amyloid and tau aggregation and clinical stage of Alzheimer’s disease
Authors: Bateman Randall J. , Barthelemy Nicolas R. , Benzinger Tammie L.S. , Bollinger James G. , Fagan Anne M. , Gordon Brian A. , Hansson Oskar , Holtzman David M. , Horie Kanta , Li Melody , Masters Colin L , Mawuenyega Kwasi G. , McDade Eric , Morris John C. , Ovod Vitaliy , Budelier Melissa , He Chloe , Petersen Ronald C. , Mielke Michelle M. , Sato Chihiro , Schindler Suzanne E. , Shaw Leslie M. , Trojanowski John Q , Weiner Mike W. , Xiong Chengjie
Published: December 2021

Background

Recent advances in the development of novel Alzheimer’s disease (AD) measures of amyloid, tau, and neurodegeneration in cerebrospinal fluid (CSF) and blood have enabled a better understanding of the links between amyloid‐beta (Aβ), tau species and neurodegeneration in the brain, CSF, and blood. The discoveries of novel tau species in CSF and blood, including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, have greatly expanded our understanding of tau biology and tau target development. The longitudinal Aβ, tau, and neurofilament light chain (NfL) changes previously measured in CSF are now being measured accurately in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.

Method

We analyzed longitudinal CSF and/or blood plasma mass spectrometry measures of Aβ42/Aβ40, multiple p‐tau species (including p‐tau217, 231, 181, 205, etc.), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in sporadic AD and dominantly inherited AD cohorts. Mass spectrometry results were compared to amyloid and tau aggregation measures by Positron Emission Tomography (PET) scans and clinical and cognitive measures in local and international clinical cohorts including ADNI, AIBL, BioFINDER, Mayo Clinic, the Knight ADRC, and the DIAN.

Result

The longitudinal results indicate that a pathophysiological cascade of events begin with altered CSF and blood plasma Aβ42/Aβ40 ratio, followed by increases in amyloid plaques as measured by amyloid PET, associated with increased phosphorylation of specific CSF tau species (e.g., p‐tau217, p‐tau181, etc.), before increases in p‐tau205, NfL, total tau concentrations, hypometabolism, and atrophy. Finally, some species of MTBR‐tau increase before or with tau aggregation by tau PET and onset of clinical symptoms and correlate with longitudinal tau aggregation and clinical progression.

Conclusion

These findings indicate that CSF and blood plasma Aβ, p‐tau, MTBR‐tau and NfL measures are highly precise biomarkers of brain amyloidosis, tauopathy, and neurodegeneration and can accurately identify stages of preclinical and clinical AD.
The diagnostic challenge among young onset dementia syndromes and primary psychiatric diseases: Results of a retrospective, 20‐year cross‐sectional study
Authors: Tsoukra Paraskevi , Velakoulis Dennis , Wibawa Pierre , Malpas Charles B , Walterfang Mark , Evans Andrew H , Farrand Sarah , Kelso Wendy , Eratne Dhamidhu , Loi Samantha M
Published: December 2021

Background

Distinguishing a dementia syndrome from a primary psychiatric disease in younger patients can be challenging and may lead to diagnostic change over time. The aim of this study was to examine diagnostic stability in a cohort of patients with younger‐onset neurocognitive disorders.

Method

We retrospectively reviewed records of patients that were admitted to our unit between 2000 and 2019, were followed‐up for ≥12 months and received a diagnosis of young onset dementia at any time point. Initial diagnosis included Alzheimer disease (AD)‐type dementia (n= 30), frontotemporal dementia (FTD) syndromes (n=44), vascular dementia (VaD, n=7), mild cognitive impairment (MCI, n= 10), primary psychiatric diseases (n=6) and other conditions such as Lewy Body Dementia (n=30).

Result

In a total of n=127 patients, 49 (39%) changed their initial diagnoses during follow‐up. Behavioural variant FTD (bvFTD) was the least stable diagnosis, followed by dementia not otherwise specified and MCI. Compared to patients with a stable diagnosis, those who changed exhibited: a higher cognitive score at baseline, a longer follow‐up period, greater delay to final diagnosis, and no family history of dementia. Patients switching from a neurodegenerative to a psychiatric diagnosis more likely had a long psychiatric history, while those changing from a psychiatric to a neurodegenerative diagnosis had a recent manifestation of psychiatric symptoms.

