bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of inflammatory proteins with cognitive aging, brain MRI markers, and incident dementia
Authors: Fang Yuan , Doyle Margaret F , Mez Jesse B. , Alosco Michael L , Satizabal Claudia L. , Qiu Wendy , Chen Jiachen , Lunetta Kathryn L. , Murabito Joanne M
Published: June 2023

Background

Inflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer’s Disease (AD) dementia. We hypothesized that individual blood‐based inflammatory biomarkers would associate with cognitive function, brain magnetic resonance imaging (MRI) volumes, and risk for dementia in Framingham Heart Study (FHS) participants.

Method

Protein biomarkers related to immune cells or associated with inflammatory responses including CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO were measured at FHS Offspring exam 7. We identified FHS Offspring participants who underwent neuropsychological (NP) testing (n = 2394) or brain MRI (n = 2135) within five years of the examination; and who were followed up 10 years after age 60 for incident all‐cause dementia (n = 1650). We used linear mixed effect models accounting for family relationships to investigate the associations between the protein biomarkers and NP test performance and brain MRI volumes and Cox proportional hazards models to examine the association with incident dementia. A false discovery rate (FDR) within each outcome set was computed to adjust for multiple testing and FDR ≤ 0.1 indicated significance.

Result

Participants from the NP and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (mean age 68 years) included 126 incident dementia cases within 10 years. In addition to CD14 which has an established association, we observed significant associations between higher CD40L and MPO with poorer NP performance from the executive function domain. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher sRAGE was associated with larger TCBV. Associations persisted after further adjusting for APOE ϵ4 carrier status and cardiovascular risk factors. None of the protein biomarkers included were significantly associated with risk of incident dementia, with trend towards an association for CD5L.

Conclusion

Since the proinflammatory factors CD5L, CD40L, sRAGE and MPO are associated with immune cells and are involved in vascular pathology, our study suggests the immune‐vascular axis is associated with cognitive and brain aging. If confirmed in other samples, our findings may provide informative biomarkers of abnormal brain aging.
Is there link between hypoxemia severity and impaired functional connectivity? electrophysiological evidence from patients with obstructive sleep apnea syndrome
Authors: Yerlikaya Deniz , Bircan Behice , Öztura Ibrahim , Yener Görsev
Published: June 2023

Background

Apneas occur more than 30 times per hour in severe obstructive sleep apnea syndrome (OSAS) patients. Each apnea results in decrease of oxygen saturation that leads to recurring intermittent hypoxemia (IH). IH was suggested as a possible factor to contribute cognitive impairment in OSAS. In the present study, we aimed to investigate the functional connectivity in low and high hypoxemia OSAS sub‐groups.

Method

The study included 56 severe OSAS patients and age‐, gender‐ and education matched 33 healthy controls (HC). The OSAS group was divided into two subgroups according to their minimum SO2 level: low‐hypoxemia OSAS (SO2 dropped never below 80%, LHO, n = 29) and high‐hypoxemia OSAS (SO2 dropped below 80%, HHO, n = 27). All participants underwent detailed neuropsychological testing and an EEG recording, using auditory classical oddball paradigm. Imaginary coherency (ICOH) was calculated for intra‐hemispheric, inter‐hemispheric and midline electrode pairs in delta, theta, alpha, beta, and gamma frequency bands.

Result

LHO patients did not differ from HC in any frequency band. HHO patients showed reduced intra hemispheric ICOH values at delta, theta and beta frequency bands compared to LHO patients. HHO patients also showed decreased intra hemispheric ICOH values at theta, alpha and beta frequency bands compered to HC. Inter hemispheric group differences were found at beta band indicating decreased ICOH values in HHO patients compared to LHO patients. Midline gamma ICOH values decreased in HHO patients compared to both HC and LHO patients. HHO patients showed decreased memory scores compared to both HC and LHO groups and decreased attention scores compared only to HC.

Conclusion

As far as we know, this is the first study to investigate event‐related ICOH changes in OSAS. Above results indicates that decreased connectivity in OSAS may be due to increased IH. Patients with low levels of hypoxemia did not differ from healthy controls, yet patients with high hypoxemia showed diffuse functional connectivity changes. Coherency measures revealed a parallel pattern with the neuropsychological tests underpinning the adverse effect of IH on cognitive functions. Considering OSAS as a modifiable risk factor for developing Alzheimer’s disease, treatment methods to prevent intermittent hypoxemia (i.e., positive airway pressure treatment) gains additional importance.
Prediction of amyloid‐beta accumulating normal cognitive elderly
Authors: Kim Young Ju , Chun Min Young , Jang Hyemin , Kim Hee Jin , Woo Sook‐Young , Jeong Jee Hyang , Seo Sang Won
Published: June 2023

Background

Amyloid‐β (Aβ) accumulation, a major biomarker in Alzheimer’s disease (AD), induces tau accumulation, eventually resulting in cognitive decline. However, Aβ trajectory in cognitively normal participants has not been extensively investigated, yet. Modeling of Aβ trajectory remains an important goal, as future treatments targeting Aβ are expected to be developed. In the present study, we therefore investigated whether they might be divided into the normal aging group and the pathological group with increased amyloid. We also compared the differences between the non‐accumulating group and accumulating group.

Method

We included 297 subjects from the Alzheimer’s Disease Neuroimaging Initiative database, who showed normal cognition at baseline. All subjects underwent neuropsychological test, apolipoprotein E (APOE) genotype test, brain MRI, and an average of 3.03 follow‐up 18F‐florbetapir (AV45) PET scans. The original dataset was divided by 6:4 to create a training set and a validation set. Latent Class Growth Analysis was used for statistical analysis.

