bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Systemic Arterial Hypertension on Memory and Motor Recovery after Permanent Focal Cerebral Ischemia in Spontaneously Hypertensive Rats
Authors: Rohden Francieli , Moreira João Victor Matos e , Bernardi Luis Pedro , Paz Nicolly , Schlickmann Thomas Hugentobler , Da Ros Lucas Uglione , Zimmer Eduardo R. , Souza Diogo O.
Published: January 2025

Background

Systemic Arterial Hypertension (SAH), distinguished by a persistent elevation of blood pressure, emerges as a risk factor for stroke and Alzheimer’s Disease (AD). Additionally, recent evidence suggests that stroke may adversely affect memory, potentially playing a role in the development of AD. This study aimed to investigate the influence of permanent focal ischemic stroke on memory, as well as on sensorimotor function (asymmetry of the front paws) and cerebral infarct size in adult male spontaneously hypertensive rats (SHR), compared to normotensive Wistar Kyoto (WKY) rats.

Method

We assessed the stroke effects on short‐ and long‐term memory through the open field task (7 and 21 days after stroke), on sensorimotor functions through the cylinder test and adhesive removal test (over 42 days after stroke), and on infarction volume through 2,3,5‐Triphenyltetrazolium chloride staining (3 and 7 days after stroke).

Result

Short‐term memory was observed in both naive WKY and naive SHR rats, while SHR naive animals did not exhibit long‐term memory. Stroke disrupted short‐term memory in both WKY and SHR rats and long‐term memory in WKY rats (Fig. 01). In regards to the sensorimotor function, (cylinder test and adhesive removal) WKY rats totally recovered from the stroke‐induced asymmetry in the front paws, while SHR rats did not (Fig. 02). Concerning infarction volume, WKY rats showed decreased infarction volume from the third to the seventh day after stroke, while SHR rats did not exhibit this reduction (Fig. 03).

Conclusion

These results emphasize the impact of hypertension on memory, as well as on motor outcomes and brain infarct size following stroke, potentially contributing to the risk for AD.
Tau exacerbates the development of distinct neuropsychiatric symptoms in late braak stage – the head study
Authors: Aguzzoli Cristiano Schaffer , Povala Guilherme , Ferreira Pamela C.L. , Lussier Firoza Z , Bauer‐Negrini Guilherme , Amaral Livia , Soares Carolina , Ferrari‐Souza João Pedro , Zalzale Hussein , Bellaver Bruna , Rohden Francieli , Abbas Sarah , Leffa Douglas Teixeira , Schilling Lucas Porcello , Zimmer Eduardo R. , Tudorascu Dana , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , Soleimani‐Meigooni David N. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick Ali
Published: January 2025

Background

Recent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer’s disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum. We hypothesize that tau plays a comparatively greater effect on the emergence of psychotic symptoms compared to other NPS domains.

Method

We assessed 56 individuals (21 cognitively unimpaired (CU), 23 MCI, and 12 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. We selected individuals with an NPI‐Q total score ≥1. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as reference region. Leave‐one‐out voxel wise and linear regression tested the association between each NPI‐Q domain and biomarkers accounting for age, sex, cognitive status, and study site.

Result

CI individuals had significantly higher NPI‐Q score and Braak VI PET SUVR than CU individuals (Table 1). NPI‐Q score was significantly associated with tau‐PET in the periRolandic and supplementary motor cortex (Figures 1A). Linear regression showed that NPI‐Q associates with tau‐PET in the Braak stage VI (Figure 1B). Leave‐one‐out regression analysis revealed that delusions, motor disturbances, and anxiety contributed most to the association between tau‐PET and NPS (Figure 2A, C). These domains presented a higher magnitude of association compared to each other NPI‐Q domain (Figure 2B). Notably, irritability, agitation, and disinhibition exerted a negative effect to the association, emphasizing that tau may not play a role in the development of these symptoms (Figure 2A, D)

Conclusion

Our study supports previous evidence suggesting that irritability and agitation may not be triggered by tau, but rather by other pathological process such as neuroinflammation. These findings provide additional rationale for the therapeutics aiming to mitigate irritability and agitation in AD patients.
Visual imagery ability in the continuum of Alzheimer’s disease: the mind’s eye compared in patients with MCI and early AD
Authors: Gabrielli Giulia Bechi , Margiotta Roberta , Panigutti Massimiliano , D'Antonio Fabrizia , Vita Antonella Di , Boccia Maddalena , Palermo Liana , Piccardi Laura , Sepe‐Monti Micaela , Talarico Giuseppina , Salati Emanuela , Bruno Giuseppe , Guariglia Cecilia
Published: January 2025

Background

Visual Mental Imagery (VMI) is the ability to represent stimuli in the mind without sensory visual input. Previous studies have shown alterations in visual imagery in Alzheimer’s disease (AD). However, VMI has not been investigated in the AD prodromal stage, i.e., the Mild Cognitive Impairment (MCI). In this study, we aimed to investigate the VMI ability in AD and MCI patients. We hypothesized that VMI ability could be compromised from the early disease stage.

