bluuebunny/crossref_metadata_2025 huggingface dataset:
Center for Alzheimer Research at Karolinska Institutet, Sweden
Authors: Ankarcrona Maria , Religa Dorota
Published: December 2023

Center for Alzheimer Research (CAR) is a hub for the research in Alzheimer’s disease and other dementias conducted at Karolinska Institutet (Stockholm, Sweden). CAR started in 2014 with Professor Bengt Winblad to unite basic, clinical, and epidemiological dementia research from several divisions of the department of Neurobiology, Care Sciences and Society (NVS). Since then, the goal of CAR is to (i) promote the connection between the CAR’s research and the clinics at adjacent Karolinska University Hospital, (ii) strengthen and promote the visibility of dementia research, and (iii) coordinate and increase the quality of the research and education on dementia.

CAR has around 300 affiliates and is supported by administrative personnel of NVS. Director and steering group composed of one member from each of NVS’s divisions run the center. This representation of basic, clinical, and epidemiological research provides the foundation for a unique model of translational science and education.

CAR accelerates Alzheimer’s and dementia research through extensive activities. Some examples are the role of CAR’s researchers in leading world‐recognized projects such as FINGER, SNAC‐K, and SVEDEM, as well as participation in EU and NIH projects like MOPEAD, EPAD, and RADAR‐AD. CAR researchers contribute to developing biobanks like GEDOC, which includes brain tissue, cerebrospinal fluid and blood samples; and support clinical trials in collaboration with Karolinska University Hospital and pharma industry situated around hospital and institute. Education is central activity with many CAR affiliates involved in under‐ and post‐graduate teaching.

CAR catapults the Alzheimer’s research community by providing the structure for social interaction and gathering. Examples are research seminars every Wednesday, monthly theme‐specific seminars, opponent lectures connected to PhD dissertations, initiation of working groups, and organization of workshops, webinars and open‐house days for patients and relatives. All these are open and announced at ki.se/en/nvs/center‐for‐alzheimer‐research. In 2019 and 2022, CAR organized a national conference for Alzheimer’s research.

CAR increases social awareness about Alzheimer’s disease and dementias through collaborations with main Swedish foundations like the Aging Center from Stockholm Region, Silviahemmet, and Alzheimer Funding. Recently, CAR coordinated with Alzheimer Funding a national popular science report about Alzheimer’s disease, with participations from all across Sweden.
Characteristics of oldest‐old individuals with ‘Pure’ Limbic‐predominant age‐related TDP‐43 encephalopathy: a 90+ Study case series
Authors: Melikyan Zarui A. , Leiby Anne‐Marie C , Scambray Kiana Alexis , Nguyen Hannah L. , Basith Farheen , Fakhraee Shahrzad , Bukhari Syed A. , Montine Thomas J. , Corrada María M. M. , Kawas Claudia H. , Sajjadi S. Ahmad
Published: December 2023

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is an important contributor to dementia at age 90+. Given the high prevalence of multiple pathologies in the oldest old, the prevalence of ‘pure’ LATE and its clinical and cognitive features are poorly understood. The aims of this report are: (1) to determine the prevalence of ‘pure’ LATE among participants of
The 90+ Study
and (2) to describe clinical and cognitive features of ‘pure’ LATE.

Method

Individuals for this report were identified from a total of 364 consecutive autopsies of
The 90+ Study
. We compared medical histories and cognition in three groups: those with ‘pure’ LATE, ‘pure’ Alzheimer’s disease neuropathologic change (ADNC), and ‘pure’ primary age‐related tauopathy (PART). ‘Pure’ LATE was defined as TDP‐43 in the hippocampus or neocortex, no moderate/severe ADNC, and no limbic/cortical Lewy bodies. ‘Pure’ ADNC group was defined as moderate/severe ADNC, no TDP‐43, and no limbic/cortical Lewy bodies. ‘Pure’ PART group was defined as limbic/cortical phosphorylated tau inclusions (Braak tau stage ≥2), no amyloid (A score = 0 and C score = 0), no TDP‐43, and no limbic/cortical Lewy bodies. All groups had <2 microvascular lesions.

Result

LATE pathology was prevalent in the cohort (36%) but only 5 participants (1.4%) had ‘pure’ LATE. ‘Pure’ LATE group was on average older at death, more educated, and had lower proportion of women (Table) compared to the other two groups. Duration of cognitive impairment was longest and dementia was more prevalent in ‘pure’ LATE (6 years, 80%) compared to ‘pure’ ADNC (3 years, 43%) and ‘pure’ PART (3 years, 22%). Memory and executive function were more frequently impaired in ‘pure’ LATE compared to the other two groups (Table). Furthermore, histories of cardiovascular disease, syncope, depression, and extrapyramidal signs were more common, whereas osteoarthritis was less common, in ‘pure’ LATE compared to the other two groups (Table).