Result

Based on the information criterion, the model consisting of three classes was found to be the best with a high entropy of 0.979: class 1 (non‐accumulating group; n = 117, 65.7%), class 2 (accumulating group; n = 46, 25.8%), and class 3 (high accumulation group; n = 15, 8.4%) (Figure). The accumulating group had more APOE ε4 carriers and a higher tau burden than the non‐accumulating group (Table).

Conclusion

Our study showed that there is the heterogeneity of Aβ trajectories according to aging in the normal cognitive elderly. Heterogeneity of Aβ accumulation and early detection of accumulating group may be helpful in early diagnosis and treatment of AD.
Amyloid pathology is associated with semantic loss in patients with subjective cognitive decline
Authors: van den Berg Rosanne L. , de Boer Casper , Zwan Marissa D. , van Harten Argonde C. , Dubbelman Mark A. , Mank Arenda , Kroeze Lior A. , Verberk Inge M.W. , van Berckel Bart N.M. , Teunissen Charlotte E. , van der Flier Wiesje M. , Sikkes Sietske A.M.
Published: June 2023

Background

Evidence is emerging that subtle language decline is an early indicator of Alzheimer’s disease (AD). This study assessed change in semantic and letter fluency in individuals with subjective cognitive decline (SCD), and examined whether trajectories differed between individuals with and without amyloid‐beta (Aβ)‐pathology.

Method

Longitudinal data from 437 individuals of the memory clinic‐based Amsterdam Dementia Cohort were included (Age 61±8 years, 184(42%) Female, follow‐up time 5.3±3.7 years; Table 1). Participants were classified as SCD at baseline, had available baseline Aβ‐information and had at least 1 follow‐up on semantic or letter fluency. Baseline Aβ‐status was dichotomized as positive/negative based on local cut‐offs for Aβ1‐42 concentrations in cerebrospinal fluid, or visual inspection of amyloid positron emission tomography‐imaging (Florbetapir or PiB). Two linear mixed models (LMM) were used to investigate change on semantic and letter fluency. Models included time and time*Aβ‐status as predictors of interest, a random intercept for participant, and age, sex, education were adjusted for. LMMs were subsequently stratified for Aβ‐status.

Result

At baseline, the groups did not differ in semantic (p = 0.313) or letter fluency (p = 0.294). Over time Aβ‐positive individuals changed more rapidly on semantic fluency compared to Aβ‐negative individuals (β = ‐0.32,CI = ‐0.49 – ‐0.14;p<.001). The Aβ‐positive group declined with 0.35 words per year (CI = ‐0.49 – ‐0.20;p<.001), while Aβ‐negative individuals did not show change (β = 0.03;CI = ‐0.12 – 0.06;p = 0.496) (Figure 1). On letter fluency Aβ‐positive individuals changed differently compared to Aβ‐negative individuals (β = ‐0.38;CI = ‐0.72 – ‐0.04;p = 0.028), to the extent that the Aβ‐positive group did not progress (β = 0.10;CI = ‐0.21 – 0.41;p = 0.533), while Aβ‐negative individuals improved with 0.47 words per year (CI = 0.29 – 0.65;p<.001) (Figure 2).

Conclusion

Our results indicate that Aβ‐positive individuals decreased on semantic fluency, but remained stable on letter fluency. In contrast, Aβ‐negative individuals remained stable on semantic fluency, while they improved on letter fluency over time, which might suggest a learning effect. These findings suggest that the presence of Aβ‐pathology is characterized by semantic loss, highlighting the potential of language based performance as a biomarker for Aβ‐pathology in SCD.
Brain free‐water increases in mild behavioral impairment
Authors: Ji Fang , Kan Cheuk Ni , Lau Jia Ming , Chong Eddie , Xu Xin , Tan Boon Yeow , Venketasubramanian Narayanaswamy , Pasternak Ofer , Chen Christopher Li‐Hsian , Zhou Juan Helen
Published: June 2023

Background

Mild behavioural impairment (MBI) is proposed as a diagnostic construct to identify dementia‐free individuals with sustained neuropsychiatric symptoms as an early manifestation of dementia. Our previous study has demonstrated that MBI predicts faster cognitive decline and progression to dementia. Other studies have shown that MBI was associated with Alzheimer’s disease biomarkers for Aβ and tau. However, cerebrovascular disease (CeVD), which is another critical pathology in dementia, has not been investigated in MBI. Here, we sought to test brain free‐water (FW) alterations, a marker for CeVD, in MBI compared with non‐MBI participants and their associations with longitudinal changes in cognition, function, and neuropsychiatric symptoms.

Method

Longitudinal global cognitive scores, clinical dementia rating sum‐of‐boxes (CDR‐SoB), neuropsychiatric inventory (NPI) scores, over 5 years were reported in 281 dementia‐free participants (40 MBI and 241 non‐MBI). MBI was diagnosed using established criteria. All participants underwent T1‐weighted structural and diffusion MRI at baseline. FW imaging method was applied to derive individual‐level white matter (WM) and grey matter (GM) FW maps from diffusion MRI. We compared baseline GM‐FW and WM‐FW between non‐MBI and MBI subjects. We then tested the associations of MBI‐related FW increase with baseline and longitudinal changes in global cognition, CDR‐SB, and NPI scores using linear regression models.

