bluuebunny/crossref_metadata_2025 huggingface dataset:
Tau deposition in the locus coeruleus and depression in cognitively unimpaired older adults
Authors: Kim Min Jung , Yi Dahyun , Byun Min Soo , Jung Joon Hyung , Kong Nayeoung , Jung Gijung , Lee Jun‐Young , Lee Yun‐Sang , Lee Dong Young
Published: June 2023

Background

Depression is a common manifestation of Alzheimer’s disease (AD) and frequently observed at the early phase of the disease. Several postmortem studies demonstrated that tau deposition was found at the brainstem nuclei including the locus coeruleus (LC) and dossal raphe nucleus (DRN) (3, 4), even before early Braak stages of neurofibrillary tangle pathology. Given the disturbance of monoaminergic system is related to depression in general, tau deposition in the LC or DRN may underlie depression in late‐life, as suggested in a couple of postmortem studies. In this context, we tried to examine the hypothetical association between in vivo tau depostion at the brain stem monoaminergic nuclei and depression in cognitively unimpaired older adults.

Method

A total of 69 cognitively unimpaired older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including the Hamilton Rating Scale for Depression (HRSD) and [18F] AV‐1451 positron emission tomography. Tau deposition in the LC and DRN was measured using the Harvard Ascending Arousal Network Atlas (AAN). Tau deposition in the pons was also assessed as a non‐monoaminergic control for comparison. Age, education, sex, and apolipoprotein E ε4 positivity were controlled as covariates in the analyses for the association between brain stem tau and HRSD score.

Result

Tau deposition in the LC was significantly associated with HRSD total score (β = 3.861, P = .009). In contrast, there was no significant association between tau deposition in the DRN and HRSD score (β = 2.229, P = .090). Tau deposition in the pons was also not related to HRSD score (β = 1.632, P = .207).

Conclusion

The findings support the possibility that alteration of the noradrenergic neurons in the LC by tau pathology may underlie depressive manifestation in cognitively unimpaired older individuals.
Reactive astrocytes as imaged with 11C‐DED in patients with different dementia disorders
Authors: Chiotis Konstantinos , Jelic Vesna , Rodriguez‐Vieitez Elena , Savitcheva Irina , Wall Anders , Antoni Gunnar , Nordberg Agneta K
Published: June 2023

Background

Neuroinflammation, which receives ever increasing interest in neurodegenerative diseases, comprises a heterogeneous cascade of events that are thought to be related to the downstream neurodegeneration. The aim of this study was to evaluate the binding of 11C‐Deuterium‐L‐Deprenyl PET (DED) as a measure of reactive astrocytes in patients with different dementia disorders, and to assess its association with other disease biomarkers.

Method

Eleven patients with a clinical diagnosis of semantic variant of primary progressive aphasia (svPPA, n = 5) and behavioral variant of frontotemporal dementia (bvFTD, n = 6) were recruited. All patients had a cerebrospinal fluid biomarker profile that was inconsistent with Alzheimer’s disease (AD) or a negative amyloid‐β PET scan. The imaging protocol included 11C‐DED‐PET, 18F‐FDG‐PET, and a 3D T1 MRI. A group of amyloid‐beta positive patients with AD (n = 20) that underwent similar investigations were used for comparison. Z‐scores were created for 11C‐DED binding (Patlak slopes) and tracer relative delivery (R1 parameter) relative to that of healthy controls (HC; n = 20), for assessing the load of reactive astrocytes and cerebral perfusion, respectively.

Result

The patients with svPPA and bvFTD showed significantly higher 11C‐DED binding in frontotemporal areas, compared to HC. Patients with AD showed significantly higher 11C‐DED binding in temporo‐occipital areas, compared to HC. The regional distribution of 11C‐DED binding in the patients with svPPA and bvFTD was consistent with the expected underlying pattern of neurodegeneration in those disorders, although the load of binding was heterogeneous across patients with the same clinical diagnosis.

Conclusion

Reactive astrocytes appear to be a common feature of different dementia disorders, although the regional pattern of reactivity differs. Ongoing work evaluates the relationship between patterns of reactive astrocyte activation, cerebral perfusion, glucose metabolism, atrophy, and cognitive performance.
Tau‐PET in retired contact sport athletes
Authors: Vasilevskaya Anna , Taghdiri Foad , Multani Namita , Ozzoude Miracle , Tarazi Apameh , Khodadadi Mozhgan , Wennberg Richard , Rusjan Pablo , Houle Sylvain , Green Robin , Colella Brenda , Blennow Kaj , Zetterberg Henrik , Karikari Thomas K , Mikulis David , Davis Karen Deborah , Tator Charles , Tartaglia Carmela
Published: June 2023

Background

Long term effects of concussions and sub‐concussions in athletes can include delayed neurodegeneration as seen in Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). The PET tracer [18F]AV1451 has high affinity and selectivity for paired helical filament‐tau in vivo, the pathological form of tau in CTE and AD. The aim of this study was to assess the effect of tau‐PET binding on brain atrophy in former contact sports athletes and evaluate differences between subjects with and without tau‐PET binding.

Method

31 retired athletes (age:53±15; sex: 29M, 2F; concussions/athlete: 7±6) negative for AD (CSF: p‐tau <68 pg/mL and ATI >0.8 and/or normal range of plasma p‐tau181) and 54 normal controls (age: 50±13) were included. All athletes completed MRI, [18F]AV1451 tau‐PET, the Sport Concussion Assessment tool 2 (SCAT2) and the Personality Assessment Inventory (PAI) depression and anxiety scales. Tau‐PET standardized uptake value ratios (SUVR) images were created using cerebellar gray matter (GM); tau‐PET positivity was set to ≥1.30 SUVR. Normal control MRI scans were used to create age/intracranial volume corrected GM volume maps.