Conclusion

Given the high prevalence of multiple pathologies, ‘pure’ LATE is a relatively rare finding in the oldest old. Identifying differences between ‘pure’ LATE and other dementia related neuropathologies in this case series, may provide valuable insight to inform proper ante‐mortem diagnosis of LATE.
Role of nutrition and metabolic regulation in multidomain trials for dementia risk reduction: findings from FINGER and FINGER 2.0 studies
Authors: Kivipelto Miia , Lehtisalo Jenni , Wang Rui , Thunborg Charlotta , Lorenzo Thais , Rosenberg Anna , Mangialasche Francesca , Ngandu Tiia , Solomon Alina
Published: December 2023

Background

The successful FINGER multidomain intervention model combined dietary intervention (healthy Nordic diet) with exercise, cognitive training, social activities, and cardiovascular risk monitoring. The FINGER model is being tested and optimized in the World‐Wide FINGERS network of multidomain dementia prevention trials (45+ countries). Advanced FINGER 2.0 models combine lifestyle interventions with multi‐nutrients and/or putative disease‐modifying drugs.

Method

The 11‐year extended follow‐up of FINGER trial participants (N:1260, at‐risk general population) was completed in Q1‐2023. The MIND‐AD pilot‐trial (N:93, prodromal Alzheimer’s disease (AD)) included medical food (Fortasyn Connect), tested alone or in combination with multidomain lifestyle intervention for 6 months. The MET‐FINGER trial (N:600, at‐risk general population enriched with APOE4‐carriers, 2‐year intervention) includes different dosages of metformin (in combination with upgraded FINGER lifestyle intervention).

Result

New nutrition/metabolic related data will be presented from FINGER where eg. adherence to healthier diet was still relatively high in the multidomain arm after the extended follow‐up. Higher adherence was also related to better cognition. Several dietary and metabolic biomarkers have been analyzed revealing underlying mechanisms and responders (eg persons with insulin resistance, higher HOMA, responded less). In the MIND‐AD trial, participants from 4 European countries were randomized to the multidomain lifestyle intervention alone (N:32), or in combination with medical food (N:31), and 30 to the control group. Adherence was high for all intervention domains (78‐87%). Compared with the control group, the group with lifestyle+medical food showed a decrease in vascular risk burden (P = 0.027) and an increase in healthy diet patterns (P = 0.045), and better cognition after the intervention (CDR‐SOB). There were no significant differences between the lifestyle only and control group. MET‐FINGER trial recruitment started in January 2023 (preliminary data presented).

Conclusion

Longer‐term dietary and lifestyle changes are feasible and effective in older adults in the at‐risk spectrum of AD/dementia. Beneficial effects (adherence to and effects of interventions) seemed to improve with the inclusion of medical food in prodromal AD. The unique long follow‐up of FINGER provides important information about long‐term effects and methodological aspects. The MET‐FINGER trial will provide data on synergistic effects between FINGER intervention and a drug targeting both glucose metabolism and AD pathology.
Primary prevention of cognitive decline in older individuals with the MIND diet
Authors: Barnes Lisa L. , Dhana Klodian , Carey Vincent , Grodstein Francine , Tangney Christy C , Aggarwal Neelum T. , Arfanakis Konstantinos , Morris Martha Clare , Sacks Frank
Published: December 2023

Background

The Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet is a hybrid of the Mediterranean and DASH diets, with added foods designed to target brain health. Observational studies demonstrate inverse relations with cognitive decline but clinical trial evidence is lacking.

Method

We assigned at random 604 older adults without cognitive impairment, a family history of dementia, BMI>25, and a MIND diet score ≤8 on a 14‐item screener, to the MIND diet or placebo (usual diet) for three years (January 2017 ‐ June 2021); all participants received diet counseling for weight loss, monthly cooking sessions, and other support over 3 years. Cognition was assessed with a 12‐test battery from which a measure of global cognition was derived. The trial was interrupted due to the COVID‐19 global pandemic and analyses were conducted to account for the interruption. Using random effects analyses we assessed rate of cognitive decline from baseline to trial close in each group, both pre‐ and post‐COVID.

Result

Overall, 564 participants (93%) completed the trial. In an intent‐to‐treat analysis, those assigned to MIND diet maintained better global cognition compared to placebo control (difference in standard units = 0.015 per year, 95% CI: ‐0.005, 0.034); findings were borderline significant. To help interpret findings, the effect estimate was equivalent to being 4.3 years younger in age for this sample population. Pre‐pandemic, we observed a significant, positive effect of MIND on change in cognition over two years compared to placebo/usual diet (beta = 0.026, 95% CI: 0.001, 0.052).

Conclusion

Over three years, the MIND diet was beneficial for cognition compared to usual diet, although results were not formally statistically significant. However, there was evidence of a statistically significant effect of the MIND diet before the start of the COVID‐19 pandemic, which impeded the intervention protocol and outcome ascertainment.
Effects of homo‐ and heterozygous TREM2 mutations on natural killer cell activity
Authors: Ulukan Çağrı , Samancı Bedia , Erzurumluoğlu Ebru , Hanagasi Hasmet , Deniz Günnur , Bilgiç Başar , Çetin Esin
Published: December 2023

Background

Nasu‐Hakola disease (NHD) is a rare genetic neurodegenerative disorder characterised by progressive presenile dementia and bone cysts. Dysfunctions in myeloid‐derived innate immune cells such as microglia due to loss‐of‐function mutations in the TREM2 (trigger receptor 2 expressed on myeloid cells) gene cause the clinical manifestations. Heterozygous carriers have strongly increased risk of developing Alzheimer’s Disease but do not present with NHD symptoms. TREM2 is associated with DAP12 protein, which contains an immunoreceptor tyrosine‐based activation motif that is structurally similar to natural killer (NK) cell receptors. In this study, we aimed to analyse the effects of TREM2 mutation and its effect on the peripheral immune system represented by NK cell functions.