Result

MBI had greater GM‐FW in executive control (prefrontal), motor sensory (precentral), attention (insula) and memory (left temporal and right cingulate and cuneus) networks and widespread higher WM‐FW compared with non‐MBI (Fig‐1). Both higher GM‐FW and WM‐FW were associated with lower global cognition, higher CDR‐SB, and higher NPI scores across all participants at baseline (Table‐1). There was no interaction effect of MBI status on such association. Moreover, higher baseline GM‐FW and WM‐FW were associated with longitudinal worsening in global cognition, CDR‐SB, and NPI scores (Table‐2). Interestingly, such associations were greater in MBI than in non‐MBI (Fig‐2).

Conclusion

This study demonstrated that MBI was associated with increased brain FW, which may have contributed to the relationship between persistent neuropsychiatric disturbances and clinical and cognitive outcomes. Early detection of cerebrovascular‐related FW alteration may allow for timely management of MBI individuals before development of dementia.
Stages of retinal tauopathy and its relation to age and non‐AD retinal pathologies
Authors: Thal Dietmar Rudolf , Ronisz Alicja , Van Ginderdeuren Rita , Lemmens Sophie , Stalmans Ingeborg , De Groef Lies , Walkiewicz Grzegorz
Published: June 2023

Background

Retinal imaging for Alzheimer’s disease (AD) pathological features is a potential biomarker for AD. Amyloid β‐protein (Aβ) containing plaques and abnormally phosphorylated tau (p‐tau) pathology have been reported in retinas of AD cases. However, little is known about these pathologies in the retinas of patients without clinically known AD. Therefore, we analyzed retina samples from autopsy and biopsy cases from individuals without known AD for Aβ and tau pathology, to clarify the role of these lesions in non‐AD individuals with and without other eye disorders.

Method

We analyzed retina samples from 140 biopsy and 3 autopsy cases (age: 34 – 96 years; mean: 67 years). Paraffin‐embedded cross‐sections of the retina were stained with hematoxylin & eosin and with antibodies against Aβ and different p‐tau species. Additionally, we screened for the presence of fibrillar tau aggregates with the Gallyas silver method.

Result

Aβ plaques were not detected. We found a hierarchical sequence of the expansion of p‐tau pathology in the retina, which allowed to distinguish four stages of retinal tauopathy distribution: 0 = no retinal tauopathy (n = 36); 1 = pS202/pT205‐tau pathology restricted to the outer plexiform layer (OPL) (n = 41); 2 = pS202/pT205‐tau pathology restricted to OPL and inner nuclear layer (INL) (n = 23); stage 3 = pS202/pT205‐tau pathology in OPL, INL, and inner plexiform layer (n = 43). Antibodies against pS202/pT205‐tau, pT231‐tau, and MC1‐tau showed comparable results. Neurofibrillary tangles were not found. The distribution of the stages was not associated with age. However, all three non‐diseased controls did not exhibit retinal tauopathy whereas more than 70% of the cases with ocular tumors, inflammation, retina degeneration, and/or gliosis showed signs of a retinal tauopathy.

Conclusion

Here, we describe the presence of a retinal tauopathy in individuals over 33 years of age. It shows three stages in its evolution, which were in our sample not associated with age but with the occurrence of significant ophthalmopathological alterations. Whether these changes represent a primary retinal tauopathy or an initial stage of retinal AD pathology requires future studies.

Funding

Stichting Alzheimer Onderzoek SAO‐FRA 2020‐017
Different cutoffs definitions to evaluate the concordance between CSF Ab42 and Ab42/Ab40 across neurodegenerative diseases
Authors: Delaby Constance , Estellés Teresa , Zhu Nuole , Arranz Javier , Barroeta Isabel , Carmona‐Iragui Maria , Illán‐Gala Ignacio , Santos‐Santos Miguel A , Altuna Miren , Sala Isabel , Sánchez‐Saudinós Mª Belen , Videla Laura , Valldeneu Sílvia , Subirana Andrea , Tondo Mireia , Blanco‐Vaca Francisco , Lehmann Sylvain , Belbin Olivia , Blesa Rafael , Fortea Juan , Lleó Alberto , Alcolea Daniel
Published: June 2023

Background

Cerebrospinal fluid (CSF) Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio are markers of amyloid pathology. We aimed to compare their agreement in different neurodegenerative disorders applying different cutoffs.

Method

We included 1564 participants from the Sant Pau Initiative on Neurodegeneration (SPIN), with AD, dementia with Lewy bodies (DLB), frontotemporal lobar degeneration‐related syndromes (FTLD), cognitively impaired but non‐neurodegenerative conditions (others), and cognitively normal individuals (CN). Cutoffs were defined as one‐sided 97.5%, 95% and 90% (Q97.5%, Q95% and Q90%, respectively) quantiles values in a middle‐aged cognitively normal population. These cutoffs for Aβ1‐42 (617 pg/mL, 637 pg/mL and 732 pg/mL, respectively) and Aβ1‐42/Aβ1‐40 (0.060, 0.070 and 0.082, respectively) were used to classify all participants as “positive” or “negative” according to each marker. We compared concordance of Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio between groups through X2 test and correlations with Spearman test.

Result

Correlation between Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio in CSF was strong (0.71, p<0.001) in the whole cohort, DLB and others groups (0.69 and 0.64, respectively, both p<0.0001); correlation was weak in AD, FTLD and CN groups (0.33, 0.52 and 0.51, respectively, all p<0.0001). Using Q97.5%, Q95% and Q90% cutoffs, Aβ1‐42 and ratio had an overall agreement of 76.6%, 78.3% and 82.9%, respectively in the whole sample. Both measures were normal (« negative ») in 46.1%, 41.6% and 35.8%, and both were abnormal (« positive ») in 30.5%, 36.7% and 47.1% of participants, respectively. Within each diagnostic category, the agreement ranged from 64% (AD) to 91.5% (CN) using Q97.5%, from 69.6% (AD) to 88.7% (CN) using Q95% and from 78.9% (DLB) to 85.9% (AD) using Q90%. Regardless of the cutoff definition, most discordant cases in AD and DLB were due to normal Aβ1‐42 and low ratio, while discordant cases in FTLD were more frequently due to low Aβ1‐42 and normal ratio.