Result

GM volumes were significantly lower in tau‐PET positive voxels in retired athletes ≥40 y.o. (N = 25; ‐0.48±0.40 vs. ‐0.42±0.41; p = .02) and there was a trend for lower GM volumes in tau‐PET positive voxels across athletes of all ages (N = 30; ‐0.40±0.42 vs. ‐0.35±0.41; p = .09), compared to tau‐PET negative voxels. Mean tau‐PET SUVR values in the cortical GM were used to divide retired athletes into tau‐PET positive (N = 20; SUVR ≥1.30) and negative (N = 11; SUVR <1.30) groups. The tau‐PET positive group did not differ in age (52±16 vs. 56±12; p = .4) or concussion number (9±7 vs. 7±5; p = 1.0) from the tau‐PET negative group; the tau‐PET positive group had significantly higher SCAT2 symptom severity (28.26±25.15 vs. 8.89±12.67; p = .01), PAI anxiety t‐scores (49.90±11.25 vs. 42.55±4.13; p = .01), and a trend for higher PAI depression t‐scores (54.75±16.58 vs. 47.09±8.08; p = .095), compared to the tau‐PET negative group.

Conclusion

Tau‐PET may be useful for identifying those at risk for delayed neurodegeneration. Older athletes showed relatively greater brain atrophy in tau‐PET positive regions, suggesting that detection of tau‐PET at a younger age may enable interventions to prevent future degeneration.
Consumption patterns of dementia patients compared to the MIND diet
Authors: Waterman Anna , Labyak Corinne A , Sealey‐Potts Claudia
Published: June 2023

Background

It is well‐documented that nutrition plays a role in the development and the progression of dementia. There have been numerous suggestions on how to combat this issue from the pre‐diagnosis stage and throughout as nutritional deficiencies and malnutrition persist. Certain dietary patterns have been shown to be protective against this disease, namely the MIND diet. There is limited data on the current intake of individuals living with dementia therefore it is important to identify nutrition patterns in order to improve outcomes.

Method

Researchers compared the dietary intake of diagnosed dementia patients compared to the dietary pattern recommended in the MIND diet. Dementia caregivers filled out food frequency questionnaires (FFQ) for loved ones with dementia on recent nutrition intake. Current intake was compared to the MIND diet categories for adequacy.

Result

Caregivers (n = 28) completed FFQs on the eating patterns of respective dementia participant. Compared to the MIND diet serving recommendations, most participants reported under consumption of whole grains, leafy vegetables, and nuts, and over consumption of poultry, other vegetables, fast/fried foods, and cheese. Participants adhered to the recommendations for red meat, and all (100%) reported consumption patterns of steak, hamburgers and roast beef as less than 4 times per week. Fifty‐two percent reported fish consumption of one week or less; 50% ate 1 serving of nuts; 46.7% consumed the recommended amount of beans per week, and only 2 individuals reported alcohol consumption and it was kept to 1 serving per day. Pattern for frequencies for berries consumption was split evenly: 29.4% met the recommendation for consumption, while 29.4% reported lower than recommended consumption of this food item.

Conclusion

Results indicate that individuals with dementia are eating well below the recommended levels of suggested foods in the MIND diet. Excess consumption of items that should be limited was observed. These findings indicate a call to action for input from Registered Dietitians to counsel patients and caregivers after dementia diagnosis.
Are lifestyle factors and mental attitude 30 years earlier associated with being a 90+ SuperAger? Results from the 90+ study
Authors: Biswas Roshni , Kawas Claudia H. , Paganini‐Hill Annlia , Corrada María M. M.
Published: June 2023

Background

Individuals with superior cognitive performance despite older age are known as SuperAgers. However, gaps in our knowledge of factors related to the ability to maintain this superior level of cognition remain. Our aim was to identify lifestyle factors and mental attitudes 30 years earlier that were related to superior cognition in the oldest‐old.

Method

Participants of The 90+ Study, a population‐based longitudinal cohort of people aged 90+, are survivors from the Leisure World Cohort Study (LWCS). We assigned a participant’s cognitive diagnosis during a multidisciplinary consensus conference after their death. We analyzed data from participants without dementia who had an evaluation within a year of death. Individuals who scored ≥28 in their last Mini Mental State Examination within one year to two months before death, were categorized as SuperAgers (SA) and the rest as non‐SuperAgers. At the time of enrollment into the LWCS, 30 years earlier, all participants completed a questionnaire on lifestyle factors (body mass index, physical activity, smoking habits, alcohol intake) and seven positively worded items from the Zung self‐rating depression scale. To assess the relationships between being a SA and lifestyle and positive mental attitudes, we calculated odds ratios (OR) and 95% confidence intervals using multiple logistic regression.

Results

Participants were 317 individuals (102 men and 215 women) with a mean age at the last visit of 96.6±3.3 years. Of them, 120 participants (37.8%) were identified as SA. Women and younger individuals were more likely to be SA while college education was unrelated (Table). Lifestyle factors and positive mental attitude were not associated with being a SA, although a greater proportion of SA tended to have healthful lifestyle habits, with normal body mass index, one or more hour of daily physical activity, and in the highest tertile for positive mental attitude (Table).

