bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of Antemortem Cerebrospinal Fluid Biomarkers with Alzheimer’s Disease Neuropathologic changes at Autopsy
Authors: Kurihara Masanori , Matsubara Tomoyasu , Morimoto Satoru , Saito Yuko , Kanemaru Kazutomi , Murayama Shigeo , Iwata Atsushi
Published: December 2023

Background

Cerebrospinal fluid (CSF) amyloid‐beta 42 (Aβ42) and tau phosphorylated at threonine 181 (p‐tau181) have been widely used as biomarkers for Alzheimer’s disease (AD). AT(N) classification even proposes each substance as a direct biomarker of amyloid (A) and tau (T) pathologies, respectively. However, recent studies suggest that increased CSF p‐tau181 may rather be associated with amyloid pathology. Although neuropathological evaluation at autopsy is the gold standard for assessing these changes, studies evaluating the association between CSF biomarkers and AD neuropathologic changes are limited.

Method

We retrospectively studied patients who underwent antemortem CSF AD biomarker measurement and neuropathological evaluation at autopsy at our institution from 1995 to 2021. CSF biomarkers were measured by ELISA (Fujirebio, Belgium). Neuropathological evaluation of AD was performed routinely regardless of diagnosis and Thal phase, Braak neurofibrillary tangle (NFT) stage, and CERAD score were assessed according to current guidelines.

Result

The mean age of the 119 patients was 76.2 ± 8.9 years; 49 were women. The duration from lumbar puncture to autopsy was median 2 years (0‐13 years). AD pathology was observed in 29 patients (24%). Other common pathologies were Lewy body disease and frontotemporal lobar degeneration. Antemortem CSF Aβ42 and p‐tau181 results were obtained in 119 and 68 patients, respectively. As expected, CSF Aβ42 decreased with increasing Thal phase and CERAD score. CSF p‐tau181 increased with increasing Thal phase, Braak NFT stage, and CERAD score. Even when the analysis was restricted to patients with Braak NFT stage 3 or less (n = 48), CSF p‐tau181 increased mildly with increasing Thal phase and CERAD score. In patients with moderate or severe amyloid pathology by Thal phase or CERAD score (n = 34), CSF p‐tau181 increased more highly at Braak NFT stage 5 or more.

Conclusion

The results of this study, which directly compared antemortem CSF biomarkers with AD neuropathologic changes at autopsy, support the current theories that increased CSF p‐tau181 is caused by both amyloid and tau pathology related to AD while decreased CSF Aβ42 is associated with amyloid pathology.
Enlarged Perivascular Spaces in a Diverse Community‐based Sample. The Multi‐Ethnic Study of Atherosclerosis
Authors: Charisis Sokratis , Rashid Tanweer , Liu Hangfan , Ware Jeffrey B. , Jensen Paul N. , Austin Thomas R. , Li Karl , Fadaee Elyas , Hilal Saima , Chen Christopher Li‐Hsian , Hughes Tim M. , Romero Jose Rafael , Toledo Jon B. , Longstreth William T , Hohman Timothy J. , Nasrallah Ilya M. , Bryan Nick , Launer Lenore J J. , Davatzikos Christos , Seshadri Sudha , Heckbert Susan R. , Habes Mohamad
Published: December 2023

Background

Enlarged perivascular spaces (ePVS) have been associated with small vessel disease of the brain (SVD). Nevertheless, the burden, correlates and significance of ePVS have been studied predominantly in White individuals, so the generalizability of these findings to other racial/ethnic groups remains uncertain. Herein, we present an investigation of ePVS in a large, multi‐ethnic, community‐based cohort.

Method

ePVS volumes were quantified in 1,026 participants (median age 71 years; 47% men) from the Multi‐Ethnic Study of Atherosclerosis, using a fully‐automated deep learning model with 82% lesion‐wise sensitivity. Based on previously‐described clinical rating systems, ePVS were grouped in four brain regions: basal ganglia, thalamus, frontoparietal region, and temporal region, and were normalized to the respective regional volumes. Cognition was assessed with the Cognitive Abilities Screening Instrument, the Digit Symbol Coding, and the Digit Span test. APOE‐ε4 isoforms were estimated from single nucleotide polymorphisms (rs429358,rs7412). The relationships of normalized regional ePVS volumes with demographic and vascular risk factors, neuroimaging indices, cognition, and APOE genotype were explored using generalized linear models.

Result

Basal ganglia was the anatomic region with the largest ePVS burden (median[IQR] = 1.9[1.4] % of total regional volume), followed by the frontoparietal region (0.6[0.5]), temporal region (0.4[0.4]), and thalamus (0.3[0.3]) – Figure 1,Table 1. Basal ganglia ePVS volume was positively associated with age, systolic blood pressure (SBP), use of antihypertensives, white matter hyperintensity volume (WMHV), and microbleeds (MBs), and negatively associated with white matter fractional anisotropy (FA) and Black race (Tables 1,2). Thalamic ePVS volume was positively associated with age, use of antihypertensives, WMHV, and MBs, and negatively associated with FA. Frontoparietal ePVS volume was positively associated with SBP, and negatively associated with age. Temporal region ePVS volume was negatively associated with age, Chinese and Hispanic ethnicity. No significant associations were observed between regional ePVS volumes and cognition or APOE genotype.