Conclusion

Although Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio may reflect the same pathophysiological pathway, their agreement depends on cutoff definition. Our results confirm that both parameters show medium to high concordance, and that in case of discordance, Aβ1‐42 positivity with negative ratio is more associated to non‐AD dementias, independently of the cutoff used.
The predictive turn in Alzheimer’s disease (PreTAD)
Authors: Snijders Katharina Elisabeth , Stümpel Johanne , Rostamzadeh Ayda , Ribaldi Federica , Marquié Marta , Schmitz‐Luhn Björn , Boada Mercè , Frisoni Giovanni B , Jessen Frank , Woopen Christiane , Schwegler Carolin
Published: June 2023

Background

Diagnostics for early detection and risk prediction in Alzheimer’s disease (AD) are constantly evolving. Blood‐based biomarkers may replace more invasive and expensive methods (such as CSF and PET) and lead to a higher accessibility in the detection of AD pathology. These developments may result in an extended availability of risk prediction, also for patients with subjective cognitive decline (SCD) or symptom‐free individuals at risk. The PreTAD project aims at providing data and analyses on people’s perspectives towards prediction as well as the effect of predictive medicine on individuals and society from a clinical, ethical, legal and linguistic point of view.

Method

The empirical survey of PreTAD will focus on three different groups: 150 healthy participants with a family history of AD or APOE4 carriership; 150 participants with previously diagnosed SCD and 90 participants with newly diagnosed SCD ≤ 4 weeks. The participants will be studied with standardized quantitative tests, including newly developed assessments and will be provided with hypothetical scenarios of AD‐biomarker risk outcomes and disclosure. The longitudinal survey will be conducted by specialized Memory Clinics in Cologne, Geneva and Barcelona over a period of 6 months. To achieve a comprehensive approach, the trial design of our interdisciplinary collaboration combines quantitative assessment with qualitative (narrative) interviews, as well as ethical and legal analyses. In this presentation, we report the design of the study.

Result

Our study serves to understand the perspectives, needs and preferences of cognitively healthy individuals with increased risk for AD regarding early AD‐biomarker testing and risk prediction of dementia. We will also obtain information on the participants understanding of risk and expectations towards risk prediction. It will also focus on psychological distress during the process of risk prediction, subjective well‐being, quality of life, identity and self‐perception measures as well as the willingness to undertake lifestyle changes and prevention.

Conclusion

Our trinational project aims to contribute to the urgent need of creating a framework for good clinical practice regarding the prediction of AD in presymptomatic at‐risk‐stages.
Evaluating Dementia Neuroanatomic Risk of a Clinical Cohort Using MRI
Authors: Casanova Ramon , Barnard Ryan , Hsu Fang‐Chi , Lockhart Samuel N. , Bateman James R. , Rundle Melissa M. , Gaussoin Sarah A. , Hughes Tim M. , Whitlow Christopher T. , Sai Kiran K Solingapuram , Hayden Kathleen M. , Espeland Mark A. , Craft Suzanne
Published: June 2023

Background

MRI is a widely used modality to evaluate dementia risk. Here, we extend previous work by estimating the Alzheimer’s disease pattern similarity (AD‐PS) scores for participants of a community‐dwelling older adult cohort to evaluate neuroanatomic risk of AD using MRI.

Method

Baseline MRI data were available from 522 participants from the Wake Forest Alzheimer’s Disease Research Center’s (ADRC) Clinical Core with mean age 70.2, 81.2% White and 17.6% African American. Of those, 253 were cognitively impaired (dementia and mild cognitive impairment (MCI)) and 138 underwent [11C]PiB PET (MCI = 48 and dementia = 19). Global PiB SUVR was averaged from a cortical region of interest sensitive to early AD. Participants were classified as amyloid positivity using a previously defined threshold (≥1.21 SUVR). AD‐PS scores were estimated based on GM probability maps according to previously reported machine learning methodology[1]. High‐dimensional classifiers were trained using ADNI MRI data. To generate the AD‐PS scores, MRI data from the ADRC cohort was provided as input to the classifiers.

We investigated associations that AD‐PS scores [range 0‐1] had with amyloid positivity and cognitive impairment. All analyses were adjusted for age, sex, race and education. AD‐PS scores discrimination of participants with dementia versus normal cognition (CN) was compared to hippocampal volume and cortical thickness in temporal regions based meta‐ROI which are sensitive to AD.

Result

AD‐PS scores were strongly associated with cognitive impairment: OR = 4.1, CI: 95% [2.9‐5.9], p<0.0001. In addition, they were associated with amyloid positivity with OR = 2.8,CI: 95% [1.7‐4.7], p<0.001, N = 138. These amyloid positivity results did not hold in analyses limited to CN participants only(N = 71). Performance when discriminating patients with dementia from CN individuals was highest for AD‐PS score (AUC = 92.2, CI: 95% [86.9‐97.5]), followed by hippocampal volume (AUC = 86.5, CI: 95% [81.1‐91.2]) and cortical thickness in temporal regions based meta‐ROI (AUC = 81.5 CI: 95% [74.4‐88.6], See‐Figure).

Conclusion

This work highlights further the generalization performance of our machine learning algorithm. AD‐PS scores, a measure of dementia neuroanatomic risk, strongly discriminated individuals with dementia from CN individuals in the Wake Forest ADRC.