Conclusion

Factors like higher education, positive lifestyle choices and positive mental attitude, all related to living longer in this cohort, were not related to superior cognitive performance after ages 90 and older. Future research should try to identify other characteristics that may distinguish oldest‐old SuperAgers.
Dietary sulfur amino acid restriction to prevent Alzheimer’s Disease
Authors: Sambamurti Kumar , Krug Elaine , Cromwell Ian , Pappolla Miguel A , Vasu Chenthamarakshan , Lahiri Debomoy K. , Greig Nigel H , Padmaraju Vasudevaraju
Published: June 2023

Background

High serum homocysteine is a risk factor for Alzheimer’s Disease (AD). It has been reported to influence the accumulation of its characteristic lesions ‐ senile plaques (SP) and neurofibrillary tangles (NFT) ‐ containing amyloid β protein (Abeta) and microtubule‐associated protein Tau (MAPT), respectively. Reduced food or calorie intake or branched‐chain amino acids are reported to benefit AD model mice. Restriction of Methionine (Met), an essential amino acid, contributes to increased longevity without calorie restriction.

Method

We treated APP/PS1 transgenic mice with a 75% Met restricted (MR) diet and compared it to an isocaloric isonitrogenous complete diet (CD) for up to 12 months. We subsequently evaluated amyloid loads by ELISA and other APP metabolites by western blotting as described previously (Barnwell et al., 2014, Teich et al., 2018). We collected fecal matter from the colon, extracted DNA, and evaluated the gut microbiome.

Result

Our data show that MR treatment substantially lowered brain soluble Abeta at 3 and 6 months. Abeta levels are excessively and presumably saturated in older mice, accounting for the lack of statistically significant differences between the different diets evaluated after twelve months. Nevertheless, older mice showed substantial improvement in behavior in a novel object recognition task after MR treatment. MR treatment is known to be senolytic, and therefore, we are currently examining related processes, such as preservation of lysosomal capacity changes in metabolome, mRNA, and miRNA profiles. Future work involves evaluating methionine and branch‐chain amino acid restriction in AD animal models, such as in human tau‐overexpressing Tg mice, and evaluating miRNAs.

MR diets significantly alter gut microbiota. As expected, the bacteria that metabolize Met and Cys were decreased. Specifically, several major species of bacteria were reduced, and the overall diversity of microbiota was increased. Senolysis and improvements in AD pathology may also be mediated by reduced inflammation due to the increased diversification of the microbiome. Thus, such diets may play an important role in strategies to prevent AD, retinal degeneration, and other age‐associated disorders.

Conclusion

Sulfur amino acid restriction reduces amyloid production and preserves cognitive function in mice. Reduced protein diets may be useful in preventing proteinopathies that lead to neurodegeneration.
Generalized q‐sampling imaging‐based fiber tracking measures of white matter tracts in cognitive impairment
Authors: Duran Tugce , Bateman James R. , Williams Benjamin J. , Hughes Tim M. , Barcus Richard A. , Peavey Jeremy J. , Okonmah‐Obazee Stephanie E. , Whitlow Christopher T. , Craft Suzanne , Lockhart Samuel N.
Published: June 2023

Background

Diffusion magnetic resonance imaging (dMRI) is a non‐invasive technique for exploring white matter fiber organization of the brain. As traditional diffusion tensor imaging (DTI) methods may provide inaccurate descriptions of local crossing and diverging fibers, we examined generalized q‐sampling imaging (GQI), a novel method providing better directional and quantitative information using dMRI data from community‐dwelling older adults.

Method

We examined baseline dMRI data from 227 adults aged 71±8 on average from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core, who had baseline and year‐1 follow‐up global Clinical Dementia Rating (CDR) score of 0 (indicates normal cognitive function) and 0.5 (akin to MCI). The primary outcome measure was cognitive migration status determined by CDR increase/decrease between baseline and follow‐up (mean difference = 13.9 months), shown in Figure. We performed atlas‐based fiber tracking analysis using GQ in DSI Studio to generate normalized quantitative anisotropy (NQA), DTI fractional anisotropy (DTI_FA) and restricted diffusion (RDI) measures in several AD‐related white matter (WM) tracts: Corpus Callosum (CC), Fornix, Cingulum bundle/Parahippocampal tracts (see Table 2: CFP; CP; CPP), Uncinate Fasciculus (UF), Superior Longitudinal Fasciculus (SLF) and Inferior Fronto‐Occipital Fasciculus (IFOF). We performed multinomial logistic regression (MLR) models adjusted for age, sex, and education, using cognitive migration status as the outcome and standardized GQI‐based diffusion indices sNQA, sRDI, and sDTI_FA as predictors.

Result

Table 1 lists the baseline demographics and biomarker characteristics for cognitive migration groups. MLR results in Table 2 show significant associations between diffusion indices and tracts for outcome 4 (Reversion) in reference to outcome 1 (stability of normal cognition). Decrease in sNQA in bilateral CP and right Fornix was significantly associated with higher odds of Reversion relative to the reference. Increase in sDTI_FA in left IFOF was associated with higher odds of reversion relative to reference. Decrease in sRDI in bilateral CFP, CPP, Fornix and UF and right CP was associated with higher reversion relative to reference.

