bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Acquisition Protocol on Advanced Diffusion MRI Measures
Authors: Mishra Virendra R , Sreenivasan Karthik , Cordes Dietmar , Ritter Aaron
Published: December 2022

Background

Several studies have suggested that advanced diffusion MRI (dMRI) measures derived through the analytic techniques of diffusion kurtosis imaging (DKI) and neurite orientation density and dispersion imaging (NODDI) might provide better sensitivity to predict the progression of Alzheimer’s disease (AD) when compared to conventional single tensor diffusion tensor imaging. Two popular simultaneous multislice (SMS) sequences, namely Alzheimer's Disease Neuroimaging Initiative (ADNI)‐3 and Human Connectome Protocol (HCP) are currently widely used in the acquisition of such advanced dMRI data. Since HCP sequences require a custom connectome scanner, several variants of HCP protocol compatible with clinical MRI are in wide use. Before such techniques are used widely across the globe to understand AD, it is imperative to understand whether the absolute WM measures derived through such advanced dMRI measures are reproducible and whether harmonization of dMRI across sites employing different acquisition protocols is applicable. In this study, we hypothesize that higher spatial and angular resolution dMRI data will result in higher quantification of DKI and NODDI metrics, as compared with comparatively lower spatial resolution advanced ADNI‐3 sequences.

Method

A 32‐year‐old healthy male participant was scanned over five weeks, both with Advanced ADNI‐3 protocol (114 directions, 2mm3 isotropic, b‐values=500s/mm2, 1000s/mm2, and 2000s/mm2) and 2 variants of the HCP sequence (1.5mm3 and 2mm3) both with 3 b‐values (500s/mm2, 1000s/mm2, and 2500s/mm2) and 213 directions on a 3T Skyra scanner. Total scan time for the ADNI‐3 sequence was 11:37 minutes, 2mm3 CCF sequence was 18:41 minutes, and 1.5mm3 CCF sequence was 23:13 minutes. Various DKI and NODDI measures were computed on all repetitions in‐house. JHU atlas of WM tracts was used as a mask to extract values along each tract at each run separately.

Result

As shown in Figs 1‐4, dMRI‐derived measures were underestimated for most of the WM tracts for the ADNI‐3 sequence, although they had less variance across different runs. Second, NODDI measures were more reproducible across most WM tracts when compared to DKI measures across protocols.

Conclusion

Acquisition parameters affect the absolute quantification of advanced dMRI measures. Our data suggest that the pooling of dMRI data across various protocols should be performed with caution
Visual Sensory Binding is Associated with CSF Neurogranin in Cognitively Healthy Older Adults
Authors: Jacobs Diane M. , Festa Elena K , Galasko Douglas R. , Salmon David P. , Smirnov Denis S. , Marangi Camille A. , Heindel William C
Published: December 2022

Background

Cognitive tasks that require conjunctive binding – i.e., the integration of distinct features into a coherent representation – are sensitive to AD even in the preclinical stage. To further explore the sensitivity and utility of conjunctive binding tasks, we examined the association of visual sensory binding with novel CSF biomarkers of neurodegeneration in cognitively healthy older adults.

Method

Two versions of a visual search paradigm were used to compare sensory conjunctive binding under conditions that differ in terms of the demands placed on cross‐cortical interactions. In these tasks, the binding of motion direction (up/down or left/right) must be integrated with either luminance contrast (black or white; within stream binding) or isoluminant color (red or green; across‐stream binding). We examined the association of cross‐cortical sensory binding efficiency (the difference in overall median response time between the color and luminance conditions) with CSF biomarkers of AD pathology (Aß42/Aß40 and p‐tau 181) and synapse function (neurogranin, NPTX2, and SNAP25) in N = 32 cognitively healthy older adults (mean age = 74.6, SD = 5.5; mean Dementia Rating Scale score (max score: 144) = 139.9, SD = 2.9).

Result

Bivariate correlations revealed that cross‐cortical sensory binding efficiency was significantly associated with neurogranin (r = .36; p<.05) but not with Aß42 (r = .08; p = .68), p‐tau 181 (r = .25; p = .17), NPTX2 (r = .04; p = .82), or SNAP25 (r = .16; p = .41). In multiple regression analyses, neurogranin remained significantly associated with binding efficiency (ß = .46; p = .02) after controlling for age (ß = .03; p = .87), sex/gender (ß = .17; p = .33), and Aß42/Aß40 (ß = .30; p = .14). The addition of p‐tau 181 (ß = .45; p = .12) to this model slightly attenuated the association between neurogranin and binding (ß = .27; p = .24).