Conclusion

Increased ePVS burden in the basal ganglia and thalamus was associated with hypertension and imaging biomarkers of vascular brain damage in a multi‐ethnic population of older adults, likely reflecting underlying SVD. Compared to other racial/ethnic groups, White race was associated with higher ePVS burden in the basal ganglia and temporal regions.
Path integration deficits predict phosphorylated tau accumulation in the entorhinal cortex: Assessment of Braak stage I,II using 3D Virtual reality goggles
Authors: Takashima Akihiko , Koike Riki , Soeda Yoshiyuki , Fujioka Yusuke , Ishigaki Shinsuke , Watanabe Hirohisa
Published: December 2023

Background

We aimed to develop behavioral tasks that can identify early signs of Alzheimer’s disease (AD) in order to facilitate the development of preventative and therapeutic interventions.

Method

To do this, we created a 3D virtual reality task that is sensitive to the activity of grid cells in the entorhinal cortex, a region that is affected early on in AD. We tested path integration in a spatial navigation task in 177 volunteers between the ages of 20 and 89 who did not have a self‐diagnosed AD.

Result

Our results showed that the percentage of subjects showing impaired path integration correlated with the percentage of subjects showing neurofibrillary tangles in the entorhinal cortex, as seen in previously published autopsy data. To further confirm this relationship, we also tested a tauopathy mouse model and found that mice with accumulation of phosphorylated tau in the entorhinal cortex had impaired path integration without impairments in spatial cognition or novel object recognition.

Conclusion

These findings suggest that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex and may allow for early identification of individuals at risk for developing AD.
Rhythmic Musical Intervention Improves Short‐term Memory Function in Healthy Elderly: A Prospective Pilot Study of a Group‐based African Drum Training
Authors: Hao Ziyu , Chan Aaron TC , Tran Joshua YS , Cheung Ruby SM , Lam Amy SM , Leung Philip SK , Tsoi Kelvin KF
Published: December 2023

Background

Memory complaints are the early symptoms of cognitive impairment, and it usually brings anxiety about cognitive deterioration among the elderly population. Musical interventions were demonstrated to relieve dementia symptoms1. This study is to investigate the potential benefits of African drum intervention on cognitive functions.

Method

Participants were recruited in July 2022 through social media advertisement. Classes were organized in a drumming activity center in downtown, Kowloon. Participants joined 8 sessions of African drum training which covered rhythmic clapping and drumming, power control, and overall performance with songs. The inclusion criteria were participants (1) aged over 50 years old and (2) able to use a smartphone. Participants who could not understand Chinese or had been diagnosed with active psychosis or dementia were excluded. Cognitive function was screened by an online platform, ScreenMat2, for short‐term and long‐term memory, orientation, calculation, visual function, and followed up with the Hong Kong version of the Montreal Cognitive Assessment (HK‐MoCA). Anxiety and depression levels were assessed by State‐Trait Anxiety Inventory (STAI) and Geriatric Depression Scale (GDS). All assessments were performed before and after the drumming classes (Figure 1). The outcomes were evaluated using Wilcoxon Signed Rank Test with 0.05 as the significance level.

Result

Twenty‐four participants joined this study with an attendance rate of 83%. The overall cognitive function of the participants was good with an average score of 27 for HK‐MoCA. After 8 sessions of African drum intervention, the cognitive function did not show significant improvement (p = 0.108), but the response time of answering the digital cognitive questions was significantly faster than that before the intervention (‐39.9 seconds, p = 0.03) (Table 1). The response time for the short‐term memory function was the most significantly reduced better after the African drum training (‐13.5 seconds, p = 0.005) The STAI and GDS scores also significantly decreased (p<0.001).

Conclusion

Rhythmic Musical Intervention, such as the African drum, can improve the response time of cognitive tests and also relieve anxiety and depression levels.

1. Tsoi et al. J Am Med Dir Assoc. 2018;19(7), 568‐576. https://doi.org/10.1016/j.jamda.2017.12.009

2. Lam et al. In Proceedings of the 51st HICSS. 2018. doi:10.24251/HICSS.2018.353
Socioeconomic position, modifiable dementia risk and cognitive decline: results of 12‐year Maastricht Aging Study
Authors: Heger Irene , van Boxtel Martin P.J. , Deckers Kay , Bosma Hans , Verhey Frans R.J. , Köhler Sebastian
Published: December 2023

Background

Evidence of modifiable risk factors for cognitive decline and dementia is accumulating, showing the potential of dementia risk reduction via lifestyle modification and cardiovascular risk management. People with low socioeconomic status (SES) have increased dementia risk and on average worse health. This study investigated whether the association between a modifiable dementia risk score and rate of cognitive decline differs across SES strata.

Method

Data were used from Maastricht Aging Study (MAAS), a prospective cohort study with a 12‐year follow‐up. Participants aged ≥40 years with complete dementia risk profiles were included (n = 1223). The validated ’LIfestyle for BRAin health’ (LIBRA) index was used to assess the modifiable dementia risk fraction. Cognitive performance was serially assessed at baseline, 6 and 12 years and measured in the domains of information processing speed, executive functioning and verbal memory function. A SES compound score was calculated from equivalent income and educational level and divided into tertiles (low, middle, high). Linear mixed models were used to study the association between LIBRA, SES and their interaction on the rate of cognitive decline.