Conclusion

In early trajectories of cognitive impairment, RDI may be a sensitive diffusion marker for cognitive reversion in several AD‐related WM tracts. Future work will validate these markers in other cognitive migration groups (negative migration and MCI stability).
Ancestry‐Specific eQTL Associations in AA/NHW Alzheimer Disease Cohorts
Authors: Wheeler Nicholas R. , Benchek Penelope , Van Booven Derek , Gu Tianjie , Starks Takiyah D. , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: June 2023

Background

Although the genetic etiology of Alzheimer’s Disease (AD) has been shown to vary among ancestrally diverse populations, the influence of genetic variation on the transcriptome within these populations has not yet been extensively investigated. Multi‐ancestry AD datasets featuring both genetic information and gene expression measurements are needed to support expression quantitative trait loci (eQTl) studies in historically underrepresented populations. In this work, we have compared eQTL signals in case/control AD sample populations of both African American (AA) and non‐Hispanic white (NHW) ancestries.

Method

We analyzed cohorts of AA and NHW ancestries (Naa = 232, Nnhw = 241) with corresponding array‐based genotypes and RNA‐seq mRNA expression levels from whole blood, along with clinical AD diagnoses (Naa_case = 115, Naa_control = 117, Nnhw_case = 121, Nnhw_control = 120). Transcriptome‐wide eQTL associations between genetic variants and gene expression levels were assessed via regression across 17,638 gene units, adjusting for age, sex, experimental factors, and genetic principal components. This was repeated across all sample set combinations of ancestry‐AD pairings (ancestry = [aa, nhw, both] * AD = [case, control, both]).

Result

The number of significant (p‐value < 10e‐7) eQTL signals varied by ancestry, with the AA cohort showing 76,742 raw eQTL associations, the NHW cohort 19,734, and both ancestries combined 81,763. When further sub‐setting sample sets to AD cases only, 770 and 788 significant eQTL signals were observed for AA and NHW cohorts respectively, which impacted 135 (AA) and 130 (NHW) genes. Interestingly, these ancestry‐aware, case‐only eQTLs were remarkably distinct between the two ancestries, with only 71 (∼9.1%) of the eQTLs and only 19 (∼14.3%) of the impacted genes being shared by both ancestral cohorts. Of particular interest is the appearance of WWOX (a gene of wide neurological importance, and known AD risk loci), as differentially significant in the AA cohort (P = 8.07e‐7) as compared to the NHW cohort (P = 9.06e‐3).

Conclusion

We have observed differences in eQTL signals relative to AD diagnosis status between AA and NHW sample populations, which may indicate the presence of novel ancestry‐specific effects impacting the genetic etiology of AD through changes in gene expression.
Impact of the COVID‐19 pandemic on moral distress of care home staff caring for people with dementia
Authors: Haslam‐Larmer Lynn , Grigorovich Alisa , Quirt Hannah , Pia Kontos , Astell Arlene J. , McMurray Josephine , Maxwell Colleen J , Rodrigues Kevin , Flint Alastair , Iaboni Andrea
Published: June 2023

Background

Healthcare providers caring for people living with dementia may experience moral distress when faced with an ethically challenging situation, such as an inability to provide care that is consistent with their values. The COVID‐19 pandemic both created new and exacerbated pre‐existing factors which contributed to the experience of moral distress amongst healthcare providers in LTCHs.

Method

We conducted an online survey to examine changes in mortal distress during the first wave of the pandemic, its contributing factors and correlates, and its impact on the well‐being of LTCH staff. A total of 227 health care providers from LTCHs across Ontario, Canada completed the online survey. Using a Bayesian approach, we examined the associations between moral distress and staff demographics and roles, and characteristics of the LTCH in which they worked.

Result

More than 80% of LTCH healthcare providers working with people with dementia reported an increase in moral distress since the start of the pandemic. They frequently experienced physical and emotional symptoms related to moral distress more than once a week, with the most common symptoms being physical exhaustion (55%) powerlessness (39%), sadness/anxiety (38%) frustration/anger (31%), and difficulty sleeping (33%). There was no difference in the severity of distress by age, sex, role, or years of experience. The most common situations associated with moral distress were lack of activities and family visits, insufficient staffing and high turnover, and having to follow policies and procedures that were perceived to harm residents with dementia. Respondents working in not‐for‐profit or municipal homes reported less sadness/anxiety and feelings of not wanting to go to work than those in for‐profit homes. Front‐line staff were more likely to report not wanting to work than those in management or administrative positions. In the survey’s free‐text responses, respondents elaborated on the emotional impact of the change in care delivery for LTCH residents.

Conclusion

Moral distress increased during the pandemic, negatively affecting the well‐being of healthcare providers in LTCHs, with preliminary evidence suggesting that individual and systemic factors may intensify this negative effect.
Comparison of white matter hyperintensities between early‐onset Alzheimer’s disease participants and their cognitively normal and early‐onset nonAD peers from LEADS
Authors: Eloyan Ani , Vemuri Prashanthi , Gatsonis Constantine , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Dickerson Bradford C.
Published: June 2023

Background

The Longitudinal Early‐onset Alzheimer Disease study (LEADS) aims to robustly characterize biomarkers of early‐onset AD (EOAD). Here we quantified white matter hyperintensities (WMH) in EOAD and compared the volume of WMH with that of cognitively normal (CN) and amyloid‐negative early‐onset dementia (EOnonAD) groups.

Methods

We compared WMH of 194 amyloid‐positive EOAD, 59 amyloid‐negative EOnonAD, and 88 cognitively normal participants. WMH in left and right frontal, temporal, parietal, and occipital regions was compared between the group, as well as the sum total in each hemisphere. For distributional considerations, the logarithm of the WMHs was used in the analyses. Group comparisons were performed using t‐tests. Analyses of variance were used to compare the groups after correcting for the effects of age, sex, and education. Linear regression analyses were used to investigate the association between cognitive impairment and WMH using age, sex, and education as covariates. Cognitive impairment was measured using the Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) scale sum of boxes (CDR‐sb). All p‐values were corrected for multiple comparisons using the false discovery rate method.