Conclusion

In cognitively healthy older adults, efficiency of cross‐cortical conjunctive binding on a visual search task was significantly associated with CSF neurogranin, a post‐synaptic protein that is abundant in dendritic spines. Increased CSF neurogranin signifies synaptic degeneration and is specific to AD. Results suggest that visual sensory binding is a cognitive marker that is sensitive to changes in synaptic function in older adults who perform normally on traditional neuropsychological measures. Follow‐up investigation will determine if visual sensory binding efficiency is predictive of cognitive decline and subsequent dementia.
Vascular health is associated with locus coeruleus‐related entorhinal tau deposition
Authors: Riphagen Joost M. , Chhatwal Jasmeer P. , Becker Alex , Kwong Kenneth , Engels Nina , Yau Wai‐Ying Wendy , Prokopiou Prokopis C. , Schneider Christoph , Koops Elouise A. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L.
Published: December 2022

Background

Autopsy studies reported that the locus coeruleus (LC) is one of the first sites of tau accumulation. In addition, LC‐mediated norepinephrine (NE) signaling is thought to play a role in blood‐brain‐barrier maintenance and neurovascular coupling through its projections to the microvasculature, suggesting that the NE‐LC system interacts with cerebrovascular disease and Alzheimer’s disease (AD) pathology. Since vascular risk factors are prevalent in older individuals and contribute to vascular pathology, a common co‐pathology of AD, understanding interrelationships among vascular health, tau and LC integrity as early as possible, can guide prevention.

Method

We included 124 individuals (Table1) from the Harvard Aging Brain Study with MRI and 18F‐Flortaucipir and 11C‐Pittsburgh‐Compound‐B PET‐imaging within one year of each other. LC‐MRI signal intensity was extracted from 5 maximum‐intensity voxels and normalized to pontine tegmentum. White matter signal abnormalities (WMSA intracranial volume adjusted) were obtained from FreeSurfer6. PET measures were partial‐volume corrected. The Framingham‐Risk‐Score (FRS‐CVD, likelihood of a cardiovascular event in 10 years) was calculated. Structural Equation Models were used to test hypothetic models (1: WMSA mediate the relationship between FRS‐CVD and LC, leading to entorhinal (EC) tau; 2: FRS‐CVD is associated with WMSA and LC, and the LC influences WMSA, both leading to EC tau) against the null model (independent paths of LC and WMSA between FRS‐CVD and EC tau;Figure1). Models were bootstrapped (n = 2000). Model fit measures determined which model described the data best (CFI >0.90, RMSEA <0.08, SRMR <0.08). Age and sex were included as covariates.

Result

Models null and 2 had poor fit. Model‐1 had an excellent fit, suggesting that a higher likelihood of a cardiovascular event in ten years is positively associated with WMSA, WMSA is associated with LC intensity, which in turn is associated with EC tau (Table2). Posthoc, global Aβ (DVR) was added as covariate in model‐1, this did not change the model‐fit or outcomes.

Conclusion

Previous work demonstrated that LC‐intensity correlates strongly with entorhinal tau. Our findings now suggest that presence of increased cardiovascular risk is associated with lower LC‐intensity through its effects on white‐matter damage, emphasizing the importance of mitigating risk factors earlier in life.
Impact of reduced injected dose on semi‐quantification of in vivo amyloid‐β pathology using [18F]flutemetamol
Authors: Young Peter , Heeman Fiona , Lubberink Mark , Rieckmann Anna , Axelsson Jan , Sanaat Amirhossein , Frisoni Giovanni B , Zaidi Habib , Gispert Juan Domingo , Barkhof Frederik , Farrar Gill , Baker Suzanne L. , Garibotto Valentina , Schöll Michael
Published: December 2022

Background

Reduced injected doses in PET examinations result in lower radiation exposure, reduced acquisition times, reduced costs for institutions and ethically allow for additional scans within the same subject. Previous research has demonstrated that the injected dose of several different PET tracers can be reduced without substantial effects on quantitative outcome measures. Here, we studied the effect of reduced injected doses on signal‐to‐noise ratios (SNRs) and standardised uptake value ratios (SUVRs) for the FDA‐approved amyloid‐β (Aβ) PET tracer [18F]flutemetamol.

Method

Thirty [18F]flutemetamol PET scans from previously classified Aβ‐positive and Aβ‐negative individuals were included in this study (Table 1). Amyloid positivity was derived using a validated centiloid pipeline. Subsets of the PET data containing 70%, 50%, 40% 30% and 20% of the total events was extracted randomly from the list‐mode data to generate sinograms and reconstructed using e7 tool. SUVRs were computed for a whole brain region‐of‐interest from an intracranial volume mask using whole cerebellum as a reference region. Reference and target ROIs were derived in MNI space. Next, group separation between Aβ‐positive (A+) and Aβ‐negative (A‐) using mean SNRs was computed using formula 1. Additionally, the differences in SUVR and SNR for true and the respective reduced injected dose were calculated.

Group Separation= (meanA+ ‐ meanA‐)/(0.5√((SDA+)2+(SDA‐)2) (1)

Result

Initial results (Table 2) show an absolute change in group separation from 0.65 to 0.62 (4.8% change) for original injected dose and a reduction of injected dose to 20% respectively. Whole cortical SUVRs changed by a maximum of 0.01 (<1% change) in both Aβ‐positive and ‐negative individuals. Figure 1 shows scans of a representative Aβ‐positive individual derived from true and different simulated reduced injected doses.

