bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropsychiatric Symptoms and Neuropathological diagnoses of Alzheimer’s Disease and Related Dementias
Authors: Devanand Davangere P. , Lee Seonjoo , Huey Edward D , Goldberg Terry E.
Published: December 2022

Background

The associations of Alzheimer’s disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) is not well‐established.

Method

This retrospective cohort study used 1,808 brains from 39 sites in the National Alzheimer’s Coordinating Center (NACC) V.10 collection for participants with the Neuropsychiatric Interview‐Questionnaire (NPI‐Q) administered annually and without consideration of clinical diagnosis. Brain autopsy diagnoses of AD, Lewy Body Disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration (FTLD), cerebrovascular disease (CVD), hippocampal sclerosis, and “no known pathology” were examined. NPI‐Q domain score if present at any timepoint was the primary outcome and average NPI‐Q domain score during follow‐up was secondary. The associations of ADRD diagnoses with twelve NPI‐Q symptom domains were examined in regression analyses, correcting for multiple comparisons.

Result

The study sample of 1,808 adults had a mean [SD] age 80.0 [11.0] years and 54.6% were male. Apathy was the most prevalent NPS, reaching 80% in hippocampal sclerosis. CVD showed few NPS associations. FTLD was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared to AD. Hippocampal sclerosis was associated with increased apathy (OR 2.60, 95%CI 1.86‐3.66, pfdr<.05) and disinhibition (OR 2.15, 95% CI 1.63‐2.84, pfdr<.05). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was associated consistently with increased NPS, e.g., LBD showed increase in hallucinations from brainstem (β=0.23, 95% CI 0.07‐0.76, p<.05) to limbic (β=1.69, 95% CI 1.27‐2.27, p<.01) to neocortical (β=4.49, 95% CI 3.27‐6.16, p<.001) pathology. Hallucinations were more common in participants with AD+LBD (168/534=31.5%) compared to AD without LBD (152/704=21.6%) and LBD without AD (23/119=19.6%).

Conclusion

Visual hallucinations may characterize LBD with AD more than LBD without AD. NPS criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported. In hippocampal sclerosis, the novel findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was related to NPS severity, indicating that NPS reflect underlying ADRD pathology and highlight the importance of diagnosing and treating NPS.
Risk and protective factors for dementia: epidemiological evidence and windows of opportunity
Authors: Suemoto Claudia Kimie , Nitrini Ricardo , Grinberg Lea Tenenholz , Leite Renata Elaine Paraizo , Pasquallucci Carlos Augusto , Bertola Laiss , Vidal‐Ferreira Naomi , Szlefj Claudia , Caramelli Paulo , Bensenor Isabela M , Lotufo Paulo A , Aliberti Marlon Juliano Romero , Ferri Cleusa Pinheiro , Jacob‐Filho Wilson
Published: December 2022

Background

Most people with dementia already live in low‐ to middle‐income countries (LMIC). However, most evidence regarding dementia prevention comes from high‐income countries that have different socioeconomic status (SES) and risk factors prevalence than LMIC. In this session, we will present results on risk and protective factors for dementia from the Longitudinal Study of Adult Health (ELSA‐Brasil), the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), and the Brazilian Biobank for Aging Studies (BAS).

Method

The ELSA‐Brasil follows 15,105 public servants since 2008‐10. The ELSI‐Brazil is a nationally representative study with 9,412 adults aged 50 years and older, who were enrolled in 2015‐16. The BAS is a neuropathology study that started in 2004 and is the largest brain bank in Latin America with a collection of 1,441 brains. The focus of this presentation will be on the associations of education, SES, and cardiovascular factors with dementia using data from these three studies.

Result

In the BAS, 77% of the sample has less than 5 years of education and 56% unskilled occupations. Compared to the group without education, those with formal education had better cognitive performance (1‐4 years: 𝛽 = ‐0.99, 95%CI = –1.85; –0.14, p = 0.02; ≥5 years: = –1.42, 95% CI = –2.47; –0.38, p = 0.008). On the other hand, occupation complexity and demands were unrelated to cognition. Similarly, we showed that education and early‐life SES were the main contributors to cognitive performance in the ELSA‐Brasil, while later SES had a lower influence on cognitive scores. Cardiovascular factors are also important contributors to brain health. Ideal vascular health was related to better cognitive function in the ELSA‐Brasil. Participants with intermediate (β = 0.064, 95%CI = 0.033; 0.096) and optimal health (β = 0.108, 95%CI = 0.052; 0.164) had better cognitive z‐scores. Moreover, carotid artery atherosclerosis evaluated by morphometric measurements was related to cognitive impairment in BAS and with cognitive decline in the ELSA‐Brasil after 8 years of follow‐up (β = ‐0.028, 95%CI = ‐0.036; ‐0.020, p<0.001). Finally, hypertension was related to worse cognition (β = ‐0.09; 95%CI = ‐0.15, ‐0.04; p = 0.001) in ELSI‐Brazil, mainly in non‐frail participants.

Conclusion

Studies from LMIC regarding dementia risk factors are essential to implement tailored public policies for dementia primary prevention.
eRADAR detects primary care patients at risk of having undiagnosed dementia in two real‐world healthcare systems
Authors: Coley R Yates , Smith Julia J , Karliner Leah , Lee Sei J , Fuller Sharon , Lam Rosemary , Barnes Deborah E , Dublin Sascha
Published: December 2022

Background

Fifty percent of people living with dementia are undiagnosed. The electronic health record (EHR) Risk of Alzheimer’s and Dementia Assessment Rule (eRADAR) was developed to identify older adults at risk of having undiagnosed dementia using routinely collected clinical data. We aimed to externally validate eRADAR in two real‐world healthcare systems, including examining performance over time and by race/ethnicity.

