bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower cortical thickness is associated with reduced gray matter cerebral blood flow across the AD continuum
Authors: Sanderlin Ashley H. , Okonmah‐Obazee Stephanie , Craft Suzanne , Bateman James R. , Cleveland MaryJo , Jung Youngkyoo , Rogers Samantha D. , Whitlow Christopher T. , Williams Benjamin J. , Yang Mia , Lockhart Samuel N.
Published: December 2020

Background

Cortical thinning is an early marker of Alzheimer’s disease (AD) neurodegenerative changes. We examined relationships of cortical thickness and cerebral blood flow (CBF) to assess whether structural brain changes in AD‐related regions are associated with functional changes in blood flow dynamics. Previous reports of CBF indicate reduced blood flow progressing along the AD continuum from normal cognition (NC) to mild cognitive impairment (MCI) to AD. We hypothesized that reduced cortical thickness in AD‐specific brain regions would relate to reduced global gray matter (GM) CBF.

Method

Participants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N=373, mean age=70.5 years) underwent neuropsychological assessment, and T1 and pcASL MRI to assess brain structure and CBF. Participants were adjudicated as cognitively unimpaired (NC, N=212) or impaired (MCI or AD, N=161) using NIA‐Alzheimer’s Association criteria. T1 MRI were processed using FreeSurfer v5.3; an “AD‐signature” meta‐ROI cortical thickness value was calculated, which was thresholded to classify participants as neurodegeneration‐negative (N‐, above threshold) or ‐positive (N+, below threshold). PcASL MRI were processed to yield CBF images that were normalized to MNI space (Fig.1). A 2‐tissue partial volume correction was applied to yield voxelwise GM CBF. Mean GM CBF across a set of cortical AAL ROIs was calculated for each participant. A MANCOVA model adjusted for age, sex and education measured differences in GM CBF between N‐ and N+ groups. We additionally assessed cognitive status as a moderator of these associations.

Result

We found a significant difference in GM CBF between N‐ and N+ groups (p=0.010). Participants with lower meta‐ROI cortical thickness had reduced GM CBF compared to participants above the threshold (Fig.2). The interaction of cognitive status and N+/‐ group revealed lower CBF for impaired participants (Fig.3, unadjusted p<0.001), which remained significant after adjustment (p=0.014).

Conclusion

In our ADRC cohort, neurodegenerative changes within brain regions vulnerable to AD pathology were associated with global GM CBF reductions. Cognitively unimpaired N+ participants exhibited similar levels of GM CBF as impaired N‐ participants. Future studies will assess whether unimpaired N+ participants with reduced CBF have a higher risk of conversion to MCI or AD.
A high‐throughput drug screen identifies berberine as a potent inducer of tau clearance
Authors: van der Kant Rik , Langness Vanessa , Rissman Robert A. , Goldstein Lawrence S.B.
Published: December 2020

Background

Berberine is an isoquinoline alkaloid derived from plants of the Berberis genus. Berberine has been clinically evaluated for Type 2 Diabetes and has been shown to reduce blood glucose levels and improve lipid metabolism. Through an unbiased high‐throughput drug screen in human induced pluripotent stem cell‐derived neurons, we recently discovered that berberine also potently reduces Tau pathology in Alzheimer’s disease (AD) neurons.

Method

We used human iPSC‐derived neuronal models and Tau‐transgenic mice to uncover the mode of action by which Berberine reduces Tau pathology.

Result

We show that berberine acts on mitochondrial respiration and induces a switch in neuronal metabolism from oxidative phosphorylation to glycolysis. This switch induced by berberine, and mimicked by other mitochondrial targeting drugs such as metformin, drives activation of the energy sensor AMPK and leads to downstream activation of autophagosomal and proteasomal clearance of Tau. We show that berberine potently reduce Tau levels in a large panel of iPSC‐derived neuron from AD patients, as well as in Tau‐transgenic mice.

Conclusion

Berberine is a well‐tolerated oral agent that passes the blood‐brain‐barrier. Our data indicate that berberine could be repurposed for the treatment of AD and frontotemporal dementia with Tau pathology (FTD‐Tau).
Heterogeneous distribution of pathology in behavioral variant Alzheimer’s disease
Authors: Singleton Ellen H. , Hansson Oskar , Dijkstra Anke A. , Joie Renaud , Mantyh William G. , Tideman Pontus , Stomrud Erik , Leuzy Antoine , Johansson Maurits , Strandberg Olof , Smith Ruben , van Swieten John C. , Papma Janne M. , Wolters Emma E. , Coomans Emma M. , Golla Sandeep S.V. , Tuncel Hayel , Berendrecht Evi , Blujdea Raluca E. , Van Berckel Bart N.M. , Bouwman Femke , Scheltens Philip , Pijnenburg Yolande A.L. , Rabinovici Gil D. , Ossenkoppele Rik
Published: December 2020

Background

A distinct subset of patients with Alzheimer’s disease (AD) experience early and predominant behavioral and personality changes, while the neurobiological origins of these symptoms are largely unknown. In this study, we examined the distribution of tau pathology using PET imaging or post‐mortem evaluation in patients with the behavioral variant of AD (bvAD).