Conclusion

Misdiagnosis in younger patients with neurocognitive disorders is not uncommon, especially in cases of behavioural variant FTD. Late‐onset psychiatric symptoms may be the harbinger to a neurodegenerative disease. Close follow‐up and monitoring of these patients are necessary.
Cerebellar atrophy in non‐fluent variant primary progressive aphasia correlates with disease severity and cognitive decline
Authors: Akhmadullina Diliara , Konovalov Rodion , Fedotova Ekaterina , Illarioshkin Sergey
Published: December 2021

Background

The role of the cerebellum in cognitive function has been extensively investigated in the last decades. The aim of our work was to characterize cerebellar atrophy in non‐fluent variant primary progressive atrophy (nfvPPA) and to determine whether its atrophy is associated with cognitive impairment.

Method

Sixteen patients with nfvPPA (mean age 59.6±9.2 years, 7 males) and 10 healthy controls (65.6±11.3 years, 4 males) were included in the study. Disease duration ranged from 12 to 84 months. Notably, the patients had no clinical signs of cerebellar involvement. All participants underwent brain MRI and cognitive assessment. A whole brain VBM analysis between patients and controls was carried out using SPM12. The relationship between clinical data and grey matter atrophy of cerebellum and its distinct areas (anterior lobe, posterior lobe, vermis, left and right hemispheres) was assessed by correlation analysis using the Spearman's rank correlation coefficient.

Result

VBM revealed a significant decline in grey matter (GM) volume in the anterior (specifically, 4, 5 and 6 lobules) and posterior (specifically, Crus I and II, 7b and 8 lobules) cerebellar lobes bilaterally compared to controls (Figure 1). Correlation analysis revealed a significant correlation between the posterior lobe GM volume and disease severity and total Addenbrooke Cognitive Examination score (r = ‒0.62, p = 0.01 and r = 0.69, p = 0.028, respectively). No correlations with other clinical manifestations and neuropsychological findings (disease duration, total MoCA and FAB scores, semantic and literal verbal fluency, Trail Making Test part B) were detected.

Conclusion

The findings demonstrate that, even in the absence of clinical signs of cerebellar involvement, prominent cerebellar atrophy is characteristic of nfvPPA. This atrophy is associated with disease severity and contributes to cognitive dysfunction.

The study was supported by RFBR 19‐015‐00533.
Levels and trajectories of domain‐specific cognition differ across lifestyle engagement subgroups of older adults
Authors: Moored Kyle D , Parisi Jeanine M , Snitz Beth E , DeKosky Steven T , Williamson Jeff D , Fitzpatrick Annette L , Carlson Michelle C
Published: December 2021

Background

Engagement in lifestyle activities may be neuroprotective, but longitudinal data is needed to best inform health interventions. Characterizing the prospective impact of shared lifestyle activities among older adults may both identify subgroups who could benefit most from intervention and reveal contextual/motivational differences in lifestyle that are relevant to group‐level intervention design. We used latent class analysis to characterize qualitatively distinct lifestyle engagement groups and examined whether they had differential declines in global and domain‐specific cognition.

Method

Participants were 3068 individuals from the Ginkgo Evaluation of Memory (GEM) Study who completed neuropsychological testing up to 8 years (M=5.0, SD=2.4). We assessed 18 physical, intellectual, and social activities using the Lifestyle Activity Questionnaire. Linear mixed effects models adjusted for demographic and health covariates were used to examine lifestyle engagement group differences in cognitive level and changes over time.

Result

The four‐class model fit best (Figure 1). The Variety lifestyle group (22%) had high engagement in both intellectual (e.g., taking classes) and social activities (e.g., concerts, church, social clubs). The Intellectual (18%) group had high engagement in intellectual and some social leisure activities (e.g., concerts). The Social (32%) group had high engagement in social institutional activities (e.g., church). Compared to the Least Active (28%) group, the Variety (B’s=.14‐.25, p’s<.05) and Intellectual (B’s=.10‐.29, p’s<.05) groups had greater levels of cognitive performance across all domains, whereas the Social group was only higher in memory (B=.11, SE=.04, p=.013; Table 1). The Variety group also had attenuated declines in memory (B=.02, SE=.01, p=.035) and attention (B=.02, SE=.01, p=.023) over time.

Conclusion

Higher lifestyle engagement, especially in intellectual activities, was associated with higher levels of cognition later in life. Yet, only those with the greatest diversity of activities (Variety group) were protected against subsequent declines in memory and attention. These results extend prior findings that these lifestyle groups differ in risk of incident dementia, by suggesting that memory and attention (vs. visuospatial construction) drive this protective relationship. Our findings also highlight subgroup differences in activity types (e.g., primarily social vs. intellectual) that may lead to more targeted interventions to reduce cognitive declines with age.
Clinical and biological heterogeneity in autosomal dominant Alzheimer's disease
Authors: Quiroz Yakeel T. , Aguilar Laura Ramirez , Giraldo‐Chica Margarita , Aguillon David , Baena Ana Y. , Bocanegra Yamile , Vila‐Castelar Clara , Fox‐Fuller Joshua T. , Pluim Celina F. , Aduen Paula , Lopera Francisco
Published: December 2021