Methods

External validation was conducted in Kaiser Permanente Washington (KPWA), an integrated health system providing insurance coverage and medical care, and three primary care practices at University of California San Francisco Health (UCSF), an academic medical system. This retrospective cohort study included 688,599 person‐years from 129,315 KPWA members and 42,371 person‐years from 12,567 UCSF patients aged 65 years or older without prior EHR documentation of dementia diagnosis or medication. Analyses validated performance of eRADAR scores, calculated annually from EHR data (including vital signs, diagnoses, medications, and utilization in the prior 2 years), for predicting EHR documentation of incident dementia diagnosis within 12 months.

Results

7,631 dementia diagnoses were observed at KPWA (11.1 per 1,000 person‐years) and 189 at UCSF (4.5 per 1,000 person‐years). AUC was 0.84 (95% confidence interval: 0.84‐0.85) at KPWA and 0.78 (0.74‐0.81) at UCSF. Using the 90th percentile as the cutpoint, sensitivity was 54% (53‐56%) at KPWA and 45% (38‐52%) at UCSF. All performance measures were similar over time, including across the transition from International Classification of Diseases, version 9 (ICD‐9) to ICD‐10 codes, and across racial/ethnic groups.

Conclusions

eRADAR showed strong external validity for detecting undiagnosed dementia in two health systems with different patient populations and differential availability of external health care data for risk calculations. In this study, eRADAR demonstrated generalizability from a research sample to real‐world clinical populations, transportability across health systems, robustness to temporal changes in health care, and similar performance across racial/ethnic groups.
Comparison of group‐level and individualized ROIs for predicting change in longitudinal tau‐PET in preclinical and prodromal AD
Authors: Leuzy Antoine , Binette Alexa Pichet , Vogel Jacob W , Klein Gregory , Borroni Edilio , Tonietto Matteo , Strandberg Olof , Mattsson‐Carlgren Niklas , Palmqvist Sebastian , Pontecorvo Michael J. , Stomrud Erik , Ossenkoppele Rik , Hansson Oskar
Published: December 2022

Background

Longitudinal tau‐PET is increasingly used as an outcome in clinical trials evaluating disease‐modifying therapies in Alzheimer’s disease (AD). In order to quantify change in tau‐PET signal over time, regions of interest (ROIs) are used; to date, these have been based on neuropathological studies or data‐driven approaches where the same ROI is used for each subject (group‐level ROI). However, given the inter‐individual heterogeneity in spatial patterns of tau‐PET, a key question is whether the use of subject‐specific (individualized) ROIs might offer any advantages over group‐level ROIs in AD clinical trials. We aimed to address this question by comparing group‐level and individualized ROIs across several metrics using longitudinal tau‐PET in preclinical and prodromal AD.

Methods

We included 174 participants with [18F]RO948 (97 preclinical AD [Aβ‐positive cognitively unimpaired], 77 prodromal AD [Aβ‐positive MCI] from BioFINDER‐2; average follow‐up 1.90±0.50 years). Group‐level ROIs included i) Braak and ii) event‐based modelling (EBM) stages and iii) temporal and iv) whole‐brain meta‐ROIs. Individualized ROIs included i) epicenter (regions with earliest tau), ii) Q1 (quartile closest to subject‐specific epicenter based on functional connectivity) and iii) probability‐based approach (regions selected based on their probability of being tau‐positivity at baseline using Gaussian mixture modelling). Group‐level and individualized ROIs were compared using yearly percent‐change in SUVR (ΔSUVR) and required sample size in a simulated intervention that reduces tau accumulation by 20, 30 or 40%.

Results

In preclinical AD (Figure 1A), EBM stage‐I had the greatest ΔSUVR among group‐level ROIs (4.27%). Based on 95% confidence intervals, ΔSUVR was significantly higher using the probability‐based approach (5.51%). A similar pattern was seen in prodromal AD (Figure 1B), where ΔSUVR for the best individualized ROI (probability‐based, 7.86%) was significantly greater than that for the best group‐level ROI (EBM stage‐II, 5.45%). Across interventions (20/30/40%), sample size differences were on average ∼6% lower in preclinical AD and ∼20% lower in prodromal AD using individualized ROIs, relative to group‐level ROIs (Table 1). Further analysis are ongoing using a validation cohort (n = 278) scanned with [18F]flortaucipir.

Conclusion

Preliminary findings using [18F]RO948 suggest that individualized ROIs carry an advantage over group‐level ROIs in AD clinical trials using longitudinal tau‐PET as outcome.
On the origin of a potential clearance marker: The contribution of enlarged perivascular fluid diffusion to an MRI derived proxy of interstitial fluid
Authors: van der Thiel Merel M. , Roos Nathalie A. , Drenthen Gerhard S. , Voorter Paulien H.M. , Feiweier Thorsten , Ramakers Inez H.G.B. , Backes Walter H. , Jansen Jacobus F.A.
Published: December 2022

Background

IntraVoxel Incoherent Motion (IVIM) MRI can detect the diffusion of cerebral interstitial fluid (ISF) (Dint) and its volume fraction (fint), which has the potential as a proxy of cerebral waste clearance. fint has been suggested to both be driven by fluid diffusivity within enlarged perivascular spaces (ePVS) ‐ transporting fluid from the subarachnoid space into the parenchyma ‐ and the ISF between the parenchymal cells. Both factors play a crucial role in soluble protein clearance, e.g., Amyloid‐Beta (Aβ).