Method

For our purpose, we enrolled 14 patients with a diagnosis of probable typical AD, 19 amnestic MCI (aMCI), and 23 healthy control subjects (HC), matched for sex, age, and education; MMSE scores in AD patients significantly differed from those in aMCI and HC, that not differed between them. The extensive assessment of VMI included: 1) the O’Clock test that allows disentangling the possible role of visuo‐perceptual difficulties in the VMI task’s performance; 2) a modified version of The Complete Visual Mental Imagery Battery (CVMIB), including tasks evaluating the different VMI processes (Kosslyn, 1980; 2005), that is generation, maintenance, inspection and transformation of different types of visual mental images (i.e., objects, buildings and faces).

Result

Results indicated that AD patients performed worse than HC in both perceptual and imaginal tasks of the O’Clock test and in all CVMIB’s tasks but maintenance. On the contrary, aMCI patients showed difficulties in the generation process and the imaginal task of the clock test.

Conclusion

Our findings suggested that generation, inspection and transformation processes of VMI are impaired since the early phase of Alzheimer’s disease. Moreover, we found that the generation process is selectively impaired in aMCI patients, demonstrating that VMI deficits are already present in the prodromal stage of the disease. Since alterations in VMI processing might reflect the AD neuropathological progression, according to Braak and Braak’s model, VMI abilities might represent a useful neuropsychological marker of dementia to identify AD prodromal stage.
Moderators of language change in middle‐aged and older adults. Preliminary results of the Compostela Aging Study
Authors: Facal David , Lojo‐Seoane Cristina , Felpete Alba , Campos‐Magdaleno Maria , Fernández‐Feijoo Fátima , Varela‐López Benxamin , Stern Yaakov , Rozas Arturo X. Pereiro
Published: January 2025

Background

Although there is evidence that measures of verbal fluency, naming and word memory can be good predictors of progression to dementia, language change and the main variables predicting it are not yet fully characterized. Recent research draws attention to the need to consider cognitive reserve, functional, and neurobiological indicators together to explain changes (Facal et al., 2021).

Method

The study sample was drawn from the participants of the Compostela Aging Study who completed the third and fourth follow‐up assessments, with about 18 months between assessments. Sample included 24 persons with MCI, 42 with subjective cognitive decline and 41 cognitively unimpaired participants. Language performance was assessed via Boston naming test, semantic, phonemic, and ideational fluency. The difference in performance between the assessments (T4‐T3) was calculated. General linear regression (GLR) models were developed, including the change in each language variable as dependent, and years of education, gait speed (timed‐up and go test), grip strength and mean cortical thickness in the left and right hemispheres as covariates.

Results

Though cross‐sectional differences were found in the four language measures, no differences were found in language change measures (Figure 1). The GLR model with the Boston naming test as the dependent variable was the only significant (F = 5.52, p< .01, η2 = 0.26, B‐1 = 0.99). Of the five covariates included in the model, grip strength was significant (F = 21.17, p< .01, η2 = 0,21, B‐1 = 0.99).

Conclusion

Naming tests can be good markers of linguistic change in the continuum from healthy cognitive aging to dementia (Flores‐Vázquez et al., 2022). Although this is a first approximation, and 18 months can be a too short time to register significant changes, this work stress the importance of jointly analyzing cognitive reserve, functional and neurobiological predictors.

References:

Facal, D., Burgo, C., Spuch, C., Gaspar, P. & Campos‐Magdaleno, M. (2021) Cognitive Frailty: An Update. Frontiers in Psychology 12,813398. https://doi.org/10.3389/fpsyg.2021.813398

Flores‐Vázquez, J.F., Contreras‐López, J.J., Stegement, R., Castellanos‐Maya, O., Ćurčic‐Blake, B., Andrés, P., Sosa‐Ortiz, A.L., Aleman, A., Enriquez‐Geppert, E. (2022). Extended FNAME performance is preserved in subjective cognitive decline but highly affected in amnestic mild cognitive impairment. Neuropyshology 37, 6, 650‐660. https://doi.org/10.1037/neu0000874
Longitudinal trajectories of passively monitored instrumental activities of daily living and high frequency digital cognitive assessment differ between cognitively normal and mild cognitively impaired older adults
Authors: De Vito Alyssa N. , Liu Yan , Ju Catherine H. , Wu Chao‐Yi , Lee Samuel Y. , Eichten Alyssa , Cohen Anael Kuperwajs , Beattie Zachary T. , Dodge Hiroko H. , Ferguson John E. , Hughes Adriana M.
Published: January 2025

Background

Traditional cognitive and daily functioning measures that utilize episodic assessment schedules are less sensitive to subtle within‐person change in those at risk for Alzheimer’s disease (AD). This study aimed to evaluate whether longitudinal trajectories of high frequency cognitive assessments (HFA) and passively assessed higher order instrumental activities of daily living (IADLs) differ between those with intact cognition (CN, n = 59) and mild cognitive impairment (MCI, n = 45). An exploratory aim evaluated whether the use of person‐specific distributions would detect differences in longitudinal trajectories not captured by traditional between‐group analyses.

