bluuebunny/crossref_metadata_2025 huggingface dataset:
CSF tau phosphorylation at sites 217 and 205 mediate the relationship between PET amyloid and downstream AD markers
Authors: Meeker Karin L. , Barthélemy Nicolas R. , Gordon Brian A. , McDade Eric , Karch Celeste M. , Fagan Anne M. , Strain Jeremy F. , Luckett Patrick H , Benzinger Tammie L.S. , Bateman Randall J. , Holtzman David M. , Ances Beau M ,   the Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2022

Background

Associations between amyloid and downstream measures of Alzheimer disease (AD) are often lacking. In autosomal dominant AD (ADAD), cerebrospinal fluid (CSF) phosphorylated tau 217 and 181 (pT217 and pT181) increase shortly after amyloid positron emission tomography (PET), followed by tau 205 (pT205), then tau PET. Each site also tracks closely with disease progression and is associated with longitudinal cognitive decline. Collectively these findings lead to the question of which p‐tau sites affect the relationship between amyloid and downstream AD markers (i.e., tau, MRI cortical thickness, Clinical Dementia Rating [CDR] Scale status), and more specifically whether they mediate such associations.

Method

CSF tau phosphorylation occupancy on 217, 181 and 205 residues, CSF total tau (t‐tau), amyloid PET, ADAD cortical thickness signature, and CDR status were measured in 150 individuals from the Dominantly Inherited Alzheimer Network (non‐mutation carrier [MC‐]; n=64; and mutation carrier [MC+]; n=86). Three multiple mediation analyses assuming nonlinear relationships were performed with amyloid PET as the predictor variable, CSF p‐tau sites (pT217, pT181, pT205) and t‐tau (when appropriate) as mediators, and either CSF t‐tau, cortical thickness, or CDR status as the outcome variables. For each model, estimated years to symptom onset (EYO), age, sex, and ADAD mutation status were included as covariates. All models were run with 500 iterations to bootstrap confidence intervals.

Result

Increased amyloid PET was associated with elevated CSF pT217, pT181, and pT205 (p’s<0.03). For each model, the effects of amyloid PET on downstream AD markers were jointly mediated by CSF pT217 and pT205. Specifically, elevated CSF pT217 and pT205 were associated with increased CSF t‐tau, decreased cortical thickness, and higher CDR scores (p’s<0.01). CSF t‐tau and pT181 did not mediate these relationships (p’s>0.05).

Conclusion

Elevated pT217 and pT205, but not pT181 or t‐tau, mediate the relationship between amyloid and downstream AD biomarkers in ADAD. AD‐related brain atrophy and clinical status may be dependent on specific tau sites; future mechanistic experiments are needed to fully understand such relationships. These results support the hypothesis that tau phosphorylation at specific sites plays a critical role in the progression and pathogenesis of ADAD, and may be a possible target for future treatments.
Longitudinal pathologic course of older individuals with medial temporal tau deposition in the absence of amyloid‐β pathology
Authors: Costoya‐Sánchez Alejandro , Moscoso Alexis , Silva‐Rodríguez Jesús , Aguiar Pablo , Pontecorvo Michael J. , Devous Michael D. , Schöll Michael , Grothe Michel J.
Published: December 2022

Background

Alzheimer’s disease (AD)‐like tau pathology in the medial temporal lobe (MTL) is also commonly observed in older individuals without amyloid‐β (Aβ) pathology, a condition termed primary age‐related tauopathy (PART). Little is known about the longitudinal course of this condition and its association with the AD continuum remains controversial. We used serial PET, MRI, and CSF data to study the longitudinal pathologic course of older individuals who show PET‐measured MTL tau pathology in the absence of Aβ pathology.

Method

We included older individuals with varying degrees of cognitive performance from the Alzheimer’s Disease Neuroimaging Initiative, the Harvard Aging Brain Study, and AVID’s A05 Study who had undergone baseline (n=1097) and follow‐up [18F]flortaucipir (FTP) (n=489, follow‐up: 1.83±0.84 years) and Aβ‐PET scanning (n=398, follow‐up: 2.36±0.76 years). Participants were separated into three groups according to Aβ and tau positivity (A‐T‐, A‐T+, A+T+), using a cut‐off of 12 centiloids for A+ and the 95th percentile of entorhinal (ERC) FTP SUVR values in healthy young controls (n=16, ≤39y) for T+. In complementary analyses we also assessed longitudinal changes in CSF biomarkers (n=99, follow‐up: 2.34±1.05 years) and cortical atrophy on MRI (n=650, follow‐up: 2.00±0.86 years).

Result

43% of A‐ individuals and 81% of A+ individuals were ERC‐tau positive. Cross‐sectionally, A‐T+ showed elevated FTP SUVR restricted to the medial/inferior temporal lobe, while A+T+ displayed a more AD‐characteristic pattern of widespread cortical FTP uptake (Fig. 1A). A‐T+ showed moderate FTP SUVR increases over time largely limited to the temporal lobe, whereas FTP SUVR increases were widespread in A+T+ (Fig. 1B). Notably, A‐T+ individuals did not increase Aβ accumulation over time (Fig. 1C). CSF analysis confirmed longitudinal tau increases in A‐T+ in the absence of increased Aβ accumulation (Fig. 1D). Compared to A‐T‐, A‐T+ individuals demonstrated accelerated MTL atrophy, whereas A+T+ showed more widespread AD‐typical cortical atrophy (Fig. 2).