Result

Participants in the lowest SES tertile displayed more decline in information processing speed (vs. middle SES: X2 = 7.08, p = 0.029; vs. high SES: X2 = 9.49, p = 0.009) and verbal memory (vs. middle SES: X2 = 9.28, p<0.001; vs. high SES: X2 = 16.68, p<0.001) compared to their middle‐ and high‐SES counterparts. Higher (unhealthier) LIBRA scores were also associated with more decline in information processing speed (X2 = 12.66, p = 0.002) and verbal memory (X2 = 4.63, p = 0.032). No consistent effect modification by SES on the association between LIBRA and cognition was found.

Conclusion

This study shows that lower SES and higher modifiable dementia risk predict faster decline in information processing speed and verbal memory function over 12 years. Results suggest that lifestyle is an important determinant of cognitive decline across SES groups. Yet, people with low SES had a more unfavourable modifiable risk score suggesting more potential for lifestyle‐based interventions. LIBRA could be useful as a participant selection tool or as a surrogate outcome measure in lifestyle intervention trials, and can inform people about individual risk behaviours as part of public health initiatives.
Vascular risk factors and fMRI activation in a prodromal dementia population
Authors: Kallevag Oystein
Published: December 2023

Background

Vascular risk factors (VRF) are associated with an increased risk of developing dementia (1). Functional magnetic resonance imaging (fMRI) demonstrates the ability to detect early changes in neuronal activation before cognitive changes are clinically measurable (2). We investigate whether the number of VRF in cognitively healthy persons with a minimum of two VRF present was associated with a change in neuronal activation in the brain measured with task‐based fMRI.

Methods

56 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR), elderly persons completed an fMRI examination with task‐based fMRI and N‐Back paradigm to access Working Memory (WM). Vascular risk factors included in the study were stable coronary artery disease or cerebrovascular disease according to MRI criteria, hypercholesterolemia, hypertension, diabetes mellitus and overweight (3).

We analyzed the fMRI data at a single time point using the FMRIB Software Library (FSL v6.0; Analysis Group, Oxford, UK).

Results

The mean age was 68.4 (± 5.4) years. The number of VRF present were VRF2 (n = 21), VRF3 (n = 25) and VRF4 (n = 10). The median MMSE were: VRF2: 29 (IQR 29 ‐ 30), VRF3: 30 (IQR 28.8 ‐ 30) and VRF4: 29.5 (IQR 28.3 ‐ 30). A low number of VRF (VRF2) revealed higher neuronal activation than the groups with a higher number of VRF (VRF3 and VRF4). The regional activated clusters in the VRF2 group showed activation in the superior parietal lobule, visual cortex, premotor cortex, Broca’s area and anterior intra‐parietal sulcus.

Conclusion

Our results show that a lower neuronal activation measured with fMRI is associated with a higher number of VRF. We suggest further studies to assess whether altered neuronal activation measured by fMRI in cognitively healthy elderly persons with VRFs can be associated with a higher risk of developing cognitive decline and dementia.

1. O'Brien JT, Thomas A. Vascular dementia. The Lancet. 2015;386(10004):1698‐706.

2. Chen J, Glover G. Functional Magnetic Resonance Imaging Methods. Neuropsychology Review. 2015;25(3):289‐313.

3. Khalifa K, Bergland AK, Soennesyn H, Oppedal K, Oesterhus R, Dalen I, et al. Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial. Front Neurol. 2020;11:916.
DNA methylation clustered by predicted chromatin state reveals distinct association patterns with neuropathologic and biochemical measures in the AD brain
Authors: Oatman Stephanie R , Quicksall Zachary , Reddy Joseph S. , Carrasquillo Minerva M. , Wang Xue , Liu Chia‐Chen , Yamazaki Yu , Nguyen Thuy , Malphrus Kimberly G. , Heckman Michael G. , Martens Yuka A , Zhao Na , DeTure Michael , Murray Melissa E. , Kanekiyo Takahisa , Bu Guojun , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilufer
Published: December 2023

Background

Alzheimer’s disease (AD) is neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often quantified by Thal phase and Braak stage, respectively. Aβ also frequently deposits in the cerebrovasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. These and related measures often show high variability within AD suggesting distinct underlying mechanisms, the identification of which may reveal important biological insights into AD pathophysiology. We hypothesize that, within the AD brain, neuropathology and levels of core AD‐related proteins are influenced by variations in DNA methylation (DNAm). To test this, we performed epigenome‐wide association studies (EWAS) using DNAm clusters from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathologic measures (Braak, Thal, and CAA) and brain biochemical levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).

Methods

DNAm from neuropathologically‐confirmed AD cases available through the Mayo Clinic brain bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Neuropathology was scored by an experienced neuropathologist. TCX levels of five AD‐related proteins from three tissue fractions (buffer‐, detergent‐, and in‐soluble) were measured by ELISA (Liu 2020). CpG methylation (CpGm) was binned by a 15‐state chromatin model (Kundaje 2015) and averaged. Averaged CpGm clusters were tested for their association with each endophenotype through multi‐variable linear regression. The influence of CpGm clusters on expression levels of nearby genes was also investigated through multi‐variable regression.