Method

Longitudinal trajectories of six individual sensor features, three cognition/IADL domain factors, and one IADL composite measure were evaluated using mixed‐effects models with a random intercept, cognitive status (CN vs. MCI), time, and a cognitive status x time interaction as fixed effects. Person‐specific distributions were evaluated using logistic mixed‐effects models to examine the likelihood that IADL measures fell below or above person‐specific thresholds derived from the 90‐day baseline monitoring period. A change from baseline performance was indicated if a participant’s score fell below their person‐specific 10th, 20th, 30th, 40th, or 50th percentile or if a participant’s performance fell above their person‐specific mean, mode, 60th, 70th, 80th, or 90th percentile. Exploratory analyses that fit person‐specific distributions along a continuous outcome were also conducted.

Result

Mixed effects models found longitudinal group differences for time to complete Trail Making Test B and the discrepancy between subjectively reported and objectively assessed pillbox use. See Table 1 for analysis results. Models that used person‐specific distributions identified differences in longitudinal trajectories for time to complete Trail Making Test B and the Stroop Test, the number of clicks on the Stroop Test, and subjective‐objective discrepancies in pillbox use between groups. See Figure 1 for exploratory analyses that used person‐specific distributions with a continuous outcome.

Conclusion

HFA and passively monitored IADLs demonstrate longitudinal differences between older adults with intact cognition and those with MCI. Models that utilized person‐specific distributions identified longitudinal group differences in additional features not captured by traditional between‐group analyses. HFA approaches that use individualized distributions have potential to create more reliable and sensitive disease monitoring for AD.
Usefulness of the Visual Cognitive Assessment Test in Detecting Vascular MCI in a Southeast Asian Cohort
Authors: Tanoto Pricilia , Ye Hannah En , Vipin Ashwati , Leow Yi Jin , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Chong Wayne Freeman , Seah Eunice Limin , Azam Mohammed Adnan , Sandhu Gurveen Kaur , Zailan Fatin Zahra , Tan Farid Tan Bin Hasyim , Kandiah Nagaendran
Published: January 2025

Background

Visual Cognitive Assessment Test(VCAT) is a visual‐based cognitive evaluation tool which can be administered to multilingual populations without translation. VCAT has shown to be effective in differentiating mild cognitive impairment(MCI) from cognitively normal and useful for diagnosing MCI and mild AD(Kandiah et al., 2016). However, whether VCAT is also useful for differentiating between vascular and non‐vascular MCI remains to be explored.

Method

604 non‐demented participants were recruited from the community as part of the Southeast Asian Biomarker and Cognition Study, Singapore(BIOCIS). All participants completed a comprehensive neuropsychological battery, including VCAT, Rey Auditory Verbal Learning(RAVLT) Delayed, and Color Trails 2(CT2). Classification of MCI was based on Petersen’s criteria(Petersen et al., 2001). Participants also underwent neuroimaging using a 3T MRI scanner. T1‐weighted and fluid‐attenuated inversion recovery MRI was used for white matter hyperintensity visual ratings as per the modified Fazekas scale (Vipin et al., 2021). Participants with Fazekas total score of 5 and above were classified as the vascular group. Therefore, participants were divided into three groups: Cognitively Normal without cerebrovascular disease(NV‐CN), Non‐Vascular MCI(NV‐MCI), and Vascular MCI(V‐MCI) and their tests mean scores and cerebral perfusion were compared. Additionally, all neuropsychological tests and perfusion were compared in differentiating between NV‐CN and V‐MCI.

Results

Participant demographics included a mean age of 60.34 years±10.76, Male 44%, and mean education years of 14.44 years±3.71. After adjusting for age and education years, mean of neuropsychological test, perfusion scores were significantly different between the three groups(p < 0.05). Tukey HSD post‐hoc test showed pairwise differences between all groups, except for perfusion scores(Table 1). ROC analysis was conducted to explore the discriminative performance of VCAT in differentiating between CN and V‐MCI. The analysis indicated an AUC of 0.74 with the optimal VCAT cut‐off for differentiating between CN and V‐MCI as 25.5 with specificity 0.85 and sensitivity 0.48. In an additional ROC analysis, we compared the discriminative properties of VCAT, RAVLT Delayed, CT2 and Perfusion.

Conclusion

The results of our study suggest that VCAT is useful in discriminating between CN and V‐MCI, especially in comparison to other neuropsychological tests and perfusion. Future longitudinal studies are needed for further investigation.
Beyond Traditional Measures: Exploring Cognitive Intraindividual Variability in Traumatic Encephalopathy Syndrome
Authors: Altaras Caroline , Ly Monica T. , Barr William B. , Banks Sarah , Wethe Jennifer V. , Tripodis Yorghos , Adler Charles , Balcer Laura , Bernick Charles B. , Cantu Robert C. , Dodick David W. , Mez Jesse , Palmisano Joseph N. , Martin Brett , Cummings Jeffrey L. , Reiman Eric M. , Shenton Martha E. , Stern Robert A. , Katz Douglas I , Weller Jason , Geda Yonas E. , Alosco Michael L.
Published: January 2025

Background

Traumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto‐subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures.