Conclusion

Elevated MTL tau‐PET signal is frequently observed in older individuals without notable Aβ pathology, reminiscent of pathology‐defined PART. These A‐T+ individuals exhibit a comparably slow course of progressive tau accumulation and neurodegeneration confined to the temporal lobe and do not appear to be on a pathologic trajectory towards AD.
The role of cortical microstructural changes on longitudinal accumulation of tau and cognitive decline in at risk older adults
Authors: Gagliardi Geoffroy Pierre , Rodriguez‐Vieitez Elena , Montal Victor , Sepulcre Jorge , Diez Ibai Palacio , Lois Cristina , Hanseeuw Bernard , Schultz Aaron P. , Properzi Michael J , Papp Kathryn V. , Marshall Gad A , Fortea Juan , Johnson Keith A. , Sperling Reisa A. , Vannini Patrizia
Published: December 2022

Background

Non‐invasive diffusion‐weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) was recently shown to be cross‐sectionally associated with tau in cognitively‐normal older adults (Rodriguez‐Vieitez et al., Mol. Psych. 2021), suggesting that it might be an early marker of neuronal injury. However, the impact of cMD on longitudinal accumulation of tau pathology is currently unknown. Moreover, APOE‐e4 — the strongest genetic risk factor for sporadic AD — has been shown to be related to tau aggregation (Therriault et al.,JAMA Network 2019) and cognitive impairment in older adults. Here, we investigated whether cMD at baseline can predict longitudinal accumulation of tau as well as cognitive decline in cognitively‐normal adults with and without an APOE‐e4.

Methods

122 cognitively‐normal participants from the Harvard Aging Brain Study (71.0±9.7 years; 79 women[64.8%]), 30.3% APOE‐e4‐carriers, 16.0±2.9 years of education; Table 1) underwent DWI, T1w‐MRI, 18F‐flortaucipir(FTP)‐PET imaging and cognitive assessments at baseline. All participants had at least one longitudinal follow‐up FTP‐PET scan (average follow‐up time of 2.4±0.55 years). PET data were normalized to cerebellar grey‐matter. FTP‐PET was quantified using PVC‐corrected SUVR. Longitudinal measures of Preclinical Alzheimer Cognitive Composite (PACC5) were available for all individuals over a 7.2±2.4 years follow‐up interval. We assessed whether the interaction of APOE‐e4 and cMD (in entorhinal and inferior‐temporal cortices) was associated with longitudinal local tau accumulation and with longitudinal PACC5 using separate linear mixed‐effects models. Models were corrected for demographics and baseline tau or PACC5 as appropriate.

Results

The APOE‐e4 carriers and non‐carriers had similar baseline demographics and imaging characteristics (Table 1). We found significant interaction effects of APOE‐e4 status and cMD in predicting longitudinal tau (entorhinal p=0.008 and inferior‐temporal p=0.032) and longitudinal PACC5 (both entorhinal and inferior‐temporal p<0.001), such that baseline cMD predicted the accumulation of tau and cognitive decline in APOE‐e4‐carriers only (Figures 1 and 2).

Conclusions

Our results demonstrate that the cortical microstructual changes measured by cMD are related to accumulation of longitudinal local tau and cognitive decline in at‐risk individuals. The combination of APOE‐e4 and elevated cMD may help identify individuals at short‐term risk of tau accumulation and AD‐related cognitive decline, suggesting utility in therapeutic trials.
Multiple Viruses Detected in Human DNA are Associated with Alzheimer Disease Risk
Authors: Tejeda Marlene , Farrell John , Zhu Congcong , Wetzler Lee , Lunetta Kathryn L. , Bush William S. , Martin Eden R , Wang Li‐San , Schellenberg Gerard D. , Pericak‐Vance Margaret A. , Haines Jonathan L. , Farrer Lindsay A. , Sherva Richard
Published: December 2022

Background

Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer disease (AD) by independent lines of evidence.

Method

We mapped and quantified DNA sequence reads from whole exome and whole genome sequencing data in 37,000 AD cases and controls from of the Alzheimer Disease Sequencing Project that did not align to the human genome to 318 viral reference sequences. After quality control, the sample included 1,696 samples derived from brain (cases=1,314, controls=382) and 14,588 derived from blood (cases=5,813, controls=8,775). We tested individual and cumulative normalized viral read counts, both free and inserted in the host genome, for association with AD using multiple machine learning (ML) classifiers, selecting the top 27 viral species according to an algorithm based on the species’ predictive rank weighted by the model’s overall predictive accuracy across models. These top 27 viruses were tested for association with AD using logistic regression models adjusted for PCR amplification, sequencing site, sex, APOE genotype, and ancestry. Analyses were stratified by tissue source.

Result

We detected sequence reads from 175 unique viral species, herpes simplex virus 1 (HSV‐1) being the most common. Viral read counts varied significantly by sequence center, tissue source, sex, PCR use, and ancestry in both the WES and WGS datasets. ML results indicated that herpes viruses (1, 2, 4, 5, 6A, 6B, 7, and 8), HIV, Hepatitis C, Molluscum contagiosum, several Torque Teno virus species (TTV), HPV‐71, Coronavirus 229E, Tick‐borne encephalitis, human Mastedenovirus, human polyomavirus 2, variola virus, primate t‐lymphotropic virus 1, human endogenous retrovirus K, and total normalized mapped viral reads were significant predictors of AD. Subsequent meta‐analyses of results stratified by tissue source showed that AD was significantly associated with HSV‐1(OR=4.07, P=2.22x10‐5), Human papillomavirus type 71(OR=3.26, P=0.006), TTV‐10 (OR=22.11, P=0.004) , and cumulative viral read count (OR=7.34, P=0.03). After multiple testing correction, HSV‐1 remains significant.