References

[1] Casanova et. al., Alzheimer’s & Dementia, 2021, PMID:34310039.
Region specific reduction of neurogranin immunostaining in the hippocampus of Alzheimer’s disease brains
Authors: Vontell Regina T , Davis David A. , Dallmeier Julian , Barreda Ayled , Blennow Kaj , Zetterberg Henrik , Kvartsberg Hlin , Gultekin Sakir Humayun , DeKosky Steven T , Rundek Tatjana , Scott William K. , Sun Xiaoyan
Published: June 2023

Background

Neurogranin (Ng) is a post‐synaptic protein involved in formation of long‐term potentials, and thus plays an important role in learning and memory. The concentration of Ng is increased in the cerebrospinal fluid (CSF) of people with Alzheimer’s disease (AD), and CSF Ng is considered to be a biomarker for synaptic dysfunction in AD. The expression of Ng protein in the human brain and its association with AD pathology, however, are less well studied.

Method

Using immunohistochemical detection methods we investigated the protein expression of Ng, beta‐amyloid (Aβ) and hyperphosphorylated paired helical filament tau (phospho‐tau; ptau) in the post‐mortem hippocampus from 12 AD patients and 12 cognitively unaffected controls (NC). We compared the number of positively stained cells (Ng, ptau) or plaques (Aβ) in the hippocampal sub‐regions (dentate gyrus, Cornu Ammonis (CA) fields 1‐3) from the 2 groups. Donor samples with intermediate AD (i.e., Braak stage III‐IV) or NC (Braak 0‐I/II) were analyzed using Image Pro Premier automated image analysis software (version 10.01). The data were normalized to the number of cells or clusters/mm2 and analyzed using a one‐way ANOVA. Using a test of circularity (Cir = (4*A)/Pi*MaxFeret2), we further investigated morphological differences in the Ng positive neurons by measuring the Ng expression in the apical dendrite of pyramidal neurons.

Result

There was a 40% reduction of Ng immunopositive neurons in AD compared to NC in the CA3(N = 24;p = 0.0003) and in the CA1(N = 24;p = 0.014) hippocampal sub‐regions. Ng positive cells did not change significantly in AD compared to NC in the other hippocampal regions. Additionally, we showed that CA1 region, Ng was localized mainly in the neuronal cell soma of AD donors, while its expression extended into the apical dendrites of NC donors (N = 24;p = 0.006). In AD, Ng immunostaining negatively correlated with ptau immunopositive neurofibrillary tangles (r = ‐0.70;p = 0.04)

Conclusion

Selective loss of Ng immunostaining in certain subregions of the hippocampus suggests that synaptic damage in AD maybe a region‐specific event. The mechanism underlying such regional synaptic damage and the changes in Ng expression will be key in understanding the selective vulnerability of brain regions to AD.
Investigating the effects of centella asiatica on neuroinflammation in beta‐amyloid overexpressing mice
Authors: Speers Alex B , Brandes Mikah S , Kedjejian Nareg E , Matthews Donald G , Caruso Maya , Wright Kirsten M , Quinn Joseph F , Soumyanath Amala , Gray Nora E
Published: June 2023

Background

Centella asiatica is a medicinal plant traditionally used for promoting brain health and improving cognition. Our lab has shown that a water extract of Centella asiatica (CAW), can enhance mitochondrial function, promote antioxidant response, and improve cognitive deficits in mouse models of aging and Alzheimer’s disease (AD). Because neuroinflammation is also prevalent in the AD brain and there is growing evidence that the interplay between oxidative stress, mitochondrial dysfunction, and neuroinflammation play a central role in the progression of AD, here we explore the effects of oral CAW treatment on neuroinflammation in the 5xFAD mouse model of beta‐amyloid accumulation.

Methods

Eight to nine month old male and female 5xFAD mice were treated with 0 or 1000 mg/kg/day of CAW administered in their drinking water or integrated into their diet (AIN‐93M rodent diet) for a total of 5 weeks, after which brain samples were collected. Microglial and astrocytic activation as well as beta‐amyloid pathology is currently being assessed by immunohistochemistry (IHC). Expression of pro‐ and anti‐inflammatory cytokines is also being determined by qPCR in brain samples from these treated animals.

Results

Preliminary IHC results suggest that CAW administered in the diet reduces the heightened microglial activation found in 5xFAD mice. Our ongoing analysis will determine if there are also effects on astrocytic activation and beta‐amyloid pathology, and whether these effects vary if the CAW is administered in the drinking water rather than the diet. Additionally, gene expression assessments are currently underway on these samples to evaluate the effects of CAW on the expression of pro‐ and anti‐inflammatory cytokines.

Conclusion

Initial data suggests an anti‐inflammatory effect of the CAW extract. Results will continue to be collected over the next few months, further clarifying our preliminary results as well as generating data for the potential mechanisms or cell types that may mediate the effect of CAW on neuroinflammation. Moreover, we will learn whether the mode of administration, in the diet versus the drinking water, has an effect on the response to CAW, which would have important implications for future experimental design as well as the development of CAW for clinical use.
An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE‐ε4 in Alzheimer’s disease
Authors: JIANG Yuanbing , Zhou Xiaopu , Wong Hiu Yi , Li Ouyang , Ip Fanny C. F. , Chau Vicky M.N. , Lau Shun‐Fat , Wu Wei , Wong Daniel Y.K. , Seo Heukjin , Fu Wing‐Yu , Lai Nicole Chit Hang , Chen Yuewen , Chen Yu , Tong Estella Pui‐Sze , Mok Vincent C.T. , Kwok Timothy CY , Mok Kin Y , Shoai Maryam , Lehallier Benoit , Moran‐Losada Patricia , O’Brien Eleanor , Porter Tenielle , Laws Simon M , Hardy John A. , Wyss‐Coray Tony , Masters Colin L. , Fu Amy K.Y. , Ip Nancy Y. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Background