Method

The sample included former American football players (120 professional, 60 college); participants were males, aged 45‐74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table‐1): (1) No‐TES (n = 62); (2) TES‐CTE Suggestive (n = 35); (3) TES‐CTE Possible (n = 21); (4) TES‐CTE Probable (n = 54). TES‐CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T‐score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race.

Result

Results showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES‐CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES‐no (M = .192, SE = .008, p<.001) and TES‐CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES‐no and TES‐CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293).

Conclusion

The TES‐CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18‐19% in TES‐no and TES‐CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.
The association between focal prefrontal cortical atrophy and accelerated long‐term forgetting in presymptomatic autosomal dominant Alzheimer’s disease
Authors: Young Chloe , Fraser Maggie R , Lu Kirsty , O'Connor Antoinette , Crutch Sebastian J , Fox Nick C , Weston Philip SJ
Published: January 2025

Background

Accelerated long‐term forgetting (ALF) is a form of episodic memory impairment where information is retained normally over 30‐60 minutes but lost at an accelerated rate over subsequent days to weeks, and is a very early – perhaps the earliest – cognitive change in both autosomal dominant and sporadic Alzheimer’s disease (AD). However, the neuroanatomical changes underlying ALF in AD have remained elusive. We explored associations between ALF and focal cortical thickness in presymptomatic autosomal dominant AD (ADAD).

Method

Eighteen asymptomatic ADAD mutation carriers (mean estimated years to symptom onset = 7.3) (SD = 4.4) and twelve non‐carrier controls underwent ALF testing for three tasks (list, story, figure). After learning, recall was tested at 1) 30 minutes and 2) seven days. ALF score was calculated as 7‐day recall/30‐minute recall. T1‐weighted MRI was acquired at baseline and annually over five years. Cortical thickness was estimated using FreeSurfer. Thirteen regions of interest were selected based on either a known vulnerability to AD‐related neurodegeneration or a known role in memory. Serum NfL– a neurodegeneration marker– was measured on the single molecule array platform. Spearman coefficients explored associations between ALF and 1) focal baseline cortical thickness, 2) future rates of thinning, and 3) serum NFL.

Result

Across all three tasks, ALF scores were significantly lower in mutation carriers than non‐carriers, despite no difference at 30‐minutes. In mutation carriers, verbal ALF (list and story) was associated with lower baseline cortical thickness in the prefrontal cortex (PFC) across four contiguous regions bilaterally (p<0.001 for each). This association was not present in non‐carriers. No associations were found between ALF and the thickness/volume of medial temporal lobe (MTL) structures. ALF was predictive of future cortical thinning across AD vulnerable regions. Higher serum NFL was associated with poorer long‐term list recall. Forgetting at 30 minutes was not associated with cortical thickness or NfL, i.e. associations were specific to ALF.

Conclusion

ALF is an early presymptomatic marker of AD‐related cognitive decline, underscored by changes in the PFC but not the MTL. These findings advance our understanding of the neuroanatomical substrate of early AD memory decline. ALF could be used as a biologically relevant measure in future presymptomatic trials.
Uncovering the Role of an African‐specific ABCA7 Frameshift Deletion on Lipid Metabolism and Alzheimer’s Disease
Authors: Nam Younji , DeRosa Brooke A. , Golightly Charles G. , Simon Shaina A. , Arvizu Jamie , Ramirez Aura M , Whitehead Patrice L. , Adams Larry D. , Starks Takiyah D. , Cukier Holly N. , Cuccaro Michael L. , Haines Jonathan L. , Byrd Goldie S. , Beecham Gary , Dykxhoorn Derek M. , Young Juan I , Vance Jeffery M. , Pericak‐Vance Margaret A.
Published: January 2025

Background

We previously identified a 44‐base pair deletion in (ATP‐binding cassette sub‐family A member 7) (ABCA7) that is significantly associated with Alzheimer’s disease (AD) in African Americans (AA), producing a frameshift mutation resulting in a truncated protein (p.Arg578Alafs). ABCA7 is a lipid transporter across cellular membranes. While we have shown the mutant mRNA is present in neurons, whether it is translated into a stable protein is not known due to the lack of antibodies capable of recognizing the N‐terminus of endogenous ABCA7. The abrupt ABCA7 translation due to the deletion may alter the lipid metabolism, which can be investigated using isogenic iPSC and differentiated models.

Methods

We analyzed single‐cell RNAseq (scRNAseq) data from spheroid cultures of 12 individuals. We generated a recombinant version of the ABCA7 gene with and without the deletion and bearing an N‐terminal flag tag which were transfected into HEK cells. We utilized CRISPR‐based genome editing using induced pluripotent stem cell (iPSC) lines from three independent AA‐cognitively unimpaired individuals (WT) to introduce the AA‐specific ABCA7 homozygous or heterozygous deletions. These were differentiated using standard protocols in the HIHG iPSC core into monocultures of induced neuron‐like cells. C‐terminal antibodies were used to assess the presence of native ABCA7 in HEK cells.

Results

Examination of HEK cells revealed no detectable native ABCA7. The truncated ABCA7‐tagged protein appeared stable and localized in the plasma membrane as seen for the wild‐type protein (Figure 1). ScRNAseq confirmed that expression of ABCA7 is highest in neurons, identifying them as the iPSC differentiated cell of choice. We successfully generated both homozygous and heterozygous deletion isogenic lines in the three WT iPSC lines. Differentiated neurons from these isogenic lines have a normal phenotype, allowing for functional assays and lipidomic studies.