Conclusion

These results support the hypothesis that viral infections, especially HSV‐1, is associated with AD risk and demonstrate the potential of using deep sequencing technology to detect microbial agents in multiple tissues and discerning here‐to‐for unrecognized associations of infectious agents and AD.
Factors Associated to Progression of Hippocampal Sclerosis: Contribution of a New Staging System
Authors: Heras Alicia Uceda , Villalón Diego , Zea Marian , López Mª José , Rabano Alberto
Published: December 2022

Background

Hippocampal sclerosis (HS) is a neuropathological condition with 5% to 30% of prevalence in the elderly (Nelson et al., 2013). HS is mostly associated with TDP‐43 proteinopathy, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (Nelson et al., 2019), and usually coexists with other neurodegenerative disorders like Alzheimer´s (AD) and Lewy body disease (LBD). LATE is a progressive pathology that may combine with HS (LATE_HS+) in its advanced phases. We have developed a staging scheme for HS with a high correlation with TDP‐43 staging. Here we analyze the contribution of this classification system to understand the progression of HS in the context of focal TDP‐43 pathology in the medial temporal lobe (MTL).

Method

A full postmortem neuropathological study was performed in 161 brains from a clinicopathological cohort of institutionalized dementia patients (Vallecas Alzheimer’s Center Study) (age at death = 87.4±6.6, sex ratio = 79% females) with a predominant primary diagnosis of AD (77.4%), followed by vascular dementia (11%) and LBD (7.3%), and a high prevalence of comorbid pathologies (TDP‐43 and various tauopathies). Four stages (1‐4) of HS, including early phases (pre‐HS), were applied based on histologic criteria. Demographic, clinical, and neuropathological variables showing correlation with HS stages were analyzed through factorial analysis.

Result

Some stage of HS was present in 71.1% of patients, and 24% of them displayed an early HS stage. TDP‐43 inclusions were detected in 67.5% of the patients. Variables associated to HS stages were grouped in 4 factors. While age at death, survival time and MTL atrophy, grouped together (factor 1) explained 23% of total co‐variability, other factors included Braak tau and NIA‐B stages (20%) or alpha‐synuclein stages‐HS stages (4.5%). Interestingly, HS and TDP‐43 stages were also included in factor 1 and seggregated together into a further single factor (18%) as well.

Conclusion

Our staging scheme for hippocampal sclerosis identifies patients with LATE in early stages of HS, and suggests a complex interaction of factors involved in conversion of LATE_HS‐ to LATE_HS+. While TDP‐43 stages, age, survival time and atrophy stay closer to HS in the explanation of variability, Alzheimer’s tau and Lewy body pathologies appear as secondary co‐factors.
Bilingualism Appears to be Protective Against Cognitive Decline Related to Cerebral Tau in Mexican Americans: An HABS‐HD Study
Authors: Petersen Melissa , Hall James , Johnson Leigh , Braskie Meredith N , Yaffe Kristine , Rissman Robert A. , Toga Arthur W. , O'Bryant Sid E. ,   Health and Aging Brain Study‐ Health Disparities (HABS‐HD) Study Team
Published: December 2022

Background

Bilingualism is thought to provide protective effects from neurodegeneration and age‐related diseases such as Alzheimer’s Disease (AD). The protective effect is considered to be due to differences in grey and white matter between monolingual and bilinguals; however, no work to date has looked at differences in additional AD brain pathology. The aim of this study was to examine among Mexican Americans the impact of cerebral tau levels on cognitive functioning stratified by language status.

Method

Data were analyzed on a combined sample of n=44 Mexican American (n=15 Monolingual [n=9 Cognitively Normal; n=6 Cognitively Impaired {Mild Cognitive Impairment/Dementia}]; n=29 Bilingual [n=19 Cognitively Normal; n=10 Cognitively Impaired]) participants. One outlier case (Cognitively Impaired, Monolingual participant) was removed from subsequent analyses. All participants underwent cognitive testing and PET tau imaging using Siemens Biograph Vision 450 PET/CT scanner with PI‐2620. PET scans were co‐registered with 3T MRI scans (Siemens Vida). PET tau scans were processed using FreeSurfer‐defined regions of interest (ROIs) focused on the medial temporal lobe (average across entorhinal, hippocampus and amygdala), posterior cingulate cortex (isthmus cingulate and posterior cingulate) and lateral parietal cortex (inferior parietal, superior parietal and supramarginal). Linear regression models were generated for each language status group (monolingual, bilingual) examining the impact of each ROI on cognitive outcomes covarying for age, sex, and education.

Result

Among monolingual Mexican Americans, higher Medial Temporal SUVR was significantly related to poorer performance across measures of global cognition (MMSE p<0.001), processing speed (DSST p=0.038), episodic learning and memory (WMS‐III LM I p<0.001; WMS‐III LM II p<0.001) as well as rote verbal learning (SEVLT Immediate Recall p=0.004). Posterior Cingulate and Lateral Parietal SUVRs were not found to be significantly related to cognitive functioning among monolinguals. Additionally, among bilinguals, cerebral tau (derived from select ROIs) was not found to be significantly related to cognition.

Conclusion

Higher cerebral tau, specifically in the Medial Temporal ROI, was found to be related to poorer cognitive functioning across multiple domains but only among those who were monolingual. Results provide further support for the protective effect of bilingualism.
Unexpected Findings from 8,205 Brain Magnetic Resonance Imaging Examinations of Research Volunteers ≥ 40 years old
Authors: Rowley Howard A. , Rowley Paul A , Field Aaron S , Johnson Sterling C. , Carlsson Cynthia M. , Asthana Sanjay , Chin Nathaniel A. , Bendlin Barbara B. , Okonkwo Ozioma C.
Published: December 2022

Background

Brain MRI is used routinely to study morphology in normal aging and dementia. Expert image review for clinically significant findings varies across sites and best practice is unsettled. We describe unexpected findings from 8,205 research brain MRIs from adults 40 years and older, comparing neuroradiologist presumptive diagnoses versus lesions flagged as concerning by scanning staff.