Results

EOAD showed greater WMH compared with both CN and EOnonAD groups across all regions. This relationship holds after correcting for the effects of age, sex, and education (see Figure 1 and Table 1, all p‐values < 0.05). No significant differences were observed between WMHs of CN and EOnonAD groups. Higher WMH values were associated with greater cognitive impairment: MMSE (b = ‐1.69, p‐value <0.0001) and CDR‐sb (b = 0.45, p‐value <0.0001).

Conclusions

EOAD consistently show higher WMH compared to their CN and EOnonAD peers. The extent of WMH in CN and EOnonAD groups is similar. No differences in regional distribution were observed, with EOAD having higher WMH across all brain regions. Higher WMHs were associated with worse cognitive impairment measured both using MMSE and CDR sum of boxes.
Blocking soluble TNF decreases diet‐induced hyperglycemia and modulates immune alterations in 5xFAD animal model of Alzheimer’s disease
Authors: de Sousa Rodrigues Maria Elizabeth , Blackmer‐Raynolds Lisa , Chang Jianjun , Sampson Timothy R. , Tansey Malu Gamez
Published: June 2023

Background

Regulatory interactions between the gut and the brain are essential for energy homeostasis across systems. Current evidence indicates high‐fat, high‐carbohydrate diets (HFHC) impact Alzheimer’s disease (AD) pathophysiology, however, the mechanisms underlying this association are poorly understood. We hypothesize that (1) Tumor Necrosis Factor (TNF) mediates metabolic inflammation in an obesogenic environment with impacts across the gut‐brain axis and (2) that HFHC interacts with an AD‐relevant genetic background to promote metabolic and immune dysregulation that accelerates pathological and behavioral dysfunction in an animal model of AD.

Method

To investigate the effects of chronic systemic inflammation on AD‐associated pathology, 2‐month old female 5xFAD mice were fed HFHC or a control diets (CD) for 8 weeks. One month following dietary intervention, the brain‐permeant soluble TNF inhibitor XPro1595 or a brain‐impermeant pan (sol and membrane‐bound) TNF inhibitor Etanercept (Enbrel, Amgen‐Wyeth) or vehicle (saline) were dosed twice weekly for 4 weeks. Behavioral test were performed to assess cognitive parameters. Plasma, brain and gut were collected for evaluation of insulin impairment, metabolic and immune parameters. Cortical tissues were subjected to RNAseq analysis to determine gene pathways modified by interactions between diet, genotype, and TNF inhibition.

Result

HFHC promoted metabolic syndrome features associated with increases in adiposity, body weight, and plasma glucose, cholesterol, leptin, and insulin. TNF inhibition did not rescue diet‐induced insulin increases, however XPro specifically reduced plasma glucose, while Enbrel increased HOMA‐IR in HFHC‐fed mice. HFHC diet increased circulating IL‐6, CXCL1, CXCL2 and CCL2 and TNF neutralization with either drug decreased IL‐6 in HFHC‐fed groups. In the colon, HFHC diet decreased CCL3 and TNF blockade increased colonic IL‐15 in HFHC‐fed mice. Ongoing behavioral assessment, cortical transcriptional analysis, and hippocampal protein profiles of insulin signaling and inflammatory markers will determine additional effects of TNF and HFHC in the 5XFAD animal model of AD.

Conclusion

Collectively, these results suggest that TNF modulates systemic metabolic and inflammatory pathways induced by HFHC consumption and associated with neurodegeneration and neuroinflammation. Blocking soluble TNF decreases hyperglycemia triggered during diet‐induce obesity. Future studies focusing on the impact of TNF on energy homeostasis and inflammation will provide targets for new therapeutics against neurological disease.
“Probable 4R‐tauopathy” criteria in a Corticobasal Syndrome cohort: diagnostic accuracy, clinical, metabolic and volumetric patterns in a multimodal PET/MRI study
Authors: Parmera Jacy Bezerra , Carneiro Camila de Godoi , Neto Adalberto Studart , Ono Carla R , Barbosa Egberto Reis , Nitrini Ricardo , Buchpiguel Carlos A , Brucki Sonia Maria Dozzi , Coutinho Artur Martins
Published: June 2023

Background

Corticobasal syndrome (CBS) is a neurodegenerative disease related to multiple underlying pathologies, including four‐repeat (4R) tauopathies, namely corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), among others. The Movement Disorders Society‐PSP clinical criteria proposed a diagnostic category “probable 4R‐tauopathy” to include the phenotypic overlap between PSP and CBD. These criteria were specific for 4R‐tauopathies in a previous post‐mortem validation study. We aimed to investigate this proposed criteria in a cohort of patients clinically diagnosed with probable CBS, comparing the CBS‐4R tau group regarding neurological assessment, brain atrophy patterns, functional and disease‐specific imaging biomarkers. Also, we compared this group with CBS patients that matched the clinical research (cr) criteria for CBD.