Method

Six patients with NHD with a defined homozygous TREM2 mutation, 7 carriers with heterozygous TREM2 mutations and 10 age‐ and gender‐matched controls were included. NK cell subsets, KIR expressions (NKG2A, NKG2D, NKp46), cytotoxic activity (CD107a, Perforin, Granzyme A) and cytokine secretions (IL‐4, IFN‐γ, TNF‐α, IL‐10, IL‐17, TGF‐β) were analysed by flow cytometry.

Result

CD3−CD56dimCD16− (p = 0.003) subsets were found to be increased in the NHD group compared to carriers. Activating C‐type lectin receptor NKG2D expression was increased in CD8+ (p = 0.003) NK cell subsets in the NHD group. Inhibiting C‐type lectin receptor NKG2A expression was increased in total (p = 0.011) as well as CD8+ (p = 0.007) NK cell subsets in carriers compared to controls. In total NK cells, intracellular TNF‐α (p = 0.005) and TGF‐β (p = 0.013) levels were decreased, IL‐17 (p = 0.05) and IL‐4 (p = 0.005) levels were increased in the NHD group. When NK cells were grouped due to their CD8 expression, TNF‐α levels were decreased, and IL‐17 levels were increased in both subsets in the NHD group. Cytotoxic activity showed no differentiation in both unstimulated and K562 stimulated conditions between groups.

Conclusion

Unlike previous case series, NK cell ratios did not differ between groups. Over‐expression of inhibiting receptors in the carriers group, unlike high levels of activating receptors in the NHD, might explain the lack of symptoms in the carriers. The increased ratio of CD3−CD56dimCD16− NK cell subsets that overexpress inhibitory checkpoints might explain the low levels of pro‐inflammatory cytokines in the NHD group.
Characterizing the effects of chemotherapy on the brain of patients with head and neck cancer using FDG PET
Authors: Bishay Steven , Schwartz Trent , Smith David Samuel , Lee Lok Hin , Rosenthal Eben , Hohman Timothy J. , Jefferson Angela L. , Koran Mary Ellen ,   Head and neck cancer
Published: December 2023

Background

Chemotherapy has known adverse effects on the brain. From small (N<30) studies primarily in breast cancer, we know that post‐chemotherapy brain changes can be detected with 18F ‐fluorodeoxyglucose positron emission tomography (FDG PET), but this has been relatively unexplored in other cancers, and has not been explored in patients with head and neck cancer (HNCa) (Chen, 2018). Patients with HNCa have 2‐3 times the risk of dementia after therapy compared to controls and may be particularly vulnerable given underlying lower levels of education and heavy tobacco and alcohol use (Zer, 2018). We will determine which areas of the brain are most vulnerable to the chemotherapy in HNCa with FDG PET.

Method

Patients with HNCa were identified from Vanderbilt’s Cancer Registry, limited to patients with FDG PET in the last year (2021). Clinical data was mined from the electronic health record. Images were processed with well‐established SPM12 methods (Friston, 1995). A voxel‐wise ANCOVA was performed on FDG PET images before and after chemotherapy, including covariates of age, sex, ethnicity, and time between chemotherapy and follow‐up imaging using conservative family wise error of <0.05 and voxel extent threshold of 10.

Result

68 patients with HNCa met inclusion criteria and all patients received Carboplatin‐based chemotherapy (Table 1). Compared to baseline, 17 clusters met conservative significance thresholds with decreases in glucose metabolism following treatment (Figure 1). These included large regions (46397 1.5mm3 voxels) in the frontal and temporal lobes (pFWE = <0.001). Specifically, there was significantly decreased glucose metabolism in the dorsolateral prefrontal cortex (BA 9), frontoparietal cortex (BA 10), orbital frontal cortex (BA 11), medial and superior temporal gyri (BA 21, 22), dorsal (BA 24), and the subgenual (BA 25), pregenual (BA 32), and rostral (BA 33) anterior cingulate cortex post‐chemotherapy.

Conclusion

To our knowledge, this is the first study to explore the effects of chemotherapy in HNCa, a population particularly vulnerable to these effects. We found that regions in the forebrain and temporal lobes are most vulnerable. Studies like these are important to establish and confirm spatial distributions of these effects which will be crucial for development of diagnostics and monitoring tools for these effects.
Associations of plasma lipids with CSF sTREM2 in Alzheimer’s disease
Authors: Li Danni , Glittenberg Matthew
Published: December 2023

Background

We hypothesize that plasma lipids interact with brain endothelial cells, which in turn activate microglia. To test our hypothesis, we examined cross‐sectional associations between plasma lipids and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a biomarker of microglial activation.

