bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of carbamylated erythropoietin FC fusion protein (CEPO‐FC) on learning and memory impairment and hippocampal apoptosis induced by intracerebroventricular administration of streptozotocin in rats
Authors: Moosavi Maryam , Hooshmandi Etrat , Javadpour Pegah , Maghsoudi Nader , Katinger Hermann , Ghasemi Rasoul
Published: December 2020

Background

Intracerebroventricular (ICV) administration of streptozotocin (STZ) has been used as a metabolic model of sporadic Alzheimer’s disease (AD). Erythropoietin (EPO) possesses neuroprotective and memory‐improving effects, which might be advantageous in treating different characteristics of AD. Nevertheless, the hematopoietic effect of EPO has hindered its application as a neuroprotective agent. Previous studies have shown that a new Epo derivative called carbamylated Erythropoietin‐Fc (CEPO‐Fc), yield noticeable neuroprotective effects without affecting hematopoiesis. In this study, the neuroprotective effects of CEPO‐Fc on icv‐STZ induced memory impairment and hippocampal apoptosis were examined.

Method

Adult male Wistar rats weighing 250‐300 g were used. STZ was administered on days 1 and 3 (3 mg/kg in divided doses/icv), and CEPO‐Fc was administered at the dose of 5000 IU/ip/daily during days 4‐14. The animals were trained in Morris water maze during days 15‐17, and the memory retention test was performed on the 18th day. Following behavioral studies, the animals were sacrificed and their hippocampi isolated to determine the amounts of cleaved caspase‐3 (the landmark of apoptosis).

Result

The results showed that CEPO‐Fc treatment at the dose of 5000 IU/kg/ip was able to prevent the learning and memory deficit induced by icv‐STZ. Western blot analysis revealed that STZ prompted the cleavage of caspase‐3 in the hippocampus while pretreatment with CEPO‐Fc significantly reduced the cleavage of this protein.

Conclusion

Collectively, our findings suggest that CEPO‐Fc could restore STZ‐induced learning and memory impairment as well as apoptosis in the hippocampal region in a rat model of sporadic AD induced by icv‐STZ.
Posterior cortical atrophy syndrome: Asian study
Authors: Pai Ming‐Chyi , Likitjaroen Yuttachai , Lim Levinia , Ryoo Nayoung , Chiu Pai‐Yi , Hsu Jung‐Lung , Suzuki Kyoko , Chang Ya‐Ting , Kandiah Nagaendran , Kim SangYun
Published: December 2020

Background

Posterior cortical atrophy (PCA) syndrome is a rare clinical syndrome occurred in the first several years of several progressive neurodegenerative diseases, of which the manifestations are mainly confined to the impairments in the functions of posterior cerebral cortices. The underlying pathomechanisms may include Alzheimer‘s disease, Lewy body disease, corticobasal degeneration and prion disease. A consensus of the diagnostic procedures for PCA syndrome has been published in 2017, based on cases from Western countries.

Method

We invited behavioral neurologists from five Asian countries to join the study and followed the suggestions of the paper published by Scott and Crutch (2019). Each research participant investigated their cases and submitted the results to chief principal investigator. Data were analyzed and compared with those of Western countries. Moreover, a workshop was held at Tainan, Taiwan in the winter of 2019 for all investigators to reach consensus on the results.

Result

A total of 63 cases (26 male) from Taiwan, Thailand, Singapore, Korea and Japan were included. Their mean age was 64.48 (SD 8.26) years, onset age 59.7 (8.37) years, and education 10.76 (5.43) years. 94.9% of the findings of brain MRI and 86.8% of the brain SPECT supported a diagnosis of PCA syndrome. As compared with the results of Crutch et al (2017), the Asian data showed more often in space perception deficits, simultanagnosia, construction dyspraxia, oculomotor apraxia, dressing apraxia, optic ataxia, alexia, left/right disorientation, acalculia, agraphia, finger agnosia, limb rigidity, onset before 65, prominent early memory disturbance, and prominent early language disturbance, while less often in hallucination. The PCA‐plus cases (n=12), as defined by 2017 consensus, were older and more in favor of Lewy body disease. Meanwhile, PCA‐plus cases had more dressing apraxia and more alexia. PCA patients with Parkinsonism had more optic ataxia, dressing apraxia, left/right disorientation, acalculia, more relative spared memory impairment and less relative spared executive dysfunction.

Conclusion

The public awareness of PCA syndrome is inadequate, which may delay its timely diagnosis. The differences in clinical features between Asian and Western countries need further investigation.
GMP‐1 and its analogues bind Cu2+ and Zn2+ and protect neurons against amyloid beta toxicity
Authors: Winblad Bengt , Pavlov Pavel F. , Kumar Rajnish
Published: December 2020

Background

Alzheimer disease (AD) is a complex multifactorial disease representing >60 % cases of dementia with no disease modifying therapies available in clinics largely due to its poorly understood pathology. Recently, we have shown that GMP‐1, a 2‐(methoxymethyl)pyrimido[1,2‐a] benzimidazol‐4‐ol protects mitochondrial function in drosophila and mice models of AD, improved memory and behavior indicating neuroprotective effect of GMP‐1 treatment. Here, we have found that GMP‐1 specifically binds to copper and zinc, metals that are dysregulated in AD brain.

Method

Using UV/Vis Spectroscopy we have determined specificity and stoichiometry of metal binding to GMP‐1. To investigate GMP‐1 impact on metal‐dependent enzymatic reactions we have used proteolysis assay with Zn2+‐dependent collagenase and Cu2+‐dependent cytochrome c oxidase assay. Time course thioflavin T fluorescence was used to assess the effect of GMP‐1 and its analogues on amyloid beta fibrillization in the presence of Cu2+. The effect of GMP‐1 and its analogues on ROS production and viability of differentiated SH‐SY5Y cells in the presence of amyloid beta and metals was evaluated using DCFDA and TUNEL assay, respectively.