Method

Thirty‐two patients diagnosed with probable CBS were prospectively enrolled and clinically evaluated. They were split into those who fulfilled criteria for probable 4R‐tauopathy (CBS‐4RT = 12) and probable CBD (CBS‐CBD = 28). They underwent [18F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET) and [11C]Pittsburgh Compound‐B (PIB‐PET) on a hybrid PET‐MRI to assess their amyloid status. PIB‐PET images were classified individually based on visual and 3D‐SSP semi‐quantitative analysis. Quantitative group analyses were performed with SPM12, to check both brain atrophy patterns using voxel‐based morphometry (VBM), and regional brain hypometabolism patterns with FDG‐PET. A healthy control group of 30 subjects, matched by age and education, was also included.

Result

Only one patient classified as CBS‐4RT was positive at PIB‐PET (p = 0.010), compared to 12 among 28 CBS‐CBD subjects (p = 0.458). The CBS‐4RT clinical classification had 52.6% sensitivity, 92.3% specificity, and 68.7% accuracy in predicting a negative PIB‐PET result. Also, CBS‐4RT patients presented dysarthria (p = 0.017) and motor perseveration (p = 0.032) more often than the whole group. CBS‐4RT patients showed asymmetric hypometabolism in the inferior, middle, and superior frontal gyri, supplementary motor area, and caudate compared to controls. They also demonstrated brain atrophy in the superior and inferior frontal gyri and basal ganglia.

Conclusion

The new proposed clinical 4R‐tauopathies criteria demonstrated high specificity to detect amyloid‐negative CBS patients. Patients fulfilling the criteria presented specific metabolic and volumetric patterns. Moreover, they presented clinical characteristics such as dysarthria and motor perseveration previously related to tauopathies.
Tracking reactive astrocytes in autosomal dominant Alzheimer disease with plasma GFAP and multi‐modal PET imaging
Authors: Chiotis Konstantinos , Johansson Charlotte , Rodriguez‐Vieitez Elena , Pannee Josef , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Graff Caroline , Nordberg Agneta K
Published: June 2023

Background

We have proposed astrogliosis as a “first wave” of response to AD pathology with diverging longitudinal changes of reactive astrocytes and amyloid‐β positron emission tomography (PET) retention in pre‐symptomatic autosomal dominant AD (ADAD). It has been suggested that plasma glial fibrillary acidic protein (GFAP) could be a marker of neuroinflammation in AD brain, although this hypothesis remains unproven. We therefore compared plasma GFAP levels with 11C‐deprenyl (DED) with a multi‐modal PET design in ADAD mutation carriers (MC) and non‐carriers (NC).

Method

Twenty‐three individuals from families with known ADAD mutations were included (MC = 9; NC = 14). All individuals underwent PET imaging with 11C‐DED, 11C‐PIB and 18F‐FDG, for assessing monoamine oxidase B as a marker of reactive astrocytes, amyloid‐beta deposition, and glucose metabolism, respectively. Plasma sampling was performed after a median of 3 (interquartile range 1.5‐5.5) months. GFAP levels were measured using single molecule array technology. Eleven individuals had follow‐up imaging investigations and plasma sampling after a median of 2.7 (interquartile range 2.5‐2.9) years.

Result

Plasma GFAP levels and 11C‐PIB binding increased significantly from pre‐symptomatic to symptomatic stage while 11C‐DED binding and 18F‐FDG uptake significantly decreased towards estimated onset of clinical symptoms in MC. Cross‐sectionally, plasma GFAP showed negative correlations with [18F]FDG uptake in widespread cortical areas, in contrast to no correlations with 11C‐DED or 11C‐PIB binding. 11C‐DED binding showed a positive correlation with 18F‐FDG uptake. Across the follow‐up interval, plasma GFAP levels showed a four‐fold greater intraindividual variation relative to 11C‐DED binding variation (longitudinal Δ variance = 1.67 vs 0.39 z‐scores, respectively). When averaging plasma GFAP values and tracer binding across consecutive time points for the same individual, strong negative correlations were found between plasma GFAP and 11C‐DED binding and 18F‐FDG uptake, but no significant correlation was found between plasma GFAP levels and 11C‐PIB binding in MC.

Conclusion

Divergent plasma GFAP levels and PET 11C‐DED brain binding in pre‐symptomatic ADAD carriers may reflect different but associated underlying processes, including different types of reactive astrocytes. However, the levels of plasma GFAP show large intraindividual variation over time and the assessment of reactive astrocytes based solely on cross‐sectional plasma GFAP levels poses great challenges and warrants further investigations.
Neuroimaging biomarkers of the Amyloid, Tau, Neurodegeneration and Vascular framework in association with sleep duration changes over time
Authors: Baril Andree‐Ann , Koijs Daniel , Himali Jayandra Jung , Decarli Charles , Sanchez Erlan , Himali Dibya , Cavuoto Marina G. , Pase Matthew P. , Beiser Alexa S. , Seshadri Sudha
Published: June 2023

Background

Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms of this association remains unknown. This project aims to evaluate how self‐reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration and (V)ascular neuroimaging markers of Alzheimer’s disease (AD).

Method

Within the Framingham Heart Study, two samples were studied: 271 participants (age:53.6±8.0 years; 51%M) who underwent 11C‐PiB amyloid (global, precuneus) and 18F‐Flortaucipir tau (several medial cortical limbic structures) PET imaging; and 2165 participants (age:61.3±11.1 years; 45%M) who underwent an MRI. To estimate neurodegeneration, total brain volume was extracted from MRI. Vascular MRI metrics included white matter hyperintensities (continuous, and dichotomous indicator for extensive for age), covert brain infarcts, and average free‐water. Self‐reported sleep duration was assessed both at the time of neuroimaging testing and around 15 years before, and split by categories (≤6h, 7‐8h, ≥9h). Sleep duration change over time was assessed by change between categories and by continuous delta change (split by negative and positive values for decreased or increased respectively). Logistic and linear regression models were tested between self‐reported sleep duration and neuroimaging metrics, adjusted for age and age2, sex, PET camera, APOE4 carrier status, depression, diabetes, hypertension, and prevalent cardiovascular diseases.

