bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical case of VV1 Creutzfeldt‐Jakob disease subtype
Authors: Carrasco Adrianna , Okhravi Hamid
Published: December 2020

Background

Creutzfeldt‐Jakob disease (CJD) is rare form of rapidly progressive dementia due to the presence of abhorrent prion protein and affects 1‐1.5 cases per million per year.1 An estimated 85% of these cases are sporadic, and the remaining 5‐15% develop CJD from inherited mutations of the prion gene.2 Sporadic CJD (sCJD) is further subdivided into six subtypes based on genetic polymorphisms, with the VV1 subtype occurring at a rate of 1 case per one‐hundredth million population per year. 3 These subtypes have been shown to correlate with age of onset, clinical course, disease features and duration4,5. Clinical characteristics of the VV1 subtype has been reported to show, early age of onset (39 years), disease duration of 15 months, elevated 14‐3‐3 and total tau in the CSF, absent PSWCs on electroencephalography (EEG), and magnetic resonance imaging (MRI) hyperintensities in the cerebral cortex with usual negative signal in the basal ganglia or thalamus.6,7,

Method

We present an atypical case of the rarest VV1 sCJD subtype. Contrary to current data on VV1, our patient presented with an unusual age at onset (63 years), longer disease duration (20 months), and positive signal in the basal ganglia on MRI. The real‐time quaking‐induced conversion (RT‐QuIC) was negative.

Result

Presenting clinical symptoms included paranoid thoughts and agitation, progressing with rapid memory decline, prosopagnosia, and later development of myoclonus and mutism. Other findings showed positive antithyroid peroxidase antibodies (anti‐TPO), absent PSWCs on EEG, positive 14‐3‐3 and elevated tau on CSF. High dose steroid therapy treatment was administered based on positive anti‐TPO findings, which failed to illicit any improvement and the patient continued to decline.

Conclusion

To our knowledge, only two confirmed cases with the VV1 subtype, including our patient, have been reported to have a negative result on RT‐QuIC.8 This may indicate a unique characteristic to VV1 and aid in the diagnostic work up in suspected sCJD cases with this finding. However, given the rarity of our patient’s subtype, and the relatively novel RT‐QuIC, current data is based on a small number of cases and larger cohorts of confirmed VV1 cases with RT‐QuIC testing need to be reported.
Vasogenic edema in the frontostriatal tract and the anterior limb of the internal capsule predict cognitive decline in Alzheimer disease
Authors: Wang Qing , Chen Gengsheng , McKay Nicole Sarah , Gordon Brian A. , Hassenstab Jason , Morris John C. , Morris John C. , Benzinger Tammie L.S. , Wang Yong
Published: December 2020

Background

Whereas the gray matter has long been regarded by neuroscientists as the major locus of cognitive function, white matter (WM) structures of the brain are increasingly recognized as critical for cognition. In particular, the frontostriatal tract (FST) and the anterior limb of the internal capsule (ALIC) play important roles in cognition function. In order to noninvasively quantify WM integrity, inflammation, and edema, a diffusion‐based MRI method, neuro‐inflammation imaging (NII), has recently been developed and validated. Specifically, NII‐derived extracellular water fraction (NII‐EWF) has been used as a surrogate biomarker of WM vasogenic edema in Alzheimer Disease (AD) (Figure 1). This study aimed to examine: (1) whether NII‐EWF in the FST and the ALIC is associated with cognitive ability; (2) whether the baseline NII‐EWF in the FST and the ALIC predict the cognitive decline in AD.

Method

172 Participants (121 amyloid negative healthy controls, 31 amyloid positive individuals w/ normal cognition and 20 individuals diagnosed as AD with a CDR of 0.5) enrolled in ongoing studies at the Knight ADRC at Washington University in Saint Louis underwent NII measures and a test battery of cognitive tests. Our measure of cognitive ability was Trail Making test, which is a subtask within our cognitive battery that assesses visual attention and working memory abilities. NII was acquired with multi‐b value scheme (bmax =1400s/mm2 and 25 directions). A random coefficient model was used to assess correlations between NII‐EWF and cognitive measures and to assess whether the baseline NII‐EWF is predictive of cognitive decline.

Result

The significant correlations between NII‐EWF and cognitive ability has been observed in both the FST (Figure 2A) and the ALIC (Figure 2B). The measure of NII‐EWF in both tracts has been found to be significantly predictive of the rate of cognitive decline (Figure 3).