Method

We included 357 non‐demented participants (197 males and 160 females) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available plasma lipidomics data (Baker Heart and Diabetes Institute, Metabolomics laboratory), CSF Ab42, CSF sTREM2, amyloid PET (18F‐florbetapir/18F‐florbetaben), demographics and cognitive status. Participants with baseline CSF and PET data obtained beyond a window of 6 months were excluded. Participants were stratified into early‐ (Ab CSF+/PET‐; n = 53) or late‐amyloid beta accumulators (CSF+/PET+; n = 196) based on CSF Ab42 (positivity when CSF Ab42 < 976.6 pg/ ml) and amyloid‐PET status (positivity when 18 F‐florbetapir > 1.11 SUVR or 18Fflorbetaben PET > 1.08 SUVR). Participants classified as Ab CSF‐/PET‐ were included as healthy controls (n = 108); participants as Ab CSF‐/PET+ were excluded. Plasma lipids and CSF sTREM2 were log10 transformed. Multiple linear regression models were used to examine the associations between plasma lipids and CSF sTREM2, adjusting for age, sex, BMI and # of APOE4 alleles. ChemRICH software was used for lipid cluster enrichment analysis and enriched clusters were defined based on FDR p value of < 0.01 and altered ratio (# of lipids altered/# of lipids in a cluster) of 0.1 or greater.

Result

781 plasma lipids were grouped into 37 clusters based on chemical ontologies and structural similarity. We identified 12 plasma lipid clusters enriched in early accumulators (Figure 1) for their associations with CSF sTREM2, only 1 (lysoPC) for late accumulators, none for health controls. All the associations were positive (e.g., higher levels of lipids were associated with higher CSF sTREM2). We further examined the associations between plasma lipids and CSF Ab42 in early accumulators and identify a different set of plasma lipid clusters (i.e., phosphatidylethanolamine and phosphatidylinositol).

Conclusion

Our results suggest strong connections between plasma lipids and brain microglial activation before abnormal brain deposition begins, which were not mediated by decreased CSF Ab42 clearance.
Interventional clinical trial findings from targeted multiday repetitive transcranial magnetic stimulation to treat memory loss in amnestic mild cognitive impairment
Authors: Warren David E , Phipps Connor J , Heller Abi , Behm Lillian , Zatkalik Abigail L , Wilhelm Anna F , Phatak Vaishali S , Murman Daniel L
Published: December 2023

Background

Memory loss is the hallmark cognitive symptom of Alzheimer’s disease (AD), and it affects independence, autonomy, and identity. AD‐related memory deficits are associated with pathological changes in brain structure and function, and current treatments offer limited relief. Targeted repetitive transcranial magnetic stimulation (rTMS) of AD‐vulnerable intrinsic brain networks can enhance memory abilities in healthy adults (Wang et al., 2014). To test rTMS approaches as a potential treatment for clinical memory loss, we administered a local clinical trial (ClinicalTrials.gov #alz078533) that enrolled patients with amnestic mild cognitive impairment (aMCI), a frequent precursor to AD (target enrollment of 16). Here, we report cognitive and brain findings from our trial.

Methods

Patients with aMCI completed two weeklong interventions consisting of pre‐stimulation brain and cognitive measurement, rTMS for five consecutive days, and post‐stimulation brain and cognitive measurement. Brain measures included structural and resting‐state functional MRI data; cognitive assessments included measures of memory function. Interventions were identically formatted except for rTMS intensity (treatment/sham). Stimulation used β‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min (1600 pulses); stimulation location was a left lateral parietal cortex location coactive with a hippocampus‐centered functional network. Stimulation intensity varied with each participant’s resting motor threshold (treatment, 100%; sham, 10%). Condition order was counterbalanced.

Results

We identified hippocampus‐centered networks in each participant, then localized parietal rTMS targets. Critically, we observed changes in brain and cognitive (memory) measures in the treatment‐intensity condition that were not observed in the sham‐intensity condition. Furthermore, we observed changes in intrinsic network connectivity within the stimulated hippocampus‐centered network.

Conclusions

Our trial of patients with aMCI measured changes in brain and cognitive variables after rTMS of a brain network supporting memory processes. We found evidence consistent with neural plasticity, and we frequently observed memory improvement in patients with aMCI after treatment‐intensity rTMS. Our findings suggest that rTMS can improve memory in clinical populations. This is important because, counterintuitively, new disease modifying therapies for AD may increase need for symptomatic treatment of memory loss due to prolongation of prodromal/mild stages of AD. Thus, adjuvant therapies such as rTMS for memory loss could improve AD treatment outcomes.
The Effects of Hypertension on White Matter Microstructural and Vascular Imaging Metrics
Authors: Kim Donghoon , Hughes Tim M. , Wu Yu‐Chien , Lockhart Samuel N. , Craft Suzanne , Baker Laura D , Whitlow Christopher T. , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina E , Bobinski Matthew , Jung Youngkyoo
Published: December 2023

Background

Hypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM.

Method

Four‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP≥130mmHG and DBP≥80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied.

Result

Hypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF.

Conclusion

Hypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia.
Effect of Internet‐based vs in‐person cognitive interventions on patients with mild to moderate Alzheimer’s disease: A randomized, cross‐over, open‐label trial
Authors: Jung Young Hee H
Published: December 2023

Background

We aimed to investigate the effect of Internet‐based and in‐person cognitive interventions on cognition, mood, and activities of daily living (ADL) on patients with mild to moderate Alzheimer’s disease (AD) and examine whether Internet‐based intervention is as effective as the in‐person intervention.

Method

We recruited 52 patients with probable mild AD, of whom 42 completed the trial. We randomly divided participants into intervention and control groups at a 1:1 ratio and statistically compared the neuropsychological test results of the two groups. In addition, patients in the intervention group were randomly assigned to a four‐week Internet‐based or in‐person intervention, with subsequent crossover to the other group for four weeks. We statistically analyzed and compared the neuropsychological test scores between Internet‐based and in‐person interventions.