Background

Presenilin‐1 (PSEN1) mutations cause early‐onset autosomal dominant Alzheimer’s disease (ADAD) with nearly 100% penetrance, providing an opportunity to characterize the biological changes associated with preclinical AD. Over 280 different ADAD mutations are currently identified. In Antioquia, Colombia, there are two PSEN1 cohorts, including the world’s largest family with the E280A mutation (consisting of over 1,200 mutation carriers). The clinical phenotype of ADAD is similar to sporadic AD, though some cases have atypical presentations and vary in age at clinical onset and disease course. Here, we reviewed the clinical and biological profiles of these two large families with ADAD.

Method

Members of two large Colombian families with ADAD were included (PSEN1 mutations: 60 E280A carriers, 26 Ile416Thr carriers). All participants underwent a comprehensive clinical and cognitive assessment. Diagnosis of Mild Cognitive Impairment (MCI) and dementia was blind to carrier status. A subset of the E280A (n=35) and Ile416Thr (n=3) mutation carriers also underwent tau and amyloid PET imaging.

Result

The PSEN1 E280A clinical profile is characterized by memory decline beginning in the early 30s, followed by progressive impairment of other cognitive functions. These carriers develop MCI around age 44 and dementia around age 49. There is some phenotypic variability in PSEN1 E280A; some carriers present with epilepsy and ataxia. PET imaging of E280A carriers show a pattern of amyloid and tau pathology similar to that seen in sporadic AD. However, a few cases show distinct patterns of tau accumulation, involving early tau pathology in occipital and parietal regions, absence of tau in medial temporal lobe, and variable cognitive profiles. The Ile416Thr cognitive profile consists of early memory and verbal comprehension impairments. Carriers develop MCI at a mean age of 48 and progress to dementia at age 52. PET imaging of Ile416Thr carriers shows an initial pattern of tau accumulation limited to medial temporal lobe regions.

Conclusion

The clinical and biological profiles of ADAD mutations can be heterogenous. Variable cognitive and clinical phenotypes may explain different trajectories of disease progression and response to treatments in clinical trials. Future studies should examine other biological similarities and differences among ADAD mutations.
Associations between psychophysiological stress responses, inflammatory markers, and CSF biomarkers in the spectrum of Alzheimer’s disease
Authors: Oh Hwamee , Leung Hoi‐Chung , Canli Turhan , Slifstein Mark , Park Elliot Y.
Published: December 2021

Background

Although genetic factors associated with the aggregation of misfolded proteins clearly play a role in Alzheimer’s disease (AD), several individual difference factors have been seen to confer an increased risk for the clinical manifestation of AD as well as the development of AD pathology. One of the key factors is an individual’s susceptibility to psychological stress. The goal of this study was to examine the relationships between psychophysiological stress responses measured by plasma stress hormones and neuropsychiatric symptoms, inflammatory markers, and AD pathology along the spectrum of AD.

Method

Alzheimer’s Disease Neuroimaging Initiative (ADNI) consists of 819 adult subjects— 229 cognitively normal older adults (CNs), 398 participants with mild cognitive impairment (MCIs), and 192 patients with AD. Of these subjects, we included 58 CNs, 396 MCIs, and 112 AD patients whose plasma stress measures were available. Plasma cortisol and cytokines and CSF Aβ1‐42, t‐tau, and p‐tau181 data were downloaded from ADNI. Neuropsychiatric Inventory (NPI‐Q) total scores were used to indicate a psychological stress level.

Result

AD stages were significantly related to the level of plasma cortisol and NPI‐Q total scores showing that AD patients exhibit the highest level of cortisol and greater severity of psychological symptoms followed by MCIs and CNs. AD stages were also significantly related to the level of inflammatory markers measured by cytokines, although the level of inflammatory markers in relation to the diagnostic groups varied across different types of cytokines. Plasma cortisol levels did not relate to concurrent levels of CSF Aβ1‐42 either across diagnostic groups or within diagnostic groups. Higher plasma cortisol, however, corresponded to higher CSF p‐tau among CNs, but not in MCIs and ADs.

Conclusion

Psychophysiological stress responses and inflammatory markers are significantly associated with the disease severity. A positive relationship between plasma cortisol level and CSF p‐tau in CNs may indicate a role of individuals’ susceptibility to stress in neuronal hyperexcitability in the early stage of AD and confer a risk of neurodegeneration and the development of AD. Alleviating stress and regulating stress responses may be important modifiable factors that help prevent AD.