Conclusion

Our findings suggest that NII‐EWF could be used as a predictor for cognitive decline in preclinical and early symptomatic AD. Given that the measure is acquired without using contrast agent and radioactive tracer, NII holds great promise as an accessible measure for quantifying WM pathologies and investigating their roles in the cognitive decline in AD.
Microglial activation indexed by [11C]PBR28 is associated with synaptic depletion in the Alzheimer’s disease spectrum
Authors: Benedet Andréa Lessa , Ashton Nicholas J , Pascoal Tharick A. , Brinkmalm Ann , Nilsson Johanna , Kvartsberg Hlin , Mathotaarachchi Sulantha , Savard Melissa , Therriault Joseph , Tissot Cécile , Chamoun Mira , Blennow Kaj , Zetterberg Henrik , Rosa‐Neto Pedro
Published: December 2020

Background

A large body of evidence supports the link between neuroinflammation and neurodegenerative conditions, including Alzheimer’s disease (AD). In AD, high expression of immune mediators have been associated with increased microglial reactivity. Several mechanisms were proposed to explain the relationship between microglial activation and synaptic plasticity/dysfunction. However, it remains unresolved whether neuroinflammation has a primary rather than a reactive contribution to synaptic deficits. Thus, in vivo human studies are extremely important to help deciphering the immediate causes of synaptic degeneration and the role of neuroinflammation in this context. Here we investigated, in the AD spectrum, the association between cerebrospinal fluid (CSF) biomarkers of synaptic depletion and microglial activation, indexed by [11C]PBR28 PET, using data from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort.

Method

70 participants (15 young controls, 27 normal controls (CN), 20 mild cognitive impairment (MCI) and 8 AD) were evaluated with cross‐sectional CSF biomarkers and [11C]PBR28 PET. The CSF biomarkers were quantified by in‐house immunoassays for neurogranin and neuromodulin (GAP‐43), whereas SNAP‐25 and synaptotagmin‐1 (SYT1) were quantified using an immunoprecipitation mass spectrometry method. Linear models were applied to evaluate group differences in CSF biomarker concentrations, adjusting for age and sex. Voxel‐wise linear regressions examined the association between CSF‐ and PET‐based measures. ROI‐based average SUVR was used to test the correlation between CSF biomarkers and [11C]PBR28SUVR.

Result

AD participants had higher concentrations of CSF synaptic biomarkers compared with CN. Findings at the voxel level showed a good agreement between CSF biomarkers (Figure 1), with increased CSF biomarker levels being associated with greater [11C]PBR28uptake in the frontal, posterior cingulate, temporal and inferior‐parietal cortices. Amongst the biomarkers tested, CSF SNAP‐25 biomarkers showed the strongest correlations with [11C]PBR28 (RSNAP25_total=0.69; RSNAP25_long=0.67; Figure 2). Further results will indicate the relationship between sTREM2 and [11C]PBR28.

Conclusion

Results support a link between neuroinflammation and synaptic degeneration. Although causality could not be inferred, the findings corroborate a detrimental effect of neuroinflammation on synapses at later disease stages. Finally, the results also support CSF SNAP‐25as a biomarker to track synaptic dysfunction and degeneration in AD pathophysiology.
Proteomic similarities in Alzheimer’s disease and epilepsy brains highlight the important role of tau
Authors: Pires Geoffrey , Leitner Dominique , Kanshin Evgeny , Askenazi Manor , Friedman Daniel , Devinsky Orrin , Ueberheide Beatrix , Wisniewski Thomas , Drummond Eleanor
Published: December 2020

Background

Alzheimer's Disease (AD) patients are more likely to experience epileptic seizures, and cognitive impairment is a frequent comorbidity in patients with epilepsy. Emerging findings indicate a common link between epilepsy and AD, however our understanding of the pathological changes shared between these two diseases is limited. Therefore, our aim was to determine whether there are common protein changes associated with both epilepsy and AD using an unbiased proteomics approach.

Method

We used label‐free mass‐spectrometry to quantify protein differences in the human epileptic hippocampus (epilepsy vs controls; n=14/group) and compared these results to differentially expressed proteins in AD generated by a meta‐analysis of the 10 most comprehensive AD proteomics studies.

Result

777 proteins were significantly altered in the hippocampus in epilepsy. A significant proportion of these protein changes were also observed in AD (263/777 similar protein changes; p<0.0001). Proteins altered in both epilepsy and AD were predominantly excitatory neuron specific proteins (enrichment p<0.0001). Network analysis showed that proteins altered in both epilepsy and AD were most significantly involved in remodelling of epithelial adherens junctions (17/57 proteins, p=2.37x10‐16), clathrin‐mediated endocytosis signalling (21/160 proteins, p=2.98x10‐12) and phagosome maturation (17/114 proteins, p=4.81x10‐11), suggesting that the endosomal/lysosomal system dysfunction is a key factor for both epilepsy and AD pathogenesis. Shared protein alterations also indicated a decrease in synaptic proteins (enrichment p=6.52x10‐21), confirming that synapse loss or dysfunction is a common feature of both diseases. Interestingly, tau was identified as the most significant upstream regulator of proteins altered in both epilepsy and AD (p=4.53x10‐36). Furthermore, there was a significant overlap between proteins altered in both epilepsy and AD and proteins present in our recently generated phosphorylated tau interactome (32/125 pTau interactome proteins, p<0.0001). Together, this suggests that tau may have an important pathological role in both epilepsy and AD.