This study simultaneously aims to verify the contribution of ePVS fluid diffusivity to fint and highlights the ability to specifically assess ePVS fluid diffusion in the cerebrum using a non‐invasive MR method.

Method

Twenty neurotypical elderly subjects (Table 1) underwent ultra‐high field MRI (7T research system, Siemens Healthcare GmbH, Erlangen, Germany) (Table 2).

The intermediate diffusion components (Dint) in the range 1.5*10‐3<Diffusivity<4.0*10‐3 mm2/s were calculated using spectral analysis (Fig.1). The relative signal contribution of Dint was quantified by fint.

ePVS were segmented from the enhanced perivascular contrast images (Fig.2). Median fint values were extracted from ePVS and non‐ePVS voxels within the basal ganglia (BG).

fint and Dint values from within the ePVS mask were compared with values from surrounding non‐ePVS voxels in the BG using Wilcoxon Signed Ranks Tests.

Result

Figure 3 contains a graphic summary of the statistical comparison of Dint and fint values from the ePVS and non‐ePVS voxels in the BG. Higher Dint and fint values are observed in the ePVS compared to the non‐ePVS tissue.

Conclusion

The current study identified a higher IVIM‐derived proxy of ISF within the ePVS compared to surrounding non‐ePVS tissue, confirming that ePVS indeed contribute to the waste clearance markerfint.

ePVS are fluid‐filled spaces surrounding cerebral blood vessels, in which ISF diffusivity is less restricted. This explains the higher Dint values in ePVS compared to non‐ePVS.

Furthermore, this study suggests a potential method to investigate diffusivity within the microscopic ePVS, independent of the ISF diffusivity between parenchymal cells. In patients with Alzheimer’s disease, this method could be applied to investigate alterations in ISF diffusivity which could be representative of potential Aβ blockages in ePVS.
Detection of Mild Cognitive Impairment Using In‐clinic and Remote Unsupervised Digital Cognitive Assessments
Authors: White Josh , Edgar Chris J. , Siemers Eric , Maruff Paul
Published: December 2022

Background

The Cogstate Brief Battery (CBB) is a computerized cognitive assessment validated for Alzheimer’s disease (AD) and unsupervised use. The CBB assesses processing speed, attention, visual learning, and working memory and is offered to cognitively normal (CN) and mild cognitive impairment (MCI) participants in ADNI‐3. In‐clinic visits are completed annually for MCI and every other year for CN, with both groups also able to complete unsupervised assessments at‐home within 14 days of the first in‐clinic visit and at up to 3 monthly intervals.

Method

Participants were 146 CN older adults (Mage = 72.1, SD = 6.43, age range 57–90 years, 58.2% females) and 37 older adults with MCI (Mage = 74.4, SD = 7.50, age range 61–89 years, 51.4% females). All participants underwent PET scans and confirmation of diagnosis at Baseline. Only participants with confirmed amyloid status were included in these analyses (i.e., all MCI participants were Aβ+ and all CU participants were Aβ‐). Participants completed the CBB in a supervised in‐clinic setting at Baseline, and again in an unsupervised remote setting within 90 days. Receiver Operating Characteristic analyses were conducted to ascertain whether the classification performance of the CBB in detecting MCI was similar in both settings.

Result

All CBB measures showed a significant ability to discriminate between CU Aβ‐ and MCI Aβ+ participants at both the supervised in clinic baseline (AUCs 0.63‐0.75) and initial remote visit (AUCs 0.63‐0.78). There was no significant difference for any CBB measure in classification performance (measured by AUC) between remote and supervised assessment (ps > 0.146).

Conclusion

The CBB showed good ability to classify MCI‐related cognitive impairment, both supervised in clinic, and/or remotely without supervision.
Validating a set of Verbal‐Paired‐Associates word‐pair lists for Repeat, Remote, Automated Testing
Authors: Kaula Alexander J , Taptiklis Nick , Cormack Francesca K
Published: December 2022

Background

Verbal‐Paired Associates (VPA) is a widely used memory task, typically administered by a trained rater, with lists of pairs of words learned over up to three attempts, followed by delayed recall. Automated scoring and administration could enable remote testing to monitor change over time but requires parallel forms of the test with equivalent psychometric properties. Here we describe the validation process and memorability characteristics of a group of 12 parallel forms of automated VPA.

Method

We generated 15 candidate VPA word‐pair lists based on prior modelling. Piloting and simulation‐based power calculations suggested a sample size of 375 would provide power of .8 to detect lists where the mean number of errors at the first attempt was more than one error different from the Grand Mean. We recruited 375 healthy participants aged 50–90 years via the Prolific online platform. We used a mixed counterbalanced design with the aim of evaluating the memorability characteristics of the candidate set of word‐pair lists. Participants were tested twice on the VPA task using different word‐pair lists, separated by a distractor task. All testing was delivered via the NeuroVocalix platform on participants’ own devices at home and was administered and scored automatically using automatic speech recognition. Automated scoring results were reviewed by a human experimenter to ensure accuracy.