Results

No association was observed between cross‐sectional self‐reported sleep duration and neuroimaging metrics. Transitioning to longer sleep over time (≤6h to ≥9h and 7‐8h to ≥9h as compared to consistently sleeping 7‐8h) was associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:3.50[0.95‐12.92], p = 0.040;ß[SE]:0.25[0.10], p = 0.015) and higher free‐water (ß[SE]:0.021[0.007], p = 0.003;ß[SE]:0.009[0.002], p = 0.0002). When looking at continuous sleep duration change, increasing sleep duration over time was also associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:1.26[1.02‐1.55], p = 0.032;ß[SE]:0.10[0.04], p = 0.007) and higher free‐water (ß[SE]:0.002[0.001], p = 0.031). Self‐reported sleep duration change was not associated with PET amyloid or tau outcomes.

Conclusion

Vascular pathology in the brain as evidenced by higher white matter hyperintensities burden and free‐water is associated with sleep duration that is getting longer over time, thus potentially explaining its association with dementia risk. In fact, elongation of sleep duration may be an early change in the AD trajectory.
Association of structural MRI with Braak staging using neural network‐based risk scoring
Authors: Miller Matthew I. , Qiu Shangran , Joshi Prajakta S. , Lee Joyce , Au Rhoda , Kolachalama Vijaya B.
Published: June 2023

Background

The gold standard of Alzheimer’s disease (AD) diagnosis remains histopathologic examination of neuropathologic changes. However, the dependence on post‐mortem microscopic analysis limits the role of pathology in clinical care. Magnetic resonance imaging (MRI) is routinely used to diagnose suspected dementia (DE) due to AD, but correlating neuroimaging to underlying pathologic changes remains challenging. Herein, we report the development of two risk scores derived from convolutional neural network (CNN) processing of MRI scans, which we then validate against Braak staging of neurofibrillary tangles from autopsy reports.

Method

Using T1‐weighted MRIs from the National Alzheimer’s Coordinating Center (NACC), we trained two CNNs (Figure 1) to predict continuous scores for overall cognitive status (“COG” score) and AD probability (“ALZ” score). The COG score, ranging from 0‐2, graded a subject’s cognitive status on a spectrum from normal cognition (NC, 0), to mild cognitive impairment (MCI, 1), and DE due to any cause (2). The ALZ score then graded each DE individual’s probability of AD from 0 to 1. These CNNs were then applied to a subset of participants with autopsy reports available within 6 months of MRI. CNN performance was evaluated by area under receiver operating characteristic curve (AUC). Differences in risk scores were assessed by Kruskal‐Wallis H testing with post hoc Dunn testing.

Result

The CNN models for COG and ALZ score estimation were trained on 4,822 NACC participants. Thresholding of COG scores distinguished individuals with DE from those with NC and MCI (AUC = 0.87). ALZ scores distinguished individuals with AD from those with non‐AD causes of DE (AUC = 0.77). Among 74 persons with available neuropathology data, COG scores differed significantly among Braak staging groups (p<0.001), increasing from a mean of 0.99±0.36 in Stage 1 to 1.47±0.41 in Stage 6 (p = 0.010). Significant differences in ALZ scores were also observed (p = 0.039) between varying Braak stages (p = 0.039), increasing from a mean of 0.69±0.42 in Stage 1 to 0.91±0.29 in Stage 6 (p = 0.046) (Figure 2).

Conclusion

CNN processing of MRI scans may derive continuous risk scores for grading cognitive status and AD risk. This novel approach may offer practitioners a computational tool to improve AD diagnosis.
Outcome measures of cognitive gain in clinical trials of patients with primary central nervous system infections: A systematic review
Authors: Rizvi Syeda Taliya , Shah Jhankhana , Shaaya Sarah , Mollayeva Tatyana
Published: June 2023

Background

Primary central nervous system (CNS) infections are often accompanied with cognitive deficits. Cognitive deficits are assessed by a wide range of outcome measures to determine the severity of deficits and their response to intervention. The aim of this review was to provide description of outcome measures used to assess cognitive function in patients with primary CNS infections enrolled in clinical trials.

Method

We searched MEDLINE, Embase, and CENTRAL from inception to October 2022 to identify clinical trials that enrolled patients with cognitive deficits due to primary CNS infections. All outcome measures evaluating cognitive function in these clinical trials were considered. Outcome measure was defined as any standardized measure evaluating one or more of the six cognitive domains: complex attention, executive functioning, learning and memory, language, perceptual‐motor ability, and social cognition.

Result

Eight randomized controlled trials (RCTs) and one pre‐post intervention study enrolled patients with Lyme disease (infectious agent bacterium borrelia burgdorferi), herpes simplex virus type 1 (infectious agent herpes simples virus), and Creutzfeldt–Jakob disease (infectious agent prion). Within these clinical trials, 29 outcome measures were utilized to evaluate change in cognitive function in response to treatment with antibiotics (five studies), antiviral (three studies), or non‐opioid analgesic (one study). Out of all outcome measures, only two assessed all six cognitive domains: Penn computerized neurocognitive battery and Wechsler Adult Intelligence Scale; the remaining evaluated one or several cognitive domains using a variety of measures. The three most frequently evaluated cognitive domains were complex attention (19 distinct outcome measures within nine studies), executive functioning (19 distinct outcome measures within eight studies) and perceptual‐motor ability (16 distinct outcome measures within eight studies). The least evaluated cognitive domain was social cognition (four distinct outcome measures within four studies).