Result

Compared with the control group, the intervention group (Internet‐based and in‐person) showed significantly improved profile in cognition (P<0.001), depression (P<0.001), anxiety (P<0.001) and ADL (P<0.001). In addition, the effect of the Internet‐based intervention on cognition (P = 0.918) and depression (P = 0.282) was not significantly different from that of the in‐person intervention. However, in the Beck Anxiety Inventory (P = 0.009) and Seoul Instrumental Activity of Daily Living (P = 0.023), in‐person intervention was more effective than Internet‐based intervention.

Conclusion

This study suggests that both types of cognitive intervention (in‐person and Internet‐based) may be viable supplementary treatments along with approved pharmacological therapy. In terms of cognition and depression, the effect of Internet‐based interventions may not be significantly different from that of in‐person interventions.
Sex Moderates the Association Between Age and Myelin Water Fraction in the Cingulum and Fornix among Older Adults Without Dementia:A Preliminary Study
Authors: Brenner Einat K , Bangen Katherine J. , Clark Alexandra L , Delano‐Wood Lisa , Evangelista Nicole D. , Sorg Scott F , Jak Amy J. , Bondi Mark W. , Deoni Sean C.L. , Lamar Melissa
Published: December 2023

Background

Cognitive decline in normal aging and Alzheimer’s disease (AD) has been associated with changes in cerebral white matter tracts. Although women are at higher risk of developing AD, studies investigating the effect of sex on white matter integrity have been mixed. Decreased white matter integrity in limbic pathways including the fornix and cingulum have been reported in AD although underlying mechanisms and potential sex differences remain understudied. We explored sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults.

Method

Fifty‐two older adults without dementia (mean age = 72; 61% female) underwent neuropsychological evaluation and 3T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in three a priori regions of interest including the fornix, cingulum in the hippocampal formation (CGH), and cingulum in the cingulate gyrus (CGC). The California Verbal Learning Test‐Second Edition assessed learning and long‐delay free recall. Separate multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. All models adjusted for APOE e4 allele frequency, vascular risk, and site; the second analysis additionally adjusted for age and sex.

Result

(1) There was a significant ageXsex interaction for CGC MWF (p = 0.006) and fornix MWF (p = 0.016) (see Figure) but not CGH MWF (p = 0.443). Specifically, for both interactions, in women but not men, as age increased, MWF decreased. (2) Fornix MWF was associated with memory (p = 0.002), but MWF of the two cingulum regions were not (p>0.05). Results did not change when adjusting for hippocampal volume.

Conclusion

Results suggest that the relationship between age and myelin content of limbic fiber pathways depends on sex, with women but not men showing age‐related decreases. Additionally, and consistent with previous studies, we observed an association between fornix MWF and learning and memory. Understanding sex differences in MWF may facilitate earlier detection of AD risk for women. Longitudinal study with larger samples is needed to further clarify the role sex plays in limbic system myelin integrity and potentially inform interventions.
Does biological sex moderate the association of nature exposure with brain volume? A cross‐sectional analysis of the UK Biobank
Authors: Noseworthy Matt W , Falck Ryan S , Galea Liisa A , Puterman Eli , Handy Todd C , Liu‐Ambrose Teresa
Published: December 2023

Background

Neighbourhood nature spaces are associated with brain health. Biological sex moderates the associations of various lifestyle and environmental factors with brain health, but it is unclear whether sex moderates associations between nature exposure and brain structure. We thus investigated whether sex moderates the association of residential nature exposure with brain structure in the UK Biobank cohort.

Methods

We conducted a cross‐sectional analysis of the UK Biobank study. We included cognitively healthy participants with available nature exposure data at study entry (2006‐2010) who completed a 3T structural brain MRI (2014‐2021; N = 37,880). Residential nature exposure was estimated as the percentage of land classified as natural environment within 1000m of a participant’s home. We indexed total grey matter volume and total white matter volume, normalized for head size, and hippocampal volume averaged from both hemispheres. We performed linear regressions to assess the independent associations of residential nature exposure and biological sex with brain structure. We then assessed whether sex moderated the association between residential nature exposure and brain structure, and plotted simple slopes to interpret interaction effects. All models adjusted for age, body mass index (kg/m2), educational attainment, income, physical activity (min/day), time spent outdoors (hours/day), smoking status, disability status, Townsend deprivation index, and population density.

Results

At study entry, mean age was 55 years (SD = 7.53 years) and 53% of participants were female. Average residential nature exposure was 44% (SD = 26%). Every 10% increment in residential nature exposure was associated with 737 mm3 greater grey matter volume (p<0.0001) and 601 mm3 greater white matter volume (p<0.0001). Females had 24,270 mm3 greater grey matter volume (p<0.0001), 9,703 mm3 less white matter volume (p<0.0001), and 223 mm3 less hippocampal volume than males (p<0.0001). Sex moderated the association of residential nature exposure with total grey matter volume, such that every 10% increment in nature exposure attenuated sex differences in grey matter volume by 422 mm3 (p = 0.020) (Figure 1).

