bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers for the detection of progressive early Alzheimer’s Disease
Authors: Cai Yuan , Liu Wanting , Fan Xiang , Shi Lin , Au Lisa Wing Chi , Mok Vincent C.T.
Published: June 2023

Background

We investigated the ability of MRI, plasma, and cognitive biomarkers in detecting preclinical or prodromal Alzheimer’s Disease (AD) who will progress to the next syndrome stage of the cognitive continuum.

Method

589 subjects with longitudinal cognitive data were recruited from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which included 227 cognitive unimpaired (CU) and 362 mild cognitive impairment (MCI) subjects. Preclinical or prodromal AD was defined by a low amyloid beta (Aβ)42 (A+) and high phosphorylated ‐tau (p‐tau) (T+) on cerebrospinal fluid (CSF) assessment at baseline. The following baseline MRI biomarkers were derived by an automatic segmentation tool (AccuBrain®): AD‐resemblance atrophy index (AD‐RAI), quantitative medial temporal lobe atrophy (QMTA) and hippocampus volume (HV). Plasma biomarkers included p‐tau 181, neurofilament (NFL) and APOE ε4. Montreal Cognitive Assessment (MoCA) score was collected for all subjects at baseline. Conversion (C+) was defined as subjects progressed from CU to MCI and from MCI to dementia within 4 years.

Results

Of the 589 subjects (mean [SD] age, 72.2 [6.9] years; 314 men [53.3%]), 96 (16.3%) were A+T+C+ and 180 (30.6%) were A+T+C‐. In the ROC analysis, AD‐RAI achieved the best detection ability than other individual biomarker with a sensitivity of 83.4%, a specificity of 69.4% and an AUC of 87.8%. A combination of AD‐RAI, plasma p‐tau 181, APOE ε4 and MoCA score achieved the best detection ability with AUC of 89.8%, sensitivity of 85.1% and specificity of 80.2%. In the subgroup analysis, the combination of AD‐RAI, plasma p‐tau 181, APOE ε4 and MoCA score also showed good accuracy in identifying A+T+C+ subjects in the CU group (AUC = 87.6%) and in the MCI group (AUC = 89.3%).

Conclusion

A panel of MRI, plasma and cognitive biomarkers might help to detect progressive early AD subjects.
Resolvin E1 ameliorates diabetes‐related cognitive impairment via ChemR23
Authors: Zhang Jiawei , Zhao Yuwu , Wang Xiuzhe
Published: June 2023

Background

Diabetes mellitus (DM) is an independent risk factor for cognitive dysfunction. The resolvin E1 (RvE1)/ChemR23 axis is involved in the progression and complications of DM. However, the impact of the RvE1/ChemR23 axis on diabetes‐related cognitive impairment remains unclear.

Method

Aging‐related behavioral changes in db/db diabetic mice and age‐matched nondiabetic controls were assessed, and changes of ChemR23 in the hippocampus were studied.

Result

The results showed that db/db mice exhibited age dependent learning and memory impairments in the Morris water maze test, along with reduced expression of ChemR23 in the hippocampus compared with age‐matched wild‐type mice. Moreover, neuronal damage, oxidative stress, and neuroinflammation were also observed in db/db mice. A moderate dose of RvE1 for 4 weeks elicited a significant reduction in memory loss, along with reduced neuronal damage, alleviation of oxidative stress, and attenuated neuroinflammation in diabetic mice but not in ChemR23‐knockout diabetic mice.

Conclusion

Collectively, our study suggested that RvE1 could ameliorate DM‐related cognitive dysfunction by reducing oxidative stress and neuroinflammation in a ChemR23‐dependent manner.
Establishing and validating unbiased cut‐offs for tau PET with Gaussian mixture model in Alzheimer’s disease
Authors: Quattrini Giulia , Ferrari Clarissa , Alchera Nicola , Ribaldi Federica , Garibotto Valentina , Frisoni Giovanni B , Pievani Michela , Marizzoni Moira
Published: June 2023

Background

Tau PET positivity (T+) is recommended in Alzheimer’s disease (AD) trials involving preclinical and prodromal AD. As unbiased cut‐offs are still lacking, we established and validated data‐driven T+ PET cut‐offs for AD.

Method

Data were from ADNI (estimation cohort) and Geneva memory center (validation cohort). 18F‐Flortaucipir standardized uptake value ratios (SUVr) were computed for a global temporal meta‐ROI and for cortical regions corresponding to Braak‐based stages I‐VI in amyloid negative (Aβ−) cognitively normal (CN), Aβ+ CN, Aβ+ MCI and AD. For Tau PET data‐driven cut‐off estimation, Gaussian mixture model (GMM) was applied on the global and regional SUVr distributions in Aβ− CN and AD (n = 269). The GMM cut‐offs’ performance was compared with published 18F‐Flortaucipir cut‐offs (Mattsson et al., 2017) by assessing the percentage of T+ subjects within each diagnostic group.

Result

Cut‐offs were 1.36 for temporal meta‐ROI and ranged 1.20‐1.39 for stages. In the validation cohort, all Aβ− CN were tau negative (T−), while T+ percentage increased along the Aβ+ continuum (CN<MCI<AD) for temporal meta‐ROI (33<64<75) and stages I‐II (50<73<75), III (17<55<58), IV (17<57<75), V (0<18<50) and VI (0<5<33). Previously published cut‐offs reported a higher frequency of T+ in the AD spectrum and identified T+ subjects in the Aβ‐ CN group.