Method

For the PET study, seven amyloid‐β positive clinically diagnosed patients with bvAD from the Amsterdam Dementia Cohort (ADC, n=2), University of California San Francisco (UCSF, n=3) and the Swedish BioFINDER study (n=2) underwent [18F]flortaucipir or [18F]RO948 (tau) PET (Table 1). Regional standardized uptake value ratios (SUVR) in entorhinal, temporoparietal, frontal, and insular cortex as well as mean cortical SUVR and frontal‐to‐parietal SUVR ratios were contrasted against patients with typical (memory‐predominant) AD (tAD; n=55, n=60 and n=90, respectively). For the post‐mortem component of the study, the percentages of AT8 (tau)‐positive areas in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between 9 cases with bvAD and 7 with tAD.

Result

Visual inspection of subject‐specific tau PET patterns revealed more pronounced frontal involvement in 6/7 bvAD patients compared to patients with tAD (Figure 1). Regional SUVR analyses revealed higher‐than‐average tau uptake in 3/7 bvAD cases in the temporoparietal cortex, 5/7 in the frontal cortex, and 3/7 in the insular cortex compared to patients with tAD (Figure 2). Furthermore, 4/7 cases showed higher‐than‐average mean cortical SUVR and 6/7 cases had higher‐than‐average frontal‐to‐parietal SUVR ratios (Figure 2 & Table 2). Postmortem evaluation revealed that bvAD cases had a lower tau load in the CA1 region of the hippocampus compared to patients with tAD (p<.05); no differences were found, however, in temporal, parietal, frontal or insular regions (all p>.05, Figure 3 & Table 3).

Conclusion

This multicenter case series with tau PET and neuropathological examination demonstrates a heterogeneous distribution of tau pathology across patients with bvAD, ranging from pronounced anterior involvement to a more temporoparietal pattern. Further work is needed to explore alternative pathophysiological mechanisms underlying the bvAD phenotype.
Brain transcriptome wide association study (TWAS) implicates 8 genes across 6 loci in Alzheimer’s disease
Authors: Gockley Jake , Montgomery Kelsey S. , Poehlman William L. , Liu Yue , Gerasimov Ekaterina S. , Greenwood Anna K. , Wingo Aliza P. , Wingo Thomas S. , Mangravite Lara M. , Logsdon Benjamin A.
Published: December 2020

Background

Alzheimer’s disease (AD), an incurable neurodegenerative disease, currently affects 1.75% of the United States population, with projected growth to 3.46% by 2050. Common genetic variation linked transcript expression differences which confer AD‐risk isl necessary to elucidate AD mechanism and develop therapeutic interventions. We modified the FUSION pipeline to ingest expression from multiple neocortical regions, provide a set of 6780 gene weights which is abstracatable across the neocortex, and leverage these to find 8 genes with associated AD risk validated through summary mendelian randomization (SMR) utilizing IGAP summary statistics.

Method

Ancestry matching based on 1000 genomes supervised clustering utilizing yielded 2003 Northern European (CEU) profiles, 888 of which had matched genotype‐RNASeq profiles. Expression Z‐scaling within‐tissue allowed weights to be trained from multiple Neo‐cortical tissues (TCX = 248, FP = 50, IFG = 41, STG = 34, PHG = 34, DLPFC = 461) after RNA‐Seq profiles were corrected for covariate and AD diagnosis stage within study.

Result

Cis‐variant architecture alone was informative to train weights for 6780 (49.67%) autosomal genes, the majority of which signficantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). The median correlation to observed gene expression was 0.2176 (IQR = 0.179‐0.277). Validation rate in 621 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (71.08%) in DLPFC and (22.52%) in anterior cingulate cortex (ACC) profiles. After correction for joint conditional probability (JCP) and SMR validation, 8 genes were significantly associated with AD (FDR < 0.05); APOC1 (JCP = 2.22e‐22, SMR = 3.41e‐4), EED (JCP = 3.373e‐5, SMR = 2.50e‐4), CD2AP (JCP = 2.96e‐5, SMR = 2.66e‐4), CEACAM19 (JCP = 3.27e‐5, SMR = 1.00e‐2), CLPTM1 (JCP = 4.04e‐3, SMR = 2.58e‐3), MTCH2 (JCP = 0.011, SMR = 3.32e‐6), TREM2 (JCP = 0.021, SMR = 2.64e‐3), KNOP1(JCP = 0.039, SMR = 2.50e‐4).

Conclusion

We provide evidence of cis‐genetic variation confering AD risk through 8 genes across six distinct genomic loci. Moreover, we provide a valuable resource to the community in the form of predictive gene expression weights that are abstractable to multiple neocortical regions and neuronal phenotypes.
Tau therapeutics: Clinical development status and future directions
Authors: Boxer Adam L.
Published: December 2020

Background

Accumulation of insoluble, misfolded tau protein is a hallmark of AD, chronic traumatic encephalopathy and approximately half of frontotemporal lobar degeneration (FTLD), including progressive supranuclear palsy (PSP) and individuals with autosomal dominant mutations in the tau gene (MAPT), collectively termed tauopathies. While the protein structure and isoform composition differ among diseases, a general principle is that disease severity and clinical phenotype are strongly related to the amount and anatomical distribution of tau protein throughout the brain. In preclinical models generated from human MAPT mutations, strong evidence suggests that disease progression could be explained by transcellular spread of misfolded tau protein, and that reduction of misfolded tau protein levels or prevention of transcellular spread may be viable therapeutic strategies.

Method

Review of tau therapeutics currently in clinical development and the tauopathies in which clinical trials may be most feasible at different stages of development.