Method

N=8,205 consecutive brain MRIs were prospectively reviewed by neuroradiologists from April 2002 to March 2020 under an IRB directive intended to identify clinically relevant unexpected findings. The final study population (M= 3,625, F= 4,580; ages 40–94 years (y); median 62 y) included normal volunteers and subjects with known diagnoses. Neuroradiologists detailed their findings using a structured reporting form, using only the scans included for research purposes. Scans were categorized normal, abnormal without follow‐up recommended, or abnormal with follow‐up recommended. Only the last category was considered to have a clinically relevant, unexpected abnormality and was referred for notification. Scanning staff and research personnel were also instructed to document concerns they noticed at the time of scanning, a common screening approach at other sites, usually followed by referral for expert reading. Scans were subcategorized and compared by presumptive abnormality type, both for the neuroradiologists and scanning staff.

Result

Unexpected findings of potential clinical significance were discovered by neuroradiologists in 442/8,205 (5.4%) research volunteers ≥40 years. The most common abnormalities prompting follow‐up were vascular (204/439 (46%)), neoplastic (117/439 (27%), and inflammatory lesions (35/439 (8%)). Fewer than 2% of these 442 concerning abnormalities were prospectively reported by scanning staff, who most commonly flagged normal anatomic variants for further review.

Conclusion

Five percent of research volunteers ≥40 years who undergo brain MRIs have an unexpected, potentially clinically significant finding reported by a neuroradiologist. Very few relevant abnormalities are detected using spontaneous reports by scanning staff. This result could be predicted based on personnel training and roles in research protocols. Our results clarify how often significant abnormalities may be missed if scans are not formally interpreted. Ideally, neuroradiologist review should be included in aging research protocols using brain MRI.
Investigating the functional significance of presynaptic tau in ageing and disease
Authors: Groves Emily E , Sung Katherine , Flores‐Dominguez Diana , Pollack Saskia J , Croft Cara L , Golde Todd E , Hanger Diane P , McAdam Robyn , Giese Karl Peter , Noble Wendy
Published: December 2022

Background

Synaptic dysfunction is an early pathological feature of neurodegenerative disease and is a close correlate of cognitive decline. Modified tau mislocalises to the synaptic compartment in disease, where some forms of tau interact with synaptic proteins and disrupt synapse function. This study seeks to further explore synaptic tau accumulation, and the impact on synaptic health and tau release, during ageing and tauopathy progression.

Method

Post‐mortem Brodmann area 9 (BA9) pre‐frontal cortex from control or Braak stage I‐VI tissues were obtained. Formalin‐fixed paraffin‐embedded sections were subject to immunohistochemistry. Total lysates, cytosolic and synaptoneurosome fractions were isolated for western blotting, imaging and analysis of synaptic protein interactions.

Organotypic brain slice cultures were prepared from P9‐10 wild‐type mice and Tau35 mice in which a disease‐associated tau fragment is expressed. In addition, some wild‐type slices were transduced with AAV2/TM8‐WT‐htau0N4R‐EGFP (WT) or AAV2/TM8‐P301L/S320F‐htau0N4R‐EGFP. Slices were cultured for 21‐28 DIV. Total lysate, cytosolic, and synaptoneurosome fractions were isolated for western blot, immunocytochemistry, or immunoprecipitation. Culture medium was used for tau sandwich ELISA.

Result

We observed progressive neurodegenerative changes, including the accumulation of sarkosyl‐insoluble tau, in organotypic brain slices expressing Tau35 and mutant (AAV‐expressed) human tau. Mislocalisation of phosphorylated and aggregated tau to the synaptic fraction in the tauopathy slice models mirrors, at least in part, changes observed in postmortem AD brain. Tau mislocalisation was associated with significant loss of specific pre‐synaptic proteins in Tau35 mice and AD brain. Mutant AAV‐expressed tau, but not WT AAV‐expressed tau, interacts with specific presynaptic vesicle proteins. Furthermore, alterations in basal tau release from slices was observed when disease‐like tau was expressed.

Conclusion

Slice cultures from mice in which disease‐associated tau is expressed at physiological levels (Tau35) or in which mutant tau is virally induced recapitulate key elements of human tauopathy. These long‐term brain slice cultures allow sensitive characterisation of presynaptic alterations that occur early in tauopathy. These models are now being used to determine if interactions between tau and pre‐synaptic proteins are essential for tau‐mediated synaptic dysfunction and/or tau release.
Comparison of plasma amyloid, tau, and astrocyte biomarkers to identify AD pathophysiology
Authors: Ferreira Pamela C.L. , Tissot Cécile , Ferrari‐Souza João Pedro , Bellaver Bruna , Brum Wagner S. , Leffa Douglas Teixeira , Therriault Joseph , Benedet Andréa Lessa , Servaes Stijn , Lussier Firoza Z , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Tudorascu Dana L , Klunk William E , Villemagne Victor L , Cohen Ann D , Zimmer Eduardo R. , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A
Published: December 2022

Background

Although it has been alredy demonstrated that plasma amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillar protein (GFAP) can predict with high accuracy Alzheimer's disease (AD) pathophysiology, no previous study has compared their performance in the same set of individuals. Here, we compare the performance of plasma Aβ42/40, p‐tau, GFAP, and NfL against Aβ and tau PET across the AD spectrum.