Genetic factors are increasingly being recognized as important contributors to the pathogenesis of Alzheimer’s disease (AD). While the expression of most AD risk genes is enriched in microglia, which leads to microglial dysfunction and amyloid‐beta (Aβ) accumulation, emerging studies suggest that changes in the brain micro‐environment—typically changes in the levels of soluble factors—also modulate microglial functions and disease‐related pathological changes. Therefore, understanding the genetic regulation and pathogenic roles of those soluble factors in AD will help clarify the pathophysiological mechanisms of the disease.

Method

We examined the changes in the level of soluble ST2 (sST2), a decoy receptor of IL‐33/ST2 signaling, in the blood and brains of patients with AD, and performed a genome‐wide association study (GWAS) for sST2 to understand its genetic regulations.

Result

We showed that elevated sST2 levels are associated with more severe neurodegeneration and Aβ pathological lesions in patients with AD. Our GWAS analysis identified a genetic variant in IL1RL1 (the gene encoding sST2) that is associated with decreased sST2 levels in the blood and brain in AD. Furthermore, we demonstrated that female APOE‐ε4 carriers harboring the genetic variant exhibit decreased sST2 level and reduced risk of AD as well as decreased Aβ accumulation through enhancing microglial activation and colocalization with Aβ.

Conclusion

These findings demonstrate how sST2 level in the brain milieu is modulated by a genetic variation and plays a disease‐causing role in AD through microglial clearance of Aβ, and might thus be a novel target for AD therapy.
Degeneration of the cholinergic system in subjective cognitive decline: A systematic review
Authors: Alemany Iris , Rodriguez‐Hernandez Marta A. , Diaz‐Galvan Patricia , Nemy Milan , Westman Eric , Barroso Jose , Ferreira Daniel , Cedres Nira
Published: June 2023

Background

Subjective cognitive decline (SCD) is topic of mayor interest when identifying individuals at risk for future cognitive impairment and dementia. The degeneration of the cholinergic system is linked to the onset of cognitive symptoms in mild cognitive impairment (MCI) and dementia. Yet, it is uncertain whether the neurodegeneration of the cholinergic system is already present in SCD individuals. This review is the first to synthetize the available data on the association of SCD with multiple markers of degeneration in the cholinergic system.

Method

Following the PRISMA guidelines, original articles focused on the association of SCD and the cholinergic system were extracted from three databases: Pubmed, WOS and Scopus, in November 2021. Two researchers reviewed the studies independently in a 2‐stepwise approach. The quality of the studies and risk of bias were assessed using FLC 3.0, that allows to systematically evaluate the studies and summarize them easily.

Result

Among 119 studies found in our systematic search, 11 were included in the current review. Seven were cross‐sectional and 4 had a longitudinal design. Most of the studies operationalized SCD based on amnestic cognitive complaints (n = 9, 82%). The cholinergic system measures were based on neuroimaging markers for volume of the basal forebrain and/or functional connectivity, transcranial magnetic stimulation, or biofluid markers (i.e. cerebrospinal fluid (CSF) and plasma). The studies focused on association of SCD with basal brain atrophy, 75% reported reduce volumes in SCD; From those focused on functional connectivity of the cholinergic system, 33% reported poorer connectivity in SCD.

Conclusion

Based on scientific evidence, neurodegeneration of the cholinergic system is already evident during SCD. Using multiple cholinergic biomarkers, degeneration of cholinergic system in SCD seems to occur with significant structural and functional degeneration of cholinergic nuclei in the basal forebrain and their connections with other brain areas. These findings have implications on identifying individuals with increased vulnerability to cognitive impairment and for targeting individuals that might benefit from cholinergic‐target treatments. Further research is needed to elucidate potential contributors to the cholinergic degeneration in SCD and its impact on cognition and clinical progression.
The performance of connected speech is correlated with cognitive tests in very early Alzheimer disease
Authors: Liu Yi‐Chien , Chang Chih‐Ting , Lee Chia‐Ying , Chou Chia‐Ju
Published: June 2023

Background

Language impairment is one of the most important clinical features of Alzheimer disease. However, it is very difficult to detect at a very early stage. In this study, we try to analyze the language performance via a set of language tests. At the same time, various biomarkers were also checked and compared.

Method

From 2020 to 2021, we recruited 11 aMCI and 24 normal controls from the memory clinic of Cardinal Tian Hospital in Taiwan. The clinical diagnosis of aMCI is based on clinical history (with short‐term memory impairment over 6 months), brain MRI, amyloid PET, and various neuropsychological tests. All the participants received the Picture Description Test (PDT), Taiwanese Boston naming test (T‐BNT, 30 items) and semantic fluency test. In PDT, the participants were requested to describe three Taiwanese‐culture‐based pictures to evaluate their performance of connected speech. The responses were recorded, transcribed, and subsequently analyzed by the Chinese tokenize system. Linguistic variables such as the number of total words, content words, grammatically intact sentences, long‐pauses (more than 2s), and fillers were recorded and analyzed.