Conclusion

Preliminary findings in our pilot sample suggest that lower injected tracer‐doses for [18F]flutemetamol yield robust SUVRs at injected doses as low as 20% of the original dose. We will report further validation in a larger dataset. In addition, a whole cortex region was used for SUVR derivation, and investigations of smaller ROIs will be added. The effect of scanner and reconstruction settings as well as the effect of reduced injected doses on separating Aβ‐positive from ‐negative individuals will be investigated.
Sex differences in the protective effects of APOE ε2 on longitudinal cognitive decline
Authors: Wood Madeline , Xiong Lisa Y. , Buckley Rachel F. , Swardfager Walter , Masellis Mario , Black Sandra E. , Rabin Jennifer S.
Published: December 2022

Background

The APOE ε2 allele confers protection against cognitive decline and Alzheimer’s disease. There is some suggestion that APOE ε2 may have sex‐specific effects on cognition. We investigated sex differences in associations between APOE ε2 and longitudinal cognitive trajectories in a large sample of older adults.

Method

We used data from the National Alzheimer’s Coordinating Centre (NACC) database. We included participants who were ≥ 50 years old, White, free from dementia at baseline, and completed at least one follow‐up cognitive assessment. We categorized participants as APOE ε2 carriers (combining heterozygous and homozygous ε2 carriers) or APOE ε3 homozygote carriers. APOE ε4 carriers (including ε2/ε4 carriers) were excluded. Cognition was assessed approximately annually. We computed composite scores for memory, language, attention, and executive function. We examined the interaction between APOE allele (ε2 vs ε3), sex, and time on longitudinal cognition in linear mixed models, adjusting for baseline age, baseline MMSE, education, number of follow‐up visits, NACC test version, and their interactions with time.

Result

We included 6,733 participants classified as cognitively normal at baseline (mean age=72.9±9.12 years, mean education=16.0±2.87 years, 62.5% female), and 1,932 participants classified as mild cognitive impairment (MCI) at baseline (mean age=75.2±8.91 years, mean education=15.6±3.28 years, 44% female). Among participants with normal cognition, we observed significant interactions between sex, genotype, and time on longitudinal memory (β=0.022, p=0.039) and language (β=0.015, p=0.038), but not attention (β=0.01, p=0.09) or executive function (β=0.006, p=0.30). In sex stratified analyses, relative to male APOE ε3 carriers, male APOE ε2 carriers showed slower rates of decline in domains of memory and language. This effect was not observed in females. No significant interactions between sex, genotype, and time were observed in participants with MCI (memory: β=‐0.04, p=0.1; language: β=‐0.02, p=0.4; attention: β=‐0.01, p=0.5; executive function: β=‐0.02, p=0.3).

Conclusion

Among cognitively normal adults, APOE ε2 carriage protects males but not females against longitudinal memory and language decline. The sex‐specific effect of APOE ε2 may contribute to the lower incidence of Alzheimer’s disease in males compared to females. Future research is needed to elucidate the mechanisms behind the observed sex disparities in cognitive decline.
Treatment with C5aR1 antagonist attenuates short‐term hippocampal memory decline and prevents DAM signature in Arctic mice.
Authors: Schartz Nicole D , Carvalho Klebea , Liang Heidi Yahan , Chu Shu‐Hui , Mortazavi Ali , Tenner Andrea J
Published: December 2022

Background

Upregulation of complement genes in Alzheimer’s disease (AD) mouse models is associated with inflammation and cognitive decline. Genetic ablation of C5aR1 reduces loss of neuronal complexity and cognition in the Arctic mouse model. Inhibition of C5aR1 with PMX205 has shown success in preclinical studies of AD, reducing recruitment of reactive glia and amyloid deposition in the Tg2576 AD model. However, the molecular and cellular mechanisms underlying this neuroprotection are unclear. Thus, we used single cell RNA‐seq to interrogate gene pathways involved in C5aR1‐mediated deficits in the Arctic mouse model.

Method

WT and Arctic mice were treated with PMX205 or vehicle via drinking water (20 µg/mL, equivalent to ∼5 mg/kg/day, consistent with previous studies) from 7.5 to 10 months of age. Effects of PMX205 on long‐ and short‐term memory were tested with object location memory (OLM) with a 24hr inter‐trial interval (ITI) and y‐maze spatial reference memory test with a 1hr ITI, respectively. Hippocampi were dissected and immediately prepared for microglial isolation and fixation. The single cell whole transcriptome kit (Parse Biosciences) was used to prepare single cell microglia libraries for RNA‐seq. Libraries were sequenced using NextSeq 2000. Parse Bioscience split‐pipe v0.7.6 was used to demultiplex reads into single‐cells, Scrublets to remove doublets, and Seurat for quality control, normalization, and clustering.

Result

PMX205 protected against short‐, but not long‐, term memory deficits. Arctic‐PMX205 mice spent more time in the novel arm (44%) than Arctic‐vehicle mice (30%) in Y‐maze. Microglial single cell RNA‐seq identified 7 microglial clusters. Within these clusters, we probed for genes previously described as homeostatic, DAM1, and DAM2. DAM1 (Tyrobp, Apoe, Trem2) and DAM2 (Cst7, Itgax) genes were enriched in Arctic‐vehicle mice compared to WT mice, and expression was downregulated with PMX205 treatment in Arctic mice, most notably in DAM1 genes.