Method

We used the ROC curve to test the predictive performance of Simoa plasma Aβ42/40, p‐tau (at threonine 181 and 231), NfL, and GFAP to identify Aβ and Pau PET positivity in 138 cognitive unimpaired (CU) and 87 cognitive impaired (CI) from the McGill TRIAD cohort. Pearson correlation and linear regression tested the association between markers.

Result

We showed that plasma p‐tau231, p‐tau181, GFAP, and NfL correlated with each other (Figure 1), while Aβ42/40 did not. In CU, voxel‐wise linear regressions (Figure 2A) showed that p‐tau231, p‐tau181, and GFAP concentrations were significantly associated with Aβ‐PET (Figure 2A). While for Tau‐PET (Figure 2B), there was a significant association only with p‐tau231 and p‐tau181 (Figure 2B). P‐tau231 outperformed the other plasma biomarkers to identify both Aβ‐ and Tau‐PET positivity (AUC 0.877 and 0.796, respectively) in CU individuals. In CI, Aβ‐ and Tau‐PET were significantly associated with p‐tau231, p‐tau181, and GFAP, whereas NfL was only associated with Tau‐PET. The discriminative accuracy of GFAP in identifying both Aβ‐PET and Tau positivity (AUC 0.936 and 0.944, respectively) outperformed the other plasma biomarkers in CI individuals (Figure 3, Table 1).

Conclusion

We showed that plasma p‐tau231, a novel biomarker of early AD, best depicted AD pathophysiology in CU individuals. Interestingly, GFAP, an astrocyte reactivity marker, was better associated with brain Aβ and tau pathologies than plasma p‐tau and Aβ markers in CI individuals. Our results highlight that the performance of the novel plasma biomarkers of amyloid, tau and neuroinflammation to detect brain AD pathophysiology is disease stage specific.
Longitudinal genetic and environmental relationships between structural‐ and diffusion‐based Alzheimer’s disease neuroimaging signatures
Authors: Williams McKenna E. , Gillespie Nathan A. , Bell Tyler Reed , Dale Anders M. , Elman Jeremy A. , Eyler Lisa T. , Fennema‐Notestine Christine , Franz Carol E , Hagler Donald J. , Lyons Michael J. , McEvoy Linda K. , Neale Michael C. , Panizzon Matthew S. , Reynolds Chandra A. , Sanderson‐Cimino Mark E. , Kremen William S.
Published: December 2022

Background

Composite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures,' are tools developed to identify brain changes specific to mild AD. In recent work from our group, we found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s aided prediction of 12‐year progression to MCI beyond age and polygenic risk for AD. Results held up after accounting for general brain age. In contrast, a cortical thickness/hippocampal volume‐based signature did not improve prediction. Given the importance of genetic influences on brain structure and AD, here we examined the phenotypic and genetic relationships among diffusion and structural AD signatures and brain age, and how those relationships change across midlife and early old age.

Method

Our validated thickness/volume signature, novel MD signature, and a validated brain age measure were used in biometrical twin analyses to examine phenotypic, genetic, and environmental relationships both cross‐sectionally and longitudinally across 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA; baseline age=56.1, SD=2.6, range=51.1‐60.2). Subsequent waves were at approximately 5.7‐year intervals.

Result

Both AD signatures and brain age are heritable (56%‐72%), but each signature captured unique phenotypic and genetic variance that is also not explained by general brain aging. Genetic correlations across time within each signature were high (0.77‐0.98). Baseline MD signatures (age=56 years) predicted thickness/volume signatures over a decade later (r= ‐0.53, 95% CI: ‐0.62, ‐0.42), but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures (r= ‐0.13, 95% CI: ‐0.24, ‐0.01). Interestingly, by wave 2 (average age=62 years), the thickness/volume signature appears to have caught up with the MD signature in terms of predictive ability.

Conclusion

Findings lend further support to the idea that a signature based on brain microstructure captures very early AD‐related changes that are later reflected in the macrostructural signature. This MD signature explains substantial genetic variance that is consistent throughout midlife and into early old age, supporting the utility of the MD signature as a very early AD‐related neuroimaging biomarker and its potential role in clinical trials.
Plasma biomarkers contribution to the structural alteration of perivascular spaces in Alzheimer’s disease
Authors: Sibilia Francesca , Sheikh‐Bahaei Nasim , Mack Wendy J , Choupan Jeiran
Published: December 2022

Background

Perivascular spaces (PVSs) are fluid‐filled spaces in the brain surrounding blood vessels. Their function is to facilitate the cerebrospinal fluid (CSF) drainage between the interstitial space and the blood vessel space, allowing the outflow of waste soluble proteins in the brain. Aging leads to the increase of PVS number and volume, especially in basal ganglia and centrum semiovale. Stress was found to alter the cerebral flow of metabolites in the brain and to accelerate Aβ accumulation. High level of cortisol causes hypertension, contributing to increase of blood pressure. Angiotensin‐II raises arterial blood pressure quickly, and its production is associated to levels of Angiotensin‐converting enzyme (ACE). This study objective is to investigate the relationship between plasma biomarkers and the PVS volume fraction, and their effect on cognitive impairment process.

Method

Older adults from the ADNI‐1 population (n=108, age range= 56‐89 years old, http://adni.loni.usc.edu), were divided into healthy control, mild cognitive impairment (MCI) and Alzheimer’s (AD) patients. MRI T1w images were acquired at 3T for all participants. PVS volume fraction was obtained by using parcellation and quantitation within white matter volume at global and regional levels. Linear regressions were run considering PVS volume fraction as dependent variable, calculated both in the total white matter and in the basal ganglia. Levels of cortisol, ACE and matrix metallo‐proteinases (MMPs) 2 and 9 were treated as independent variables. Pulse, age, sex, apolipoprotein E4, and diagnosis were included as covariates.