Conclusion

Clinical trials included in this review were designed to improve cognitive function in patients with primary CNS infection. Selection of outcome measures that have been previously used is desirable as it would allow between‐study comparisons. Assessment of social cognition is important to consider. Evaluations using multiple outcome measures might be tiring and intrusive to patients, and therefore implications of practical constraints should be tested.
Racial disparities in advance care planning and end‐of‐life care preferences among decedents in the health and retirement study (2002‐2019)
Authors: Rahemi Zahra , Cidav Tom , Malatyali Ayse , Montaner Olga F Jarrín , Dye Cheryl
Published: June 2023

Background

Alzheimer’s Disease and Related Dementias (ADRD) is more prevalent among racial/ethnic minority older adults who also experience disparities in end‐of‐life care quality. The rate and timing of advance care planning conversations among individuals living with ADRD vary by race/ethnicity and other sociodemographic factors. As cognitive impairment progresses, caregivers, communities, and healthcare providers face challenges related to end‐of‐life care planning and management. Early advance care planning provides the opportunity to align care management with the wishes of the patients with ADRD. Our purpose was to examine EOL care preferences and ACP in racial minority ADRD patients.

Method

The Health and Retirement Study (HRS) Exit files (2002‐2019) were used to conduct a descriptive analysis of advance care planning and end‐of‐life care preferences among decedents.

Result

Of the 7,214 decedents from the HRS sample, 13% had a diagnosis of dementia, 30% were cognitively impaired but not diagnosed with dementia, and 57% were cognitively intact. The results showed significant relationships between cognitive functioning, race, gender, and marital status. The mean cognitive impairment scores were worse for racial/ethnic minority participants compared to white participants, women compared to men, and widowers compared to married participants.

Among the 3,102 participants with cognitive impairment or ADRD diagnosis, Black participants were 78.5% less likely to have a living will and 57.8% less likely to have a discussion about end‐of‐life care compared to non‐Hispanic white participants. Similarly, participants of other racial minority groups were 88% less likely to have a living will and 57.5% less likely to have an end‐of‐life discussion compared to white participants. Gender and marital status were not significant predictors of having discussed end‐of‐life care preferences. In terms of end‐of‐life care preferences, Black participants were 3.29 times more likely to prefer all possible end‐of‐life care and 66% less likely to refuse extensive care measures compared to white participants.

Conclusion

Black older adults with ADRD had lower rates of advance care planning and preferred intensive care measures vs. comfort care compared to their white counterparts. Recognition of these differences can inform the design and provision of interventions and educational programs to improve equity in end‐of‐life care.
Applicability of an actuarial neuropsychological method to diagnose mild cognitive impairment in a diverse sample
Authors: Carlew Anne R , Goette William , Schaffert Jeffrey , Rossetti Heidi , Lacritz Laura
Published: June 2023

Background

The Jak/Bondi actuarial neuropsychological method for detection of mild cognitive impairment (MCI) has been shown to identify subjects less likely to revert to normal and more likely to have Alzheimer’s Disease (AD) biomarkers compared to conventional clinical methods. Various iterations of this method have been applied to datasets of predominately White, highly‐educated participants, limiting generalizability to more diverse cohorts. This project investigated the applicability of the actuarial MCI diagnostic method to the Texas Alzheimer’s Research and Care Consortium (TARCC) cohort.

Method

All subjects from the TARCC cohort with expert consensus diagnoses of normal control (NC) and MCI at baseline (n = 1911; 65.72% female; 47.11% Hispanic; Mage = 67.49; Medu = 12.80) were re‐classified as NC or MCI using actuarial criteria of 2 impaired (>1 SD below normative mean) tests in any of 4 cognitive domains OR 1 impaired test in at least 3 cognitive domains. The clinically‐diagnosed MCI (MCIc) sample (n = 655; 58.47% female; 42.44% Hispanic; Mage = 71.34; Medu = 13.01) and the actuarially‐diagnosed MCI (MCIa) sample (n = 837; 71.21% female; 68.82% Hispanic; Mage = 66.30; Medu = 10.87) were separately submitted to cluster analysis. McNemar’s test was used to investigate frequency of APOE4 allele by diagnostic group.

Result

Cluster analysis of the MCIa group yielded 3 distinct clusters: a purely amnestic cluster (n = 332), a primary language‐impaired cluster (n = 381), and a multidomain/mixed cluster (n = 124). The MCIc group yielded 2 clusters: a multidomain/mixed cluster (n = 538), and a cognitively normal cluster (n = 117). The MCIc cases were significantly more likely to have APOE4 alleles (33% vs. 28% of MCIa group).

Conclusion

Similar to previous research, the MCIa group fell into 3 distinct cognitively‐impaired groups. Despite 18% of MCIc participants falling in a “cognitively‐normal” cluster, MCIc subjects were more likely to have the AD biomarker APOE4. These findings warrant further investigation, particularly in relation to ethnicity, as individuals of Hispanic origin are less likely to carry APOE4 alleles, and APOE4 confers less AD risk in Hispanics compared to non‐Hispanic Whites. Future research will investigate the prognostic utility of the actuarial method for racial/ethnic minorities using cognitive and functional longitudinal data.