Result

In our cohort, their baseline MMSE scores are lower (24.1 ± 3.1 V.S. 28.9 ± 1.6, p<0.001). The amyloid positive rate is significantly higher in the aMCI group (54.8% V.S. 29.1%, p = 0.05). The scores of T‐BNT (19.9 ± 4.7 V.S. 24.9 ± 2.3, p<0.001) and semantic fluency test (9.7 ± 3.8 V.S. 17.3 ± 4.0, p<0.001) were significantly lower in the aMCI group. The multiple regression model showed that the variable of non‐repeated words and numbers of long‐pauses were significant in the final model and explained of 32% the total variance of the MMSE (R2 = 0.32; p<0.01).

Conclusion

Even in the MCI stage, the language‐based examinations can be very different from the normal controls. More non‐repeated words and less long‐pauses in connected speech predict better cognitive performance. Combining with biomarkers, these linguistic variables may detect AD at the earlier stage.
Blood DNA methylation biomarkers for cognitive decline in older adults with type 2 diabetes
Authors: Manzali Sigalit , Ravona‐Springer Ramit , Jacob‐Hirsch Jasmine , Heymann Anthony , Beeri Michal Schnaider , Greenbaum Lior
Published: June 2023

Background

Individuals with type 2 diabetes (T2D) are at particularly high risk for cognitive decline and dementia. Finding early, pre‐clinical biomarkers for detecting and tracking cognitive impairment and dementia in this population is important for personalized medicine approach. Our study aims to find blood DNA methylation biomarkers for cognitive decline among elderly T2D patients.

Method

Two groups of 30 T2D subjects each, from the Israel Diabetes and Cognitive Decline (IDCD) cohort, were included. One group (converters) was cognitively normal at baseline, yet at 36‐54 months follow‐up deteriorated from a Clinical Dementia Rating scale CDR = 0 (no dementia) to CDR≥0.5 (questionable dementia or frank dementia). The control group (non‐converters) was cognitively normal at baseline and maintained normal cognition during the follow‐up period (CDR = 0). We performed an epigenome‐wide association study, using the Illumina Infinium MethylationEPIC microarray, and searched for differentially methylated positions (DMPs) with significant methylation alterations (≥ 2 fold and FDR corrected p value <0.05) between the baseline and the follow‐up time points for each of the two groups.

Result

Participants were 65‐83 years of age (mean‐73.6 ± 4.1), 72% were men. The mean hemoglobin A1C value was 6.9 ± 0.8%, and T2D duration was 9.4 ± 4.7 years. Converters and non‐converters did not differ in any of these characteristics. Results show significant changes in multiple DMPs among the converters, but only in a few DMPs in the non‐converters. Gene ontology analyses indicates primarily involvement of central nervous system‐related pathways, mainly neurodevelopmental disorders.

Conclusion

These preliminary results, employing a high‐throughput approach for methylation profile in blood, suggest methylomic alterations as a potential biomarker for cognitive decline in T2D elderly. A priori identification of patients at risk for cognitive decline may lead to early intervention in modifiable risk factors in this population, which is highly susceptible to dementia.
Atypical mixed logopenic and semantic progressive primary aphasia (PPA) in Arabic with white matter abnormalities
Authors: Taiebine Mohamed , Faris Mustapha El Alaoui
Published: June 2023

Background

The concept of primary progressive aphasia (PPA) or Mesulam syndrome (Mesulam, 2014) is an isolated and progressive deterioration of language, usually due to progressive focal atrophy of the left perisylvian regions (of the dominant hemisphere). Four types of PPA have been already identified: Non‐fluent variant or Nfv‐PPA; Logopenic variant or Lv‐PPA; Semantic variant or Sv‐PPA and Mixed variant M‐PPA (Gorno‐Tempini et al., 2011; Mesulam et al., 2014).

Method

We report MH who displayed a Mixed‐variant of PPA (M‐PPA) in Arabic. Her daily activities were preserved. Neuroimaging using MRI coronal cut (FLAIR) showed a bi‐hippocampal atrophy, an increase in the sylvian valley and ventricular dilation; signs of cortical and subcortical vascular leukoencephalopathy. While the axial T2 cut showed a peri‐ventricular leukoencephalopathy. In FDG‐PET, there was a hypometabolism in the left anterior and the upper temporal gyrus. A neuropsychological battery was administered to the patient as well as a neurolinguistic assessment using an adapted and validated version of Moroccan Mini‐Linguistic State Examination (MLSE). It has been developed in English and Italian (Catricalà et al, 2017; Patel et al, 2020).

Result

The clinical profile of MH clearly showed an atypical overlap of neuropsychological, neurolinguistic and neuroradiological features which objectified a mixed variant of PPA predominantly logopenic and semantic with a slight syntactic impairment. These linguistic disturbances included some elements of Lv‐PPA (impaired sentence repetition and dysnomia) and some features of Sv‐PPA (dysnomia, impaired word comprehension, semantic association and sentence comprehension).

Conclusion

The findings of this case study were mainly based on clinical and semiological criterias which are consistent with Mesulam’s descriptions (2014). It is possible that the presence of multi‐domain linguistic deficits may be linked eventually to a mixed underlying neuropathology which might be both neurodegenerative and vascular. This study is a call for a cross‐cultural neuropsychological, neuro‐anatomical and neurolinguistic characterization of PPA and Mixed‐PPA in non‐European languages
Incidence trends of dementia in Czechia: A national registry‐based study over 15 years
Authors: Kučera Matěj
Published: June 2023

Background

The number of people living with dementia in Czechia reached 156 thousand in 2015. According to estimates, prevalence of dementia is supposed to reach 250 thousand by year 2050, but little is known about current trends of dementia incidence. In our study we aimed to identify trends in age‐ and sex‐specific incidence of dementia in the Czechia between years 1999 and 2017.