Result

A main effect of MMP‐9 was seen on the PVS of the total white matter (p=0.046), with the covariates age and diagnosis showing a significant effect. Mediation analyses showed that diagnosis was the factor leading such relationship (p<0.05). PVS in the basal ganglia had a trend of being significantly associated to decreases of MMP‐2 (p=0.052). No significant effect was seen between PVS and cortisol, nor ACE.

Conclusion

This study shows for the first time that there is a significant relationship between higher levels of MMP‐9 and alterations in PVS, when considering the cognitive impairment in older adults. This confirms previous findings that associated increase levels of MMP‐9 to faster Aβ accumulation.
Tau‐derived Locus coeruleus degeneration as a driver for sleep‐wake alterations and neuropsychiatric symptoms in early and late‐onset Alzheimer’s Disease
Authors: Martínez Neus Falgàs , Muñoz‐Moreno Emma , Guillén Núria , Sarto Jordi , Ramos‐Campoy Oscar , Bosch‐Capdevila Beatriz , Marrero‐González Paula , Bargalló Núria , Balasa Mircea , Fernandez‐Villullas Guadalupe , Walsh Christine M , Neylan Thomas C. , Iranzo Álex , Lladó Albert , Grinberg Lea Tenenholz , Sanchez‐Valle Raquel
Published: December 2022

Background

Early‐onset Alzheimer’s Disease presentations (EOAD, under 65) frequently present with atypical phenotypes and a more aggressive disease course with a higher burden of neuropsychiatric symptoms than late‐onset AD (LOAD). Current treatments for sleep and behavioral disturbances are still non‐specific, causing side effects (e.g., sedation, falls). Identifying the underlying changes driving behavioral differences between EOAD and LOAD is crucial to developing tailored treatment avenues. The noradrenergic locus coeruleus (LC), one of the first sites of tau deposition in AD, has been implicated in sleep‐wake patterns and mood regulation. We aim to test the hypothesis that the LC is more affected in EOAD than LOAD by comparing LC volume (neuromelanin‐sensitive MRI) and sleep‐behavioral symptoms in biomarker‐confirmed EOAD and LOAD cohorts.

Method

Fifty‐four subjects with AD biomarker‐based diagnosis (20 EOAD, 34 LOAD) were recruited at the Hospital Clínic de Barcelona. All participants and informants completed the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Neuropsychiatric Inventory (NPI) questionnaires to assess the severity of sleep‐wake alterations and neuropsychiatric symptoms. In addition, they underwent a 3T turbospin‐echo MRI to measure LC volume. We compared mean values of LC volume, ESS, PSQI, and NPI between EOAD and LOAD. Furthermore, linear regression models controlling by cognitive status (MMSE) were performed.

Result

EOAD and LOAD had similar cognition (MMSE 21.3±5 vs. 22.6±4, respectively), functional status (CDR 0.92±0.1 vs. 0.68±0.1), and prevalence of amnestic phenotype (57 vs. 70%). EOAD compared to LOAD, trended towards higher scores for ESS (7.4±1 vs. 5.1±1, respectively), PSQI (7.3±2 vs. 5.6±1), NPI (21.6±8 vs. 14.6±8), and caregiver distress (9.4±3 vs. 4.7±3). LC volume was lower in EOAD according to preliminary MRI data [n=18, 9 EOAD (21.8±3 mm3), 9 LOAD (29.5±3 mm3)]. Linear regression models showed that MMSE did not influence the EOAD/LOAD effect on LC volume (coef. 7.7, p=0.032).

Conclusion

The current preliminary study suggests that LC degeneration is greater in EOAD than LOAD. This difference may explain the EOAD‐associated worse sleep‐wake dysfunction and neuropsychiatric symptoms. Deep phenotyping/comparison of EOAD and LOAD can inform tailored treatment strategies for these behavioral symptoms.
Chronic electrophysiology reveals age related loss of coherence between hippocampus and entorhinal cortex in ThyTau22 mice
Authors: Zwang Theodore J , Hyman Brad
Published: December 2022

Background

Recent studies suggest spatial learning and memory impairment, which is an early clinical sign of Alzheimer’s disease (AD), is caused by dysfunction of neurons that communicate between the hippocampus and entorhinal cortex. Technological limitations have prevented chronic cellular‐level tracking of these interconnected brain regions during the many months or years before onset of age‐related cognitive deficits. This study aims to take advantage of recent progress in chronic electrophysiology probes to explore how cellular and circuit‐level changes progress with aging across these two brain regions in a mouse model of AD.

Method

Two flexible electrophysiology probes were implanted with into a single hemisphere of ThyTau22 or WT mice. One probe was targeted to the hippocampus, and the other to the medial entorhinal cortex. Recordings were made from 32 electrodes from each probe once per week over 6 months while mice were walking along a linear track in virtual reality.

Result

Longitudinal electrophysiology in ThyTau22 mice show an aging and tau‐pathology correlated decrease in local field potential (LFP) coherence at multiple frequencies. Decoherence is observed both within and between the hippocampus and entorhinal cortex.