Conclusion

The truncated protein p.Arg578Alafs appears to be expressed and stable in HEK cells, and surprisingly located in the plasma membrane despite the absence of most transmembrane domains. Our three isogenic iPSC pairs will be a great resource for studying the pathogenic effects of the ABCA7 truncation in differentiated cells.
Recruitment Efforts for the study “Development and Validation of TeleNeuropsychology Normative Data for Older Adults”
Authors: Perez‐Lao Ambar R , Ying Gelan , Marra David E , Santos Lauren , Arias Franchesca , Smith Glenn E.
Published: January 2025

Background

Remote administration of well‐established neuropsychological instruments (TeleNeuropsychological or TeleNP) can reduce assessment wait times and expand access to cognitive assessments for medically compromised and socially disadvantaged patients. A major limitation in the widespread uptake of TeleNP relates to the need for more normative data compared to in‐person assessments. This presentation describes a novel ascertainment strategy used in Florida’s Older Adults TeleNeuropsychology (FLOAT) project to identify and recruit “cognitively healthy” older adults to norm well‐established neuropsychological instruments administered remotely. This abstract summarizes recruitment efforts during Phase I and II of this study.

Method

We utilize a previously developed machine learning algorithm to identify participants aged 50+ with a low‐to‐high probability of developing Alzheimer’s disease and related dementias (ADRD). We select those with low probabilities for invitation to participate. Prospective participants with severe psychiatric disorders (i.e., schizophrenia, bipolar disorder) or no internet access are excluded. About 7000 prospective participants between 51 to 104 years of age from the OneFlorida Data Repository were identified. Phases I and II used email to reach participants ages 60‐79 with the lowest ADRD risk.

Result

Of the 5112 persons eligible for Phases I and II, 606 participants did not include emails in their contact information. Of those contacted, 4,347 did not respond to the first outreach contact, 55 declined to participate, and three did not meet the study criteria. Overall, 107 agreed to participate, and 30 are currently enrolled. As recruitment waves continue, these numbers will include participants aged 50‐59 and 80+.

Conclusion

FLOAT incorporates machine‐learning‐based informatics to efficiently identify a robust sample of cognitively healthy older adults to norm a TeleNP protocol. Our initial affirmative response rate (2.4%) is promising. Additional strategies to improve response and enrollment rates are underway. New methods to leverage the algorithm while enriching the cohort for underrepresented groups are being explored and discussed, and preliminary normative data will be presented. Recruiting older adults for norm development is resource‐intensive and requires efficient yet flexible methods.
Rapid Identification of Patients with Rapidly Progressive Dementia
Authors: Piura Yoav D , Tipton Philip W , Dunham S Richard , Satyadev Nihal , Graff‐Radford Neill R , Day Gregory S
Published: January 2025

Background

Patients with the precipitous onset of cognitive symptoms (i.e., suspected rapid progressive dementia [RPD]) may continue to decline (true RPD) or may stabilize or improve (non‐RPD). Recognizing patients with RPD early in the disease course is important to support clinical care and enrollment in research.

Method

Patients referred for the evaluation of suspected RPD were prospectively enrolled and followed for up to 2 years at Mayo Clinic in Florida (Jacksonville, FL; Jan‐2020 – Oct‐2023) and Washington University in St. Louis (Saint Louis, MO; Jun‐2016 – Dec‐2019). Clinical data were independently reviewed by two dementia specialists who established clinical diagnoses, referencing published criteria. Patients were diagnosed with RPD if they progressed to dementia (global Clinical Dementia Rating® [CDR] ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. Univariate statistics compared demographics, clinical details, and test results between patients with RPD and non‐RPD. Variables with p<0.1 were entered into a multivariate logistic regression model to identify factors associated with RPD.

Result

Of 248 patients referred for suspected RPD, 187 (75.4%) met stated criteria for RPD. Patients with RPD were older (62.6±14.4 years vs 55.0±18.3 years; p<0.001), and more likely to be diagnosed with Alzheimer disease or related dementias (28.3% vs 9.8%; p = 0.003) or Creutzfeldt‐Jakob (19.1% vs 4.6%; p = 0.008). Non‐RPD cases were more often attributed to autoimmune/inflammatory disease (42.6% vs 29.4%, p = 0.061) or other causes (e.g., psychiatric, neoplasms, toxic/metabolic; 34.4% vs 16.6%, p = 0.006). After controlling for age, hallucinations (OR, 2.81; 95%CI: 1.21‐6.52), elevated CSF protein (OR, 2.43; 95%CI: 1.17‐5.03), and CSF white blood cell count <5 cells/mm3 (OR, 2.77; 95%CI: 1.32‐5.85) were independently associated with RPD. Cortical visual loss (15/183, 8.2%) and substantial brain atrophy on MRI (27/184, 14.7%) were specific to patients with RPD, representing additional distinguishing features.