Results

Our innovative binning method demonstrated expected and biologically relevant CpGm patterns. We identified multiple epigenome‐wide significant CpGm clusters unique to each AD‐related endophenotype and brain region. Comparisons between the TCX and CER further revealed brain region‐specific enrichment of distinct CpGm clusters. Significant CpGm clusters were further characterized by their influence on gene expression.

Conclusions

Although all neuropathologic and biochemical endophenotypes tested are core to AD pathophysiology, our results suggest each has a distinct epigenetic architecture underlying their variability in the AD brain. By discovering brain region‐specific DNAm changes that contribute to each neuropathologic or biochemical outcome, we can identify core components of complex mechanisms that individually and jointly contribute to AD.
POINTER‐zzz: Study Design and Baseline Characteristics from the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Sleep Ancillary
Authors: Hayden Kathleen M. , Scales Margaret , Howard Marjorie , Desai Pankaja , Leng Xiaoyan , Lim Andrew , Molina‐Henry Doris P. , Redline Susan , Snyder Heather M , Stone Katie L , Woolard Nancy , Espeland Mark A. , Baker Laura D
Published: December 2023

Background

Sleep disordered breathing (SDB) leads to nocturnal hypoxemia and sleep disruption, which are linked to adverse health conditions, particularly in older adults at risk for dementia. Few prospective studies of SDB examine cognitive decline among those at increased risk for cognitive impairment and dementia. POINTER‐zzz, a sleep ancillary study of U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), allows us to examine the role of lifestyle intervention on sleep quality, and potential moderating effects of sleep on cognition to the intervention in medically and cognitively vulnerable older adults.

Method

U.S. POINTER was designed to investigate the effects of two 2‐year lifestyle interventions on cognitive trajectories in 2,000 older, cognitively normal adults (aged 60‐79 yrs) at increased risk for cognitive decline and dementia due to physical inactivity, poor diet and cardiovascular disease. POINTER‐zzz enrolled a subset of parent trial participants and administered in‐home sleep assessments using WatchPAT (1 night) and ActiGraph (6 nights) devices. We summarize participants’ baseline characteristics including apnea hypopnea index (AHI), sleep duration and sleep efficiency.

Result

To date, 688 POINTER‐zzz participants enrolled and completed baseline WatchPAT and/or Actigraph assessments. Participant ages averaged 68.6 years old (standard deviation, 5.13); 21% of participants self‐identified as Black/African American, 4% Hispanic/Latino, and 66% White. More than half (68%) were female, and 69% had a Bachelor’s degree or higher. Overall, 87% of participants had at least mild sleep apnea (AHI>5). Severe sleep apnea (AHI≥30) was observed in 14% of participants overall, and 21% of those aged ≥75 yrs. Severe sleep apnea was more prevalent among males (19%) than females (11%). Overall, nightly sleep duration for the cohort averaged 6.6 hours, with 83% sleep efficiency, and an average of 79.3 minutes awake after sleep onset.

Conclusion

POINTER‐zzz participants have sleep characteristics that align with expectations for a cohort that is broadly representative of a diverse older adult population in the US. POINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep disturbances that are linked to cognitive decline and AD in a well‐characterized, diverse cohort of at‐risk older adults.
Apathy, cognition and beta amyloid in African Americans in the AA‐FAIM cohort
Authors: Fischer Barbara L. , Van Hulle Carol A. , Wyman Mary F. , Norton Derek L. , Carter Fabu P. , Salazar Hector , Bouges Shenikqua , Gooding Diane C. , Umucu Emre , Chin Nathaniel A. , Kirmess Kristopher M. , Meyer Matthew R. , Gleason Carey E. , Zuelsdorff Megan
Published: December 2023

Background

The prodrome of cognitive declines and/or dementia may include late‐life neuropsychiatric symptoms such as apathy. In primarily non‐Hispanic White samples, apathy associates with both cognition and amyloid deposition in cognitively intact patients and those with Alzheimer’s disease (AD). However, little is known about these relationships in African Americans, who are both disproportionately affected by AD and under‐represented in AD research. Apathy could reflect higher levels of proteinopathy or occur co‐morbidly, exacerbating its deleterious effects. We examined associations between apathy and cognition and their potential moderation by plasma beta amyloid in cognitively healthy African American participants.

Method

Study participants enrolled in African Americans Fighting Alzheimer’s In Mid‐Life(AA‐FAIM, a linked study to the WRAP and Wisconsin ADRC) were included in the analytic sample (N = 166; Table 1) if they had ≥1 cognitive visits, plasma amyloid biomarker data, and apathy ratings by study partners using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) or the Apathy Evaluation Scale (AES). Cognitive outcomes included performance on measures of processing speed, mental flexibility and immediate and delayed memory. We used linear mixed models to examine association of baseline apathy with cognitive performance measures at multiple time points, and the moderation of apathy‐cognition relationships by plasma Aβ42/40 ratio (C2N, USA). Apathy‐cognitive outcome pairings were selected based on significant findings from a proof‐of‐concept linear mixed effects analysis of the full Wisconsin ADRC sample.

Result

Results are shown in Table 2. Among AA‐FAIM participants, NPI‐Q apathy was associated with RAVLT immediate (estimate = ‐7.7, p = .001) and delayed recall (estimate = ‐3.2, p = .001). However, AES was unrelated to Trails A or B performance. There were no associations between plasma amyloid or the Aβ42/40*apathy interaction term with any cognitive outcomes.