Conclusion

These results suggest that tau pathology plays a significant role in the loss of neuronal network integrity with age.
Pain interference, cognition, and depressive symptoms in Alzheimer’s disease
Authors: Dimitrov Theodore , Iversen Wm. Larkin , Anderson Alison R , Monroe Todd B , Failla Michelle D , Wang Jinjiao
Published: December 2022

Background

Underrecognized and untreated pain in people with Alzheimer’s disease (AD) is a public health concern1 and is associated with sleep disturbances, loss of appetite, and depressive symptoms2. As cognition worsens, people with AD may be unable to reliably report their pain3; 4. While previous studies have examined self‐reported pain intensity in persons with AD5; 6, there has been limited investigation into how this pain interferes with daily living (i.e. pain interference). Wang et al (2017) reported that cognition has a positive association with pain interference and depression7 in AD. However, the relationship of the specific aspects of pain interference with cognitive function and depression has not been explored. Here we investigate the association of specific pain interference subscores with cognitive function and depressive symptoms in verbally communicative older adults with mild to moderate AD. We hypothesized that (1) AD individuals with better cognitive function will report more pain interference in all categories; and (2) all elements of pain interference will be positively associated with depressive symptoms.

Method

For this secondary analysis, we investigated the relationship between pain interference (Brief Pain Inventory‐ Short Form), cognitive function (Mini‐Mental Status Exam), and depressive symptoms (15‐item Geriatric Depression Scale) in 52 older communicative adults (ages ≥ 65) with AD. Data analyses were conducted in R using Spearman correlation coefficients to assess the univariate associations between study measures.

Result

We found significant positive correlations between cognitive function (median MMSE = 17.00) and pain interference subscores of general activity, mood, walking ability, normal work, sleep, and enjoyment of life (r = .30‐.37, p < 0.05), but not “relations with other people.” Further, the relationship between depressive symptomatology (median GDS‐15 = 2.00) with pain interference was significant in all measures except “general activity” (r = .26 ‐.38, p < 0.05).

Conclusion

Among adults with AD, nearly all aspects of pain interference were positively associated with cognitive function and depressive symptoms. Regular assessment of specific pain interference measures and screening for depressive symptomology can be used as another tool to help identify unreported and underrecognized pain. Moreover, distinguishing individual elements of pain interference may allow for more individualized management of pain and depressive symptoms in this vulnerable population.
Daily Stressors, Social Support, and Mental Health Experiences of Dementia Family Caregivers
Authors: Puga Frank , Wang Danny , Rafford Meghan , Pickering Carolyn E
Published: December 2022

Background

Family members providing informal care to individuals living with dementia have an increased risk of depression and anxiety. While risk and protective factors of poor mental health outcomes have previously been identified, little is known about the day‐to‐day circumstances in which depression and anxiety‐related symptoms are more likely to appear among dementia caregivers. The purpose of this study was to identify contextual factors associated with daily depression and anxiety symptom experience among dementia family caregivers.

Method

A national sample of family caregivers (N = 165) completed daily diary surveys over 21 days (n = 2,841). Mixed‐level models were used to examine relationships between daily behavioral symptoms of dementia (BSDs), emotional and instrumental social support, and depression and anxiety‐related symptoms.

Result

Depression and anxiety symptoms were endorsed by 141 (85.45%) and 155 (93.94%) caregivers, respectively. Dementia caregivers were more likely to report depression (OR = 1.15, 95% CI: 1.11‐1.18, p < 0.001) and anxiety (OR = 1.12, 95% CI: 1.09‐1.16, p < 0.001) on a given day when BSDs were present and perceived as more bothersome than usual. Specific BSDs, including restless behaviors and intense emotions, also increased the daily odds of experiencing depression and anxiety symptoms. Further, the daily odds of depression decreased on days when caregivers reported informal instrumental support (OR = 0.67, 95% CI: 0.4‐0.92, p < 0.05), while the daily odds of anxiety increased on days when caregivers reported emotional support (OR = 1.46, 95% CI: 1.07‐1.99, p < 0.05).

Conclusion

The risk of experiencing depression and anxiety symptoms varies daily based on the presence of specific contextual factors. The results from this study demonstrate the dynamic nature of mental health in the context of dementia caregiving. These findings support the need for ecologically‐valid interventions to improve the day‐to‐day well‐being of dementia family caregivers.
Subiculum fiber degeneration within the fornix white matter tract in 5xFAD mice
Authors: Bienkowski Michael S , Becerra Marlene , Montagne Axel , Korobkova Laura , Cabeen Ryan P , Khanjani Neda , Sagare Abhay P , Jacobs Russell E. , Zlokovic Berislav V
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects all components of the neurovascular unit. The hallmark pathology of AD, amyloid plaques and tau neurofibrillary tangles, aggregate within gray matter areas and spread across neural networks. Although AD pathology is scarce within white matter brain regions, white matter abnormalities have been observed in AD patients using diffusion tensor imaging (DTI; Sachdev et al 2013) and white matter tracts are putative therapeutic targets for deep brain stimulation (Lam et al 2020). Particularly, the fornix is a white matter tract which connects the hippocampus to brain regions of the classic Papez circuit and Default Mode Network (DMN). A recent whole brain analysis using transgenic 5xFAD/Thy1‐GFP mouse (Zhang et al 2020) found evidence of fornix degeneration and dystrophic axon terminals within the mammillary body (a major SUB target) occurring as early as 2 months of age. However, due to the broad expression of GFP under the Thy1 promotor, it is difficult to determine the origin of axon fibers and further characterize if other SUB pathways are also affected.

Method

To investigate white matter changes in AD and further characterize SUB axon degeneration, we performed triple anterograde tract‐tracing of SUB axon fibers and post‐mortem DTI tractography imaging within the same 8‐9 mo. old 5xFAD mice.