Method

To assess changes in the incidence of dementia in Czechia we examined linked data about the entire Czech population aged 65 year and over from national healthcare registers (National Register of Hospitalized Patients, National Register of Paid Health Services, Register of Deaths). We traced dementia based on a combination of information about the clinical diagnosis (Alzheimer’s disease, vascular dementia, unspecified dementia, dementia with Lewy bodies, Parkinson’s disease with dementia, frontotemporal dementia) and use of drugs for dementia (Donepezil, Rivastigmine, Galantamine, Memantine). Incidence rates (calculated for both genders in strata of five years) were measured with survival analysis techniques using Poisson regression analysis, testing the calendar year as a time‐dependent covariate.

Result

There were 30587776 person‐years during the follow‐up. Total crude incidence rates per 10000 person‐years between years 1999 and 2017 were higher in women with 118,62 to 89,46 in men and steeply increasing with age. The crude yearly incidence was increasing for men and women during the entire follow‐up period with rapid decline in the last two years of the follow up. The age‐ and sex‐stratified results indicate different trends in age groups with age between 65‐79 year being relatively stable compared to older age groups.

Conclusion

Our results provide evidence that number of new patients diagnosed with dementia may be currently declining and this trend may continue in future.
Can You Hear Me? Exploring the use of a sing‐along audio program as a method for creative community engagement in times of continued isolation
Authors: Mize Cheyenne M
Published: June 2023

Background

Loneliness in older adults has been linked to accelerated cognitive and functional decline. Furthermore, lonely individuals are twice as likely to develop Alzheimer’s disease. This was before COVID‐19 and the isolation that older adults are experiencing disproportionately. Engagement in singing groups and other creative experiences has been shown to address the health and wellbeing of older adults, including their experience of connectedness, loneliness and isolation. Can You Hear Me? was developed as an alternative to in‐person singing groups in times of continued isolation due to the COVID‐19 pandemic.

Method

Can You Hear Me? is a sing‐along audio program highlighting the voices and music of elders in Louisville, Kentucky, USA. Unlike typical receptive audio programs, Can You Hear Me? has participatory elements that give listeners the opportunity to sing along to familiar songs, learn about organizations in the area and how to get involved, and contribute to the show by sending in their responses to creative prompts. The program will also implement a repeat design 25‐item Listener Survey, which will be utilized to understand more about listeners’ wellbeing and perceptions of loneliness and aging, as well as for quality improvement.

Result

Now in its second season, this podcast‐style audio program is exploring an alternative model for creative individual and community engagement. Strategic community partners are assisting in the development of the program as a resource for individuals living in the community with Alzheimer’s disease and their carers, as well as in care homes when group engagement is still not feasible or possible.

Conclusion

In the absence of a cure for dementia, Alzheimer’s, or COVID‐19, it is imperative that we work to build ways for elders to be socially connected wherever they live and provide opportunities for them to engage actively and creatively. Can You Hear Me? provides just such an initiative, to be a model for arts‐driven community engagement through an audio program that not only addresses health inequities and stigmas of aging and dementia, but also has the capacity to enhance wellbeing and connect people, even in times of isolation.
Neuropsychiatric symptoms of Alzheimer’s dementia and their association with dorsolateral prefrontal cortex TMS evoked potentials
Authors: Asare Gifty , Joseph Shaylyn , Alhabbal Hiba , Zomorrodi Reza , Blumberger Daniel M. , Daskalakis Zafiris J. , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. , Kumar Sanjeev
Published: June 2023

Background

Alzheimer’s Dementia (AD) is characterized by cognitive and neuropsychiatric symptoms (NPS). Recently, cognitive decline in AD has been linked to increased cortical excitability. However, the relationship between NPS and cortical excitability remains unclear. This study investigated the relationship between NPS and cortical excitability in the dorsolateral prefrontal cortex (DLPFC).

Method

24 participants with probable AD diagnosed using National Institute of Aging‐Alzheimer’s Association criteria (Mage (SD) = 74.1 (7.2) years) were recruited and followed for up to 6 months. Global cognition was assessed with the Montreal Cognitive Assessment (MoCA). NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) total score and subdomain scores. Single pulse transcranial magnetic stimulation (TMS) was applied at the DLPFC (localized using MRI‐based neuronavigation) at a frequency of 0.1 Hz, at sufficient intensity; and collected using 62 channel electroencephalography (EEG) recorded from the scalp. TMS‐evoked potential (TEP) peak amplitudes for individual TEP peaks (P30, N45 and P60) were calculated.

Result

NPI‐Q severity score was positively correlated with DLPFC TEP peak P30 (r (19) = .64, p = .003) and negatively correlated with DLPFC TEP peak N45 (r (22) = ‐.46, p = .033). These associations remained significant after controlling for age, sex and cognition (DLPFC TEP peak P30 (ß = .93, p = .001) and N45 (ß = ‐.47, p = .031)). Further, NPI‐Q severity score at 6 month follow up negatively correlated with baseline DLPFC TEP peak N45 (r (16) = ‐.56, p = .025). Among NPI‐Q subdomains, apathy was positively correlated with DLPFC TEP peak P30 (r (19) = .64, p = .003) and negatively correlated with DLPFC TEP peak N45 (r (22) = ‐.42, p = .049).

Conclusion

NPS burden in AD was positively associated with excitatory activity (i.e., P30) and negatively associated with inhibitory activity (i.e., N45) using combined TMS‐EEG over the DLPFC. These associations were largely driven by the apathy domain. These findings may have implications for developing neurophysiological biomarkers and targeted treatment interventions for NPS in AD.