Conclusion

GMMs unbiased 18F‐Flortaucipir SUVr cut‐offs showed lower T+ percentage in Aβ− CN than published cut‐offs, possibly indicating lower false positive rates and suggesting that they might be useful for the in‐vivo assessment of participants eligibility in future preclinical and prodromal AD trials.
Renal function affects circulating levels of neurofilament light chain: MarkVCID‐CHARGE
Authors: Aparicio Hugo J , Himali Jayandra Jung , Satizabal Claudia L. , Li Zhiguang , Mbangdadji Djass , Pase Matthew P. , Gonzales Mitzi M. , Ghosh Saptaparni , Gudnason Vilmundur , Beiser Alexa S. , Longstreth W.T. , Psaty Bruce M. , Fornage Myriam , Tracy Russell P. , Launer Lenore J. , Bis Joshua C , Seshadri Sudha
Published: June 2023

Background

Plasma NfL is a promising fluid biomarker for risk stratification and quantifying the extent of neuronal injury in conditions such as vascular cognitive impairment and dementia (VCID) and Alzheimer’s dementia. However, systemic factors such as kidney function can affect circulating levels and this requires further investigation to ensure appropriate use as a biomarker.

Method

We examined the cross‐sectional association between plasma NfL levels and renal function among adult participants from four community‐based studies in the MarkVCID‐Cohorts for Heart and Aging Research in Genomic Epidemiology consortium who were free from stroke, multiple sclerosis, dementia, and renal failure. Estimated glomerular filtration rate (eGFR, mL/min/1.73m2) was calculated using the CKD‐EPI equation and categorized using Kidney Disease: Improving Global Outcomes (KDIGO) classification. Plasma NfL was measured using single molecule array technology. Multivariable linear regression models were used to investigate the linear relationship between eGFR and NfL, overall and stratified by KDIGO category. Study level estimates were combined in meta‐analysis. Models were adjusted for age, sex, sub‐cohort, hypertension, diabetes, body mass index, smoking, and race. Factors affecting eGFR can also cause MRI brain injury, hence we examined whether any apparent increase in NfL levels in persons with a lower eGFR merely reflected greater brain injury by performing a sensitivity analysis in a subsample with brain MRI, additionally adjusting in a single model for brain volume, white matter hyperintensities, and free water.

Result

In meta‐analysis (n = 5,954), lower eGFR was associated with higher plasma NfL (β = ‐0.0073, standard error[SE] = 0.0021, P = 0.0006). This relationship persisted within categories of reduced renal function, eGFR 60‐74 (mild), 45‐59 (moderate), and 15‐44 (severe) (P‐values<0.0001), but was not evident with normal eGFR ≥90 (P = 0.3) or mildly decreased eGFR 75‐89 (P = 0.2). Further adjustment for white matter hyperintensities, brain volume, and free water among a subgroup with brain MRI (n = 2192) did not change the associations of eGFR and NfL (β = ‐0.0065,SE = 0.0025, P = 0.0091).

Conclusion

Reduced renal function is associated with higher circulating NfL, even at an eGFR range (60‐74) considered normal in clinical practice. Adjusting for renal function may improve the accuracy of plasma NfL as a biomarker for risk stratification or for assessment of neuronal injury in conditions such as VCID.
Aerobic exercise prevents white matter microstructural degeneration in MCI adults
Authors: Kim Jeongchul , Barcus Richard A. , Lipford Megan E. , Lockhart Samuel N. , Jung Youngkyoo , Craft Suzanne , Baker Laura D , Whitlow Christopher T.
Published: June 2023

Background

While the use of non‐pharmacological interventions—such as physical activity, nutritional supplementation and cognitive stimulation—to prevent or delay cognitive decline and the onset of Alzheimer’s disease (AD) has received increasing attention, evidence supporting the benefits of these interventions have been mixed, and underlying mechanisms are not well‐understood.

Method

In participants enrolled in the PACE‐2 trial, which examined the impacts of 6‐month physical activity intervention on brain and cognitive outcomes, we evaluated the effects of aerobic exercise (n = 15, 63±10 yrs) on longitudinal changes in brain morphometry and white matter microstructure compared to stretching exercise controls (n = 17, 67±7 yrs.) using MRI among pre‐diabetic mild cognitive impairment adults. High‐resolution structural T1‐weighted and diffusion‐weighted images (DTI) were acquired before and after exercise intervention. Group differences in MRI markers (cortical volume and thickness, white matter DTI and free water metrics) after intervention and their longitudinal changes were compared for 68 cortical (Desikan‐Killany Atlas) and 48 white matter (JHU WM Atlas) regions using FreeSurfer SPM, FSL and Nextflow.

Result

No statistically significant group difference in cortical thickness, volumes and conventional DTI metrics was observed. On the other hand, free water (FW)‐corrected fractional anisotropy (FA) remained unchanged in aerobic exercise group (p = 0.32) while FA decreased in stretching controls in the right cerebral peduncle(p<0.001), resulting in group differences in FW‐corrected FA after 6‐month exercise intervention (p = 0.02 after Bonferroni correction). These changes in stretching exercise group were negatively correlated with FW fraction changes (marker related with neuroinflammation) (r = ‐0.71, p = 0.001).