Result

GMP‐1 specifically binds to copper and zinc, metals that are dysregulated in AD brain. Addition of GMP‐1 does not inhibit metal‐dependent enzymatic reactions. Binding of Zn2+ and Cu2+ by the GMP‐1 is weaker than the 8‐hydroxyquinoline scaffold compound clioquinol (CQ) previously tested in AD clinical trials. However, GMP‐1 affects Cu2+‐dependent Ab fibrillization as well as oxidative damage and viability of SH‐SY5Y cells upon addition of Cu2+ and Ab.

Conclusion

Our data provide new insight on GMP‐1 as Zn2+ and Cu2+ specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models.
Clinical study on intracranial venous system lesions and cognitive impairment
Authors: Qian Hairong
Published: December 2020

Background

Vascular cognitive impairment and Alzheimer's disease are the two major causes of cognitive impairment. Previous studies have focused on the relationship between arterial‐derived diseases and/or small cerebrovascular disease and cognitive impairment, but the cognitive impairment caused by intracranial venous system lesions has received less attention. Intracranial venous system lesions include venous sinus thrombosis, deep vein thrombosis, cortical venous thrombosis, chronic subdural hematoma, dural arteriovenous fistula, venous collagen disease, etc. The pathogenesis and clinical characteristics of cognitive impairment caused by different lesions are different.

Method

48 cases of intracranial venous lesions including venous sinus thrombosis, deep vein thrombosis, cortical venous thrombosis and dural arteriovenous fistula admitted to the department of neurology of the sixth medical center of PLA general hospital were retrospectively analyzed.

Result

24 cases of venous thrombosis related lesions were male and 14 were female, aged 18‐80 years, including 20 cases of venous sinus thrombosis, 8 cases of deep venous thrombosis, 10 cases of cortical venous thrombosis, with 8 cases of acute cognitive impairment. There were 10 cases of dural arteriovenous fistula, with 6 cases of cognitive impairment. The main clinical manifestations of cognitive impairment were decreased execution speed, forgetfulness, dysarthria, mental changes, urinary incontinence and gait abnormalities. The patients with subcortical white matter, thalamus and other white matter areas involved have more obvious cognitive impairment, while those with mild cortical involvement have relatively less cognitive impairment. The incidence of cognitive impairment of older people was higher than that of younger people, and the incidence was higher in those with significant white matter damage.

Conclusion

Cognitive impairment caused by intracranial venous system lesions are tightly linked with cerebral white matter lesions in addition to lesions of key parts of brain damage, which may be related to increased intracranial pressure and other factors caused by venous reflux obstacle. Cognitive impairment with venous system lesion deserves more clinical attention and may provide more insights into the causes of dementia.
The IMI‐EU H2020 project MOPEAD: Outcome of different screening methods to identify MCI/early AD
Authors: Winblad Bengt , Jessen Frank , Kramberger Milica G. , Visser Pieter Jelle , Rodrigo Adrián , Jamilis Laura , Rodriguez‐Gomez Octavio , Sannemann Lena , Zwan Marissa D. , Bon Jaka , Johansson Gunilla , Nelvig Anders , Haglund Anders , Jelic Vesna , Campo Laura , Wimo Anders , Boada Mercè , Consortium MOPEAD
Published: December 2020

Background

The MOPEAD project (Rodríguez‐Gómez O et al, Alzheimers Dement 2019) aims to explore different ways to stimulate early diagnosis of Alzheimer Disease (AD). Four innovative pre‐screening strategies are pursued to identify individuals at high risk for mild cognitive impairment (MCI) or early AD. We aimed to validate positive results from these pre‐screening strategies by performing a full clinical evaluation of the patients at specialized memory clinics.

Method

Individuals with a positive pre‐screening result were referred to one of the five participating memory clinics in Ljubljana (Slovenia), Barcelona (Spain), Stockholm (Sweden), Amsterdam (Netherlands), and Cologne (Germany). A harmonized clinical evaluation including physical, neurological, neuropsychological and functionality assessment was performed in these centers as well as MRI neuroimaging and optional cerebral spinal fluid sampling. Based on the result of this evaluation, we estimated the positive predictive value (PPV) of the different pre‐screening strategies, as the proportion of patients with MCI or AD among all referred individuals.

Result

A total of 402 individuals with a positive pre‐screening result were evaluated: 91 from a web‐based pre‐screening tool, 161 from an open house initiative, 94 patients from a primary care‐based pre‐screening, and 56 patients identified at diabetes clinics. The number confirmed cases of MCI/AD and PPV were 49(53.8%), 82(50.9%), 58(61.7%), and 47(83.9%) respectively. Within pre‐screening strategy, the results varied greatly between participating countries. Thus, PPV for the web‐based tool was 0% in Germany, and over 70% in Spain and Sweden. Similarly, PPV for the open house initiative was 3% in the Netherlands, but over 95% in Spain. Germany and the Netherlands showed the lowest PPVs (20% and 17% respectively) for the primary care‐based strategy, whereas the all remaining countries had PPVs well over 70%. Country‐specific PPVs estimates in the diabetes clinic strategy were not very reliable due to the small number of patients evaluated.