Conclusion

Pharmacological C5aR1 inhibition confers some protective function even when treatment is initiated months after amyloid pathology onset in this aggressive mouse model of AD, and alters microglial polarization, suppressing detrimental inflammation. These findings complement previous data from genetic ablation of C5aR1, and suggest that C5aR1 may be a viable therapeutic target for individuals with an AD diagnosis.
Perceived Stress and Loneliness During the COVID‐19 Pandemic in a Cognitive Aging Cohort
Authors: Bateman James R. , Waugh Christian E , Kershaw Kiarri N , Quillen Ellen E , Lockhart Samuel N. , Peavey Jeremy J. , Hughes Tim M. , Cole Steve W , Seeman Teresa E. , Craft Suzanne
Published: December 2022

Background

The COVID‐19 pandemic has had disproportionate effects on the health and well‐being of older adults. Little is known about the effects of isolation and social distancing measures on the mental health of older adults with cognitive impairment.

Method

194 participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort adjudicated as cognitively normal (CN, n = 129), and mild cognitive impairment (MCI, n = 65) were given questionnaires cross‐sectionally measuring loneliness, perceived stress, well‐being, and coping style. We created multivariable regression models (adjusted for age, sex, race, and education) to assess relationships among dependent variables, loneliness and perceived stress, and independent variables of interest, well‐being and coping style (Table 2).

Result

Overall, the mean age was 72±8 years. Table 1 lists baseline demographic and study measures for CN and MCI groups. Table 2 shows associations between dependent variables (perceived stress, loneliness) and independent variables of interest. Participants with MCI had significantly higher levels of loneliness (B = 3.30; p = 0.03) than CN participants. Participants who reported lower eudaimonic and hedonic well‐being had higher levels of perceived stress and loneliness (p < 0.01), and those who endorsed using self‐blame and behavioral disengagement to cope with stress had higher perceived stress (B = 3.06, = < 0.01) and loneliness (B = 7.84, p < 0.01). There was no interaction by cognitive diagnosis.

Conclusion

Participants with MCI had higher levels of loneliness, but not perceived stress, than those with normal cognition. We found that participants expressing high feelings of well‐being had significantly lower, and participants reporting a coping style with self‐blame and behavioral disengagement had significantly higher perceived stress and loneliness. Next steps involve exploring associations of neuroimaging and Alzheimer’s disease biomarkers with perceived stress and loneliness and evaluating transcriptional measures of stress measured concurrently.
Does cognitive reserve or brain maintenance explain heterogeneity in episodic memory trajectories in late middle age?
Authors: Schwarz Claudia , Franz Carol E , Lyons Michael J. , Kremen William S. , Vuoksimaa Eero
Published: December 2022

Background

Aging‐related episodic memory (EM) decline and Alzheimer’s disease (AD)‐related brain changes begin in late middle age around age 60. However, rate and severity of cognitive decline do not consistently correspond to the extent of neuropathological changes, suggesting a high degree of heterogeneity in EM trajectories. We tested if brain maintenance (BM; relative absence of changes in neural resources as a determinant of preserved cognition) and/or cognitive reserve (CR; a property of the brain that allows for sustained cognitive performance in the face of age‐related changes and brain insult or disease) explain individual differences and heterogeneity in EM in late middle age.

Method

Participants were 1604 men from the Vietnam Era Twin Study of Aging. A practice effect‐adjusted composite EM score based on six measures was calculated at three time points with mean ages of 56, 62, and 68. Young adult general cognitive ability (GCA) and lifetime years of education were used as proxy measures of CR. BM was assessed as relative change (from age 56 to 68) in cortical thickness and surface area in a bilateral cortical signature of AD regions‐of‐interest (N = 321). We used linear mixed effect modeling.

Result

On average, there was a significant decline in EM from age 56 to 68 (p<0.001). Education (p = 0.042) and young adult GCA (p<0.001) were positively related to EM, but there were no significant effects of education or GCA on the rate of EM change (all p’s≥0.316). Relative brain changes were not related to EM (all p’s≥0.067) and there were no significant interactions of CR proxies and brain changes on EM (all p’s≥0.379).

Conclusion

Higher education and higher young adult GCA were related to better EM performance across late middle age – with a stronger contribution of GCA compared to education – but EM change did not differ as a function of these proxy CR measures. Our results did not support effects of BM or CR on EM change in late middle age but rather reflected baseline differences in memory in those with low versus high education/cognitive ability. Whether differential change occurs at later ages or with increased AD pathology remains to be determined.
Towards a more representative Alzheimer’s disease clinical trial: Ethnic differences in underlying pathology call for demographic consideration in drug label development
Authors: Anderson Nicolas , Stanek Jessica , Swearingen Blake , Gabriel Hoda , Strittmatter Warren , Chamberlain Stan , Didsbury John
Published: December 2022

Background

Clinical trials have historically underrepresented racial and ethnic minority groups, often exhibiting sub‐par external validity and representing a population that is exceedingly White and not Hispanic or Latino (H/L). An understanding of the underlying pathology and safety profile of racial and ethnic minority groups is important to interpretation of clinical trial results and the development of accurate drug labels. T3D Therapeutics’ Phase 2 PIONEER Study (evaluating the safety and efficacy of lead candidate drug T3D‐959) provides a unique opportunity to examine safety data in an Alzheimer’s disease (AD) trial with a relatively high percentage of H/L subjects.