Conclusion

Aerobic exercise could have neuroprotective effects by preventing white matter degeneration, and FW fraction and FW‐corrected imaging markers could be useful for more sensitive detection of early AD sign.
Cholesterol‐related APOB Thr98Ile correlates with brain cortical APOB mRNA levels
Authors: Picard Cynthia , Aumont‐Rodrigue Gabriel , Poirier Judes
Published: June 2023

Background

Apolipoprotein B (APOB) is well‐known for its role in cholesterol metabolism. We recently showed that APOB protein levels are elevated in the CSF of patients suffering from sporadic Alzheimer’s disease (AD) compared to control individuals (Picard et al, Alzheimers Dement. https://doi.org/10.1002/alz.12442). Since rare coding APOB variants were discovered in association with early‐onset familial Alzheimer’s disease (Wingo et al, JAMA Neurol. 2019), we hypothesized that common APOB variants could influence molecular mechanisms leading to sporadic AD.

Method

Publicly available genomic and transcriptomic data were screened for possible interactions between APOB single nucleotide polymorphisms (SNPs) and brain APOB mRNA levels. Potential regulatory SNPs were contrasted with blood cholesterol levels obtained from the Global Lipids Genetics Consortium (GLGC), in order to highlight their systemic effects. Brain tissue cholesterol levels were measured in frontal cortices of autopsy‐confirmed controls and AD subjects from the Douglas‐Bell Canada Brain Bank (DBCBB) using high performance liquid chromatography (HPLC). DNA extracted from those samples was used to perform APOB locus genotyping with the help of the Illumina Global Screening Array (GSA) chip.

Result

The APOB Thr98Ile variant commonly associated with familial hypercholesterolemia was found to correlate with a significant reduction of brain cortical APOB mRNA levels in three different cohorts. In GLGC cohort, this SNP strongly associates with elevated LDL‐cholesterol levels measured from blood samples of 188 578 individuals (p = 9.48E‐183). Our preliminary analysis shows that APOB Thr98Ile also correlates with elevated cholesterol levels (r2 = 0.36; p < 0.005) measured in brain cortical samples. Using public databases with available genotypic and AD‐related neuropathological data, inconsistent associations were found between APOB Thr98Ile variant and sporadic AD pathophysiological changes in the brain. Ongoing studies in our laboratory are examining the impact of APOB Thr98Ile variant on APOB mRNA and protein levels in relation to classical AD pathological markers in a large group of AD and control subjects.

Conclusion

Although APOB Thr98Ile is significantly associated with gene regulation and cholesterol levels measured in blood and brain samples, its effect on AD neuropathology remains to be clearly defined and is the subject of current investigations.
Plasma p‐tau181 for the differential diagnosis of cognitive impairment in a prospective, daily clinical practice cohort
Authors: Sarto Jordi , Guillén Núria , Ramos‐Campoy Oscar , Contador José , Fernandez‐Villullas Guadalupe , Tort‐Merino Adrià , Juncà‐Parella Jordi , Martínez Neus Falgàs , Borrego‐Écija Sergi , Ruiz‐García Raquel , Naranjo Laura , Vergara Miguel , Antonell Anna , Lladó Albert , Sanchez‐Valle Raquel , Balasa Mircea
Published: June 2023

Background

Currently used biomarkers for the differential diagnosis of cognitive impairment are expensive and/or relatively invasive, limiting their availability to the general population. Blood protein biomarkers have showed promising results for screening, differential diagnosis, and prognosis. We aimed to study the diagnostic performance of plasma p‐tau181 in a daily clinical practice, prospective memory clinic cohort.

Method

All patients referred for a first clinical evaluation with suspected cognitive impairment between January 1st, 2020 and March 30th, 2021, were invited to participate in the study. Plasma p‐tau181 was measured using SIMOA technology (Quanterix). Clinical diagnoses were made following current diagnostic criteria and blinded to plasma p‐tau181 results.

Result

A total of 232 participants were recruited (mean age 69y, mean MMSE 24), including 25 cognitively unimpaired (CU) controls (mean age 67y, MMSE 28). Clinical diagnoses were AD (82 subjects, 43 of them with prodromal AD [CDR = 0.5]), 83 non‐neurodegenerative cognitive impairment (non‐ND, 75 of them CDR = 0.5), 22 frontotemporal dementia (FTD) and 20 Lewy body disease (LBD).

Plasma p‐tau181 levels were statistically higher in AD (mean 2.39 pg/mL) compared with CU (mean 1.09 pg/mL), non‐ND (mean 1.43 pg/mL), FTD (mean 1.69 pg/mL) and LBD (mean 1.64 pg/mL) with a relatively good diagnostic performance for the differential diagnosis between AD and CU, non‐ND, LBD and FTD (AUC of 0.89, 0.80, 0.73 and 0.71, respectively).

128 subjects (55% of the cohort) had specific AD biomarkers (CSF or PET) available. In this subgroup, p‐tau181 differentiated AD from CU and non‐ND (AUC 0.91 and 0.92, respectively) and prodromal AD from CDR = 0.5 non‐ND participants (2.32 vs 1.02 pg/mL, p<0.001, AUC 0.90). Plasma p‐tau181 discriminated between a positive and negative amyloid beta status (defined by CSF/PET) with an AUC of 0.87 and AD subjects from those with a clinical diagnosis of LBD and FTD who had a negative amyloid beta status (AUC of 0.94 and 0.86, respectively). Plasma p‐tau181 correlated with CSF p‐tau181 (rs = 0.48, p<0.001).

Conclusion

In our cohort of everyday clinical practice, plasma p‐tau181 is an accurate biomarker for predicting the AD pathophysiological process and discriminating AD from other neurodegenerative and non‐neurodegenerative causes of cognitive impairment.
Early identification of cognitive impairment among vulnerable older adults living at home
Authors: Brown Maria Teresa , Brangman Sharon A
Published: June 2023

Background

African Americans are twice as likely as Caucasians to develop Alzheimer’s Disease and Related Dementias (AD/ADRD) and less likely to seek a diagnosis before experiencing a crisis. This study evaluated the impact of adding Mini‐Cog© screenings to Area Agency on Aging (AAA) assessments on early detection of cognitive impairment among low‐income older adults.