Result

Three classes of tau therapeutics are currently in clinical development: 1) small molecules designed to alter post‐translational modification, aggregation or clearance, 2) immunological therapies (anti‐tau monoclonal antibodies and vaccines) and 3) genetically‐targeted approaches (antisense oligonucleotides, siRNA, AAV‐mediated gene therapies). A few small molecules have completed phase 2 or 3 clinical trials in AD, FTLD or PSP, and two anti‐tau monoclonal antibodies have completed phase 2 studies in PSP. To date, there has been no evidence of clinical efficacy, although a few compounds have demonstrated target engagement.

Conclusion

The availability of blood, CSF and PET biomarkers of AD tau pathology suggests that, early stage clinical trials focused on proof of biological concept are likely to be most informative in AD‐spectrum diseases, whereas there are potential advantages to conducting later stage clinical trials focused on clinical efficacy in primary tauopathies such as PSP. Regardless of clinical indication, genetically targeted therapies may have development advantages because of the potential responsiveness of biomarkers to these interventions. Questions to be addressed include: Which diseases are most likely to respond to tau therapeutics given that most were developed in preclinical models that overexpress human MAPT mutations? Do we have adequate biomarkers to demonstrate biological proof of concept and determine appropriate dose?
Potentially inappropriate medication use associated with lower mobility reserve among individuals with preclinical Alzheimer’s disease
Authors: Martinez Ashley I. , Jicha Gregory A. , Lee Kara , Beech Brooke F. , George Rosmy , Hall Megan , Abner Erin L. , Schmitt Frederick A. , Khouli Riham H. El , Eckmann Lynne , Huffmyer Mark , Moga Daniela C.
Published: December 2020

Background

Falls, a leading cause of disability and mortality in older adults,1 are associated cognitive impairment and inappropriate medication use.2 We propose a novel construct, “mobility reserve” (MR), which describes an individual’s resilience against mobility decline. We hypothesize that augmenting MR may delay fall‐associated morbidity. Here, we investigate the association between MR and inappropriate medication use among participants with and without preclinical Alzheimer’s disease (pAD) enrolled in a randomized medication therapy management trial.3

Methods

Non‐demented older adults who used ≥1 potentially inappropriate medication4 were recruited for the RCT. The Medication Appropriateness Index was calculated for all medications (MAI) and for potentially inappropriate medications (MAI‐PIM). Participants’ gait speed (cm/s) was measured under normal conditions and while challenged with 1.5mg of scopolamine to unmask vulnerability. The difference in gait speeds was calculated as mobility reserve change score (MRCS). PET amyloid total brain relative standardized uptake values > 1.4 was used to define pAD.5Spearman correlation coefficients (rs) assessed the relationship between medication appropriateness and MRCS.

Results

36 participants were included in this analysis (mean age 75.0 years [SD 6.0]; 78% female); 10 (27.8%) were classified as pAD. The mean (SD) MAI and MAI‐PIM were 10.3 (5.1) and 5.4 (4.0) respectively, not differing by pAD status (p=0.92 and 0.11 for MAI and MAI‐PIM). The mean (SD) MRCS was ‐0.39 cm/s (9.4) (no difference by pAD status; p=0.84). Among those with pAD, MAI and MAI‐PIM were negatively correlated with MRCS (r = ‐0.53 and ‐0.46 respectively), which was not the case among those without pAD (r = 0.37 and 0.34), though a larger sample size is needed to add confidence to these estimates.

Conclusion

Among community‐dwelling non‐demented older adults, more inappropriate medication use was associated with lower mobility reserve among those with pAD. These results support the hypothesized relationship between MR and medication appropriateness. Future studies should further operationalize measures of MR to open a novel intervention pathway for reducing fall‐related morbidity in cognitively at‐risk populations. References: 1. Katz R, Shah P. JAMA. 2010;303(3):273‐274. 2. Enderlin C et al. Geriatr Nurs. 2015;36(5):397‐406. 3. Moga DC et al. Trials. 2019;20(1):806. 4. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246. 5.Jack CR et al. Brain. 2015;138(12):3747‐3759.
Accounting for cognitive practice effects results in earlier detection and more accurate diagnosis of MCI: Biomarker confirmation
Authors: Kremen William S. , Sanderson‐Cimino Mark E. , Elman Jeremy A. , Tu Xin M. , Gross Alden L. , Panizzon Matthew S. , Eglit Graham M.L. , Jak Amy J. , Edmonds Emily C. , Thomas Kelsey R. , Eppig Joel S. , Williams McKenna E. , Bondi Mark W. , Lyons Michael J. , Franz Carol E.
Published: December 2020

Background

Practice effects (PEs) mask true cognitive decline. Even with declines at follow‐up, PEs can still obscure even steeper declines. Accounting for PEs means that impairment cutoffs are reached earlier. Importantly, mild cognitive impairment (MCI) would be detected earlier. If these diagnoses are valid, there should be more biomarker‐positive MCI cases and fewer biomarker‐positive cognitively normal subjects (CNs). We tested this hypothesis using a replacement‐subjects method.

Method

We examined 722 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects who were CN at baseline (mean age=74.9±6.8). MCI at follow‐up was diagnosed by Jak‐Bondi and Petersen criteria. We identified “pseudo‐replacements” whose baseline age was matched to the age of returnees at their 1‐year follow‐up. Education and estimated premorbid IQ were also matched. Difference scores were calculated at Time 2 between returnees on their second testing and the demographically‐matched pseudo‐replacements on their first testing. Attrition effects were estimated by comparing returnee baseline scores with the full baseline sample. PEs = difference scores – attrition effects. PEs are then subtracted from follow‐up scores, with the resultant scores used in diagnosing MCI. CSF Aβ42 and phosphorylated (p)‐tau were measured 6‐12 months prior to retesting.