Result

Memory performance in individual word‐lists conformed broadly to our model‐based expectations, with significant correlations between predicted and observed performance (p < 0.05). We observed expected significant improvement in recall performance with repeated administration, showing learning of word pairs over the task. In this healthy sample there was only modest forgetting at delayed recall. Although performance was broadly equivalent across the different lists, the final selection of lists excluded three with the highest numeric difference in performance versus the overall grand mean, yielding 12 lists for repeated administration. Qualitative feedback showed good levels of acceptability and engagement with the task by participants.

Conclusion

We now have a set of 12 parallel‐form word‐pair lists for use with the automated NeuroVocalix system, with consistent performance characteristics enabling long‐term repeat testing remotely and at scale.
Association of sleep quality and diffusion MRI derived interstitial fluid content – insights in cerebral waste clearance
Authors: van der Thiel Merel M. , Backes Walter H. , Drenthen Gerhard S. , Voorter Paulien H.M. , Feiweier Thorsten , Ramakers Inez H.G.B. , Jansen Jacobus F.A.
Published: December 2022

Background

Disruptions in sleep are associated with Alzheimer’s disease (AD) progression. As cerebral waste clearance is most active during sleep, these reductions in sleep quality could induce impaired clearance function. Waste products are washed through the parenchyma in the interstitial fluid (ISF), its volume being regulated by the sleep‐wake cycle. A smaller ISF‐volume is found in awake states and after sleep deprivation. IntraVoxel Incoherent Motion (IVIM) MRI can detect the diffusion of cerebral ISF (Dint) and its volume fraction (fint).

Using IVIM, the current exploratory study investigates whether alterations in a proxy of ISF‐volume (fint) are related to hours of sleep or self‐reported sleep quality.

Method

Twenty neurotypical elderly subjects (Table 1) underwent ultra‐high field MRI (7T research system, Siemens Healthcare GmbH, Erlangen, Germany) (Table 2).

The intermediate diffusion components (Dint) in the range 1.5*10‐3<Diffusivity<4.0*10‐3 mm2/s were calculated using spectral analysis (Figure 1). The relative signal contribution of Dint was quantified by the ISF‐fraction (fint). Median fint values were extracted from the white matter (WM) and gray matter (GM).

Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). In addition to the clinically used total PSQI (sum of all 7 components), the PSQI1 (Subjective sleep quality) and PSQI3 (Sleep duration) components were considered.

Pearson correlations were computed between the PSQI scores and fint for WM and GM. To check for potential confounding influences, partial correlations were performed adjusting for age and time of MRI‐acquisition.

Result

The sample characteristics and descriptive statistics are summarized in Table 1. Worse reported sleep quality (PSQI1) significantly relates to lower WM fint (Table 3 and Figure 2). After adjusting for potential confounding influences, a trend towards significance remained (R=‐0.437, p=0.061).

Conclusion

The current explorative study identified a lower diffusion MRI‐derived proxy of ISF‐volume in the WM of subjects who reported a subjective feeling of long‐term sleep deprivation. A reduction in ISF‐volume may leave less space for waste products, such as soluble Amyloid‐beta, to be cleared from in‐between the cells. Thereby, this study puts forward a potential method for future studies to investigate impaired clearance function in relation to sleep in patients with AD pathology.
Plasma glial fibrillary acidic protein in Alzheimer’s disease and other neurodegenerative disorders: relationship to diagnosis, biomarkers, neuropathology and longitudinal progression
Authors: Shen Xue‐Ning , Huang Shu‐Yi , Yu Jin‐Tai
Published: December 2022

Background

Plasma glial fibrillary acidic protein (GFAP) was associated with Alzheimer’s disease (AD), but its usefulness for diagnosis and prognosis still need validation.

Method

Plasma GFAP was measured using Simoa assays in cohorts of AD, non‐AD dementia, and controls (585 participants in total and 118 with follow‐up).

Result

Plasma GFAP was significantly higher in AD spectrum than in controls and non‐AD dementia, except for the dementia with Lewy bodies. It increased in a stepwise fashion from preclinical AD, through prodromal AD to AD dementia. Plasma GFAP effectively distinguished AD from controls (area under curve [AUC]>0.97), non‐AD dementia (AUC>0.80), preclinical AD (AUC>0.89), and prodromal AD (AUC>0.85). Additionally, it correlated with other AD‐related fluid and imaging markers, and displayed prognostic values for conversion to AD dementia (adjusted hazard ratio 4.49, P=0.027) and cognitive decline (standard β 0.34, P=0.002).

Conclusion

Our findings highlight the value of plasma GFAP as a diagnostic and prognostic biomarker for AD.
CHARACTERISTICS OF SUBJECTIVE COGNITIVE IMPAIRMENT, DEPRESSION, AND FUTURE COGNITIVE DECLINE ‐ A POPULATION BASED STUDY
Authors: Zullo Leonardo , Popp Julius , Clark Christopher
Published: December 2022

Background

Subjective cognitive impairment (SCI) is common in the elderly and it is associated with increased risk of developing dementia. The aim of the present study is to investigate the relationship between SCI characteristics and cognitive and functional decline in community dwelling older people.

Method

Longitudinal analysis of a cohort of 752 dementia‐free community‐dwellers aged 65 years and older from CoLaus/PsyColaus, a population‐based study from the urban area of Lausanne, Switzerland. The presence of SCI was determined using a validated 10‐item questionnaire. We used a semi‐structured interview to assess depression symptoms. A comprehensive neuropsychological test battery along with activity of daily living questionnaires were administered to assess cognitive and everyday functioning at inclusion and at follow‐up visits 5 years and 10 years later. Decline was defined as a change of the Clinical Dementia Rating (CDR) Sum of boxes > 1. Statistical analysis was based on logistic regression.