Conclusion

Hallucinations, cortical visual loss, substantial atrophy on MRI, elevated CSF protein, and normal CSF white blood cell count were independently associated with RPD. Early detection of these features in patients with suspected RPD may inform clinical care and enrollment in research studies of RPD.
New psychometric analysis and normative data for the Argentinean Psycholinguistic Naming test in color: PAPDIC
Authors: Vivas Leticia , Manoiloff Laura , Paolantonio Patricia , Lamenza Miguel Horacio , Aragones Carla Andrea , Moreno Maria Celeste López
Published: January 2025

Background

Naming test are a very common tool in neuropsychological batteries. Some years ago, the Argentinean Psycholinguistic Naming test was developed, first with black and white drawings (Manoiloff et al., 2018) and then in colors (PAPDIC) (Vivas et al., 2020). Items were selected and organized on the basis of Argentinean psycholinguistic norms. At that time evidence of validity was reported (concurrent validity and contrasted groups analyses). Here we present new psychometric analysis and normative data for the Argentine population.

Method

The sample comprised 292 participants: 195 healthy, 70 MCI, 14 stroke patients without aphasia and 13 stroke patients with aphasia. They went through a complete neuropsychological battery to ensure that no other cognitive function alteration (apart from language) could interfere with the task. Items were rated as dichotomous responses, and the final score only included those correct responses given before the phonological cue.

Result

o assess the test’s internal consistency a KR20 analysis was performed (as items were dichotomous) which showed a value of .879. Besides, a one factor ANOVA was performed to compare the full test score between groups and significant differences were observed (F(3,288) = 51.867; p < .001). Particularly, healthy participants differentiate from the MCI (p < .001) and stroke with aphasia (p < .001) groups, but no with stroke patients without aphasia (p = .133). Another comparison was performed between this version of the test and a previous black and white version by a chi‐squared analysis with each item, and it showed a similar performance for 24 items, a better performance in the color version for 5 items and a worse performance in one item. Additionally, a regression analysis was performed in order to obtain normative data for the Argentine population. As age was the only demographic variable that showed significant effect on the test score (R2 adjusted = .140; F(1,192) = 32.545; p < .001), it was considered for this calculus.

Conclusion

These results show that the PAPDIC is a reliable naming test for the Argentine population that can be used both for patients with neurodegenerative diseases and post stroke aphasia.
The role of common structural variants in Alzheimer’s disease
Authors: Lee Songmi , Xia Rui , English Adam C , Peloso Gina M. , Bis Josh , Lin Honghuang , Choi Seung Hoan , Heard‐Costa Nancy , DeStefano Anita L. , Sedlazeck Fritz J , Fornage Myriam
Published: January 2025

Background

Structural variants (SVs), genomic alterations exceeding 50 base‐pairs, are known for their significant impact on disease pathology. However, the role of SVs in Alzheimer’s Disease (AD) remains unclear. Using a novel high‐accuracy SV calling pipeline, we analyzed a diverse sample from the Alzheimer’s Disease Sequencing Project (ADSP). Our study investigated the role of SVs in known AD loci, providing insights into the genetic architecture of AD.

Methods

We included samples from ADSP 17K whole genome sequence data. SV discovery was performed using Biograph SV caller that leverages an assembly‐based method and graph‐based representation. After quality filtering at the sample‐ and variant‐ levels, there were 68,831 segmented deletions, 25,281 insertions, and 198 inversions with minor allele frequency > 1% in 11,890 individuals (5,585 cases and 6,305 controls). We focused on common SVs in linkage disequilibrium (LD) (R2 > 0.2) with 124 SNPs tagging known AD loci derived from previous genome‐wide association studies of AD. LD was calculated using PLINK 1.9. Association analyses of AD status were performed for each identified SV adjusting for sex, technical covariates, associated principal components, and familial relatedness using GENESIS.

Results

We identified 15 deletions and 3 insertions in LD with 12 SNPs tagging known AD loci (Table). Of these, 9 SVs and 8 tagging SNPs showed nominal associations with AD (P<0.10) in the ADSP sample. The strongest AD associations were with two deletions located in an intron of KANSL1, in moderate LD (R2 = 0.65) with a SNP tagging the MAPT haplotype, which is known to associate with multiple neurodegenerative diseases including AD. Several SVs were in high LD with SNPs tagging AD loci. Notably, a 319‐bp deletion (R2 = 0.97) in the TPCN1 locus overlapped fully with a known 309‐bp deletion known to be associated with Lewy Body dementia. A 322‐bp Alu deletion in exon 8 of TMEM106B, previously identified through long‐read sequencing, also demonstrated strong LD with two AD‐related SNPs (R2 = 0.91 and 0.89, respectively).

Conclusion

Using a novel SV calling pipeline, we identified multiple AD‐related SVs, which provides additional insights into the genetic architecture of AD. Integration of omics data is warranted to explore the functional impact of these SVs.
The heterogeneity of regional cortical atrophy in early Alzheimer’s disease
Authors: Page Frederick A , Suseelan Shayam , Kulkarni Gayatri , Nowell Joseph , Edison Paul
Published: January 2025

Background

Cortical atrophy in Alzheimer’s disease (AD) is typically thought to commence in the medial temporal lobe. However, growing evidence suggests that this may not be true for all patients. Here, we explored atrophy patterns in patients with mild cognitive impairment (MCI) and AD and whether atrophy patterns are associated with specific clinical and neuropathological outcomes.