Method

PIONEER is an ongoing randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients dosed orally once‐a‐day for 24‐weeks. Exploratory analyses examine ethnic differences in medical data including screen fail reasons, medical history, and adverse events.

Result

Medical history and screen fail reason data suggest differences in underlying pathology between H/L and non‐H/L subjects. For example, data show a higher rate of screen failure due to elevated HbA1c among H/L subjects vs. non‐H/L subjects. Conversely, H/L subjects show lower rates of surgical and medical procedures as well as other medical history events. Rates of reporting adverse events as well as types of adverse events reported are also significantly different between the two groups.

Conclusion

Ethnic differences drive differential safety profiles across study subjects, challenging the applicability of non‐H/L clinical trial data to the H/L population. Our data suggest that more weight should be put on ethnicity and other demographic characteristics in developing drugs’ side effects listings. We stress that ethnic background should play a larger role in label development, and urge the clinical trial community to continue in the direction of enrolling underrepresented racial and ethnic minority groups.
Validating Frontal Memory‐related Neuromarkers for Mild Cognitive Impairment using Identical Protocols in Two Racial and Culturally Distinct Cohorts
Authors: Jiang Yang , Zhao Xiaofeng , Zheng Zhiwei , Latham Jeremy J , Wang Baoxi , Liu Ziming , Zhao Xiaopeng , Jicha Gregory A , Li Juan
Published: December 2022

Background

Studies using standardized cognitive assessments across disparate populations are often confounded by sociocultural differences, leading to a lack of comparative standards to assess the degree of Mild cognitive impairment (MCI). Thus, testing in diverse populations is essential in validating biomarkers for MCI and avoiding race and cultural confounders. Applying an identical, cross‐culturally accepted, non‐invasive, electrophysiological protocol, we test the hypothesis that the frontal neuromarkers for MCI are consistent in two samples of older adults in the US and China.

Method

Using an identical, clinically friendly protocol with a wireless 14‐channel headset (eMotiv), we recorded EEG signals along with accuracy and reaction times during a visual object working memory task in two samples of older adults. The Kentucky sample includes 12 Normal Cognition NC; (Mean age 68); 7 MCI (age 81) while the Beijing sample includes 11 NC (age 64) and 16 MCI (age 65). Each participant also received assessments in NACC UDS 3.0. The 10‐min task asked each subject to remember two visual objects and then determine whether the subsequent object is a Match or Nonmatch to one of the two held in working memory.

Result

We found that left frontal sites showed significant mean amplitude differences between MCI and NC during target match retrievals. The persons with MCI showed reduced responses to memory targets at the F3 and F7 sites in Kentucky. The MCIs’ reduction patterns were significant in the left frontal F3 but not significant at F7 in Beijing sample. The Beijing participants were on average younger than KY participants, leading to a reduction in quantitative signal change, however, the effect remains robust and parallels those from Kentucky. The current results using a fast and two‐target memory task are consistent with previously reported results using 64‐channels and a longer version of the memory task with single‐target.

Conclusion

We have validated frontal neuromarkers for MCI risk in two diverse samples. The current finding has significant implications for clinical practice which creates a path for the next step: large‐scale, low‐cost, and culturally‐accepted screening for risk of cognitive decline in individuals, irrespective of their socio‐cultural, geographical, or societal background.
Alzheimer’s disease treatment with Transcranial Pulse Stimulation using shockwave pulses is increasingly successful: Patient’s feedback is very positive
Authors: Novak Pavel
Published: December 2022

Background

Due to the aging world population is the number of patients suffering from dementia continuosly increasing. There are currnently worldwide 46.8Mio. cases, the estimation for 2050 are 131.5Mio. Most common cause of dementia is the Alzheimer’s disease, which is curently uncurable. It is a progressive neurologic disorder that causes brain cells to die and the brain to shrink.

Method

Shockwaves are used in medicine since 1980. Starting with kidney stone disintegration, low intensity shockwaves are used for soft tissue stimulation since 1990. Mechanical stimulation of biological processes by shockwaves called mechanotransduction results in increased cell metabolism, release of nitric oxide and numerous growth factors, as VEGF and BDNF. There is also an anti‐inflammatory effect, stimulation of stem cells and of the innate immune system. The treatment of pain and spasm were the first neurological shockwaves applications. In 2004, first patients with spinal cord injury were treated. In parallel, the scientific investigations demonstrated that shockwaves not only stimulate, but also regenerate the nerves after lesions. Finally, since 2010 followed the brain treatment of patients with unresponsive wakefulness, Parkinson’s and Alzheimer’s disease. Alzheimer’s disease two‐center study resulted in regulatory clearance in the European Community in 2018. Shockwave stimulation of the brain is meanwhile called TPS (Transcranial Pulse Stimulation). Typical treatment consists of 6 sessions within 2 weeks, each session with 6000 pulses at 0.2mJ/mm2.

Result

There is worldwide an increasing number of clinical sites (over 75) with successfully treated Alzheimer’s patients. There have been meanwhile over 5000 sessions performed. No side effects have been reported. The feedback from patients, their relatives and physicians is overwhelmingly positive. Examples of testimonials will be presented. Additionally, placebo controlled trial is ongoing.