Conclusion

We were able to confirm more than half of patients with a positive result in all four pre‐screening strategies being evaluated. However, our results suggest that despite the harmonization efforts, PPVs of these innovative pre‐screening strategies are highly dependent on the study site.
Small vessel disease neuroimaging markers contribute robustly and independently to longitudinal cognitive decline in older adults
Authors: Bown Corey W. , Khan Omair A. , Liu Dandan , Cambronero Francis E. , Moore Elizabeth E. , Jindal Ria , Pechman Kimberly R. , Schrag Matthew , Davis L. Taylor , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L.
Published: December 2020

Background

Cerebral small vessel disease (SVD) is visible on brain magnetic resonance imaging (MRI) as white matter hyperintensities (WMHs), perivascular spaces (PVS), cerebral microbleeds (CMBs), and lacunes. This study expands our prior cross‐sectional work and examines how these four markers contribute to longitudinal cognitive trajectory to assess whether these markers represent common versus unique pathways of injury.

Methods

Vanderbilt Memory and Aging Project participants free of baseline clinical stroke and dementia (n=327, 73±7 years, 41% female) completed multimodal 3T brain MRI to quantify WMHs, PVS, CMBs, and lacunes at baseline and neuropsychological assessment at multiple time points (baseline, 18‐month, 3‐year, 5‐year). Linear mixed‐effects regression models related each baseline SVD marker to longitudinal neuropsychological trajectory through interaction with follow‐up time, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, diagnosis, apolipoprotein E‐e4 status, and intracranial volume.

Results

Mean follow‐up time was 3.9±1.1 years. Increases in each SVD marker related to faster episodic memory decline (p‐values≤0.04). Increased lacunes (p=0.04), WMHs (p≤0.008), and CMBs (p≤0.001) related to information processing speed decline. Increased WMHs (p=0.02) and CMBs (p=0.03) related to executive function decline. Increased WMHs related to language decline (p=0.02). Increased CMBs related to visuospatial decline (p=0.03). In combined models simultaneously considering multiple statistically significant SVD markers in relation to cognitive outcomes, WMHs independently predicted faster information processing speed (p=0.03), executive function (p=0.05), and episodic memory decline (p=0.02) beyond all other SVD biomarkers. CMBs independently predicted information processing speed decline beyond lacunes and WMHs (p‐values≤0.04). PVS independently predicted episodic memory decline beyond lacunes and CMBs (p=0.03).

Conclusions

Increased SVD, including PVS, CMBs, lacunes, and especially WMHs, was associated with faster longitudinal cognitive decline. In competitive models, WMHs consistently predicted faster decline in multiple domains despite inclusion of other significant SVD predictors. In a subset of models, CMBs and PVS independently predicted faster longitudinal cognitive decline yet lacunes did not. Thus, WMHs, CMBs, and PVS may each reflect a unique pathway of injury whereas lacunes may not. Funding: F31‐AG066358, T32‐AG058524, Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373.
Abnormal brain structure mediates the association between ApoE4 and slow gait among patients with pathological cognitive impairment: Results from the Ontario Neurodegenerative Research Initiative
Authors: Sakurai Ryota , Faria‐Pieruccini Frederico , Dilliott Allison Ann , Hegele Robert , Tartaglia Carmela , McLaughlin Paula , Binns Malcolm , Blue Korbin , Cornish Ben , Sunderland Kelly M , Beaton Derek , Haddad Seyyed M.H. , Tan Brian , Swartz Richard H. , Kwan Donna , Masellis Mario , Ramirez Joel , Roberts Angela C , Black Sandra E. , Symons Sean , Strother Stephen C , Borrie Michael , Pasternak Stephen H. , Freedman Morris , Bartha Robert , Lang Anthony , Munoz Douglas , McIlroy Bill , Montero‐Odasso Manuel
Published: December 2020

Background

Presence of at least one copy of the polymorphic apolipoprotein E ε4 allele (ApoE4) increases the risk of impairments of gait performance, particularly in elderly individuals with cognitive impairment or at risk of dementia; however, its underlying neural mechanism are unclear. This study examined the association among ApoE4, gait performance, and brain structural changes among elderly individuals with cognitive impairment.

Method

Overall, 269 older adults with Alzheimer’s disease, cerebrovascular disease with and without cognitive impairment, and mild cognitive impairment were included from the Ontario Neurodegenerative Disease Research Initiative, who were either ApoE4 carriers (n=98) or non‐ApoE4 (n=171) carriers. Gait speed was measured using an electronic walkway; speed <1 m/s was defined as slow gait. Participants were stratified into four groups according to the presence of at least one copy of ApoE4 and slow gait. Region of interest volumes were derived by automated segmentation using a 3.0T magnetic resonance imaging system.

Result

Among ApoE4 carriers, 65 (24.2%) participants had slow gait. ApoE4 carriers with slow gait showed significantly higher burden of white matter hyperintensities compared with ApoE4 carriers without slow gait. Moreover, they had significantly lower hippocampal volume and greater total sulcal cerebrospinal fluid volume compared with non‐ApoE4 carriers with slow gait. These differences remained significant despite controlling for covariates (e.g., demographic and clinical characteristics, including participant type).

Conclusion

Our results suggest that brain structural changes, attributable to Alzheimer’s pathology, may mediate the association between ApoE4 and slow gait among elderly individuals with pathological cognitive impairment.
The relationship of a white matter hyperintensities rating scale and cognition among Mexican Americans
Authors: Vintimilla Raul , King Kevin , Braskie Meredith N. , Yaffe Kristine , Toga Arthur W. , Johnson Leigh Ann , Hall James R. , O'Bryant Sid
Published: December 2020

Background

White matter hyperintensities (WMHs) are a common manifestation of white matter damage. Mexican Americans (MAs) comprised 65% of the Latino population in the US, and they suffer a higher burden of cardiovascular risk factors that can influence the prevalence of WMHs. The purpose of this study was to examine the relationship between a WMHs rating scale and cognitive functioning in a sample of MA elders. This study extends the limited literature about WMHs and cognition in this underserved population.