Methods

1124 AD and MCI patients were selected from the Alzheimer’s Disease Neuroimaging Initiative. Baseline 3T magnetic resonance imaging scans were processed for all patients who were then subtyped based on regions of predominant atrophy. Baseline cognitive performance and rates of cognitive decline over one year were compared between atrophy subtypes. Regional tau pathology was also evaluated with [18F] AV1451 positron emission tomography.

Results

The following atrophy subtypes were identified: medial‐temporal dominant, frontal‐dominant, parietal‐dominant, diffuse, and occipital‐dominant. Baseline cognitive performance and tau were indicated to differ between subtypes.

Conclusion

Initial cortical atrophy in AD and MCI may be highly heterogeneous. Additionally, since atrophy subtypes showed unique cognitive performances and tau distributions, they may respond differently to treatment. This study provides grounds for an increased research focus on cortical atrophy in regions outside the medial temporal lobe, especially the parietal lobe.
Degradation of gaze‐speech synchronization due to mild cognitive impairment in picture description tasks
Authors: Kleiman Michael J. , Galvin James E
Published: January 2025

Background

When performing a picture description task, healthy individuals tend to look only briefly at a target before beginning its description, after which they move promptly onto the next target. This sequence may be disrupted in those with cognitive impairment. Just as cognitively impaired individuals produce greater numbers of disfluencies and pauses, those with mild cognitive impairment (MCI) may delay speech production by extending their gaze behavior towards a target before beginning its description.

Method

To explore this, we examined the gaze and speech behavior of 39 participants (27 HC, 12 MCI) while engaging in the Cookie Theft picture description task. Transcriptions with word‐level timings were generated using OpenAI’s Whisper in combination with the whisper‐timestamped Python package utilizing Dynamic Time‐Warping for more accurate timestamps with reduced hallucinations. Gaze was collected using a Tobii Pro Spectrum 300Hz eye tracker and processed using custom‐developed fixation filters, with gaze target timing identified as the first full fixation directed towards that area of interest. Speech timing was determined as the beginning of the sentence containing the target description.

Result

MCI participants initiated speech production after a longer delay following target fixation than HC participants, and produced shorter and less descriptive responses. Gaze behavior was also more sluggish in MCI participants; visits onto targets were less frequent and longer, and saccadic movements between targets were less frequent.

Conclusion

The intersection of gaze and speech behavior is a potentially powerful avenue for identifying early‐stage cognitive impairment, but is currently under‐utilized. Future research in gaze‐speech synchronization may identify patterns that could target biomarker‐confirmed preclinical Alzheimer’s disease.
Sex differences in familial forms of frontotemporal dementia
Authors: Memel Molly B , Staffaroni Adam M. , Illán‐Gala Ignacio , Kornak John , Saloner Rowan , VandeBunte Anna M. , Paolillo Emily W. , Cadwallader Claire J. , Chen Coty , Gendron Tania F , Heuer Hilary W. , Forsberg Leah K. , Boeve Brad F. , Boxer Adam L. , Rosen Howard J. , Casaletto Kaitlin B. , Consortium ALLFTD
Published: January 2025

Background

Sex differences in neurodegenerative diseases can impact accurate diagnosis and management. Emerging data suggest there may be sex differences in frontotemporal dementia (FTD) prevalence and clinical manifestation. However, prior studies lacked longitudinal assessment and were limited in capturing sex differences in earliest stages of disease (e.g., preclinical). We evaluated how sex impacts longitudinal clinical outcomes in individuals carrying autosomal dominant variants for FTD.

Method

337 participants carrying pathogenic variants in MAPT, GRN, or C9orf72 completed longitudinal evaluations (2.4 average visits, range = 1‐6), including neuropsychological and functional assessments, and plasma analyzed for neurofilament light chain (NfL). FTLD Clinical Dementia Rating Scale (FTLD‐CDR) classified disease stage at study entry (FTLD‐CDR = 0: asymptomatic; FTLD‐CDR = 0.5: MCI; FTLD‐CDR> 0.5: Dementia). Linear mixed‐effects models evaluated the effect of sex on longitudinal clinical trajectories, including the effect of disease stage at study entry.

Result

Male and female carriers were similarly distributed with respect to baseline demographics and most clinical outcomes. However, women exhibited higher baseline NfL than men. Not accounting for disease stage, men and women did not show statistical differences on cognitive, functional, or NfL trajectories. However, when accounting for disease stage, there was a significant interaction between baseline disease stage, sex, and time on cognitive, NfL, and functional trajectories. While sex differences were not statistically significant among asymptomatic carriers, women with MCI/dementia evidenced more rapid cognitive, NfL and functional decline over time compared to men. To evaluate the role of pathology burden, we tested the interaction between baseline NfL, sex, and time on clinical outcomes stratified by disease stage. In asymptomatic participants, women showed an attenuated adverse relationship between baseline NfL and clinical trajectories compared to men. No statistically significant sex differences were evident in the relationship between baseline NfL and clinical outcomes in participants with MCI/dementia.