Conclusion

TPS treatment of the mild and moderate Alzheimer’s disease with shockwaves results in significant reduction (10‐15%) of the disease symptoms. Treatment protocols for maintaining this improvement over longer period of time are under evaluation. The treatment is effective and safe.
Pre vs post‐task modulation of resting state EEG functional connectivity and network topology
Authors: Požar Rok , Giordani Bruno , Kavcic Voyko
Published: December 2022

Background

Recently, we have shown a significant decrease in resting‐state EEG (rsEEG) spectral power at post‐task as compared to pre‐task cognitive engagement in older adults. Further, older adults with mild cognitive impairment (MCI) showed greater decreases in rsEEG in temporal and central cortical regions at post‐task than healthy controls (HC). Here, we present functional connectivity (FC) and network topology derived from the same pre‐ to post‐rsEEG changes.

Method

We studied a sample of community dwelling African American older participants over age 60 years, consisting of consensus‐based diagnosis for 58 HC and 41 MCI. rsEEGs were recorded before and after approximately 20 minutes of a visual motion direction discrimination task. FC between channels was assessed by the phase lag index, while minimum spanning tree (MST) was used to characterize network topology.

Result

For both HC and MCI groups, when compared to pre‐task measurements, the post‐task FC was significantly increased within the middle frontal, middle central, and left temporal regions in the lower alpha frequency band. An opposite pattern with decreased FC was found within the right parietal region in the delta, theta, lower alpha, upper alpha, and beta frequency bands. In contrast, compared to HC, the MCI group did show significantly decreased FC within the middle frontal region in the delta band, following the cognitive task. All results from network topology failed to demonstrate differences between HC and MCI. On average, both groups' post‐task functional network topology showed significant decreased eccentricity and diameter in the delta and beta bands, indicating a higher global network integration.

Conclusion

Our findings suggest that visual‐based cognitive engagement affects both post‐task FC and network topology similarly in both HC and MCI. For the most part, increased FC and functional topology in both groups are likely associated with after‐task effects, resulting from additional time to return to baseline, though decreased FC in MCI as compared to HC was seen within the middle frontal region in the delta. Our results demonstrate that both FC and topoloty are responsive to cognitive challenge, though frontal/executive‐driven differences in FC may be an area of future promise in distinguishing HC and MCI.
Neurovascular Uncoupling in TgF344‐AD Rats is Associated with Reduced Cerebral Capillary Endothelial Kir2.1 Expression
Authors: Fang Xing , Border Jane J. , Crumpler Reece F. , Strong Luke B. , Roman Richard J. , Fan Fan
Published: December 2022

Background

Alzheimer’s disease (AD) is an emerging global health care crisis. Although reduced cerebral blood flow (CBF) is an early and persistent symptom in developing cognitive deficits, the underlying molecular and cellular mechanisms remain unclear. Recent studies suggested that restoration of capillary endothelial cells (ECs) inward‐rectifier potassium channels (Kir2.1) currents reversed cerebral hypoperfusion and enhanced neurovascular coupling in AD mice. The present study aims to investigate whether capillary ECs Kir2.1 expression is reduced in TgF344‐AD rats and whether it contributes to neurovascular uncoupling and cognitive deficits.

Method

Three to six months old TgF‐344 AD rats expressing mutant human APP and PS1 and their age‐matched wildtype (WT) rats were studied. An eight‐arm water maze was used to test spatial learning and short and long‐term memory. Brain perfusion was mapped with a laser speckle imaging system. Whisker stimulation‐induced functional hyperemia was measured using laser Doppler flowmetry in vivo. Brain Kir2.1 expression was compared using western blot. Cerebral parenchymal arterioles (PAs) with attached capillaries were freshly isolated from AD and WT rats and mounted in a pressure myography. PAs response to capillaries focally injected KCL (10 mM) and Kir2.1 inhibitor (ML133) was compared.

Result

AD rats exhibited learning and memory dysfunction at 6‐month of age compared with WT controls. However, cerebral hypoperfusion was observed in AD rats starting from 4‐month of age. Similarly, impaired functional hyperemia in AD rats started at 4‐month of age, which was exacerbated in 6‐month old AD rats. The expression of Kir2.1 in 6‐month AD brain tissue was significantly lower than in WT rats. AD PAs displayed less vasodilation (110.96 ± 3.92 % vs. 122.93 ± 1.97 %) and vasoconstriction (92.16 ± 3.47 % vs. 78.04 ± 2.96 %) in response to capillary administered KCL and ML133, respectively, compared to WT vessels.

Conclusion

Reduced brain hypoperfusion precedes cognitive impairment in AD rats, associated with attenuated capillary EC Kir2.1 expression and neurovascular uncoupling.
Preclinical Detection and Monitoring of Alzheimer’s Disease Using a Multi‐Disease Diagnostic Platform Employing Autoantibodies as Blood‐based Biomarkers
Authors: DeMarshall Cassandra , Viviano Jeffrey , Emrani Sheina , Godsey George , Sarkar Abhirup , Belinka Benjamin , Libon David , Nagele Robert ,   Parkinson's Study Group, Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

Background

Evidence for the universal presence of serum autoantibodies and their potential diagnostic utility for detection of Alzheimer’s disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. It is well known that AD‐related pathological changes in the brain can begin up to a decade before patients experience telltale symptoms, yet preclinical detection remains an unmet goal. In the present study, we demonstrate the utility of a panel of AD‐related autoantibodies capable of detecting AD at the earliest points along the AD continuum, including preclinical AD, years before the onset of symptoms, and prodromal AD (mild cognitive impairment, MCI).