Result

The presence of SCI at inclusion predicted cognitive decline 5 years later (OR 5.44, p = 0.004). Item 1 of the questionnaire, enquiring about the feeling of getting worse at remembering recent events, was a predictor of future decline (OR 5.44, p = 0.015). Further, current depression was associated with cognitive decline at 5 years (OR 2.65, p = 0.029).

Conclusion

In this population‐based study, SCI predicted cognitive decline 5 years later. The role of depression in this relationship deserves further investigation. Results considering the 10‐year follow‐up will be presented at the congress.
Memory clinic clinicians’ preferences and needs for communication with patients: A multi‐national survey study from EU‐FINGERS & LETHE projects
Authors: Hendriksen Heleen M.A. , van Gils Aniek M. , Kivipelto Miia , Mangialasche Francesca , Meester Hanneke F.M. Rhodius‐ , Smets Ellen M.A. , van der Flier Wiesje M. , Visser Leonie N.C.
Published: December 2022

Background

Increased attention to pre‐dementia stages of Alzheimer’s disease (AD) creates new challenges for clinician‐patient communication. To assist clinicians in these challenges, we aimed to: 1) identify their perspectives on communicating about diagnostic testing, biomarker test results, dementia risk, and prevention, and 2) inventory their need for communication support.

Method

Between June and November 2021, 160 memory clinic clinicians from 21 European countries (56% 31‐50yrs; 59% female, 14±10yrs of experience) completed a digital survey in which they provided their opinions based on five hypothetical patient cases: 1) AD dementia, 2) Mild Cognitive Impairment (MCI) with positive (+) AD biomarkers, 3) Subjective Cognitive Decline (SCD) with positive AD biomarkers, 4) MCI with negative (‐) AD biomarkers, and 5) SCD with negative AD biomarkers. Additionally, we asked which amount and what type of support (online tools and/or skills training) would be appreciated for 10 listed communication skills. Descriptive statistics were used to report characteristics and survey responses.

Result

Most clinicians indicated they would communicate syndrome diagnosis (66‐88% of clinicians) and biomarker results (97‐100%) to all five hypothetical patients. In case of positive biomarkers, clinicians were more hesitant to explicitly mention the presence of AD in the SCD+ case (29%) than in the MCI+ case (68%). Clinicians rather emphasized that it is not yet known what biomarker positivity means for the patient (68% in SCD+ vs. 32% in MCI+). Almost all clinicians reported discussing prognosis/dementia risk (79‐98%) and prevention (90‐99%), often tailored to patient characteristics and preferences. Of note, more than half of clinicians indicated that they preferred ‘(very) much’ support regarding 9 out of 10 listed communication skills (Figure 1), via online tools (34%), training (13%), or both (32%).

Conclusion

European clinicians have a positive attitude towards communicating about early diagnosis of AD, dementia risk, and prevention. Clinicians differ in whether and how they explain the meaning of positive AD biomarkers to patients with SCD or MCI, reflecting the current debate in the field. Moreover, we identified a need for communication support on these topics. Fulfilling clinicians’ needs might help to attune memory clinic care even better to individual patients.
Diagnostic accuracy of the Stricker Learning Span and Mayo Test Drive Composite for amnestic Mild Cognitive Impairment.
Authors: Stricker Nikki H. , Twohy Erin L , Albertson Sabrina M. , Christianson Teresa J. , Stricker John L , Machulda Mary M. , Karstens Aimee J , Patel Jay S , Kremers Walter K. , Hassenstab Jason J. , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Petersen Ronald C.
Published: December 2022

Background

Remote assessment tools offer significant promise for aiding early detection of cognitive impairment. Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). We examined the diagnostic accuracy of the SLS and a MTD composite (SLS max span, SLS trials 1–5 total correct, SLS delay correct, [Symbols correct item response time*‐1]) for amnestic mild cognitive impairment (aMCI). We also explored diagnostic accuracy for a broader group that included individuals with possible MCI (pMCI; see Figure 1).

Methods

Participants were recruited from the Mayo Clinic Study of Aging for this ancillary remote study. 226 were cognitively unimpaired (CU; concordant CU diagnosis by 3 independent raters). Fifty‐six participants had possible MCI (at least 1 of 3 raters indicated MCI) and 16 had a consensus diagnosis of aMCI. Primary outcome variables were SLS sum of trials, AVLT sum of trials, Symbols correct items response time, and MTD composite. Mean difference analyses used linear model ANOVAs (alpha = .05). Receiver operating characteristic (ROC) curves were applied; we derived optimal cutoff scores based on the Youden index method.

Results

Both aMCI and possible MCI groups showed significantly lower performance than the CU group on SLS (Hedge’s g aMCI = ‐1.72, pMCI = ‐1.04), Symbols (Hedge’s g aMCI = 1.38, pMCI = 0.64), and MTD composite (Hedge’s g aMCI = ‐1.89, pMCI = ‐1.09); see Tables 1 and 2 (all p‘s<.01 even when additionally covarying age, education, sex). Total area under the curve was high for differentiating of CU vs. aMCI (MTD Composite = 0.91, SLS = 0.91) and acceptable for CU vs. pMCI (MTD Composite = 0.77, SLS = 0.77); see Table 2. Consistent with our flexible platform, a variety of device types were used to complete remote testing (32% smartphone, 12% tablet, 56% PC).