Conclusion

Partner‐rated apathy, but not plasma Aβ42/40, was related to cognition in our African American participants, an important finding given limited data available on this population. It will be critical to address apathy and its antecedents to improve the cognitive and affective health of African American older adults. Future research needs to expand cohorts to African American and other diverse populations to investigate disease mechanisms in Alzheimer’s disease and related dementias more inclusively.
Glial changes are associated with cerebrovascular integrity in hyperhomocysteinemia‐induced VCID in mouse and human brain
Authors: Weekman Erica M , Winder Zachary , Rogers Colin B , Abner Erin L , Sudduth Tiffany L , Price Brittani R. , Woolums Abigail , Hawthorne Danielle , IV Charles E Seaks , Patel Ela , Dugan Adam , Fister Shuling X , Wasek Brandi , Bottiglieri Teodoro , Fardo David W. , Wilcock Donna M.
Published: December 2023

Background

With the aged population estimated to double by 2050 and the rate of dementia expected to triple, it is critical to identify treatments for dementia. One of the leading causes of dementia is vascular contributions to cognitive impairment and dementia (VCID), and is frequently found co‐morbidly with Alzheimer’s disease, the other leading cause of dementia. A modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), which is defined as elevated levels of plasma homocysteine (a non‐protein‐forming amino acid), and most late‐life HHcy is caused by impaired B vitamin absorption. Although HHcy is a risk factor for VCID, the mechanism through which it induces cognitive impairment remains unclear.

Method

We used human and mouse brain tissue to determine glial and vascular changes associated with HHcy. Wild‐type (C57Bl6J) mice were placed on a HHcy or control diet for 6, 10, 14, or 18 weeks. Using qPCR, we investigated pro‐ and anti‐inflammatory cytokines. We also determined changes in microglia (IBA‐1) and identified the number of microhemorrhages and cognitive changes. In humans, we identified 31 autopsied research volunteers with antemortem homocysteine levels; 13 cases had normal plasma homocysteine levels (<14µmol/L) and 18 had high plasma homocysteine levels (>14µmol/L). We determined whether the level of plasma homocysteine was associated with microglia (IBA‐1) and astrocytes (GFAP) as well as microhemorrhages and atherosclerosis severity in the frontal and occipital cortices. Both gene expression and protein inflammatory markers were measured to determine associations with plasma homocysteine.

Result

In our mouse model of HHcy, we identified a time course of glial changes that first begins with an increase in pro‐inflammatory cytokines and increases in microglial staining at 6 weeks on diet. This is followed by cognitive changes at 10 weeks on diet. Finally, at 14 weeks on diet, we see significant cognitive deficits due to HHcy. In human tissue, HHcy was associated with more microglia but fewer astrocytes, a significant decrease in inflammation and increased microhemorrhages in the frontal cortex.

Conclusion

Taken together, this data shows that in both mouse and human tissue, HHcy induces significant glial and vascular pathology that could be driven by inflammatory effects.
Longitudinal changes in driving behaviours among older adults with different A/T/N biomarker profiles
Authors: Long Kelly , Bayat Sayeh , Babulal Ganesh M.
Published: December 2023

Background

The pathophysiological process of Alzheimer’s disease (AD) spans approximately 10‐15 years. To define AD by its pathologic processes, the A/T/N classification framework was proposed constituting β‐amyloid (A), tau (T), and neurodegeneration (N) biomarkers derived from cerebrospinal fluid (CSF) or imaging. With these biomarkers, individuals can be divided into four categories: normal (A‐T‐N‐), AD pathologic change (A+T‐N‐), AD (A+T+N‐, A+T‐N+, A+T+N+), and suspected non‐AD pathology (SNAP) (A‐T+N‐, A‐T‐N+, A‐T+N+). Recent evidence indicates that daily driving behaviours can identify preclinical AD, solely based on CSF β‐amyloid (A), with high accuracy. This study aims to determine the extent to which longitudinal changes in driving behaviour vary between individuals with different A/T/N profile categories.

Method

Participants were enrolled in a longitudinal study on driving and preclinical AD biomarkers from Washington University School of Medicine. Temporospatial driving behaviours were collected with a data logger installed in participant vehicles over a period between January 2015 and March 2020. CSF collected within three years of each driving event was used to assign A/T/N categories. The cohort included 132 cognitively normal (Clinical Dementia Rating of 0) older adults (>65). Changes in driving behaviours over time were modelled for each group using linear mixed‐effects models. A Z‐test was used to determine if the slopes significantly differed between individuals with normal biomarkers and the remaining groups.

Result

Participants were classified as 59 individuals with normal biomarkers, 9 with AD pathologic change biomarkers, 45 with AD biomarkers, and 19 with SNAP biomarkers. Compared to normal aging, the AD pathology group had a statistically significantly higher increase in average occurrences of under‐speeding (p = 0.001), a significant decrease in average trip duration (p = 0.021), and a significant decrease in the average standard deviation of vehicle speed (p = 0.029). The AD group had no significant differences from the normally aging group. The SNAP group showed a significantly higher increase in the average occurrences of over‐speeding (p<0.001) than normal aging.