Method

Using a customized panel of AD‐specific autoantibody biomarkers and Luminex xMAP® technology, sera from ADNI subjects with preclinical AD or MCI were screened to demonstrate both preclinical and prodromal AD detection. A panel of eight autoantibodies with increased titer in MCI and preclinical AD relative to controls was evaluated using both Random Forest and Receiver Characteristic Operating curves for their ability to distinguish diseased subjects from age‐ and sex‐matched controls, as well as from individuals with other neurodegenerative and non‐neurodegenerative diseases.

Result

Results showed that the panel of eight autoantibody biomarkers was capable of differentiating patients with MCI from corresponding age‐ and sex‐matched controls with high overall accuracy, sensitivity, and specificity. These biomarkers were also capable of identifying cognitively normal subjects who later converted to MCI and AD, years before the clinical onset of their symptoms. This autoantibody biomarker panel readily distinguished MCI and preclinical AD subjects from Parkinson’s disease and breast cancer subjects, demonstrating excellent disease specificity.

Conclusion

Results demonstrate the utility of our custom Luminex xMAP® blood‐based autoantibody biomarker panel as an accurate, non‐invasive, and inexpensive diagnostic screener, not only for the detection of prodromal AD, but also the earlier stages of pathology, several years before the first onset of telltale clinical symptoms. This appears to be a multi‐disease diagnostic and disease‐staging strategy, since it has been demonstrated to be useful for a multitude of neurodegenerative diseases including both early‐stage AD and PD, as well as Multiple Sclerosis, with other disease applications currently underway
Scientific challenges underlying adaptation of existing cognitive tests or development of new tests to address cultural and linguistic diversity
Authors: Bowden Stephen C
Published: December 2022

Background

High quality cognitive assessments may be a requisite part of care for people with any disease associated with cognitive changes. While extensive research has been devoted to development of reliable and valid cognitive assessment in some cultures, the development of cognitive assessments that address cultural and linguistic diversity has been relatively neglected.

Method

This talk will provide a conceptual overview of the principal scientific issues involved in developing culturally‐sensitive and scientifically robust assessments of cognition. The issues will be illustrated with examples of successful application of these principles, together with limitations. Recent research highlighting the risks of over‐interpretation of normative comparisons across cultural or ethnic diversity will be highlighted.

Result

Two broad scientific precepts underpin development of any new cognitive test. The first of these involves establishing construct validity, that is, the scientifically defensible measurement of target cognitive functions. Secondly, a normative basis for individual assessment is desirable.

Regarding the first of these requirements, establishing construct validity can most efficiently triangulate from established cognitive measures, for example, informed by the best available model of cognitive abilities, namely the Cattell‐Horn‐Carroll model. Using the empirical methods of convergent and discriminant, any new test can be evaluated for convergence on construct estimation, within the limits of measurement error, with an established test of the target construct developed in another culture. The best available methods for this purpose involve multi‐group confirmatory factor analysis, which allows evaluation of measurement invariance (MI). If established, MI permits generalization of construct validity research across cultures.

Regarding the second broad requirement, representative normative samples are ideal for individual assessment, but are expensive. An alternative is to use an individual baseline approach where repeat assessment within any one patient provides the control standard against which to monitor change, for example, in response to progressive disease. Methods for evaluating the reliability or precision of repeat assessments will be briefly delineated.

Conclusion

Providing rigorous cross‐cultural assessment of dementia and other cognitive disorders entails addressing significant scientific challenges. However, all of challenges fall within established methods that are readily available to researchers.
Development and Validation of a Cognitive Evaluation tool for Multilingual Populations: The Visual Cognitive Assessment Test (VCAT)
Authors: Kandiah Nagaendran , Soo See Ann , Lim Levinia , Leow Yi Jin , Vipin Ashwati , Ng Kok Pin
Published: December 2022

Background

With increasing research into novel disease modifying therapies for mild cognitive impairment (MCI) and mild dementia, there is a need for large scale early detection of cognitive disorders. However, existing cognitive evaluation tools largely cater for native English speakers. We designed and validated a novel visual based cognitive evaluation tool that could be applied to multilingual populations worldwide without the need for translation.

Methods

The development of the VCAT included pilot testing of individual test items, test refinement and development of a field version of VCAT. The test items covered domains of episodic memory, executive function, visuospatial function, semantic language and attention. The initial validation was carried out in a single centre cohort from Singapore comprising of cognitively normal (CN), MCI and dementia participants. Subsequent validation was carried out in centres across four Southeast Asian countries including Singapore, Malaysia, Indonesia and Philippines. Additional evaluation of construct validity against comprehensive neuropsychological test battery has been performed. Further validation in Canada, Brazil, India and South Korea is on‐going.