Conclusion

In familial FTD, women evidenced steeper clinical declines than men after symptom onset. Accounting for pathology, baseline NfL was a stronger predictor of clinical decline in asymptomatic men compared to women. NfL may be a less sensitive prognostic tool for clinical progression in women with FTD, particularly early in disease. This may reflect early “cognitive resilience” to neurodegeneration in women.
“Systematic Review of Brief Cognitive Screening Tools for Identifying Dementia and Mild Cognitive Impairment in Illiterate and Low‐Educated Populations”
Authors: Zegarra‐Valdivia Jonathan Adrian , Chino‐Vilca Brenda Nadia , Tituana Kuripacha Alcamari , Zapata‐Restrepo Lina Maria , Unaucho Pilalumbo Maria M. , de Jesus Lopez Norori Milton Gerardo , Manrique Carmen Paredes , Custodio Nilton
Published: January 2025

Background

The increasing prevalence of dementia, particularly in low‐income regions, necessitates the development of effective cognitive screening methods. However, the suitability of many existing tools for illiterate and low‐educated populations is limited, resulting in significant diagnostic disparities. This review aims to evaluate global cognitive assessment instruments for the identification of Mild Cognitive Impairment (MCI) and dementia in older adults with limited education.

Method

Following the guidelines outlined by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses), a systematic review was conducted. This review encompassed searches across three databases for studies published between 2000 and 2023, with a focus on individuals aged 45 and above. Out of 1511 studies screened, 26 studies met the predefined inclusion and exclusion criteria.

Result

Numerous studies have endeavored to adapt existing cognitive assessment tools to local languages to suit low‐literacy populations. Within this group, twelve distinct tests were identified. Notably, while the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are frequently used, they exhibit a notable bias towards education levels. The Rowland Universal Dementia Assessment Scale (RUDAS) exhibited strong performance, particularly among individuals with limited education, displaying high sensitivity and specificity.

Conclusion

In summary, adjusting cutoff scores can be a valuable strategy for assessing individuals with limited education, but the development of customized cognitive assessment tools is imperative. The creation of region‐specific, sensitive cognitive evaluations, encompassing functional assessments, is pivotal to achieving a comprehensive diagnostic evaluation.
Phenotypic characterization of a novel hAb‐KIloxP;hAPOE4;Trem2R47H_NSS mouse model
Authors: Gomez‐Arboledas Angela , Kramár Enikö , Kawauchi Shimako , Da Cunha Celia , Lu Yueh Hao , Milinkeviciute Giedre , Neumann Jonathan , Wood Marcelo A , Tenner Andrea J , LaFerla Frank M , MacGregor Grant R , Green Kim N.
Published: January 2025

Background

Genome‐Wide Association Studies (GWAS) identified ApoE4 and Trem2*R47H as two of the strongest genetic risk factors for late‐onset Alzheimer’s Disease (LOAD). As part of our efforts to develop mouse models that better recapitulate LOAD, at Model Organism Development & Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) consortium at University of California – Irvine, we have created a triple homozygous mouse model that combines our previously developed hAb‐KIloxP mice (Jackson Lab #031050), Trem2R47H NSS (Jackson Lab #034036) and a humanized ApoE4 (Jackson Lab #027894), to evaluate the interactions between aging, hAPOE4, TREM2*R47H, and hAb.

Method

By breeding the hAb‐KIloxP, hApoE4 and Trem2R47H NSS, we obtained triple homozygous (HO) mice and we then generated four different groups: WT (C57BL6/J), hAb‐KIloxP HO, hAb‐KIloxP HO;hApoE4 HO and hAb‐KIloxP HO;hApoE4 HO;Trem2R47H NSS HO. All four groups were then aged to 4, 12, 18 and 24 months of age, when coronal hippocampal slices were prepared, and long‐term potentiation recordings were obtained. Additionally, we also measured soluble and insoluble Ab40 and Ab42 as well as plasma neurofilament light chain (NfL).

Result

hAb‐KIloxP mice showed a significant reduction in mean potentiation 50‐60 minutes post TBS, when compared to WT mice at 4, 12, 18 and 24 months of age, indicative of an LTP deficit associated to human Ab. Interestingly, both hAPOE4 and Trem2R47H NSS variants completely prevent the LTP deficits observed on the hAb‐KIloxP mice from 4 months of age. In addition, cortical soluble Ab40, Ab42 and the Ab42/Ab40 ratio were significantly decreased in hAb‐KIloxP;hAPOE4 and hAb‐KIloxP;hAPOE4;Trem2R47H NSS mice at 24 m of age, when compared to hAb‐KIloxP. However, plasma NfL levels were significantly increased in hAb‐KIloxP;hAPOE4;Trem2R47H NSS mice at 24 months of age, indicative of axonal damage in this mouse model.

Conclusion

hAb induces robust LTP deficits that are prevent by either hAPOE4 or TREM2*R47H, contrary to expectations. However, hAPOE4 and Trem2R47H NSS variants have a cumulative detrimental effect on axonal damage when combined with aging.