bluuebunny/crossref_metadata_2025_split huggingface dataset:
Center for Alzheimer Research at Karolinska Institutet, Sweden
Authors: Ankarcrona Maria , Religa Dorota 
Published: December 2023

AbstractCenter 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

AbstractBackgroundLimbic‐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.MethodIndividuals 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.ResultLATE 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).ConclusionGiven 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

AbstractBackgroundThe 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.MethodThe 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).ResultNew 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).ConclusionLonger‐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

AbstractBackgroundThe 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.MethodWe 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.ResultOverall, 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).ConclusionOver 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

AbstractBackgroundNasu‐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.MethodSix 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.ResultCD3−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.ConclusionUnlike 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

AbstractBackgroundChemotherapy 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.MethodPatients 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.Result68 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.ConclusionTo 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

AbstractBackgroundWe 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.MethodWe 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.Result781 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).ConclusionOur 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

AbstractBackgroundMemory 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.MethodsPatients 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.ResultsWe 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.ConclusionsOur 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

AbstractBackgroundHypertension 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.MethodFour‐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.ResultHypertensive 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.ConclusionHypertension 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.