Conclusion

Driving behaviours and their rate of change over time vary between individuals with different A/T/N profile categories. These differences provide an opportunity to strengthen our understanding of the disease trajectory.
Gestational Hypertension and Midlife Cognition: The CARDIA Study
Authors: Jiang Xiaqing , Schreiner Pamela J. , Gunderson Erica P. , Yaffe Kristine
Published: December 2023

Background

Gestational hypertension (GH) increases the risk of cardiovascular diseases, which may contribute to worse cognitive outcomes, and yet little is known about the long‐term impact of GH on cognition. We investigated the association of GH with midlife cognitive performance and decline in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Methods

We studied 1,273 parous Black and White women (106 with GH and 1167 without GH) aged 18‐30 years at baseline (1985‐86) who were followed up to Year 30 (mean age 55.2±3.6 years) when five cognitive tests measuring global cognition, memory, processing speed, executive function, and verbal fluency were administered. Accelerated decline over five years was defined as a decline ≥1.5 standard deviations from the mean change on each of the three tests available at year 25, measuring processing speed, memory, and executive function. GH, defined as having new onset hypertension in pregnancy without proteinuria, was self‐reported for each pregnancy since the previous visit up to 30 years. We conducted linear and logistic regression to assess the association of GH with cognitive performance and decline.

Results

Compared with women who did not develop GH during pregnancy, those with GH were more likely to be Black (62% vs 50%) and have obesity (22% vs 11%), and lower diet quality (CARDIA A Priori Diet Quality Scores) at baseline. After adjusting for age, race, education, number of pregnancies, and baseline cardiovascular and behavior risk factors (diabetes, obesity, smoking, alcohol use, physical activity, and diet quality), having GH was significantly associated with lower cognitive performance (z‐standardized) at year 30 in global cognition (‐0.27, 95% CI ‐0.44 to ‐0.11), processing speed (‐0.25, 95% CI ‐0.44 to ‐0.07), and verbal fluency (‐0.20, 95% CI ‐0.38 to ‐0.02). Additional adjustment for hypertension, diabetes, and obesity up to Year 30 did not change the results. GH was also associated with higher odds of experiencing an accelerated decline in processing speed over 5 years (9.2% vs. 4.5%, odds ratio 2.48, 95% CI 1.07 to 5.74), after adjustment for all covariates.

Conclusion

GH is independently associated with worse cognitive performance and accelerated decline in midlife.
Blood and CSF proteome alterations, and regional brain volumetry patterns associated with neuropsychiatric symptoms in a memory clinic cohort
Authors: Rabl Miriam , Clark Christopher , Richiardi Jonas , Maréchal Bénédicte , Bowman Gene L. , Dayon Loic , Popp Julius
Published: December 2023

Background

Neuropsychiatric symptoms (NPS) are common in older people, may precede cognitive decline, and are associated with worse long‐term prognosis. However, the underlying pathophysiology remains unclear. Therefore, our main objective was to examine systemic and central nervous system (CNS) protein signatures and regional brain volumetry patterns related to NPS as indicators of pathophysiological mechanisms that may have diagnostic or therapeutic implications.

Method

We included older subjects with normal cognition or cognitive impairment (mild cognitive impairment and mild dementia) participating in a longitudinal memory clinic study. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI‐Q). CSF biomarkers of Alzheimer’s disease (AD) were quantified in all participants. We performed untargeted proteomics in plasma and CSF, as well as MRI volumetry using the MorphoBox research application to ascertain regional brain volumes, both at baseline, and assessed their associations with NPS. Pathway enrichment analysis was used to identify systemic and CNS pathway alterations associated with regional brain volumes and NPS.

Result

The strongest correlations between regional brain volumes and NPS severity were found for white matter (WM) right temporal lobe (r = ‐0.41), third ventricle (r = 0.40), WM frontal lobe (r = ‐0.38) and right hippocampus (r = ‐0.38) (all p<0.001). Most regional brain volumes correlated with NPS severity after considering the presence of AD pathology, defined according to CSF AD biomarkers. Twenty‐four out of 282 plasma proteins and 67 out of 605 CSF proteins were altered in relation to NPS. Pathway enrichment analysis revealed brain region‐specific proteomic alterations associated with NPS (Fig.1). The most common pathway alterations were immune reaction, hemostasis, and protein metabolism.

Conclusion

Older adults with NPS have region‐specific differences in brain volumes, particularly in white matter that are accompanied by systemic and CNS signatures related to immune activation, hemostasis, and protein metabolism. These findings show the potential of combining untargeted proteomics and MRI volumetry to detect pathophysiological changes related to NPS.
Two Approaches to Advance Care Planning for People with Dementia: Acceptability among US and Dutch Healthcare Providers
Authors: Jingyuan Xu , Smaling Hanneke J.A. , Mehr David R. , Craig Kevin , Achterberg Wilco P. , van der Steen Jenny T.
Published: December 2023

Background

Advance care planning (ACP) may include concrete treatment orders or important goals or both. Providers may differ on these approaches to ACP, which may also differ across countries. We investigated the acceptability and preferences for these two ACP approaches for people with dementia among healthcare providers from the Netherlands (NL) and the US.

Method

Fifty providers from each country, whose specialty includes providing end‐of‐life care for people with dementia, viewed short animation videos about the two approaches of ACP and completed a semi‐structured interview. Qualitative content analysis summarized the comments of the providers on each ACP approach (reasons and conditions for acceptability, (dis)advantages, barriers and facilitators), and the reasons for their preferences.