Results

In the initial single centre validation in a cohort of 206 participants with a mean age of 67.8 (8.86) years and mean years of education of 10.5(6.0), the area under the curve (AUC) of VCAT for detection of cognitive impairment, CI (MCI and mild dementia) was 93.3 (95% CI 90.1 to 96.4). The Se and Sp of VCAT for the diagnosis of CI were 85.6% and 81.1%, respectively. In a wider Southeast Asian multicentre cohort of 284 participants, VCAT had an AUC of 90.5 (95% CI 87.0‐94.0) in discriminating CN from CI. The multiple languages used to administer VCAT in the four countries did not significantly influence test scores. VCAT and its subdomains demonstrated good construct validity in terms of both convergent and divergent validity and good internal consistency (α = .74). Mean time‐to‐complete VCAT was 15.7 ± 7.3 min.

Conclusions

The VCAT without the need for translation in multilingual populations has demonstrated high accuracy for the detection of MCI and mild dementia.
Development of the Figure Memory Test and the Word Accentuation Test for the assessment of cognition in Brazil
Authors: Yassuda Monica Sanches , Gil Gislaine , Apolinario Daniel , Brucki Sonia Maria Dozzi , Caramelli Paulo , Nitrini Ricardo
Published: December 2022

Background

In low‐ and middle‐income countries, the educational level of the population tends to vary significantly and persons with no literacy are in high numbers. In addition, countries with vast territories, such as Brazil, present significant differences in culture and language. These facts pose challenges for cognitive assessment. To this date, most cognitive tools used in Brazil have been developed in high‐income nations, and later, culturally and linguistically adapted for use in the country. Yet, some instruments, such as the Figure Memory Test (FMT) of the Brief Cognitive Screening Battery and the Brazilian Word Accentuation Test (WAT‐Br) have been developed in Brazil.

Method

FMT: The FMT was developed to assess episodic memory among individuals with low or no education. Twenty black‐and‐white figures were selected to compose the test because they were easily recognized and named in pilot testing with individuals with low education. Ten figures were selected as target and are named and encoded, and ten others were included as distractors in the recognition phase. In an initial study, 51 cognitively unimpaired individuals, 23 having no education, completed the FMT and other cognitive tests. WAT‐Br: The WAT‐Br was developed to assess pre‐morbid intelligence. An initial pool of 60 items was constructed and a final version of 40 items was derived by item response theory. A sample of 206 older adults underwent the WAT‐Br and a standardized neuropsychological battery. Independent ratings were performed by two observers in 58 random participants.

Result

FMT: The FMT delayed recall scores did not differ between participants with (7.26 ± 1.56) and without education (6.87 ±1.52) (p = 0.458). No differences in FMT scores were observed when the literate group was divided according to mean years of schooling. WAT‐Br: The items showed moderate to high discrimination (α between 0.93 and 25.04) and spanned a wide range of difficulty (β between ‐2.07 and 1.40). The WAT‐Br was shown to have an excellent internal consistency (Kuder‐Richardson Formula 20 = 0.95) and inter‐rater reliability (intraclass correlation coefficient = 0.92).

Conclusion

The FMT and the WAT‐Br proved to be valuable tools for estimating cognitive performance in Brazil.
Lower myelin content is associated with poorer gait variability in older adults with cerebral small vessel disease and mild cognitive impairment
Authors: Silva N‡rlon C‡ssio Boa Sorte , Liu‐Ambrose Teresa , Dao Elizabeth , Hsu Chun Liang , Tam Roger , Stein Ryan G , Alkeridy Walid Ahmed , Laule Cornelia , Vavasour Irene M
Published: December 2022

Background

Mobility decline is often observed in individuals with cerebral small vessel disease (cSVD). Loss of myelin in the cerebral white matter is a common feature of cSVD and could be one of the mechanisms contributing to poor mobility; however, this hypothesis remains to be tested. Using myelin water fraction (MWF), we investigated whether myelin content is associated with gait parameters in older adults with cSVD.

Method

Cross‐sectional data from individuals with cSVD and mild cognitive impairment were analyzed. Myelin content was assessed via MRI multi‐echo gradient and spin echo T2 relaxation sequence, indexed as myelin water fraction (MWF). Gait parameters were measured using an electronic walkway. Hierarchical regression models adjusting for total intracranial volume, age, sex, body mass index, and Mini‐Mental State Examination were conducted to determine the associations between MWF and gait parameters. Significant models were further adjusted for white matter hyperintensity burden.

Result

Sixty‐four participants were included (mean [SD], age = 75.2y [5.4], 62.5% female). In adjusted models, lower MWF in the cingulum (Unstandardized B (95% CI): ‐5.12 [‐9.21 to ‐1.04], R2change = 0.09, Fchange = 6.31, pchange = 0.015), superior longitudinal fasciculus (‐3.79 [‐7.29 to ‐0.29], R2change = 0.07, Fchange = 4.70, pchange = 0.034), posterior corona radiata (‐4.86 [‐9.45 to ‐0.27], R2change = 0.07, Fchange = 4.49, pchange = 0.039), and body of the corpus callosum (‐4.19 [‐8.19 to ‐0.20], R2change = 0.06, Fchange = 4.41, pchange = 0.040) was associated with higher cycle time variability. White matter hyperintensity burden weakened these associations.

Conclusion

In older adults with cSVD, Lower myelin content in specific white matter tracts may contribute to higher gait variability, increasing the overall risk of mobility impairment.