Method

We studied 361 (266 females, mean age 61.86) cognitively normal MAs from the Health and Aging Brain Among Latino Elders Study (HABLE). MPR and Flair images were obtained using a 3T MRI system (Skyra, Siemens Healthineers). Quantification of WMHs was performed according to the King rating scale, which is based on the lesion size regardless of location. A one‐way ANOVA was conducted to examine the association of the King rating scale (low versus high scores) with the MMSE, logical memory I and II, Trails B, FAS, digit symbol substitution, and digit span scores. Age, sex, and education were entered as covariates in the model.

Result

Subjects with low WMHs rating scale scores (grades 0 and 1 on the King scale) differ from subjects with high WMH rating scale scores (grades 2 and 3 on the King scale) in tests of global cognition and executive function. MMSE and Trails B mean scores were significantly lower in the high WMH rating scale group when compared with the low rating scale group. ANOVA revealed a difference between groups for MMSE, F(1,359) = 8.75, p = 0.003, and Trails B, F(1,335) = 20.73, p < 0.001, after adjusting for demographics. There was no association with other cognitive tests.

Conclusion

Our findings suggest a relationship between global cognition and executive function measures with WMHs, independent of age, sex, and education, among older non‐demented MAs.
Comparing versions of the memory binding test: Predictive validity for incident aMCI and incident dementia
Authors: Mowrey Wenzhu , Lipton Richard B. , Katz Mindy J. , Ramratan Wendy S. , Loewenstein David A. , Buschke Herman
Published: December 2020

Background

The Memory Binding Test (MBT) Version 1 demonstrated significant predictive validity for incident amnestic MCI (aMCI) and incident dementia. Version 2 of the MBT was developed to be briefer because brevity is essential for screening. Herein we aimed to compare the two versions in terms of predictive validity for aMCI and dementia, separately.

Method

As sub‐studies of the Einstein Aging Study (EAS), the two MBT versions were administered to two independent study samples between May 2003 and December 2007 at baseline, and these participants were followed up to Jan 2017 (For differences in versions see Table 1). The EAS enrolls a systematically recruited community sample of adults age over 70. The two versions were evaluated in parallel using the same methodologies. We evaluated a range of cut‐scores on the MBT score of choice, the Total Items in the Paired condition (TIP), including the empirical optimal cut‐score which maximized the sum of sensitivity and specificity from the cross‐sectional discriminative analyses. The predictive validity was assessed by Kaplan‐Meier curves, log‐rank tests and Cox regressions.

Result

Predicting incident aMCI: Both versions were strong predictors of incident aMCI (Table 2): For the empirical optimal scores for TIP, hazard ratio (HR)=2.33, 95% CI: (1.26, 4.29), p=.007 for Version 1, HR=3.38, 95% CI: (1.09, 10.5), p=0.04 for Version 2; for a range of TIP scores (17−22): HR range: 2.27−6.07, p ≤ .01, for Version 1, and 2.67−5.91, p≤.04 for Version 2. Predicting incident dementia: Both versions were strong predictors of incident dementia (Table 3): For the empirical optimal scores for TIP, HR=8.32, 95% CI: (3.51, 19.7), p<.0001 for Version 1, HR=9.30, 95% CI: (3.43, 25.2), p<.0001 for Version 2; for a range of TIP scores (17−23): HR range: 3.09−8.32, p ≤ .003, for Version 1, and 6.40−9.30, p<.0001 for Version 2.

Conclusion

The predictive validity for incident aMCI and incident dementia was strong and similar for the two versions of the MBT based on the overlapping confidence intervals. These results strongly support the hypothesis that poor performance on memory binding is an important marker for the early detection of aMCI and dementia.
Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer’s disease: A phase 2, double‐blind, randomized, placebo‐controlled trial
Authors: Turner Raymond Scott , Hebron Michaeline , Lawler Abigail , Mundel Elizabeth , Yusuf Nadia , Starr Nathan , Pagan Fernando , Torres‐Yaghi Yasar , Shi Wangke , Mulki Sanjana , Ferrante Dalila , Matar Sara , Liu Xiaoguang , Esposito Guiseppe , Berkowitz Frank , Jiang Xiong , Ahn Jaeil , Moussa Charbel E‐H
Published: December 2020

Background

The goal is to assess the safety, tolerability, and pharmacokinetics of nilotinib, and measure biomarkers in participants with mild to moderate dementia due to Alzheimer’s disease. We hypothesized that nilotinib is safe and detectable in cerebrospinal fluid. Nilotinib may alter disease biomarkers and potentially slow clinical decline.

Method

This is a single‐center, phase 2, randomized, double‐blind, placebo‐controlled study. Of 117 individuals approached, 13 declined, 51 were excluded, 51 were screened, and 37 were randomized 1:1 to placebo or nilotinib groups. The Alzheimer’s disease diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg vs matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg vs placebo for another 26 weeks.

Result

Of the 37 individuals enrolled, 27 were women (73%), and the mean (SD) age was 70.7 (6.48) years. Nilotinib was safe and well‐tolerated, although more adverse events, particularly mood swings, were noted at the 300 mg dose (70.6%) vs placebo (0%) groups (p<.01). In the nilotinib group, amyloid burden was reduced in the temporal (‐0.08, 90% CI, ‐0.21 to ‐0.01, p=.04) and frontal lobes (‐0.19, 90% CI, ‐2.29 to ‐0.08, p<.001) compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months (566ng/ml, 90% CI, 135 to 1018, p=.02) and Aβ42 was reduced at 12 months (73.9 ng/ml, 90% CI, 14.3 to 137.9, p=.02) in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (‐27%) at 12 months and phospho‐tau181 was reduced at 6 months (‐31.6%) and 12 months (‐39.6%) in the nilotinib group.