Method

Mini‐Cog™ assessments were offered to new and existing clients of a AAA Neighborhood Advisor. Clients with scores indicating impairment were referred to an academic geriatric practice for comprehensive evaluation. Inclusion criteria were age 65 or older, English speaking, living at home in the Advisor’s service area, and not previously diagnosed as AD/ADRD. Data collected over 9 months included Mini‐Cog™ scores, age, race, ethnicity, and geriatric referrals. Quantitative analysis included bivariate descriptive statistics (significance alpha of .10) and simple linear regression (significance alpha of .05).

Results

Of 69 study participants, 84% were female, 54% African American, and 93% non‐Hispanic. Mean age was 74.7 years and mean Mini‐Cog™ score was 3.61 (range: 0‐5). Independent t‐tests show that African American participants had lower Mini‐Cog™ scores than Caucasians (3.35±.23 vs 3.91±.22, p = .092). Caucasian males were younger with higher cognition scores than Caucasian women and African American males were younger with lower scores than African American females. Participants qualifying for referral (18 or 26%) were significantly older than those who did not (74.4 vs 70.0, p<.05). Of 11 participants offered referrals, all Caucasians (3) declined and 5 of 8 African Americans (62%) accepted. Regression analysis determined that Mini‐Cog™ scores were associated with older age (β* = ‐0.255, SE = 0.02, p<.05) and being African American (β* = ‐0.261, SE = .344, p<.05) but not with sex, ethnicity, or living alone.

Conclusion

Results show that 25% of participants were identified with previously undetected cognitive impairment and that trained social service providers can effectively administer the Mini‐Cog™ instrument to assess cognitive impairment. Large scale studies are needed to further evaluate use of the Mini‐Cog™ instrument in early detection of cognitive impairment in minority and economically vulnerable older adults in non‐clinical settings.
Amyloid and tau deposition influences cognitive and functional decline in Down Syndrome
Authors: Grigorova Monika , Mak Elijah , Brown Stephanie S G , Beresford‐Webb Jessica , Hong Young T , Fryer Tim D , Coles Jonathan P , Aigbirhio Franklin I , Tudorascu Dana L. , Cohen Ann D. , Christian Bradley T. , Ances Beau , Handen Benjamin L. , Laymon Charles M , Klunk William E , Clare Isabel , Holland Anthony J , Zaman Shahid
Published: June 2023

Background

Down Syndrome (DS) is the most common neurodevelopmental disorder caused by the presence of trisomy 21 (1:800 to 1:1000 live births worldwide). The extra copy of chromosome 21 is associated with a 4‐5 fold overexpression of the amyloid precursor protein (APP) gene, increased accumulation of cerebral beta‐amyloid (Aβ) in the brain, subsequent neurofibrillary tangle (NFT) formation and neurodegeneration. This study investigates whether tau has (i) an independent effect from amyloid on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid in the exacerbation of decline in aging DS.

Method

105 participants with DS underwent baseline PET AV‐1451 and PET PiB scans to quantify tau deposition in Braak regions II‐VI and Striatum and amyloid‐β status respectively. A longitudinal cognitive testing battery was performed consistent with previous research in the same study cohort, with all participants completing at least two timepoints, and 26 completing three timepoints, with an average of 17 months between study visits. Linear Mixed Effects models were implemented to assess how tau and amyloid deposition are related to change over three time points.

Result

Three cognitive outcome measures showed a significant effect of time: the Free + Cued Recall (t = ‐6.09, p < 0.01), Cued Intrusions (t = 3.19, p < 0.01) and NTG (z = 5.33, p = 0) variables. Tau SUVR was a significant independent predictor of cognitive and functional change. The three‐way interaction between time, PiB status and tau was significant in the models of episodic memory and visuospatial cognition (Figures 1‐3).

Conclusion

Our results contribute to an emerging framework in which the elevated risk of developing dementia involves mechanisms associated with both amyloid‐β and tau aggregation. This is supported by our finding that when including the two‐way interactions between amyloid status and time and regional tau and time in the same model, tau seems to be a more significant predictor of cognitive change over time than amyloid status. Our results suggest a synergistic relationship between PiB status and tau as predictors of change in memory and visuospatial cognition.
Sensorimotor responses and emotional perception in empathy for pain: An study in Alzheimer's disease, Parkinson's disease, and healthy older adults
Authors: Martínez‐Pernía David , Troncoso Alejandro , Blanco Kevin , Rivera‐Rei Álvaro , Olivares Daniela , Grandi Fabrissio , Soto Vicente , Forno Gonzalo , Barría Silvia , Villagra Roque , Slachevsky Andrea
Published: June 2023

Background

Motricity has been proposed to shape our perception and the pre‐reflective knowledge of the other as embodied agents. Through our motor system, we have a meaningful pre‐reflective conception of the experience of the other (empathy). We compared the sensorimotor responses and emotional perception in persons with Alzheimer’s disease (AD), Parkinson’s disease (PD), and healthy older adults (HOA) while they watched videos of sportswomen/sportsmen suffering physical accidents and videos of a neutral condition.