Result

There were significant PEs on 5 of 6 tests (average Cohen’s d=.27). For Jak‐Bondi diagnoses, accounting for PEs at follow‐up resulted in a 24.8% increase in the proportion of MCI cases (p<.000001). There were increased proportions of Aβ42‐positive (18.8%) and p‐tau‐positive cases (29.8%), and reduced proportions of Aβ42‐positive (5.8%) and p‐tau‐positive (7.9%) CNs (McNemar χ2: Aβ42: p<.0014, p‐tau: p<.028; Figure 1). Results were similar for Petersen diagnoses. Of 26 false negatives (i.e., CNs whose diagnosis changed to MCI after accounting for PEs), 9 (35%) were MCI without PE adjustment at 2‐year follow‐up.

Conclusion

Accounting for PEs led to earlier detection of MCI at 1‐year follow‐up. Biomarker data support these being more accurate diagnoses because more cases were biomarker‐positive and more CNs were biomarker‐negative. Longer‐term follow‐up indicated that MCI cases may be detected a year or more earlier if performance is adjusted for PEs. Accounting for PEs has meaningful, real‐world implications for early identification, which may, in turn, improve opportunities to slow disease progression.
Healthy dietary patterns are associated with better cognitive performance in older adults: Findings from National Health And Nutrition Examination Survey (NHANES) 2011‐2014
Authors: Gu Yian , Guo Jing , Moshfegh Alanna J
Published: December 2020

Background

Increasing evidence from community‐based population cohorts suggests that following healthy dietary patterns is protective against cognitive decline, Alzheimer’s disease, or other dementia in older adults. However, such findings have rarely been confirmed in nationally representative samples.

Method

The current study included 2,864 participants (≥60 years) of the NHANES 2011–2014 who completed both dietary and cognitive assessments. Self‐reported dietary intake was collected by trained interviewers using the USDA’s Automated Multiple‐Pass Method in two nonconsecutive 24‐hour dietary recalls. Intakes of nutrients and food groups were calculated using reference from the USDA 'Food and Nutrient Database for Dietary Studies' and 'Food Patterns Equivalents Database', 2011‐2014, respectively. Mediterranean‐type Diet (MeDi) and Healthy Eating Index 2015 (HEI15) scores were estimated from the mean intakes of the two diet recalls. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer’s disease Word Learning sub‐test (WL), Animal Fluency test (AF), and Digit Symbol Substitution test (DSST). Age, sex, race/ethnicity adjusted z‐score was calculated for each cognitive score, which were then averaged to get a composite cognitive score. Complex samples plan linear regression models were applied to examine the associations of diet and cognition, adjusted for age, sex, education, race (white/black/Hispanic/others), caloric intake, cycles (2011‐2012 /2013‐2014), and annual household income (< or ≥ $45,000).

Result

MeDi and HEI2015 were associated with 0.028 (95%CI=0.004‐0.05, p=0.023) and 0.004 (95%CI=0.0002‐0.007, p=0.038) higher mean cognitive z‐score, respectively. Compared to the lowest tertile of MeDi, the highest tertile of MeDi was associated with 0.141 (95%CI=0.029‐0.253, p=0.015; p‐trend=0.016) higher mean cognitive z‐score. Compared to the lowest tertile, the highest MeDi tertile was associated with 1.001 (95%CI=0.161‐1.840, p=0.021; p‐trend=0.021), 1.05 (95%CI=0.227‐1.875, p=0.014; p‐trend=0.015) and 3.02 (95%CI=1.004‐5.027, p=0.005; p‐trend=0.004) higher WL, AF, and DSST, respectively, and the highest HEI15 tertile was associated with 0.827 (95%CI=0.154‐1.499, p=0.018; p‐trend=0.018) higher AF. The effect size of the highest tertile of dietary score was approximately equivalent to 3‐4 less years of aging (b of 1‐year aging=‐0.316, ‐0.229, and ‐0.867 for WL, AF, and DSST, respectively).

Conclusion

Following a healthy diet is associated with better cognitive performance in a nationally representative sample of older adults.
Global networks to address inequities and disparities in dementia: The case of LAC‐CD and GLoDePP
Authors: Parra Mario A , Chan Kit Yee , Ibanez Agustin
Published: December 2020

Background

New initiatives are emerging to bridge countries from the global south and global north to identify barriers that have prevented a global approach to the dementia challenge. The Latin American and Caribbean Consortium on Dementia (LAC‐CD) has demonstrated, over 5 years of intense networking activities, that challenges faced by LAC countries are very similar. The Global Dementia Prevention Program (GloDePP), a network that pursues similar aims, has more recently revealed that this also holds for low‐ and middle‐income countries (LMICs) beyond the LAC region. LAC‐CD and GLoDePP are two initiatives that can merge agendas to widen the characterization of the inequities and disparities affecting countries of the global south and propose actions towards harmonization of research and clinical practices.

Methods

From 2015, LAC‐CD has held five workshops. Here we focus on outcomes from the 2015 (Santiago, Chile, 15 experts) and 2019 workshops (São Paulo, Brazil, 160+ members) which revealed a transition from a state of knowledge to specific actions. From 2018, GLo‐DePP has held five workshops in the UK and China involving experts from Bangladesh, Brazil, China, Ghana, India, Iran, Malaysia, Nigeria and Uruguay. GLo‐DePP workshops focused on the state of epidemic preparedness, research contexts, and readiness to join collaborative strategies focusing on prevention and management of dementia.