Conclusion

These results suggest that neighbourhood nature spaces may benefit brain health, and that males may be more sensitive than females to these potential benefits. Longitudinal analyses are needed to verify these findings.
The associations between attentional control and Alzheimer disease biomarkers of tau and neurodegeneration
Authors: Stojanovic Marta , Aschenbrenner Andrew J. , Balota David A. , Schindler Suzanne E. , Ances Beau
Published: December 2023

Background

Attentional control may be affected in both the preclinical and symptomatic phases of Alzheimer disease (AD). In addition, variability in attentional control has been associated with apolipoprotein E (APOE) genotype, a major genetic modifier of AD risk. This study examined the associations between concurrent attentional control, as well as longitudinal change in attentional control, with AD biomarkers of tau (tau positron emission tomography [PET]) and neurodegeneration (cerebrospinal fluid [CSF] concentrations of neurofilament light chain [NfL]). A secondary goal was to examine whether APOE genotype moderates these relationships.

Method

Within 395 cognitively normal (Clinical Dementia Rating [CDR] = 0) and 70 cognitively impaired (CDR>0) individuals (age range 46‐90 years), attentional control measures (n = 465), PET‐Tau (n = 465), and CSF NfL (n = 370) were obtained. Attentional control was evaluated using composites of accuracy, reaction time, and ex‐Gaussian measures from reaction time analyses, from three attentional control measures, with a primary focus on accuracy and the tau parameter. Linear regression models examined whether attentional control measures were associated with PET‐Tau and CSF NfL cross‐sectionally. Linear mixed models were used to evaluate whether longitudinal trajectories in attentional control predicted levels of PET‐Tau and CSF NfL.

Result

Worse concurrent attentional control performance, primarily high tau parameter, was associated with elevated tau‐PET (p = 0.036) and CSF NfL (p = 0.021) in cognitively impaired but not cognitively normal individuals (all p’s > 0.087). Greater decrease in longitudinal attentional control performance, particularly accuracy, was associated with greater tau‐PET (p = 0.031) and NfL (p = 0.011) in the cognitively impaired group but not cognitively normal group (all p’s > 0.325). APOE genotype did not moderate these effects (all p’s > 0.062).

Conclusion

The results indicate that cross‐sectional and longitudinal attentional control measures are associated with PET‐Tau and CSF NfL only in cognitively impaired individuals. Future studies are needed to further investigate whether attentional control measures are more sensitive to other AD biomarkers (e.g., CSF tau species), as well as other potential moderators besides APOE genotype, such as medical conditions, mood, and lifestyle factors, including exercise.
Family history and modifiable risk factors in early‐onset Alzheimer’s disease in southern Brazil.
Authors: de Albuquerque Ana Letícia Amorim , Franco Alvaro de Oliveira , Chaves Marcia L Fagundes , Castilhos Raphael Machado
Published: December 2023

Background

Alzheimer’s disease (AD) represents a burdensome health condition worldwide and has a highly clinical heterogeneity. In particular, the early‐onset presentations may be related to different risk factors and underlying pathological mechanisms. We aimed to compare the frequency of modifiable risk factors/family history of dementia in a sample of AD from a tertiary memory outpatient clinic in Southern Brazil.

Method

We reviewed the clinical data of patients clinically diagnosed with AD at the dementia outpatient clinic at the Hospital de Clínicas de Porto Alegre, Brazil, between 2014 and 2022. We collected sociodemographic, clinical, family history, and the presence of seven modifiable risk factors for dementia: hypertension, diabetes, alcohol abuse, tobacco use, traumatic brain injury, hearing loss and previous psychiatric illness. Differences between early (< 65 years) and late‐onset AD were analyzed by Chi squared and Mann‐Whitney tests, with significance defined as p<0.05. All analyses were made in the R.

Results

A total of 145 patients were evaluated, 96 (66.2%) female, mostly (80.7%) white and median (interquartile range, IQR) of 76 (69‐80) years in the first evaluation. Of these, 40 (27.6%) had early‐onset presentation, with age at onset of 59.3 (52.4 ‐ 63) years. The early‐onset group presented a higher frequency of family history of dementia with an autosomal dominant pattern, 7 (17.5%) vs 0 (p = 0.011), with two patients being diagnosed with PSEN1 mutations, and worse scores in Mini Mental State Examination (p = 0.034) at the first evaluation. The groups did not differ in years of formal education or disease duration at the first appointment. Except for a higher frequency of hypertension in the late‐onset group, 68 (64.8%) vs 18 (45%), p = 0.048, there was no difference in the other risk factors (Table 1).

Conclusion

In our sample, the profile of risk factors was similar between early‐ and late‐onset AD presentations, but the early‐onset patients had a higher frequency of autosomal dominant dementia family history. Our results suggest that in our sample the genetic and modifiable risk factors are both associated with early‐onset presentations.
CSF Plasminogen inhibitor 1(PAI‐1) levels are associated with dementia symptoms in Alzheimer disease
Authors: Dlamini Sibonginkhosi L. , Henson Rachel L. , Saef Benjamin A. , Barthélemy Nicolas R. , Hendrix Rachel , Fagan Anne M. , Morris John C , Bateman Randall J. , Cruchaga Carlos , Schindler Suzanne E.
Published: December 2023

Background

There are currently excellent fluid biomarkers of brain amyloidosis, including CSF Aβ42/Aβ40 and CSF pT217/T217 (%). However, many individuals with brain amyloidosis do not have symptoms of Alzheimer disease (AD). Biomarkers that are strongly associated not only with brain amyloidosis but also with symptomatic AD would be invaluable tool in clinical trials and clinical diagnosis. We evaluated whether CSF biomarkers in an immunoassay panel added value to existing biomarkers in prediction of cognitive impairment.