Result

Except for three nurse practitioners from the US, all participants were physicians (e.g., NL: elderly care physicians, family physicians; US: geriatricians, internists, family medicine physicians). The acceptability and preferences were similar in the two countries. Both approaches were considered acceptable for people with dementia by the vast majority of providers (concrete orders approach: 86% (both countries); important goals approach: 96% (NL) and 98% (US)). Slightly more providers preferred the important goals approach compared to the concrete one (NL: 42% vs. 34%; US: 46% vs. 36%), others had no preference. While the concrete approach may facilitate immediate decisions in emergent situations and may be easier for providers to conduct with available forms, the important goals approach takes the life view of the person with dementia into consideration, can be implemented in more situations and may be easier for the person with dementia. Differences between the two countries included the role of the family caregivers and the power of providers to make decisions.

Conclusion

Providers found both approaches acceptable, but there was diversity in the preferred approach in both countries. Future research should investigate how the preference of individual providers interacts with the preferences of people with dementia and family caregivers, and whether this influences the experience of ACP and subsequent care provision. Examining administrative, legal, and educational issues that may shape preferences may inform more patient‐centered ACP.
MiR‐431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice
Authors: Zhu Xiaolei , Xu Yun
Published: December 2023

Background

Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRNAs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. Our previous miRNA assay data have shown that miR‐431 is downregulated in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice. However, the potential role of miR‐431 in AD has not been fully defined.

Method

Lv‐miR‐431 (1×109 TU/ml, 2 µl), Lv‐Smad4 (1×109 TU/ml, 2 µl) or AAV‐sh‐Smad4 (5×1012 GC/ml, 200 nl) was slowly injected into the bilateral hippocampus of APP/PS1 mice. The behavioral or electrophysiological tests were performed 1 month following the injection, and the mice were then sacrificed for other experiments. QRT‐PCR was used to detect the expression of miR‐431 in plasma and hippocampus. Golgi staining and electron microscopy were performed to evaluate the synaptic structure. Western blot was employed to test the levels of synaptic associated proteins. Immunofluorescence staining and ELISA were utilized to assess hippocampal Aβ levels. Cut&Tag assay and ChIP were used to explore and confirm the potential targets of Smad4.

Result

The level of miR‐431 was downregulated in the plasma of amnestic mild cognitive impairment (aMCI) and AD patients, and it was also decreased in the hippocampus and plasma of APP/PS1 mice. MiR‐431 overexpression in the hippocampus ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it didn’t affect the Aβ levels. Smad4 was identified as a target of miR‐431, and Smad4 overexpression reversed the protective effects of miR‐431 in APP/PS1 mice. Furthermore, Smad4 knockdown modulated the expression of synaptic proteins including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice.

Conclusion

MiR‐431 attenuates synaptic impairment at least partially by Smad4 inhibition and miR‐431/Smad4 may be a potential therapeutic target for AD treatment.
Digitally supported lifestyle program to promote brain health among older adults (LETHE pilot trial) – Study design and progress
Authors: Rosenberg Anna , Untersteiner Helena , Guazzarini Anna Giulia , Lehtisalo Jenni , Thunborg Charlotta , Bruinsma Jeroen , Colombo Matteo , Crutzen Rik , Diaz Ana , Fotiadis Dimitrios , Hilberger Hannes , Huber Simone , Kivipelto Miia , Loukas Vassilis , Lötjönen Jyrki , Pirani Mattia , Schnalzer Bianca , Hanke Sten , Mangialasche Francesca , Mecocci Patrizia , Stögmann Elisabeth , Ngandu Tiia , Consortium LETHE
Published: December 2023

Background

Dementia prevention is a global public health priority. The FINGER multimodal lifestyle intervention is the only intervention model so far that has demonstrated significant cognitive and other health benefits in at‐risk older adults. LETHE proposes a new multimodal precision prevention approach where FINGER intervention is complemented with digital tools to optimize intervention delivery, personalize recommendations based on individual risk profile, and support risk factor self‐management. The multinational 2‐year randomized controlled LETHE pilot trial aims to test the feasibility of a digitally supported, adapted FINGER intervention among older adults at risk of cognitive decline and dementia.

Method

A total of 160 individuals aged 60‐77 years and with risk factors for dementia but no substantial cognitive impairment are recruited at four sites (Austria, Finland, Italy, Sweden; N = 40 per country). Digital readiness and experience with smart devices are required. Participants are randomized 1:1 to 1) structured multimodal lifestyle intervention (dietary guidance, exercise, cognitive training, vascular/metabolic risk management, social stimulation, sleep/stress management) where in‐person individual and group‐based activities are supported with the LETHE smartphone app developed in the project; or 2) self‐guided lifestyle intervention (regular health advice and access to a simplified app with no personalized/interactive content). Both groups wear a smartwatch to gather passive data (e.g., activity, sleep). Primary outcomes are retention rate, adherence to intervention and engagement with the app, and change in dementia risk based on validated risk scores (CAIDE, LIBRA). Secondary outcomes are lifestyle changes and changes in cognition, stress‐related symptoms, sleep, health‐related quality of life, and health literacy. Participant experiences will also be explored. The LETHE Advisory Board (members of the public) provided feedback on the trial protocol.