Conclusion

Nilotinib is safe and well‐tolerated, and achieves pharmacologically relevant brain concentrations. Biomarkers of Alzheimer's disease were altered in response to nilotinib treatment. These data support a larger, multi‐center, phase 3 study to determine the safety and efficacy of nilotinib in Alzheimer’s disease. ClinicalTrials.gov NCT02947893.
Informant's perceptions and objective cognitive decline among Mexican older adults with a history of traumatic brain injury with and without loss of consciousness
Authors: Piña‐Escudero Stefanie Danielle , de Jesús García Aviles Roberto , Chodos Anna H. , Ritchie Christine S. , Avila Jose Alberto
Published: December 2020

Background

Traumatic Brain Injury (TBI) is extremely common across the lifespan and is an established risk factor for dementia, including Alzheimer's disease. However, the effect of TBI with loss of consciousness (LOC) history on cognitive change with aging and how it is perceived by caregivers are poorly understood.

Methods

Cross‐sectional study analyzing 1681 community‐dwelling older adults from the MHAS‐Cognitive Aging Ancillary Study. TBI status (control, TBI without LOC and TBI with LOC) was defined by an affirmative answer to the questions: “Have you ever hurt your head or neck in an accident?” and “Did you lost consciousness as a result of the injury?”. Cognition was measured by a global cognitive score (GCS) that comprised the sum of six cognitive domains. Informants' cognitive perception scores were measured with the Community Screening Instrument for Dementia (CSID). For analysis, chi square and ANOVA were used to describe the sample. Linear regression models adjusting for age, sex, years education, number of comorbidities, functionality and depressive symptoms were built to test the association between TBI status and cognitive scores as well as TBI status and CSDI scores.

Results

The mean age of the population was 68(+8.6) years, 68% were women, the mean of years of education was 5.5(+4.4), and 14.6% had history of LOC. Simple linear regression models showed a positive association between TBI status and GCS status (β=‐0.078, p=0.001). This association was also observed with the following cognitive domains: orientation (β=‐0.053, p=0.28), immediate recall (β=‐0.088, p=<0.001), delayed recall (β=‐0.073, p=0.003), attention (β=‐0.062, p=0.011) and executive function (β=‐0.06, p=0.010). A significant association with CSID scores was also revealed (β=0.131, p=<0.001) and it was the only association that remained significant after adjustment (β=0.073, p=<0.001).

Conclusion

Findings from this study suggest that TBI with LOC is not independently associated with cognitive scores in older adults. However, TBI with LOC is significantly associated with CSDI scores even after adjustment. Informant's perceptions reflect that LOC might have and influence in the cognitive skills that older adults use in their everyday life that testing could not accurately capture in a population with low education.
Medication‐related problems in older adults with and without preclinical Alzheimer’s disease: A baseline description from the INCREASE study
Authors: Martinez Ashley I. , Eckmann Lynne , Huffmyer Mark , Beech Brooke F. , George Rosmy , Hall Megan , Abner Erin L. , Jicha Gregory A. , Schmitt Frederick A. , El Khouli Riham H. , Moga Daniela C.
Published: December 2020

Background

Older adults are susceptible to negative cognitive effects induced by inappropriate medication use.1 Some individuals may accumulate amyloid‐β deposits before symptomatic expression, suggesting preclinical Alzheimer’s disease (pAD). Inappropriate medication use may interact with this neuropathology to hasten symptomatic AD onset. Thus, we designed INCREASE: a randomized controlled trial (RCT) to improve medication use through targeted medication therapy management (tMTM) and ultimately delay AD symptomatic expression.2

Methods

Community‐dwelling non‐demented adults ≥ 65 years old who regularly used ≥1 potentially inappropriate medication3 were recruited for the RCT. Board certified geriatric pharmacists reviewed medication lists and identified medication‐related problems (MRPs) at baseline for all participants before conducting the tMTM intervention. Here, we describe this initial medication review, stratified by pAD status. pAD was defined as total brain relative standardized uptake values > 1.4 for PET amyloid.3 Group differences were identified using Student’s t‐tests.

Results

79 participants were included in this analysis (mean age 73.9 years [SD 5.9]; 66% female). 12.9 (4.9) baseline medication were reported on average, which did not differ significantly between participants with (14.2 [4.8]) and without (12.3 [5.1]) pAD. The most commonly reported medication classes were proton pump inhibitors, antihistamines, non‐steroidal anti‐inflammatory drugs, and vitamins/supplements. On average, 4.9 (SD 2.3) MRPs were identified per participant (389 MRPs total). The most common causes of MRPs were: 1) a medication not appropriate given the participants’ age and/or medical conditions; 2) dose/frequency too high; and 3) untreated medical condition. The most common recommendation by the pharmacist was to deprescribe the problem medication. There were no differences in the number or causes of MRPs based on pAD status.

Conclusion

Non‐demented older adults enrolled in an MTM RCT used more than ten medications concurrently, with about 5 MRPs identified in each participant. INCREASE will test the hypothesis that deprescribing these inappropriate medications may delay symptomatic AD. Given that the pharmacokinetics and pharmacodynamics of this population puts them at high risk for adverse drug events including cognitive impairment, future work should continue to optimize medication use to prevent cognitive decline. References: 1. Moga DC, et al. Trials. 2019;20(1):806. 2. Jack CR, et al. Brain. 2015;138(12):3747‐3759. 3. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246.
Left frontal white matter atrophy links to timing mechanisms relevant for apraxia of speech
Authors: Bruffaerts Rose , Schaeverbeke Jolien , Grube Manon , Griffiths Timothy , Sunaert Stefan , Vandenberghe Rik
Published: December 2020

Background

In patients with apraxia of speech (AOS), we observed impaired perceptual timing abilities, which lead us to propose a shared mechanism of impaired timing processing underlying both impaired perceptual processing and motor speech output [1]. Given that white matter damage is often observed in AOS, we here investigate whether white matter changes are related to impaired perceptual timing as one possible mechanism underlying AOS.