Method

An immunoassay panel from Rules Based Medicine was used to measure CSF levels of 52 proteins including plasminogen inhibitor 1 (PAI1). CSF Aβ42/Aβ40 was measured by Lumipulse, and CSF pT217/T217 (%) was measured by an immunoprecipitation‐mass spectrometry assay. Logistic regression and linear models were used to evaluate the association between biomarkers and cognitive status (cognitively unimpaired or symptomatic AD as defined by a Clinical Dementia Rating [CDR] of 0.5 or greater), the Mini‐Mental State Exam [MMSE] score, and CDR Sum of Boxes [CDR‐SB]. Models included the covariates of age, self‐identified gender, and years of education.

Result

The cohort included n = 179 older research participants (average age 73.0 years, standard deviation 6.6 years), of which 47 (26%) had cognitive impairment (CDR>0). Cognitively impaired individuals had higher levels of PAI1 (p = 1.18e‐05) (Fig. 1A). PAI1 levels predicted cognitive status in the entire cohort (p = 4e10−3) and the sub‐cohort with CSF Aβ42/Aβ40 levels consistent with brain amyloidosis (Aβ42/Aβ40<0.0673; p = 0.003). Even when CSF pT217/T217 (%) was included in the model of cognitive status, PAI1 was a significant independent predictor of cognitive status in both the entire cohort (p = 0.005) and the sub‐cohort with brain amyloidosis (p = 0.008) (Fig. 1B). Both the MMSE and CDR‐SB were associated with PAI1 in the entire cohort (p = 1.86e‐07 and p = 5.45e‐07), and the sub‐cohort with brain amyloidosis (p = 2.44e‐05 and p = 4.77E‐05) (Fig. 1C‐D). When CSF pT217/T217 (%) was included in the model, both the MMSE and CDR‐SB remained associated with PAI1 in the entire cohort (p = 8.85e‐06 and p = 3.02e‐05) and the sub‐cohort with brain amyloidosis (p = 0.0001 and p = 0.0003).

Conclusion

These results demonstrate that CSF PAI1 is associated with symptomatic AD and adds value to CSF pT217/T217 in predicting AD symptoms.
Cognitive performance is associated with cardiovascular and renal remodeling in young female rats with chronic kidney disease
Authors: Grigorova Yulia N , Santos Carla Rocha Dos , Haghkar Mahdi , Fox Shanaya , Long Jeffrey M , McDevitt Ross A , Morrell Christopher H , Wei Wen , Zernetkina Valentina I , Juhasz Ondrej , Sodhi Komal , Rapp Peter R. , Lakatta Edward G , Fedorova Olga V
Published: December 2023

Background

The prevalence of cognitive impairment (CI) and dementia in end‐stage chronic kidney disease (CKD) has been estimated at 30‐60%. Cardiovascular dysfunction accompanies CKD and contributes to CI in humans and animal models. Since CKD occurs more often in females in clinical studies, the aim of this study was to determine whether cardiovascular and renal remodeling is associated with cognitive performance in the female rats with CKD.

Methods

Four‐month‐old female Sprague‐Dawley rats were fed with 0.25% adenine diet to induce CKD (n = 19) or a regular control diet (n = 16; CTRL) for 8weeks. Body weight (BW), blood pressure (BP), heart rate (HR), blood urea nitrogen (BUN), sodium, potassium, creatinine, hematocrit, estradiol, and behavioral tests were assessed at the end of the study. The level of anxiety was tested in open field test (OFT) and elevated plus maze (EPM). Spatial memory was tested by the ability to find a hidden platform in Morris water maze (MWM). The data were analyzed by two‐tailed unpaired t‐test and linear regression analysis (LRA).

Results

CKD was associated with higher creatinine and BUN, lower hematocrit, and enlarged hearts, aortae and kidneys vs. CTRL (Table 1). There was no difference in BP, estradiol, sodium and potassium, MWM, OFT and EPM performance between the groups. However, the LRA revealed the association of higher heart weights with a reduced spatial memory and higher anxiety level in both CTRL and CKD (Table 2; Figure 1A,B). The association of higher aortic weight with a reduced spatial memory, and higher kidney weight with higher anxiety levels was demonstrated in CKD only (Table 2; Figure 1C,D). Estradiol was associated with better spatial memory in CKD (LRA: R2 = 0.264; p = 0.04).

Conclusion

Anxiety‐like behavior and spatial memory were associated with cardiovascular remodeling in young female rats with CKD. We suggest that (1) CKD stimulates development of cardiovascular remodeling, which may affect blood supply of cortex and hippocampus, responsible for anxiety and spatial memory, and (2) estradiol may contribute to a better cognitive performance in the young CKD female rats. The future direction is to investigate whether CKD influences the trajectory of neurocognitive and cardiovascular aging.