Method

86 participants older than 60 years were recruited (AD = 28, PD = 25, HOA = 33). Subjects with AD were diagnosed following NINCDS‐ADRDA criteria and PD with the United Kingdom Parkinson’s Disease Society Brain Bank. The assessment consisted of two parts. Firstly, a neuropsychological battery that included assessment in global cognition (ACE‐III), executive function (IFS, FAS), memory (FCRST), and social cognition (Minisea). Secondly, participants stood up without moving on a force platform while watching videos (60 seconds long and seven scenes each). One video showed sportswomen/sportsmen having physical accidents practicing extreme sports (pain condition), and the other was a neutral condition (home furnishings). At the end of each video, participants rated valence, intensity, and control (1‐9). Each scene was analyzed through six consecutive windows: three seconds before the fall and three after the fall. The six windows of the neutral condition were selected by taking the central temporal part of each scene. Subsequently, and in each window, the AnteroPosterior amplitude of the Center of Pressure (AP‐CoP) was calculated.

Results

Participants with AD showed significant impairment in practically all cognitive domains, compared to PD and HOA. An Anova (group*condition*temporal windows) revealed a simple effect on group and condition in AP‐CoP displacement. AD and PD showed higher AP‐CoP in both pain and neutral condition than HOA. PD and HOA showed higher AP‐CoP in pain condition than neutral condition, but not AD. In the ANOVA (group*condition), AD rated (p <0.01) higher the emotional valence in the pain condition (5,93±2,72) than PD (3,52±2,2) and HOA (4,06±2,29).

Conclusion

Sensorimotor responses in AD and PD showed enhanced AP‐CoP when compared to HOA. Moreover, AD patients showed a marked impairment in perceiving empathy towards the pain of others.
Uncovering proteostasis biology causing Alzheimer’s Disease using AMP‐AD transcriptomic data
Authors: Xu Dong
Published: June 2023

Background

Proteostasis biology is the network of various pathways associated with protein homeostasis and malfunction, which is the major cause of developing various neurodegenerative diseases like Alzheimer’s Disease. Recently, Accelerated‐Medicine Partnership – Alzheimer’s Disease consortia has released a huge amount of OMICS data generated by thousands of post‐mortem brains from various cohorts. Such data provides excellent opportunities to gain insight about proteostasis pathway network crosstalk behind Alzheimer’s Disease. As a part of early discovery initiatives using transcriptomic bulk RNA‐seq data derived from post‐mortem brain, AMP‐AD consortia published data‐driven identification of 30 network modules that are supposed to capture disease biology unbiased to any hypothesis. These modules are thousands of genes co‐expressed in the population in various conditions robust to any computational methods, batch effect of cohort‐specific effects.

Method

We explored these AMP‐AD modules from the proteostasis perspective by identifying proteostasis relevant network modules published from AMP‐AD and further integrating additional omics data and network properties to identify candidates associated with Alzheimer’s Disease pathology. We hypothesize that these candidates could be tested for early validation as potential drug targets.

Result

Our analysis shows that proteostasis is one of the major underlying mechanisms confounded in most of the network module. However, certain modules are more enriched for proteostasis‐relevant pathways, suggesting their role in disease progression. Furthermore, some of the proposed candidates are known to be involved in the disease, indicating utility of this analysis providing additional candidates for early validation towards AD therapeutics.

Conclusion

AMP‐AD transcriptomic data analysis provides significant insight on proteostasis biology causing Alzheimer’s Disease.
Sex as a moderator of the association between frailty and mild behavioral impairment
Authors: Guan Dylan X. , Rockwood Kenneth , Smith Eric E. , Ismail Zahinoor
Published: June 2023

Background

Frailty and mild behavioral impairment (MBI) are associated with dementia and sex differences are recognized in both. Each can facilitate early detection and treatment. This study investigated the association between frailty and MBI and whether this association is moderated by sex.

Method

Cross‐sectional data from 219 participants (48.9% female; mean and SD of age = 72.2 ± 6.5 years, and education = 15.8 ± 3.5 years) from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study was analyzed. No participants had dementia: 58 (26.5%) were cognitively normal and 161 (73.5%) had mild cognitive impairment. Frailty was measured using the frailty index (FI); higher scores indicate more health deficits/greater frailty. MBI symptoms were derived from Neuropsychiatric Inventory Questionnaire scores using a published algorithm with a cut‐off of >0 indicating MBI symptom presence. As with the FI, greater MBI severity was indicated by higher scores. Multivariable logistic and linear regressions adjusted for age, sex, education, and cognitive diagnosis were used to test the association between FI and MBI symptom presence and severity, respectively, with MBI as the outcome variable. An FI‐by‐sex interaction term was included in the linear regression model to test for sex‐dependent effects.

Result

The FI mean and SD across the entire cohort was 0.14 ± 0.06 (median = 0.14, IQR = 0.09–0.17, range = 0.02–0.38). Approximately half (51.6%) showed MBI symptoms (mean and SD of severity = 1.8 ± 2.7). Higher FI scores were associated with the presence of MBI symptoms both globally and in the domains of decreased motivation, affective dysregulation, and psychosis (Table 1). Higher FI scores were also associated with more severe MBI symptoms in a sex‐dependent manner: both sexes reported similarly low MBI symptom severity at low (‐1 SD) levels of FI but males reported 1.9x higher MBI symptom severity relative to females at high (+1 SD) levels of FI (Figure 1).