Results

Themes emerging from these workshops were: the need for contextually appropriate tools, more public awareness, identify and modify early and mid‐life risk factors, low‐cost methods to gather biomarker evidence across language and cultural groups, longitudinal brain health cohorts, contextually appropriate m‐health, e‐health, and global data science platforms for dementia prevention, detection, and intervention, evidence to inform: policy and health services delivery, investment priorities, national dementia plans and guidelines for equitable access to dementia management that are contextually adaptable across geographies and cultures (Chan et al., 2019; Parra et al., 2018).

Conclusion

LAC‐CD has recently proposed a knowledge‐to‐action framework which will turn such challenges into unprecedented opportunities. Clear strategies are emerging and paving the way towards harmonized agendas across LAC‐CD and GLoDePP (Parra et al., 2019). Such shared agendas shall provide the building blocks for future Global Dementia Strategies.
Informant‐based report of cognitive decline correlates with age‐adjusted hippocampal volume in mild cognitive impairment and Alzheimer's dementia?
Authors: Sabbagh Marwan Noel , Miller Justin , Wint Dylan
Published: December 2020

Background

Informant‐based measures can be effective screening tools for cognitive impairment. The Alzheimer’s Questionnaire (AQ; Sabbagh et al., 2010) is a subjective, informant‐based measure that captures five cognitive domains associated with Alzheimer’s disease (AD). The AQ detects amnestic mild cognitive impairment (aMCI) and Alzheimer‐type dementia with high sensitivity and specificity, and has also been shown to predict amyloid burden. We hypothesize that a higher AQ score (greater functional impairment) correlates with lower hippocampal volumes.

Method

Retrospective chart review of 131 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ‐Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ‐Total. As the AQ was used as a factor in assigning diagnostic status, thus the relationship between the AQ and diagnostic status was excluded from analyses.

Result

The analyzed sample was 53% female with a mean of 73.96±10.48 years of age and 14.74±3.51 years of education. Sample means for the MoCA and AQ score were 22.16±4.39 and 10.62±5.29, respectively. Correlation between AQ score and HC volume (as reported as percentile) revealed an inverse relationship, such that higher AQ scores were associated with smaller hippocampal volumes (r =‐0.40 (95% CI ‐0.54 to ‐0.24), p<0.0001).

Conclusion

In a mixed‐clinical sample of patients presenting to an outpatient memory disorders center, higher endorsements of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision‐making, and demonstrate an additional relationship with established AD biomarker outcomes with volumetric MRI.
The peripheral hearing and central auditory processing skills of individuals with subjective memory complaints
Authors: Jayakody Dona M.P. , Sohrabi Hamid , Martins Ralph N.
Published: December 2020

Background

With no cure or effective treatment currently in sight, it is critical to identify those factors that may prevent or delay cognitive decline and dementia in older adults, it is important to focus on potentially modifiable risk factors. Untreated hearing loss contributes up to about 9% of the modifiable risk factors in mid‐life (Livingston et al., 2017).

Method

A total of 95 participants were recruited from the larger Western Australia Memory Study and were classified as SMCs (N = 61; 20 males and 41 females, mean age 71.47 + 7.19 years) and non‐SMCs (N = 34; 10 males, 24 females, mean age 68.85 + 7.70 years). All participants completed a peripheral hearing assessment, a CAP assessment battery (Dichotic Digits, Duration Pattern Test, Dichotic Sentence Identification, Synthetic Sentence Identification with Ipsilateral Competing Message and the Quick‐Speech‐in‐Noise) and a cognitive screening assessment.

Result

The SMCs group performed significantly poorer than the control group on Synthetic Sentence Identification with Ipsilateral Competing Message ‐10dB and ‐20 dB Signal to Noise Ratio conditions. No significant differences were found between the two groups on the peripheral hearing threshold measurements.

Conclusion

The results suggest that individuals with SMCs perform poorly in CAP assessments in comparison to the controls. The poor CAP in SMC individuals may result in a greater cost to their finite pool of cognitive resources. The CAP results provide yet another biomarker that supports the hypothesis that SMCs may be a primary indication on neuropathological changes in the brain affecting various functions. Longitudinal follow up of individuals with SMCs and decreased CAP abilities should inform whether this group is at higher risk of developing dementia as compared to non‐SMCs and to those SMC individuals without CAP difficulties.
Cognitive impairment and disability after arterial stroke in older adults: A hospital‐based study
Authors: Mukku Shiva Shanker Reddy , PT Sivakumar , Kukarini Girish Baburao , Prasad Krishna
Published: December 2020

Background

Stroke and cognitive impairment often co‐exist in older adults. Every one minute three people get stroke in India, who are potentially at risk for cognitive impairment. However the literature on this area is limited from India.The objective is study the cognitive impairment in older adults with arterial stroke. To study the relation between the cognitive impairment and disability.

Method

Sample includes patients above the age of 45 years with arterial stroke seeking treatment from NIMHANS outpatient departments. Ethical clearance was obtained. Patient underwent neurological examination. Standard instruments applied were Modified Rankin scale (MRS), Barthel index (BI), Stroke specific quality of life (SS‐QOL) and Addenbrooke’s cognitive examination (ACE‐III).