Method

A psychoacoustic and multimodal neuroimaging analysis was performed in 12 patients with the nonfluent variant (NFV) of Primary Progressive Aphasia (PPA) with AOS, 11 patients with the semantic variant and 24 controls. During the four perceptual timing tasks (r1‐r4, [1]), participants had to detect the longer gap in pairs of tones (r1) or in a sequence of tones (r2) or discriminate between rhythmic sequences with a strongly (r3) or weakly (r4) metrical beat. Speech rhythm was quantified in connected speech by means of the normalized pairwise variability index (PVI). Deformation‐based morphometry (DBM) and diffusion tensor imaging (DTI) were acquired on a 3T MRI and processed using CAT12 and MRTRIX3, respectively. We determined Fractional Anisotropy (FA) and Mean Diffusivity (MD) values for the left Aslant tract, which is typically damaged in NFV.

Result

Seventy‐five percent of NFV patients displayed impaired perceptual timing, specifically when discriminating between rhythmic sequences (r3‐r4, transformed to z‐scores, Figure 1). Impaired perceptual timing correlated with abnormal vowel lengthening (correlation of r3 and PVI of strong‐weak words: r = 0.65, P = 0.029). Moreover, left frontal white matter volume loss adjacent to the supplementary motor area (SMA) correlated with impaired perceptual timing (r3) in NFV (Figure 2, cluster‐level FWE‐corr. P<.05). MD in the left Aslant tract also correlated with perceptual timing in NFV (correlation with r3: r = 0.82, P = 0.026).

Conclusion

A shared white matter substrate adjacent to the SMA links impaired perceptual timing and motor speech impairment. Our data indicates that impaired timing may be one of the neurocomputational mechanisms underlying AOS. Moreover, regional variations in left frontal lobe atrophy explain part of phenotypical heterogeneity in NFV. Resource: (1) Grube, Bruffaerts, Schaeverbeke et al., Brain 2016.
Predictors of acceptability and emotional response to computerized neuropsychological assessments in older adults: The CogSCAN Study
Authors: Rossie Matilda , Croot Karen , Allison Karen C. , Brodaty Henry , Crawford John D. , Lee Teresa , Henry Julie D. , Draper Brian , Close Jacqueline , Ong Min Yee , Lam Ben C. P. , Sachdev Perminder S. , Kochan Nicole A.
Published: December 2020

Background

Computers and related technologies are increasingly used for cognitive assessment. However, few studies have considered older adults’ experience using computerized neuropsychological assessment (CNA), or individual characteristics that may influence acceptability and emotional responses to computerized tests.

Method

205 community‐dwelling native English speakers aged 60‐95 were randomly assigned to complete two of four CNA batteries: Cogstate, CANTAB, CBS, and NIH Toolbox, on an iPad. After test completion, participants rated their emotions during testing on a Mood Adjective Checklist (MAC) with four subscales ‐ high stress (worried), low stress (relaxed), high arousal (energised), low arousal (tired), and provided ratings of test acceptability. Multiple regression analyses investigated associations of demographics (age, sex, education), cognitive level (MoCA, premorbid ability), subjective memory, mood over the past week (depression, anxiety, stress), computer/technology attitudes and experience, with the four MAC subscales and test acceptability score. Parallel analyses were performed in a subsample of participants also completing a pen‐and‐paper neuropsychological battery (PnP). Potential differences in predictors for CNA and PNP and the influence of potential confounders (PnP yes/no, CNA test pair) were examined.

Result

Over half of the participants had considerable experience with computers or tablets (Table 1). Demographics were not significantly related to emotion ratings or test acceptability and were excluded from further analyses. Higher stress over the past week was associated with feeling more worried and tired during test‐taking. Higher premorbid ability was associated with feeling less relaxed (Table 2). Greater computer anxiety, higher premorbid ability and more computer experience were associated with lower CNA acceptability. Although some predictors of PnP acceptability and emotional response differed (Table 3), interactions between predictors and testing mode were non‐significant for all outcome variables (p’s> .05). Inclusion of potentially confounding variables did not alter the overall findings.

Conclusion

Recent mood, cognitive level, computer attitudes and experience influenced emotions during testing and test acceptability. These relationships and their potential association with CNA and PnP performance will be investigated in future work. Data on emotional response to testing and test acceptability will need to be triangulated with psychometric information about CNA and PnP measures to determine the most suitable test options for individuals.
Decreased cortical thickness in individuals with subjective cognitive decline with and without CSF‐AD‐pathology: Data from the DELCODE Study
Authors: Meiberth Dix U. , Hu Xiaochen , Schild Ann‐Katrin , Spottke Annika , Brosseron Frederic , Buerger Katharina , Fließbach Klaus , Heneka Michael T. , Kilimann Ingo , Laske Christoph , Peters Oliver , Priller Josef , Schneider Anja , Teipel Stefan J. , Wiltfang Jens , Wagner Michael , Düzel Emrah , Jessen Frank ,   DELCODE Study Group
Published: December 2020

Background

Subjective cognitive decline (SCD) without objective performance deficits reflects in some individuals the earliest symptomatic manifestation of Alzheimer’s Disease (AD) at the late preclinical stage1,2. It is crucial to delineate the relationship between SCD, AD‐specific biomarkers and the localization of early neurodegeneration.