Conclusion

The FI is associated with both the presence and severity of MBI, especially for males. These findings suggest that patients with frailty should be assessed for MBI and that patients with MBI should be assessed for frailty.
The effects of carotid artery stiffness on cerebral small vessel disease and cognition
Authors: Robert Caroline , Lieng‐Hsi Ling , Tan Eugene , Gyanwali Bibek , Venketasubramanian Narayanaswamy , Lim Shir Lynn , Richards Arthur Mark , Chen Christopher , Hilal Saima
Published: June 2023

Background

Carotid artery stiffness is associated with cognitive impairment and dementia, however, the underlying mechanism remains unknown. We examined the association of carotid artery stiffness with cerebral small vessel disease (CSVD) markers, cognitive impairment, dementia with its subtypes, as well as cognitive performance.

Method

In this case‐control study, 272 subjects from a memory clinic underwent physical and medical evaluation along with carotid ultrasonography, 3T brain magnetic resonance imaging and detailed neuropsychological assessment. Carotid ultrasonography was conducted to assess arterial compliance (AC), pressure‐strain elastic modulus (Ep), β‐index, augmentation index (AI), and pulse wave velocity‐β (PWV‐β). Brain MRIs were graded for white matter hyperintensities (WMH), lacunes, and cerebral microbleeds (CMBs). Participants were classified as no cognitive impairment, cognitive impairment no dementia, as well as dementia and its subtypes; Alzheimer’s disease (AD) and vascular dementia (VaD). Cognition was assessed using NINDS–Canadian Stroke Network harmonization neuropsychological battery.

Result

Increased carotid β‐index (β = 0.73, P<0.001), Ep (β = 0.86, P<0.001), and PWV‐β (β = 0.83, P<0.001) were independently associated with WMH. Ep (OR = 1.42, 95%CI = 1.05–1.93), and PWV‐β (OR = 1.43, 95%CI = 1.05–1.94) were associated with presence of lacunes. Ep was associated with AD (OR = 1.59, 95%CI = 1.01‐2.73) and VaD (OR = 2.23, 95%CI = 1.04‐5.94). Additionally, PWV‐β was associated with VaD (OR = 2.24, 95%CI = 1.07–5.62). All carotid artery stiffness measurements, except AI, were associated with worse performance in global cognition, visuomotor speed and memory after adjusting for age, sex, education, hypertension, diabetes, hyperlipidaemia, cardiovascular disease, and smoking. These associations became attenuated but remained significant with global cognition after adjusting for CSVD markers (β‐index; β = ‐0.27, P = 0.04), Ep; β = ‐0.30, P = 0.03), and PWV‐β; β = ‐0.32, P = 0.02).

Conclusion

Carotid artery stiffening is associated with WMH, lacunes, and etiologic subtypes of dementia. Carotid artery stiffening is also associated with global cognition independent of CSVD. Elevated carotid artery stiffness may help identify patients at risk for developing CSVD and dementia.
Methylation age and inflammation in prodromal Alzheimer’s disease
Authors: Behfar Qumars , Andrade Victor , Martin Rafael Campos , Adami Pamela V Martino , Dalmasso Carolina , Kleineidam Luca , Parveen Kayenat , Tripathi Kumar Parijat , Boada Mercè , de Rojas Itziar , García‐González Pablo , Marquié Marta , Puerta Raquel , Brosseron Frederic , Duzel Emrah , Heneka Michael T. , Jessen Frank , Ruiz Agustin , Ramirez Alfredo
Published: June 2023

Background

The most relevant risk factor in Alzheimer’s disease (AD) is age. Aging is a complex process involving several biological changes which lead to chronic cellular stress and to a sterile tissue inflammation. During aging cells become senescent which is seen as morphological changes and secretion of immune signaling mediators associated with systemic low‐grade inflammation. Interestingly, during neurodegenerative processes such AD, microglia, astrocytes, and vascular unit cells become senescent. To explore the potential connection between immune signaling mediators, ageing, and biomarkers of AD, we have quantified in CSF several immune related molecules link to AD and analyzed their connection with known biological clocks.

Method

Biological age was obtained by deriving the epigenetic clock in DNA derived from peripheral blood. To this end, DNA methylation data was generated using the EPIC array from Illumina in two cohorts including 348 individuals (cognitively normal, subjective cognitive decline and mild cognitive impairment) from DELCODE study and 267 individuals (mild cognitive impairment). Data was prepared and normalized using standard quality controls. Horvath’s and Hannum epiClocks were computed for all individuals in both cohorts. AD biomarkers including Amyloid‐ß, phosphor‐tau and total tau along with a panel of inflammation markers were measured in CSF samples.

Result

Both epiClocks showed a significant strong correlation with chronological age in both cohorts. Methylation age and chronological age showed both a significant association with classical AD biomarkers, as well as a subsets of inflammation markers. The meta‐analysis confirmed the association of the Epiclocks and the chronological age with all AD biomarkers as well as with YKL40, sTREM2, C‐1 and MIF. Based on the difference between the calculated epiClock and the chronological age, we derived an index reporting on increase in biological aging rate (age‐acceleration). This index, however, did not show significant association with any of the AD biomarkers and inflammation markers.

Conclusion

Our study shows a link between inflammatory markers and methylation age in both healthy aging and pre‐dementia stages of AD. However, biological clocks derived from peripheral tissue seem to be independent of potential AD pathology and inflammation occurring in the aging brain. Thus, these biomarkers are not increasing the odds for methylation age‐acceleration.
Prognosis of patients with subjective cognitive decline in an unselected clinical sample
Authors: Whitfield Tim , Leal Gonzalo , Praharaju Janaki , Radford Darren , Marchant Natalie L , Schott Jonathan M , Oxtoby Neil P , Walker Zuzana
Published: June 2023

Background

Individuals with subjective cognitive decline (SCD) perceive that their cognition has worsened, but score normally on standardized cognitive tests. It is increasingly recognized that SCD has variable prognosis with the risk of progression to dementia being twice that of age‐matched controls without SCD. This study aimed to characterize an unselected sample of patients with SCD (n = 433) drawn from a larger memory clinic cohort (n = 2,262) and to compare baseline SCD profiles based on follow‐up diagnosis.