Results

100 stroke patients were recruited as per the inclusion criteria. The sample included 75% males (M:F‐ 3:1), with mean age of 63.98 (SD‐8.45) years. Among them majority were living with spouse (87%), from urban background (75%) and 52% had education of high school and above. Median duration of stroke at assessment was 5 months. The mean score on MRS, BI and SS‐QOL were 2.12 (SD‐1.13), 82.0 (18.64) and 180 (SD‐35.175)respectively. Among our patients 10% meets criteria for vascular dementia and 20% for mild cognitive impairment.On ACE‐III the mean score was 65.50 (SD‐17.72) with score on Attention‐13.21 (SD‐4.54), Memory‐15.11 (SD‐7.07), Fluency‐5.63 (SD‐3.174), Language‐19.92 (SD‐5.59),Visuo‐spatial‐9.69 (SD‐4.51). There was positive correlation between ACE‐ III scores and Barthel index (r= 0.526; p<0.001)and SS‐QOL (r=0.716; P<0.001).There was negative correlation between ACE‐III score and MRS (r= ‐ 0.599; p<0.001).

Conclusion

In our study, one‐third of sample had cognitive impairment, at 5 months (median) after stroke.The prevalence of post stroke cognitive impairment is on the lower side as compared to recent meta‐analysis (Barbay et al., 2018; Merriman et al., 2019) which could be due to inclusion of outpatient sample and time of assessment. Cognitive impairment has negative impact of functioning and quality of life in stroke patients which is in agreement with previous studies.
Neuropathological characteristics associated with a recently identified rare PSEN1 deletion mutation (F175del)
Authors: Vöglein Jonathan , Arzberger Thomas , Willem Michael , Trambauer Johannes , Dieterich Marianne , Biskup Saskia , Guidici Camilla , Brendel Matthias , Roeber Sigrun , Danek Adrian , Steiner Harald , Herms Jochen , Haass Christian , Levin Johannes
Published: December 2020

Background

The novel PSEN1single amino acid deletion mutation F175del causes autosomal dominant Alzheimer disease (ADAD) in the late thirties. In vitroF175del features an unusual pattern of APP fragments including an increased production of Aβ39. This Aβ species was found particularly in brain vessels and therefore may contribute to the development of cerebral amyloid angiopathy (CAA).

Method

Neuropathological examination was performed in a patient with ADAD caused by PSEN1F175del who died at the age of 45 years. Clinical, neuropsychological, genetic and biomarker findings in this patient as well effects of the PSEN1deletion mutation on Aβ processing were described before (Vöglein et al, Neurobiology of Aging, 2019).

Result

Copious cored/compact and diffuse Aβ plaques were found in the cerebral cortex. Interestingly, there were plentiful streaky and several cored/compact and diffuse Aβ plaques also in the cerebellum. A large number of cortical neuropil threads and neurons with fibrillary cytoplasmatic tau aggregates as well as several neuritic plaques were detected (ABC score: A3/B3/C3). CAA with Aβ depositions in the leptomeningeal and cortical vessel walls was detected (Thal phase 2). Furthermore, several Lewy bodies and Lewy neurites were found in the cerebral cortex (Braak stage 6).

Conclusion

The neuropathological hallmarks of AD, Aβ plaques and neurofibrillary degeneration, were present in PSEN1 F175del associated ADAD. CAA was found that could be in causal connection with the enhanced Aβ 39 generation caused by the mutation as shown in cell culture. Further, an unusually high cerebellar Aβ burden was detected. In summary, we provide neuropathological characteristics of ADAD caused by PSEN1 F175del and potentially unveiled an effect of an altered Aβ processing that was shown in vitro on brain pathology.
Subtle differences in the appearance of hippocampal layers differentiate preclinical AD from healthy aging
Authors: Xie Long , Das Sandhitsu R. , Wisse Laura , Ittyerah Ranjit , Vergnet Nicolas , de Flores Robin , Wolk David A. , Yushkevich Paul A.
Published: December 2020

Background

Degeneration of the stratum radiatum lacunosum moleculare (SRLM), located between the cornu ammonis (CA)/subiculum and dentate gyrus (DG) subfields of the hippocampus (Figure 1) and containing apical dendrites of CA pyramidal cells, may be an early feature of AD and can be observed in postmortem studies (Adler et al, 2018). The pathological change in SRLM may produce subtle alteration of image signal on high‐resolution in vivo MRI. We hypothesize that convolutional neural networks (CNNs) can detect such alterations in preclinical AD, yielding a more sensitive biomarker than conventional morphological measurements.

Methods

Cross‐sectional 0.4x0.4x2.0mm3 T2‐weighted MRI of 285 cognitively normal controls from ADNI were included. The dataset was dichotomized according to amyloid‐ß (Aß) status (+ or ‐) based on PET and divided into training (48%), validation (12%) and test sets (40%, Table 1). Volumes of medial temporal lobe subregions (CA1‐3, DG, subiculum, entorhinal cortex, Brodmann areas 35/36, parahippocampal cortex) were extracted automatically using ASHS (Yushkevich et al., 2015). Small image patches (∼6x6x6 mm3) centered on the SRLM were extracted. A CNN was trained to discriminate patches as Aß+ or Aß‐. The output of the last CNN layer was averaged over all SRLM patches to generate a CNN‐based score for each subject in the test set. ANCOVA with age, sex, education and intracranial volume as covariates was used to test for significance.

Results

We observed a significant difference in CNN score between Ab+ and Ab‐ controls in the test set (Table 2). None of the conventional volume measures show statistical significance except a trend level effect in parahippcampal cortex opposite the expected result (greater atrophy in Aß+).