Conclusions

MTD and the SLS show high diagnostic accuracy for aMCI. MTD is a flexible, brief, and easy‐to‐use remote cognitive assessment tool with great potential for scalable use in future studies seeking to maximize inclusion of individuals with aMCI in clinical trials or for cognitive screening in clinical settings.
Phenotypic features of adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): presenting symptoms and clinical course
Authors: Papapetropoulos Spyros , Portius Angela , Zappia Samantha , Brennan Matthew , Leahy Leslie
Published: December 2022

Background

ALSP is an underdiagnosed, rapidly progressive, fatal autosomal dominant neurodegenerative disease caused by CSF1R gene mutations that result in microglial dysfunction. There are no published prospective studies on the natural history of ALSP. As a result, descriptions of phenotypic features of ALSP are derived from small case series and single case reports. To better understand the phenotypic characteristics of ALSP, a systematic literature review of these published case reports was performed.

Method

A comprehensive, systematic literature review of the clinical and genetic features of ALSP was conducted to identify published case studies (January 1, 1980, through April 30, 2021) from a MEDLINE search using prespecified selection criteria. The search identified 76 published reports with data extracted from 274 ALSP patients and is the most extensive case series of ALSP to date.

Result

The mean±SD age (years) of onset of symptoms was 43.1±11.3, survival time (years) 6.3±4.6, and age of death (years) 52.9±10.8. The most common initial symptoms consisted of cognitive impairment (n = 113, 41.2%), behavioral and psychiatric dysfunction (n = 70, 25.6%), extrapyramidal motor abnormalities (n = 28, 10.2%), pseudo‐bulbar affects (n = 13 4.7%) and speech difficulty (n = 11, 4.0%) and confirmed the phenotypic heterogeneity of ALSP at disease onset, a major contributor to ALSP misdiagnosis. Clinical features associated with disease progression involved cognitive impairment (n = 216, 78.8%), behavioral and psychiatric dysfunction (n = 175, 63.9%), extrapyramidal motor abnormalities (n = 147, 53.7%), and pyramidal motor abnormalities, (n = 136, 49.6%). Less frequent clinical findings (each < 25% incidence) were pseudo‐bulbar symptoms, seizures and aphasia or speech difficulty.

Conclusion

The findings of this systematic literature review are consistent with previous, smaller reports on the phenotype of ALSP. Since cognitive impairment, behavioral and psychiatric dysfunction, and pyramidal and extrapyramidal motor abnormalities were identified as the most frequent clinical features in this review, endpoints quantifying these symptoms should be considered in the design of future interventional trials of ALSP.
Inner blood‐retinal barrier alterations associated with vascular amyloidosis in MCI and AD patients
Authors: Shi Haoshen , Koronyo Yosef , Sheyn Julia , Mandalia Krishna , Fuchs Dieu‐Trang , Gupta Vivek K , Graham Stuart , Black Keith L , Mirzaei Mehdi , Miller Carol A , Koronyo‐Hamaoui Maya
Published: December 2022

Background

Blood‐brain barrier (BBB) breakdown in Alzheimer’s disease (AD) is linked to cerebral amyloid‐beta (Aβ) accumulation and cognitive decline. Previously, we identified substantial retinal pericyte loss along with vascular amyloidosis in mild cognitively impaired (MCI) and AD patients. In double transgenic APPSWE/PS1∆E9 (ADtg) mice, we further demonstrated substantial retinal capillary degeneration and microvascular leakage in comparison to wild type (WT) mice. Here, we sought to expand our investigation of inner blood‐retinal barrier (iBRB) integrity in relation to retinal and cerebral pathological benchmarks in MCI and AD patients compared to cognitively normal (CN) controls.

Method

Postmortem human eyes and brains were obtained from USC‐ADRC. Retinas were isolated from 35 AD patients, 15 MCI patients, and 20 age‐ and sex‐matched healthy controls. Retinal cross sections spanning along ora serrata to optic disc were prepared from four pre‐defined quadrants: superiortemporal, temporalinferior, inferiornasal, and nasalsuperior. Histological examination was performed by immunostaining for different Aβ alloforms, tight junctions (zonula occulden‐1, claudin‐1 and ‐5), and blood vessels (lectin). Retinal microvessels were isolated for evaluating capillary degeneration. Stereological quantifications were performed and then correlated with the respective neuropathological reports of these patients. Mass spectrometry analysis of proteins isolated from another AD and control patients’ cohort was conducted to validate our data.

Result

Our preliminary results showed early and significant downregulation of zonula occulden‐1 in retinal blood vessels of MCI and AD patients compared to controls. Downregulation of this key tight junction molecule was associated with increased retinal vascular Aβ accumulation. In addition, significant deficiencies of vascular‐related proteins including smoothelin, vascular endothelial zinc finger 1 (VEZF1), catenin isoform 1 were detected in retinal homogenates from AD patients versus controls by global proteome analysis. Analysis of isolated retinal blood vessels revealed capillary degeneration along with Alzheimer’s‐relevant vascular pathology in these patients.

Conclusion

Our data suggested an early alteration of iBRB integrity that contributed to Aβ accumulation in retinal blood vessels, consistent with previous reports in BBB of AD patients. Our results provide new insights into AD‐related vascular pathomechanisms in the retina that can be further evaluated for retinal imaging.
Examining the effects of age and sex on tau PET binding in the absence of beta‐amyloid pathology
Authors: Gordon Brian A. , Flores Shaney , Dincer Aylin , Keefe Sarah J. , McKay Nicole S. , Hobbs Diana A. , Wisch Julie K. , Hornbeck Russ C. , Franklin Erin E. , Jack Clifford R. , Koeppe Robert A. , Xiong Chengjie , McDade Eric , van Dyck Christopher H , Klein Gregory , Pariente Jeremie , Bateman Randall J. , Morris John C. , Perrin Richard J. , Benzinger Tammie L.S.
Published: December 2022

Background

Tau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown.