Method

This study used routinely‐recorded data from the Essex Memory Clinic (UK). Baseline data included age, sex, years of education, medical and psychiatric history, and physical examination results. A range of neuropsychological measures were administered, and repeated at 12/24‐month intervals. All included patients had at least one follow‐up visit. A consensus diagnosis was made by three clinicians at each visit and was supported by structural CT/MRI investigations. Group comparisons were made using two‐tailed t‐tests, Chi‐squared or Fisher’s exact tests.

Result

The Table presents the results in full. Of 434 patients with SCD diagnosis at baseline, 189 did not progress (SCD‐stable), 169 progressed to dementia (Alzheimer’s = 113; Lewy body = 31; Vascular = 15; Frontotemporal = 4; Other = 6) and a further 76 to mild cognitive impairment (MCI) during follow‐up (median 2.9 years). At baseline there were significant differences between SCD‐stable patients and those who progressed. Patients who progressed to dementia were older than the other two groups. Patients who progressed to MCI/dementia had worse episodic memory (Logical Memory Test delayed and word list recall) and took longer to complete Trail‐Making Test‐A. The SCD‐stable group had higher baseline anxiety and were more likely to have previous psychiatric history versus patients who declined.

Conclusion

In this unselected clinical sample from a non‐academic setting, we have replicated and extended previous findings from research cohorts. Whilst anxiety is a risk factor for dementia, anxiety in the context of SCD is associated with a better prognosis and may be an expression of a subclinical affective disorder rather than prodromal neurodegenerative disease. This project demonstrated clear differences at the group level and the next step is to build data‐driven prognostic models that can be applied to individual patients in a clinical setting.
Artificial intelligence, language and Neuropsychological measures in Alzheimer’s disease
Authors: Battista Petronilla
Published: June 2023

Background

One of the current challenges in the field of Alzheimer’s disease (AD) is to identify patients with mild cognitive impairment (MCI) that will convert to AD. Artificial intelligence, in particular machine learning (ML), has established as one of more powerful approach to extract reliable predictors and to automatically classify different AD phenotypes. It is time to accelerate the translation of this knowledge in clinical practice, mainly by using low‐cost features originating from the language and neuropsychological assessment.

Method

We aim at performing a meta‐analytic evaluation of the contribution of ML and language/neuropsychological measures for the automated classification of AD and MCI patients and the prediction of MCIs’ conversion to AD‐type dementia. Specifically, we study, from the results reported by independent studies, whether ML algorithms, trained on a set of language and neuropsychological measures, could be used for the automatic diagnosis of MCI and AD‐type dementia. To tackle the issue of cross‐linguistic sensitivity, this work spans cohorts of speakers from widely different languages. The advantages and issues that should be taken under consideration for translating these approaches into reliable clinical studies are discussed.

Result

Although a high heterogeneity was observed, this meta‐analysis shows that ML applied to language and neuropsychological measures can lead to a successful automatic classification, being more specific as screening rather than prognosis tool. Relevant categories of language and neuropsychological tests can be extracted by ML that maximize the classification accuracy.

Conclusion

ML applied on language and neuropsychological measures can automatically classify AD patients, even at an early stage of the disease. This brings several advantages, such as the development of more objective and efficient language and neuropsychological batteries for improving the early diagnosis of AD. Future studies should empirically test the combination of methodological features necessary to improve patients’ classification also at the preclinical stages.
Analysis of genetic variants related to oxidative stress in patients with Alzheimer’s disease
Authors: Dorszewska Jolanta , Florczak‐Wyspianska Jolanta , Zasada Aleksandra , Korczowska‐Łącka Izabela , Szymanowicz Oliwia , Kozubski Wojciech
Published: June 2023

Background

Alzheimer’s disease (AD) is one of the common neurodegenerative diseases with an incompletely understood pathomechanism. In AD, generation of oxidative stress is observed as a result of dysfunction of the mitochondrial respiratory chain. The effect of this disturbance is the production of reactive oxygen species (ROS). The SOD2 gene is involved in the elimination of ROS. Glutathione S‐transferases (GST) are a group of enzymes with antioxidant properties that protect cells from ROS damage. GSTP1 gene variants may impair the activity of these enzymes. APOE gene, is also related to the regulation of oxidative stress. In AD patients with APOE E4, higher levels of lipid peroxidation are found. The precise nature of the association between oxidative stress and hallmarks of AD pathology is unknown.

The aim of the study was to analyze of genetic variants of SOD2 c.47T>C (exon 2) and GSTP1 c.341C>T (exon 6) genes in AD patients, control subjects related to AD cases (CR), and controls subjects without family history of AD (CU). The APOE E4 allele was included in the studies.

Method

The studies were conducted on 156 individuals (AD and controls). The APOE genotype was determined by real‐time PCR. The SOD2 and GSTP1 genetic variants were determined by HRM and sequencing. The apoE concentration was determined by the ELISA method.