Conclusions

In this proof‐of‐concept study, we demonstrated that our novel CNN‐based score is more sensitive to Aß status than standard medial temporal lobe volume measurements. Since the image patches only cover a small area around the SRLM, the score may reflect subtle change of the SRLM in preclinical AD. Better understanding the linkage of SRLM appearance and underlying pathology is required and will be investigated in future work using a dataset of antemortem and postmortem imaging in the same subjects.
Health‐related quality of life of people with dementia and their caregivers
Authors: Zoi Panagiota , Ntanasi Eva , Kalligerou Faidra , Sakka Paraskevi , Gouva Mary
Published: December 2020

Background

Over the last decades dementia has been a major public health challenge. Caregivers burden is increasing as the disease progresses and the behavior of the person who suffers from dementia is worsening. Caregivers burden has psychological, physical and financial dimensions.

The purpose of this research was to measure Health‐Related Quality of Life (HRQoL) of people with dementia and their caregivers and to investigate which parameters have an impact on caregivers burden (Zarit Burden Interview ‐ ZBI). Additionally we investigated existing differences between the estimation of health status by people with dementia, their caregivers for themselves and caregivers assessing their relatives’ condition, using the EQ‐5D‐5L questionnaire. The EQ VAS scale was used as a quantitative measure of health status of participants, both patients and caregivers.

Method

The research was conducted between December 2018 and January 2019 in the Athens Alzheimer Association Day Care Centers. The sample consisted of 200 people (100 people with dementia and their 100 caregivers). Demographic characteristics were recorded for all. People with dementia underwent neuropsychological assessment including MMSE, ACE‐R, GDS, EQ‐5D‐5L

Result

The majority of caregivers were women (70%), caring for their parents (50%) and spouses (42%). In our research 36% caregivers had moderate to severe burden (41,9 score’s ZBI). Through the EQ VAS, patients self‐assessed their health at an average of 72.9 points while caregivers rated health for their relatives at an average of 59.19 points.

Conclusion

Our findings suggest that caregivers health status correlates negatively to the amount of burden as expressed by ZBI scores. High ZBI scores rated by the caregivers also result in low HRQoL
Weight loss predicts Alzheimer’s disease biomarker positivity in cognitively unimpaired middle‐aged adults
Authors: Grau‐Rivera Oriol , Navalpotro Irene , Sánchez‐Benavides Gonzalo , Suárez‐Calvet Marc , Milà‐Alomà Marta , Arenaza‐Urquijo Eider M , Salvadó Gemma , Sala‐Vila Aleix , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Farrar Gill , Buckley Chris J , Niñerola‐Baizán Aida , Perissinotti Andrés , Simon Maryline , Kollmorgen Gwendlyn , Eichenlaub Udo , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

Background

Weight loss is common in Alzheimer’s disease (AD) and may start before cognitive impairment, but little is known about the relationship between weight change and AD biomarkers in the preclinical Alzheimer’s continuum. We aimed to assess the association between weight change and AD biomarkers and cognitive performance in cognitively unimpaired (CU) adults from the ALFA+ study.

Method

We analyzed data from 295 CU middle‐aged adults with two consecutive (mean interval 3.7 years) weight measures and neuropsychological assessments (n=267). Preclinical Alzheimer's Cognitive Composite (PACC) was computed as an average of z‐scores of episodic memory, semantic fluency and processing speed measures. We measured cerebrospinal fluid (CSF) levels of Aβ42, Aβ40, p‐tau, t‐tau, neurofilament light (NfL) and neurogranin using the Roche NeuroToolKit and Elecsys® immunoassays (n=280), and performed a [18F]flutemetamol PET scan in the follow‐up visit (n=252). PET results were dichotomized (Aβ positive or negative) based on visual read. Using established CSF cutoffs, we grouped participants in three biomarker categories: A‐T‐ (both Aβ and tau negative), A+T‐ (Aβ positive only) and A+T+ (both Aβ and tau positive). Linear and logistic regression and Kernel‐weighted local polynomial smoothing were used for analyses, which were adjusted by age, sex, body mass index, APOE genotype and years of education, as appropriate.

Result

Weight loss predicted amyloid PET positivity (odds ratio 1.1, p=0.028) and was associated with significantly higher CSF levels of p‐tau (p=0.005), t‐tau (p=0.005) and neurogranin (p=0.002) (Table 1). Weight loss ≥5% (a standard cutoff for clinically relevant weight change) yielded 87% specificity and 30% sensitivity for amyloid PET positivity. Participants from the A+T+ group experienced significantly higher weight loss compared to A+T‐ (p=0.0029) and A‐T‐ (p=0.0005) groups (Figure 1). Weight loss was not associated with longitudinal changes in cognitive performance and preceded cognitive decline when using Aβ42/40 as a proxy of AD change progression (Table 1, Figure 2).

Conclusion

Weight loss predicts amyloid PET positivity in CU middle‐aged adults. Our results suggest that weight loss is mainly related with changes in tau‐related and synaptic dysfunction biomarkers and may precede cognitive decline in the preclinical stage of the Alzheimer’s continuum.
Disruptors of the Hsp90/Aha1 complex that reduce tau aggregation
Authors: Keegan Bradley M , Koren John , Blagg Brian S.J. ,   Warren Family Research Center for Drug Discovery and Development
Published: December 2020

Background

Aberrant aggregation of misfolded microtubule‐associated protein tau (MAPT, tau) is a hallmark of Alzheimer’s disease (AD) and other neurodegenerative tauopathies. Recently, the ATP‐dependent molecular chaperone family has been identified as a critical mediator of the pathogenic accumulation of misfolded tau. In particular, studies have demonstrated that inhibiting the ATPase activity of Hsp90 reduces pathological tau accumulation and promotes the clearance of tau via the proteosome.