Method

We included the baseline‐dataset of the DELCODE‐study3 (n=943), from which 404 subjects (57 AD, 89 mild cognitive impairment (MCI), 171 SCD, and 87 healthy controls (CO)) received both CSF‐biomarker‐assessment (Aβ‐42, total‐tau, phosphorylated‐tau) and structural MRI. Cortical thickness was estimated with the FreeSurfer‐Software‐package version 6.0. ANCOVAs with one between‐subject factor of diagnosis, and age, sex, and scanner‐sites as covariates were calculated for the bilateral entorhinal cortices (EC) and bilateral parahippocampi (PH), respectively. Two‐way ANCOVAs with between‐subject factors of diagnosis (SCD/CO) and CSF‐biomarkers (positive/negative) and the same covariates were calculated for each of the regions of interests (ROIs) and CSF‐biomarkers.

Result

Significant main effects for diagnosis were found for the one‐way‐ANCOVAs for all ROIs (p<0.001; bilateral EC and left PH: HC=SCD>MCI>AD; right PH: HC>SCD>MCI>AD). Two way‐ANCOVA showed significant main effects for diagnosis for the bilateral PH‐thickness (left: p=0.031; right: p=0.013), and an interaction between diagnosis and CSF‐Aß42 for the left PH‐thickness (p=0.022). Post‐hoc analyses showed the interactions were driven by decreased bilateral PH and left EC thickness in SCD subjects compared to CO in the Aβ42 positive subgroups only (p<0.05), not between the Aß42 negative subgroups. Two‐way‐ANCOVA showed also significant interaction effects between the diagnosis and total‐tau, and between the diagnosis and phosphorylated‐tau in the right EC (t‐tau: p=0.011; p‐tau: p=0.004), where SCD subjects had lower right entorhinal thickness than controls in the tau positive subgroups.

Conclusion

We found decreased bilateral parahippocampal and left entorhinal thickness in persons with SCD compared to controls in all amyloid‐positive cases. In addition, the right entorhinal cortex seems to be affected in SCD compared to controls in all tau positive cases. These data suggest that, in addition to positive AD pathology indicated by CSF biomarkers, the first clinical symptoms such as cognitive complaints may also indicate early degenerative processes in the course of the disease.
Awareness of cognitive decline and CSF‐biomarkers in memory clinic patients: Results from the DELCODE‐study
Authors: Miebach Lisa , Kleineidam Luca , Peters Oliver , Priller Josef , Buerger Katharina , Teipel Stefan J. , Perneczky Robert , Laske Christoph , Schneider Anja , Heneka Michael T. , Spottke Annika , Wiltfang Jens , Düzel Emrah , Jessen Frank , Wagner Michael
Published: December 2020

Background

Decreased awareness of cognitive deficits is a common symptom of dementia. Less is known about the evolution of decreased awareness in earlier stages of Alzheimer’s Disease (AD). Recent studies using the discrepancy between self‐ and informant report found reduced awareness in many patients with mild cognitive impairment (MCI), but generally heightened awareness in cognitively normal individuals with Amyloid pathology. In memory clinic samples, patient and caregiver ratings of cognitive decline were associated with AD‐biomarkers. We investigated in the relationship between CSF‐biomarkers, informant ratings and reduced self‐awareness in a large memory‐clinic sample.

Methods

We analyzed data from n=323 patients with available CSF‐biomarkers (age=71.17; SD=5.71) from the DELCODE‐study (n=211 SCD‐patients; n=112 MCI‐patients). Cognitive complaints in five different domains were assessed using a self‐ and informant rated interview form (Miebach et al. 2019). Reduced self‐awareness was calculated using a self‐/informant discrepancy score. The relationship with CSF‐biomarker was examined using linear regression, controlling for demographic variables and objective memory performance. Participants were classified using the ATN‐system for the diagnosis of preclinical AD.

Results

All patients reported a cognitive decline in at least 3 domains. On average, SCD participants had positive self‐awareness scores (M=1.20; SD=1.87), indicating more self‐ than informant reported decline, while this significantly reversed in MCI (M=‐.514; SD=1.67). In the total sample, the discrepancy was associated with CSF‐Aß‐42 (ß=.213; p<.000), CSF‐t‐Tau (ß=‐.163; p<.005) and CSF‐Aß/tau‐ratio (ß=.232; p<.001). This association was similar in SCD and MCI. Regarding Biomarker profiles, n=66 participants were classified as A+/T+, n=38 as A+/T‐; n=139 participants were classified as A‐T‐N‐ and n=80 as non‐AD‐pathologic change. Participants with an AD‐typical Biomarker profile (A+/T+) had significantly higher informant than self‐ratings of cognitive decline (p<.001) and reduced awareness (p<.003).

Conclusion

In memory clinic patients, lower awareness (i.e. relatively less self‐ than informant rated complaints) was associated with CSF‐Aß‐42, t‐Tau and the Aß/tau‐ratio. The relationship with CSF‐Aß42 and Aß/tau ratio was independent from objective memory impairment, showing that in the absence of objective impairment (i.e. SCD stage) informant ratings of cognitive decline are particularly informative. Results support the use of informant ratings in memory clinic samples, and the inclusion of an informant confirmation in the SCD‐plus criteria, specifying which features increase the likelihood of AD‐pathology in SCD.
Diabetes mellitus, HBA1C, and in vivo Alzheimer’s disease pathologies
Authors: Han Dongkyun , Byun Min Soo , Yi Dahyun , Lee Jun Ho , Byeon Gihwan , Joung Haejung , Moon Seok Woo , Sohn Bo Kyung , Lee Jun‐Young , Kim Yu Kyeong , Lee Yun‐Sang , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research Group
Published: December 2020

Background

Although previous studies have reported associations of diabetes mellitus (DM) with cognitive impairment or dementia, the exact pathophysiological links underlying the associations remain incompletely understood. In this context, we aimed to investigate the associations of DM or glycated hemoglobin (HbA1c) with in vivo Alzheimer’s disease (AD) pathologies such as cerebral beta‐amyloid protein (Aβ) deposition and tau deposition.