Methods

Cross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and subthreshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT.

Results

There were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or subthreshold levels of amyloid.

Conclusions

Tau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease.
Reliability and sensitivity of two clock drawing test rubrics as screening measures for mild cognitive impairment
Authors: Kehl‐Floberg Kristen E , Marks Timothy S , Giles Gordon Muir , Edwards Dorothy Farrar
Published: December 2022

Background

Early identification of mild cognitive impairment (MCI) is critical, as MCI precipitates disability and may be a precursor to major neurocognitive disorder. The Clock Drawing Test (CDT) is a widely adopted screening measure for dementia however it is not known whether paper‐and‐pencil CDT scoring rubrics are sensitive to subtle losses consistent with MCI. We examined the reliability and sensitivity to MCI of two free‐drawn Clock Drawing Test rubrics ‐ the 10‐point Rouleau, and the 20‐point Clock Drawing Interpretation Scale (CDIS) in community‐dwelling older adults.

Method

345 adults enrolled in a study of functional cognition completed the Montreal Cognitive Assessment (MoCA), the Alzheimer’s Disease Cooperative Study Scale (ADCS‐ADL), and freely‐drawn clocks scored with CDIS and Roleau rubrics. We computed Cronbach’s alpha, receiver operating characteristic (ROC) analyses using the MoCA as the index measure, and one‐way ANOVAs with the ADCS‐ADL for each rubric.

Result

Our sample was 74% female, 83.2% white. Mean age was 70.01 ±8.89, and mean education was 15.5 ±3.735 years. Average scores were 24.28 ±3.44 (MoCA), 74.85 ±4.16 (ADCS), 8.8 ±1.68 (Rouleau) and 18.17 ±2.09 (CDIS). alphas were .65 for the CDIS and .479 for the Rouleau. ROC analyses using MoCA scores consistent with any impairment (<26) resulted in a CDIS AOC of .677, with sensitivity of .681 and specificity of .58 at a cut score of 19. The Rouleau AOC was .684, with sensitivity of .542 and specificity of .76 at a cut score of 9. ANOVAs indicated that individuals classified as impaired by the CDIS ((F = 13.095, p<.001) or the Rouleau (F = 22.2, p<.001) rubrics reported significantly more ADL/IADL difficulties than those classified as unimpaired with either rubric. Differences between impaired and unimpaired groups were larger for the CDIS, suggesting this rubric is more sensitive to ADL/IADL deficits.

Conclusion

Both rubrics produced generally similar results when compared to the MoCA and adequately identified individuals needing further evaluation given reported functional problems. The CDIS produced more robust differences suggesting that it may be more appropriate for community screening to identify individuals in need of comprehensive cognitive and functional evaluation.
Effects of antiseizure drugs on epileptic activity and synaptic and cognitive dysfunction in transgenic mice expressing A53T human α‐synuclein
Authors: Hwang Kaylin , Vaknalli Rahil , Addo‐Osafo Kwaku , Vicente Mariane Cristine , Peters Samuel T. , Phillips Allyssa , Choquette Jessica M , Bragin Anatol , Lee Michael K , Vossel Keith
Published: December 2022

Background

Abnormal α‐synuclein (αS) plays an important role in the pathology of Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). New evidence shows network hyperexcitability can accelerate synaptic and cognitive deficits in PDD and DLB. While 90% of epileptiform activity is detected during sleep in Alzheimer’s disease (AD), epileptiform activity during sleep in PDD or DLB is poorly understood. There are currently no known treatments to delay PDD or DLB progression. Although antiseizure drugs (ASDs) have been used to improve memory deficits in AD, this treatment approach has not been investigated in α‐synucleinopathies.

Methods

To explore the effect of ASDs in attenuating αS‐dependent seizure activity, we used transgenic mice expressing the A53T mutant human α‐synuclein (TgA53T) as a model of motor and cognitive decline in PDD and DLB. We have begun screening FDA‐approved ASDs using cortical electroencephalography with electromyography to examine epileptic events 24 hours before and after intraperitoneal injection. The two ASDs exhibiting the strongest efficacy in reducing epileptic activity across sleep‐wake states will be tested for effects on cognitive function and synaptic plasticity following chronic administration. We are also quantifying pathological high frequency network oscillations (HFOs), biomarkers of epileptogenesis.

Results

3‐4‐month‐old TgA53T mice experienced epileptiform events but had normal long‐term potentiation (LTP) and memory, indicating that epileptic activity onset precedes αS‐induced synaptic and cognitive deficits. Starting at 6 months of age, TgA53T hippocampal slices show the absence of LTP, with reduced c‐fos and calbindin and increased neuropeptide Y indicating alterations in hippocampal inhibitory circuitry. In behavioral testing, TgA53T mice exhibit impairment in fear conditioning, Y‐maze spatial recognition, and Barnes maze spatial learning and memory with age. Preliminary studies indicate lacosamide and brivaracetam as the most effective of ASDs tested in reducing epileptic myoclonus and interictal epileptiform events. We also found more HFOs in TgA53T mice and TgA53T mice with tau ablation.