Method

The ATPase activity of Hsp90 is regulated through interactions with a number of co‐chaperones, which direct specific proteins for interaction with Hsp90. Our team recently discovered that one of these co‐chaperones, Aha1 (AHSA1), dramatically increases the production of aggregated tau in vitro (ThT fluorescence assays) and in vivo (transgenic rTg4510 tau mice).

Result

We identified several small molecules that disrupt Aha1/Hsp90 interactions in vitro and demonstrated that one of these compounds, KU‐177, ablates Aha1‐driven enhancement of Hsp90‐dependent tau aggregation.

Conclusion

Using KU‐177 as a parent compound, we are developing small molecule disruptors of the Aha1/Hsp90 complex for the treatment of Alzheimer’s disease and have developed assays to evaluate their efficacy.
Daytime napping trajectory over time and its association with cognitive aging: A 13‐year community‐based longitudinal study of older adults
Authors: Li Peng , Gao Lei , Gaba Arlen , Yu Lei , Yaffe Kristine , Buchman Aron S , Bennett David A , Hu Kun , Leng Yue
Published: December 2020

Background

Daytime napping is common in elderly adults and has been associated with cognitive impairment. Prior studies have assessed napping at one time point, making it difficult to examine the longitudinal progression of napping and its association with cognitive aging. We examined objectively measured daytime napping longitudinally across different stages of Alzheimer’s disease (AD): from no cognitive impairment (NCI), to mild cognitive impairment (MCI), and to Alzheimer’s dementia.

Method

We studied 1,066 participants (female: 810 [76%]; age: 81.0±7.3 [SD]) in the Rush Memory and Aging Project who have been followed for up to 13 years. Motor activities of up to 10 days were recorded annually with actigraphy and used to assess napping objectively. We defined daytime napping episodes as segments between 10AM and 7PM with continuous zero‐activity for ≥10min but <1h (to avoid off‐wrist periods). Segments that were <5min apart were merged. Cognitive and clinical evaluations were administered annually to render a clinical diagnostic classification of NCI, MCI, or AD. To examine how change in napping duration and frequency was associated with progression of AD, we performed linear mixed‐effects models with 2 change points anchored at the diagnoses of MCI and AD while adjusted for age, sex, and education.

Result

At baseline, participants had 1.44±0.04 (mean±standard error) naps with an accumulated duration of 35.0±1.1 min per day. Napping duration increased by 5.2±0.3 min and frequency increased by 0.21±0.01 times every year (both p<0.0001). Compared to those who remained NCI, the rate of increase was more than doubled after MCI diagnosis with an annual increase of 11.4±0.7 min in duration and 0.40±0.02 times in frequency (both p<0.0001); these were doubled further after AD diagnosis with an annual change of 26.3±3.1 min in duration and 0.84±0.08 times in frequency (both p<0.0001).

Conclusion

Daytime napping duration and frequency increase with aging, and the increase was accelerated with AD progression.
Harmonization of amyloid PET scans minimizes the impact of reconstruction parameters on centiloid values
Authors: Shekari Mahnaz , Niñerola‐Baizán Aida , Salvadó Gemma , Battle Mark R , Buckley Christopher , Farrar Gill , Operto Greg , Falcon Carles , Arenaza‐Urquijo Eider M , Perissinotti Andrés , Molinuevo Jose Luis , Gispert Juan Domingo ,   ALFA study
Published: December 2020

Background

The Centiloid method has been proposed to enhance the comparability of amyloid PET quantification across different amyloid tracers and to provide a reference metric. In this study, we first quantified the impact of reconstruction parameters on Centiloid values for different reference regions, then we evaluated the reduction of this source of bias after PET image harmonization.

Method

A total of 71 cognitively unimpaired participants from ALFA+ cohort were included in this study. For each participant a 18F‐flutemetamol PET scan and a T1‐weighted MRI scan were acquired. A Hoffman 3D‐brain phantom filled with 0.5 mCi of 18F‐FDG was scanned in the same tomograph. Participant and phantom PET data were reconstructed with 4 different protocols used in the clinical and research settings (Table1). The reconstruction with the coarsest spatial resolution was selected as the reference. The remaining 3 were harmonized to yield the same effective spatial resolution using the protocol used in the ADNI study. All images were quantified with a validated Centiloid pipeline using an AAL composite and different reference regions (Whole Cerebellum, Cerebellar Gray, Pons and White Matter). The mean absolute difference in Centiloids (CL) between different reconstructions of the same scan was calculated using the coarsest resolution as reference. Differences below 2.5 CL were considered to be irrelevant based on published test‐retest data.

Result

Respectively, Figures 1 and 2 show the Hoffman phantom and the amyloid PET scans before and after harmonization. While mean absolute differences were below the test‐retest threshold for the Cerebellar Gray and whole cerebellum, differences up to 9 CL were observed for the Pons (Table2). White matter as reference region showed the biggest sensitivity to reconstruction parameters and the bias was dependent on the amyloid load (Figure 3c). After harmonization differences were always below the test‐retest threshold.

Conclusion

Reconstruction parameters impact the Centiloid values as a function of reference region. While the impact using Cerebellar gray and the Whole Cerebellum was minor, important differences were observed when using the pons and white matter as reference regions. In all cases, harmonization of the effective spatial resolution was able to bring these biases below the test‐retest threshold.