Method

Total 136 participants (71 cognitively normal, 31 mild cognitive impairment, and 34 AD dementia) from the Korean Brain Aging Study for Early Diagnosis & Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study, were included for this analysis. All participants underwent comprehensive clinical and neuropsychological assessment, 11C labelled Pittsburgh Compound B (PiB) positron emission tomography (PET), 11F AV‐1451 PET, magnetic resonance imaging, apolipoprotein E genotyping, and HbA1c measurement.

Result

Neither the presence of DM nor HbA1c level was associated with global Aβ deposition after controlling for age, sex, education, vascular risk score (except DM), apolipoprotein e4 positivity, and clinical diagnosis. In contrast, higher HbA1c was significantly associated with lower AD‐signature region tau deposition and the presence of DM showed a trend level association with decreased tau deposition. Additionally, we found significant Aβ deposition x HbA1c (or the presence of DM) interaction effect on tau deposition. While higher Aβ deposition was significantly related to increased tau deposition in lower HbA1c (or DM negative) subgroup, there was no such relationship between Aβ and tau deposition in higher HbA1c (or DM positive) one. Sensitivity analyses including only cognitively normal individuals also showed similar results.

Conclusion

Our results indicate that DM or higher blood glucose may not contribute to cognitive impairment or dementia via AD‐specific pathologies, especially amyloid deposition. Therefore, other non‐AD pathophysiological contributions including vascular pathologies should be considered. Although being very cautious, high blood glucose may relate to delayed brain tau deposition.
Transcutaneous vagal nerve stimulation effects on the salience network in patients with amnestic mild cognitive impairment
Authors: Williamson John B. , Lamb Damon G. , Porges Eric , Murphy Aidan J. , Cohen Ronald , DeKosky Steve
Published: December 2020

Background

Better treatments are needed to improve cognition and reduce the disability associated with MCI and Alzheimer’s disease (AD). Transcutaneous vagal nerve stimulation (tVNS) may impact brain networks relevant to AD through multiple mechanisms: the vagus projects to the nucleus tractus solitarius (NTS) which in turn projects to the locus coeruleus (LC), the brain’s primary source of norepinephrine (NE). The NTS also projects directly to the hippocampus, as does the LC. Neuropathological data suggest that the LC may be an early site of AD pathology. Thus, tVNS may modify the activity of several networks that are impaired and that progressively deteriorate in patients with MCI and AD.

Method

24 patients with mild cognitive impairment (MCI) confirmed via diagnostic consensus conference (sources of info: Montreal Cognitive Assessment Test [MOCA], Clinical Dementia Rating scale (CDR), Functional Activities Questionnaire (FAQ) , Hopkins Verbal Learning Test – Revised [HVLT‐R] and medical record review) were assessed during rest using functional magnetic resonance imaging (fMRI) on a Siemens 3T scanner during tVNS (left tragus, n = 12) or under sham control conditions (ear lobe, n = 12).

Result

During unilateral left tVNS, patients with MCI showed increased functional connectivity between nodes of the salience network, the anterior cingulate, and the supramarginal gyrus from both the right and left temporal poles.

Conclusion

In patients with MCI, tVNS modified cognitively relevant brain networks whose degeneration predicts deterioration in AD. These findings demonstrate afferent target engagement of tVNS which carries implications for noninvasive therapeutic intervention in this population.
Noradrenergic contributions to cognitive decline and treatment potential in progressive supranuclear palsy and Parkinson’s disease
Authors: Rowe James B.
Published: December 2020

Background

The Locus coeruleus is the principal source of Noradrenaline to the cerebrum, modulating diverse functions from attentional and behavioural control, learning and perception, arousal and autonomic control. The locus coeruleus is vulnerable to many neurodegenerative disorders, with post‐mortem evidence of early and substantial cell loss in Alzheimer’s disease, Parkinson’s disease (PD) and Progressive Supranuclear Palsy (PSP). The relevance of locus coeruleus pathology and noradrenergic denervation in vivo has come largely from psychopharmacological studies, and PET imaging of the noradrenergic transporter.

Method

We exploited advances in ultra‐high field magnetic resonance imaging at 7T that now provide excellent sensitivity to the loss of neuromelanin containing neurons in the locus coeruleus, enabling quantification of the spatial extent and signal intensity (cf. cell density) in patients. We developed an optimised atlas of locus coeruleus in older adults (>50), and applied this to independent cohorts of patients with idiopathic Parkinson’s disease and PSP (Richardson’s syndrome) with a magnetisation transfer weighted sequence to scan the brain stem at 7T.

Result

Patients in both groups showed a marked reduction in locus coeruleus signal intensity, relative to a mid‐pontine reference regions, especially in the caudal locus coeruleus. In Parkinson’s disease, the contrast‐to‐noise of the locus coeruleus correlated with apathy and motor disease severity. A corresponding reduction of noradrenergic cells was confirmed at post‐mortem in a parallel group of patients with PSP, in whom cell loss was proportional to disease severity.

Conclusion

7T MRI is well tolerated and sensitive to pathology of the locus coeruleus in PSP and PD. We propose the use of 7T‐MRI to quantify the integrity of the locus coeruleus in stratified trials of therapeutic strategies for cognitive and motor control in neurodegenerative disease.