Result

DTI imaging revealed a significant decrease in fiber density of the fornix white matter tract in 5xFAD mice. Quantification of tracer‐labeled fluorescent fiber density in the 5xFAD mice vs control mice also revealed significant degeneration of SUB fibers within the fornix white matter as well as downstream SUB targets including mammillary body, retrosplenial cortex, and anterior thalamus. Furthermore, SUB axon terminals in 5xFAD mice appeared dystrophic and terminal field topography was disrupted.

Conclusion

DTI imaging and anatomical tract tracing approaches reveal white matter degeneration in 5xFAD mice and the fornix/SUB fibers are particularly vulnerable in AD. Diminished SUB input to brain regions of the Papez circuit/DMN likely leads to neural network dysfunction. Whether amyloid pathology, neurovascular dysfunction, or inflammatory response in the 5xFAD mouse contributes to white matter degeneration remains to be determined by future studies.
An Educational Platform about Current and Future Paradigms of Neuroimaging in the Management of Alzheimer’s Disease
Authors: Van Phan Thanh , Praet Jelle , Guarnieri Roberto , Löwenthal Elise , Bettens Laurent , Ribbens Annemie
Published: December 2022

Background

The first disease‐modifying treatment (DMT) for Alzheimer’s disease (AD) has been approved by the U.S. Food and Drug Administration (FDA) in 2021, with potentially more DMTs becoming available in the coming years. Neuroimaging was shown to support clinical decision making in the management of AD and will play a crucial role in determining patient eligibility and monitoring treatment efficacy and adverse events [1]. However, while neuroimaging takes center stage, image acquisition and analysis is rapidly becoming more complex. Training and education are critical for successful implementation of new imaging tools by (neuro)radiologists in daily clinical practice [2].

Methods

ALZimaging.com is a free e‐learning platform about current and future neuroimaging paradigms in AD management, written by three medical experts. It offers six chapters containing a thorough literature review, retaining more than 250 peer‐reviewed papers and guidelines about AD pathophysiology, neuroimaging protocols and tools for early and differential diagnosis, patient monitoring and safety reading. Additionally, all chapters are complemented by a quiz to test the users’ knowledge. Four webinars with Accreditation Council for Continuing Medical Education (ACCME) are also included, presenting expert discussion panels and case studies. We present the qualitative assessment on the general acceptance and feedback about the e‐learning platform, while the educational content was released gradually during the first year.

Results

Since the launch, over 2000 persons have visited the e‐learning platform. The registered participants have read in average 71.5% of the content and the average quiz score is 3.5 out of 5 per chapter. For the Alzheimer’s webinar series, more than 500 participants watched the live versions and completed the courses, resulting in the attainment of ACCME‐accreditation. As feedback, the majority of (neuro)radiologists using the platform expressed their positivity and that knowledge gaps on neuroimaging were filled.

Conclusion

The changing healthcare landscape of neuroimaging in dementia results in a strong interest in educational material. Platforms like ALZimaging.com providing curated and interactive educational resources leading to ACCME accreditation can play a crucial role to support the neuroradiology community in improving management of AD in care practice.

References:

[1] Banerjee, CUREUS (2020)

[2] Vavasseur, Insights Imaging (2020)
Native American Ancestry is associated with lower risk of Alzheimer’s Disease: results from the Genetic of Alzheimer’s disease in Peruvian Populations (GAPP) study.
Authors: Custodio Nilton , Soto‐Añari Marcio , Montesinos Rosa , Caipa Maritza Pintado , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Reyes‐Dumeyer Dolly , Tosto Giuseppe
Published: December 2022

Background

Alzheimer’s Disease Related Dementias (ADRD) is not equally distributed among racial and ethnic groups. The APOE‐ɛ4 allele alone does not explain the different frequency of the disease. In fact, Hispanics (HI) and African Americans e4 non‐carriers still show a two‐to‐four‐fold higher incidence of ADRD, compared with non‐Hispanic Whites. Ancestry is an understudied yet a critical aspect of health disparities, as it may explain observed differences in frequency of ADRD across ethnic groups. We recently launched a genetic study in Peruvians, whose genome is characterized by large Native‐American ancestry proportions (higher than other HI populations such as Caribbean Hispanics or Mexicans), and studied the association between Ancestry, APOE‐e4 and ADRD.

Method

We recruited 264 Peruvians across three main sites in Peru (Lima, Arequipa, Puno). Genotyping was conducted on GSA Illumina platform, and, after QC, global ancestries (Native American [NAT], European [EUR], African [AFR]) were estimated using the Human Genome Diversity Project as reference (Figure 1). Number of APOE‐e4 alleles were entered as predictor along with proportion of global ancestries in regression models, adjusting for age, sex and education. AD status was employed as main outcome; episodic memory scores were used as secondary outcomes in healthy controls.

Result

51 were diagnosed with AD, 213 were healthy controls (mean age 72 years old). Average ancestry was estimated to be 73.0% NAT, 23.8% EUR, 3.2% AFR. APOE‐e4 was found associated with AD (OR [95%CI] = 4.09 [1.98‐8.47], p<0.001). NAT ancestry proportion was found protective at trend in the whole cohort (OR = 0.73[0.50‐1.06], p = 0.096). When restricted to e4 non‐carriers, NAT ancestry was found significantly associated with lower AD risk (OR = 0.57[0.36‐0.91], p = 0.019). Consistently, higher NAT ancestry was associated with better episodic memory scores in healthy controls (e.g. delayed recall: betastandardized = 0.26, p<0.001).

Conclusion

To our knowledge, this is the largest collection of individuals with predominant Native American ancestry showing protective effect towards ADRD. This is particularly evident in those individuals not carrying the APOE‐e4 allele. APOE is confirmed as strong risk factor for ADRD (larger than other HI populations).