Result

Trial is registered at ClinicalTrials.gov (NCT05565170), and ethical approval has been obtained in each country. Recruitment started in September 2022 and will be completed in Spring 2023. Updates and results on study progress will be presented.

Conclusion

LETHE pilot trial will inform about the feasibility of technological solutions and a digitally assisted lifestyle program to support brain health among older adults. If proved to induce sustained behavioural changes, digital tools could offer potential for large‐scale, cost‐effective dementia prevention programs.
AT(N) Classification and Clinical Characterization by CSF Biomarkers in Patients with Corticobasal Syndrome
Authors: Ishiguro Takanobu , Kasuga Kensaku , Tokutake Takayoshi , Tsukie Tamao , Konno Takuya , Onodera Osamu , Ikeuchi Takeshi
Published: December 2023

Background

Corticobasal syndrome (CBS) is clinically characterized by asymmetric cortical and extrapyramidal deficits. CBS is caused by various pathological conditions including primary tauopathy and Alzheimer’s disease (AD). To clarify whether there are differences in clinical features of CBS between AD pathology and non‐AD pathology, we classified CBS patients based on AT(N) system by cerebrospinal fluid (CSF) biomarkers and assessed the clinical characteristics of the classified groups.

Method

We assessed retrospectively 19 CBS patients (7 males and 12 females) diagnosed by neurologists at our hospital between 2014 to 2021. They all fulfilled the clinical symptoms of probable or possible CBS according to the Armstrong criteria of corticobasal degeneration. CSF AT(N) biomarkers, A marker: Aβ42 and Aβ42/Aβ40 ratio, T marker: phosphorylated tau (Thr181) [p‐tau], N marker: total tau [t‐tau] and neurofilament light chain [NfL], were evaluated. The positive/negative of each biomarker was judged according to the cutoff value calculated in a cohort independent of this study. We used Aβ42/Aβ40 ratio as the A marker and NfL as the N marker in this study. Each patient was classified AT(N) group. Clinical characteristics were compared between biological AD (i.e., A+T+) group and non‐AD group.

Result

The concordance of A markers (Aβ42 and Aβ42/Aβ40 ratio) was 68.4%, and that of N markers (t‐tau and NfL) was 15.8% in patients with CBS. NfL had more positive rates than t‐tau in CBS patients. Based on CSF biomarker profile, CBS patients were classified as AD group (n = 4, 21%), Alzhehimer’s and concomitant suspected non‐Alzheimer’s pathologic change group (n = 2, 11%) and non‐AD pathologic change group (n = 13, 68%). AD group showed lower scores of MMSE (p = 0.037), more frequent presence of Gerstmann syndrome (p = 0.007), predominance of right limb symptoms (p = 0.015), and more common in non‐motor symptoms onset (p = 0.029) than non‐AD group.

Conclusion

By applying the AT(N) classification to CBS patients, we found that 21% of patients exhibited AD pattern by CSF biomarkers. The clinical differences between AD group and non‐AD group may reflect the different pathological backgrounds. NfL could be more sensitive than t‐tau as the N marker in detecting neurodegeneration of CBS.
The influence of the ApoE genotype on regional amyloid beta progression and interregional correlations in nondemented elderly
Authors: Wybitul Maha , Langer Nicolas , Hock Christoph , Gietl Anton F. , Treyer Valerie
Published: December 2023

Background

Previous examinations have explored the spatiotemporal pattern of amyloid beta (Ab) deposition, one of the first pathogenic events in Alzheimer’s disease (AD). However, the literature presents with a limited characterization of early spatial Ab progression differences and interregional correlations related to the major genetic AD risk factor, the Apolipoprotein E (ApoE) genotype.

Method

The impact of ApoE genotype on dynamic spatiotemporal Ab patterns was investigated using longitudinal amyloid positron emission tomography (PET) imaging. A first analysis used data of 100 nondemented participants who were characterized as having an Ab increase over time. Standardized uptake value ratios (SUVRs) of 31 cortical and subcortical regions were extracted. Regional average SUVRs were clustered per genotype based on longitudinal trajectory shapes. A second analysis focused on the ApoE genotype impact on interregional correlations of annual change rates in 81 cognitively normal individuals. We explored the difference in the distribution of correlations and performed permutation statistics. All analyses were replicated and validated applying partial volume correction.

Result

E4 carriers and noncarriers displayed different regional Ab trajectories. In general, noncarriers displayed a more homogeneous Ab increase over time in comparison to more diverse trajectories in carriers. Six regional clusters ranging from lowest Ab‐baseline values and none‐to‐small increases (cluster 1) to highest Ab‐baseline values and considerable increases (cluster 6) were identified for both carriers and noncarriers. Independent of genotype, cluster 1 contained the amygdala, the medial part of the anterior temporal lobe, the caudate nucleus, the parahippocampal gyrus, the anterior part of the superior temporal gyrus, and the hippocampus. Other clusters differed between genotypes with several regions being assigned to higher Ab‐baseline and higher increase clusters in carriers. The correlational analysis found a distinct pattern in noncarriers with most regions presenting significant positive intercorrelations except for the hippocampus, which demonstrated almost exclusively null‐to‐negative correlations. This pattern was not found in e4 carriers.

Conclusion

The results suggested an ApoE genotype impact on the heterogeneity of the spatiotemporal Ab pattern and a dissociative hippocampal role.