Conclusion

Suppression of epileptic activity by ASDs would support ASDs as a novel treatment for reducing or preventing cognitive dysfunction in DLB and PDD. Furthermore, ASD‐induced reversal of synaptic and cognitive deficits would provide evidence that epileptic activity plays a causal role in αS‐dependent pathology.
Plasma glial fibrillary acidic protein as a moderator along the Alzheimer’s disease biomarker cascade
Authors: Saloner Rowan , Asken Breton M. , Gontrum Eva Q. , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Miller Bruce L. , Rabinovici Gil D. , Casaletto Kaitlin B , Kramer Joel H.
Published: December 2022

Background

Astrocyte reactivity may contribute to pathogenic relationships between β‐amyloid (A), phosphorylated tau (T), neurodegeneration (N), and cognition (memory). We examined whether severity of astrocyte reactivity, characterized by plasma glial fibrillary acidic protein (GFAP), moderates relationships along the A/T/N and memory cascade in non‐demented adults.

Method

Plasma phosphorylated tau181 (P‐tau181) and GFAP concentrations (Quanterix Simoa) were measured in cognitively unimpaired (CU) individuals and patients with mild cognitive impairment (MCI). Analyses were conducted on overlapping sample subsets (aged 52‐92) with florbetapir Aβ‐PET (112 CU [80 Aβ‐, 32 Aβ+; SUVR>1.11], 29 MCI [all Aβ+]), structural MRI (139 CU, 39 MCI), and memory testing (168 CU, 45 MCI). Linear regression tested statistical moderation of plasma GFAP on the association of Aβ‐PET (A) with plasma P‐tau181 (T), and on associations of plasma P‐tau181 with hippocampal volume (N) and composite memory z‐scores (cognition). To probe moderation effects, region of significance analyses identified percentile thresholds along the plasma GFAP distribution at which statistically significant A/T/N and cognition associations emerged. Covariates included age, sex, APOE genotype, education (cognitive analysis), and intracranial volume (MRI analysis).

Result

Plasma GFAP significantly moderated the relationship between Aβ‐PET and plasma P‐tau181 (β=0.23, p=.003) and the relationship between plasma P‐tau181 and memory (β=‐0.18, p=.027). Region of significance analyses detected significantly higher plasma P‐tau181 concentrations in Aβ+ (vs. Aβ‐) only above the 17th percentile of plasma GFAP, whereas the significant relationship between higher plasma P‐tau181 and worse memory was only detected above the 73rd percentile of plasma GFAP. Plasma GFAP did not moderate the relationship between plasma P‐tau181 and hippocampal volume (p=.648); however, both plasma P‐tau181 (β=‐0.20, p=.004) and GFAP (β=‐0.16, p=.035) independently related to smaller hippocampal volume.

Conclusion

Adverse associations along the A/T/N and memory cascade only emerged with increasing plasma GFAP concentrations, with a higher GFAP threshold needed to detect plasma P‐tau181‐related memory associations than Aβ‐related elevations in plasma P‐tau181. These adverse associations were absent at low GFAP levels, suggesting less severe astrocyte reactivity may buffer against AD pathological changes. As a non‐invasive marker of astrocyte reactivity, incorporating plasma GFAP into AD biomarker models may enhance characterization of AD risk and resilience.
Role of Fragile X Mental Retardation protein in Amyloid Beta 1‐42 Induced Translational Suppression
Authors: Lizarazo Simon
Published: December 2022

Background

Alzheimer’s Disease (AD) is the most common cause of dementia where the accumulation of the peptide Amyloid‐Beta (Aβ) is the main theory linked to the pathogenesis of the disease. Fragile X Mental Retardation Protein (FMRP) is an RNA‐binding protein that functions to suppress global translation. Because Aβ is known to be a toxic peptide capable of inducing the Endoplasmic Reticulum (ER) stress response and because augmented translational suppression is one of the main molecular phenotypes in ER stress response, we ask whether and how FMRP is involved in Aß induced translational suppression.

Method

Primary mouse cortical neuronal cultures from wild type (WT) or Fmr1 KO pups were treated with Aβ (Aβ1–42) during 24 hours. For protein expression identification and quantification we used western blot and ImageJ software respectively. Protein translation was assessed by inhibition with puromycin. Neuronal networking assessment was made with multielectrode array system (MEA).

Result

In this study, we observed that treatments of synthetic Aβ peptides in culture primary mouse cortical neurons induces the expression of FMRP and FMRP‐dependent ER stress response and subsequent translational suppression. Also Aβ induces FMRP‐dependent neuronal hyposynchronicity . We further characterized that two translational regulators, eukaryotic translation initiation factor 2α (eIF2α) and eukaryotic translation elongation factor 2 (eEF2), are involved in Aβ induced translational suppression and are dysregulated in the absence of FMRP. Mechanistically we found that FMRP is responsible for regulating the levels of Protein Phosphatase 2 (PP2A) and Protein Phosphatase 1 (PP1) that differentially modulate the phosphorylation status and thereby activity of eIF2α and eEF2 following treatment of Aβ. Using a pharmacological approach to inhibit PP2A and PP1 with Okadaic Acid, we were able to rescue the impairment of eIF2α and eEF2 as well as the translational suppression and lack of neuronal hyposynchrony in the absence of FMRP.

Conclusion

These results suggest a novel function of FMRP in regulating translational suppression and neuronal networking function following Aβ treatment by fine‐tuning two distinct signaling pathways involved in global translation.