Result

Variant CC c.47T>C SOD2 was more frequent in CR, while CT in CU. The TT variant of this gene tended to occur more frequently in patients with AD. In AD, the TT variant was more common in the subject without E4 allele (p<0.05). The CC and CT variants of the c.341C>T GSTP1 gene occurred with equal frequency in AD and CR. The TT variant of this gene was not found in the examined subjects. Regardless of the genetic variant of APOE, SOD2, GSTP1, a significantly higher level of apoE was found in CR.

Conclusion

Genes involved in the regulation of oxidative stress may play an important role in the pathogenesis of AD.
A machine learning‐based quality control tool for functional MRI images
Authors: Peraza Luis R , Weatheritt Jack , Wolz Robin
Published: June 2023

Background

Changes in functional MRI (fMRI) have been associated with Alzheimer’s disease and other neurological disorders. Quality control (QC) of images prior to their computational analysis is a key step in a clinical trial analysis workflow, and it is traditionally implemented visually by image analysts. However, the number of images acquired from large clinical studies makes neuroimaging QC a difficult task that diverts skilled resources and introduces inter‐rater variability. This problem is accentuated in fMRI, where image analysts need to visually inspect 4D sequences, and although image processing reports can be used as aid, the problem of having to inspect each report remains.

Method

We implemented an automated fMRI QC process using a stacking classifier (STC), random forest + support vector machine, with imaging quality metrics (IQM) as inputs. The IQMs were estimated with MRIQC. We also added a designed IQM that measures how centred the participant’s brain is within the image. As train/test dataset we used the ABIDE multisite database. For our experiments, only adult brains from the ABIDE database were used, leaving 14 sites available for a leave‐one‐site‐out (LOSO) cross‐validation experiment. All images included in the experiment were visually QC’d using validated protocols at IXICO.

Result

The LOSO validation procedure resulted in a mean pass‐vs‐fail accuracy of 92% (with 5.7% standard deviation, SD). Pass/fail sensitivity and specificity resulted in 97% (6.7% SD) and 69% (29% SD) respectively. We tested a fully trained STC model on an independent dataset of healthy ageing participants from OpenNeuro (ds002872), which resulted in 87% accuracy, 94% sensitivity and 50% specificity, which validates our modelling procedure.

Conclusion

It is possible to design and deploy an automatic QC model for fMRI. Although sensitivity was high in all models from the LOSO experiments, specificity was on average low, highlighting the difficulty of detecting fails in a QC pipeline. However, the STC model can be deployed to detect clear passes that will not need visual QC, reliably reducing the number of cases that require visual inspection. Our future work will focus on testing our developed model on additional datasets (e.g. ADNI) to validate its performance before roll‐out to clinical trial applications.

aging after age 90.
A case study of urban design for wellbeing and mental health in Lagos, Nigeria
Authors: Akindejoye Funmi
Published: June 2023

Background

There are increasing interests in the impact and contribution of urban planning and design on mental health disorders. However, studies are scarce around such concepts within the densely populated urban city of Lagos State, Nigeria. This study explores the literature and expands on experts' opinions on mental health within Lagos’s urban design and planning.

Method

The reviewed literature presents mental health in the context of Lagos’s past, present and future urban planning and design; and identified those factors in the government policies on urban planning and design towards improving mental health. Next, a qualitative analysis of opinions extracted following a semi‐structured interview with experts was presented.

Result

Our findings show that improving mental health in Lagos requires awareness, a safe and aesthetic environment, access to public spaces, reliable transportation, affordable housing and wetland protection.

Conclusion

Although this study suggests that political and socioeconomic factors limit Lagos state’s urban planning and design towards improved mental health, these factors provide opportunities for the state to be a model in Nigeria.
Remote clinical cognitive assessment: Validation of mobile interactive cognitive self‐assessment scale
Authors: Xie Kexin , Cui Yue , Chu Min , Liu Li , Chen Zhongyun , Xia Tianxinyu , Wu Liyong
Published: June 2023

Background

The diagnosis of Alzheimer’s disease relies on trained clinicians and specialized diagnostic tests. Under the circumstances of COVID‐19, the clinical interview is restricted, which caused an additional delay in diagnosis. Emerging demand for remote interactive cognitive assessment aroused for diagnosis and mass screening. We aimed to develop a mobile interactive cognitive self‐ assessment scale (ICSAS)

Method

The ICSAS was created by an expert group applying nominal group techniques and focus groups. Initial examination and iterative rounds were conducted in participants from the community and hospital to optimize the scale. The final version of ICSAS included 4 tasks, covering executive function, logic memory, visual memory, and logic memory recall. Validation was conducted in 387 cognitively impaired participants and 297 participants with normal cognition from the institution. 2034 participants were enrolled from the community.

Result

No significant difference was found in age and sex between cognitively impaired participants and normal controls. Years of education, the score of MMSE and MoCA were higher in normal controls. The Cronbach’s alpha was 0.79 which indicated relative good reliability. The KMO value was 0.76, and the optimal cutoff point was 228.90, leading to the sensitivity of 0.90 and specificity of 0.71. The positive likelihood ratio was 3.10, and the negative likelihood ratio was 0.14, which suggested ICSAS as an ideal scale. 284 participants from the community were predicted to be cognitively impaired, accounting for approximately 15% of participants from the community, which corresponds to the prevalence research.

Conclusion

Our research developed a remote interactive cognitive self‐assessment scale (ICSAS) which has relatively good reliability and sensitivity. The ICSAS may ease the struggle of remote clinical cognitive assessment brought by the COVID‐19 pandemic. Also, from the long‐term perspective, the application of ICSAS may enhance the feasibility of cognitive assessment, and it may be ideal for mass screening and cognitively impaired patients’ monitoring.