Supported by NIA/NIH/IRP
Effects of structural and social determinants of health and comorbidities on ethno‐racial differences in ATN plasma biomarkers of Alzheimer’s disease: A HABS‐HD study
Authors: Meeker Karin L. , Ances Beau , Petersen Melissa , Barber Robert , Yaffe Kristine , Zhou Zhengyang , Llibre‐Guerra Jorge J , Zhang Fan , Hall James , Kind Amy J. , Lee Joseph H. , Vardarajan Badri N , Cohen Annie , Mielke Michelle M. , Mapstone Mark , Babulal Ganesh M. , O'Bryant Sid E.
Published: December 2023

Background

Ethno‐racial differences are observed in amyloid (A), tau (T), and neurodegeneration (N) plasma biomarkers of Alzheimer’s disease (AD). In neuroimaging studies, structural and social determinant of health (SSDOH) factors and associated health outcomes may mediate observed racial differences in neurodegeneration markers. However, little is known regarding the potential effects of SSDOH and downstream comorbidities on ethno‐racial differences in AT(N) plasma biomarkers. This study A) assessed potential differences in plasma Aβ42, Aβ40, Aβ42/40, t‐tau, and NfL among Mexican Americans (MA), non‐Hispanic Blacks (NHB), and non‐Hispanic Whites (NHW); B) determined whether SSDOH and comorbidity factors mediate potential ethno‐racial differences in AD plasma biomarkers.

Method

Data were obtained from the diverse and well‐characterized Health and Aging Brain Study – Health Disparities (HABS‐HD) and included MAs (n = 931), NHBs (n = 258), and NHWs (n = 942). Group differences in AT(N) plasma biomarkers were assessed using analysis of covariance. Age, sex, and cognitive status (Clinical Dementia Rating Scale Sum of Boxes) were included as covariates. Two multiple mediation models were performed with SSDOH (acculturation, chronic stress, income, area deprivation index) and comorbidity factors (body mass index [BMI], blood pressure, diabetes history) as the potential mediators, respectively. Models accounted for age, sex, and cognitive status, assumed nonlinear relationships, and allowed for mediators to be considered simultaneously.

Result

Plasma Aβ42 was significantly lower in MAs compared to NHWs (p<0.05). Plasma NfL was significantly higher in MAs compared to NHBs (p<0.01) and for NHWs compared to NHBs (p<0.05). No other significant differences in plasma variables were observed (p’s>0.05). Group differences in plasma Aβ42 were mediated by comorbidity factors (BMI and history of diabetes), but not SSDOH. MAs had greater BMIs and history of diabetes compared to NHWs, both of which were associated with lower plasma Aβ42 levels. SSDOH and comorbidity factors did not mediate group differences in plasma NfL.

Conclusion

Using a large and diverse community‐based cohort, we demonstrate that ethno‐racial differences in AD‐specific plasma biomarkers are, in part, due to modifiable health and comorbidity factors. This work informs the conditions that give rise to ethno‐racial differences in plasma ATN biomarkers while highlighting potential ethno‐racial disparities in AD research.
A high‐dimensional incomplete‐modality transfer learning method for early prediction of Alzheimer’s disease
Authors: Ku Dohyun , Zheng Zhiyang , Mao Lingchao , Chen Rui Qi , Su Yi , Chen Kewei , Weidman David , Wu Teresa , Lure Fleming , Lo ShihChung , Li Jing
Published: December 2023

Background

Prediction of Alzheimer’s disease (AD) risk for individuals with mild cognitive impairment (MCI) provides an opportunity for early intervention. Neuroimaging of different types/modalities has shown promise, but not every patient has all the modalities due to the cost and accessibility constraints. To integrate incomplete multi‐modality datasets, we previously developed a machine learning (ML) model called incomplete‐modality transfer learning (IMTL). We extended the capacity of IMTL to handle high‐dimensional feature sets, namely, HD‐IMTL, to further improve accuracy and robustness.

Method

Our dataset included 1319 T1‐MRI scans from MCI patients in ADNI; among them, 1002 had FDG‐PET and 612 had amyloid‐PET. 156 regional volumetric and thickness features were computed from MRI and 83 and 83 regional SUVR features from FDG‐PET and amyloid‐PET, respectively. The dataset is randomly split into training and test sets. The goal of HD‐IMTL was to jointly train 4 ML models to predict MCI conversion to AD in 36 months, with each model based on a certain combination of available modalities, namely, MRI, MRI+FDG, MRI+amyloid, and MRI+FDG+amyloid. These correspond to patient sub‐cohorts that differ in their access to imaging modalities. To handle high‐dimensional features, we employed feature screening to remove uninformative features, performed modality‐wise partial least squares (PLS) to condense remaining features into PLS components, and used correlation tests to select components. To jointly train the 4 ML prediction models, IMTL was used, which is a generative model that uses expectation‐maximization (EM) in joint parameter estimation to facilitate transfer learning. To account for sample imbalance in training, the Synthetic Minority Over‐sampling Technique (SMOTE) was used. The trained models were applied to the test set. 20 training/test splits were repeated and AUCs on the test set were averaged. For comparison, three existing ML models for incomplete‐modality fusion were applied to the same dataset.

Result

The AUCs by HD‐IMTL were 0.802, 0.840, 0.868, and 0.880 for sub‐cohorts with MRI, MRI+FDG, MRI+amyloid, and MRI+FDG+amyloid, respectively. The AUCs by existing methods were lower, with ranges of 0.749‐0.793, 0.769‐0.826, 0.816‐0.863, and 0.832‐0.868.

Conclusion

HD‐IMTL demonstrated high accuracy in predicting MCI conversion to AD for patients with varying access/availability of imaging modalities.