Conclusion

AD and epilepsy have many common protein changes in the brain. Tau may have an important role in mediating many of these common protein changes in AD and epilepsy.
Idiopathic normal pressure hydrocephalus as a novel window for Alzheimer’s disease
Authors: Leinonen Ville , Rauramaa Tuomas , Malm Tarja , Luikku Antti J. , Junkkari Antti , Koivisto Anne M. , Hiltunen Mikko
Published: December 2020

Background

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait apraxia, cognitive deterioration and urinary incontinence. Differential diagnosis with other neurodegenerative disorders like Alzheimer’s disease (AD) can be challenging. Furthermore, AD‐related brain pathology is frequent comorbidity and can predict subsequent clinical AD. Here we aim to describe a diagnostic and treatment protocol of iNPH optimized for prediction of clinical outcome, especially future AD, and research value on neurodegenerative diseases.

Method

Since 1993 until the end of 2019, 990 patients with possible NPH underwent diagnostic right frontal cortical brain biopsy during intraventricular pressure measurement or CSF shunt surgery. Brain biopsies are routinely evaluated by immunohistochemistry against amyloid‐β (Aβ) and hyperphosphorylated tau (HPτ). Patients are follow‐up until death to gain all available outcome data.

Result

We have found an increased occurrence of clinical AD (up to 25%) in previously shunted iNPH patients as compared with rate of dementia in general population (15%). Cortical biopsy with Aβ pathology (seen in around 40% of all biopsies) during shunt insertion was the best predictor of future comorbid AD. These patients would be ideal for clinical trials of potential preventive therapies.

Conclusion

Diagnostic work‐up of NPH offer large amount of CSF, repeated brain imaging and cognitive testing. Most importantly, CSF shunt surgery open an ethically sustainable window to living brain including various comorbid neuropathological findings by chance. Along with optimized patient care, Kuopio iNPH work‐up (Figure) offer unique platform for biomarker discovery and validation.
Biopsychosocial determinants of cognitive impairment in a representative sample of English older population
Authors: Cadar Dorina , Abell Jessica , Steptoe Andrew
Published: December 2020

Background

To investigate various biopsychosocial determinants of cognitive health in later life, using the neuropsychological battery of tests administered in the Harmonised Cognitive Assessment Protocol Sub‐Study of the English Longitudinal Study of Ageing (ELSA‐HCAP).

Method

ELSA‐HCAP is a neuropsychological sub‐study of 1273 participants completed in 2018, as part of an international research collaboration designed to better measure and identify neurocognitive disorders in representative population‐based samples. ELSA‐HCAP was administered to participants across all range of cognitive abilities, but we oversampled those identified as having low cognitive scores in the most recent ELSA waves. The HCAP respondent interview covered a broad range of cognitive domains (memory, language, executive function, psychomotor speed, problem‐solving, and numeracy) known to be affected by the ageing process. We also linked ELSA‐HCAP with the previous measures collected across ELSA waves, including biomarkers, psychosomatic and social economic information of these individuals collected in ELSA main waves 4 years before in 2016. We used Structural Equation Modelling (SEM) to estimate direct and indirect associations between Apolipoprotein (APOE) e4 status, education, wealth, inflammatory markers, chronic conditions, quality of life, depression and overall cognitive performance based on multiple domains, as well as the potential mediating effects.

Result

Higher levels of education and increased quality of life were protective of the overall cognition, independent of the level of wealth. Depression and chronic conditions were strong predictor of cognitive impairment. We also found significant effects of age and sex, with women showing a slight cognitive advantage compared to men. We did not found an effect of APOE4 allele on cognitive impairment in this study. We find a pathway between higher levels of education leading to higher wealth, which impacting the number of chronic conditions and indirectly impacting on the overall cognition. We also found an indirect effect of inflammatory markers via chronic conditions and depressive symptoms.

Conclusion

In a subset sample of a nationally representative sample of English population, we found that specific psychosocial risk factors were associated with the overall cognition in later life. Biological inflammatory markers were indirectly associated with overall cognition via depressive symptoms and chronic conditions pathways.
Effect of comprehensive, individualized, person‐centered management on antidepressant usage in advanced Alzheimer’s persons in a 28‐week, randomized, controlled trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Torossian Carol , Saad Muhammad , Dafflisio Gianna , Vedvyas Alok , Reisberg Barry
Published: December 2020

Background

We published results of a clinician‐blind, parallel‐group study of Comprehensive, Individualized, Person‐Centered Management (CI‐PCM) in moderate‐to‐severe, community‐residing, Alzheimer’s persons (Reisberg…Kenowsky, Dement Geriatr Cogn Disord, 2017). CI‐PCM intervention subjects (n=10) showed 967% greater global improvement than subjects randomized to Usual Community Care (UCC, n=10). Behavioral Pathology in Alzheimer’s Disease‐Frequency Weighted (BEHAVE‐AD‐FW) total scores showed significant benefit in the intervention group at week 28 (p<0.05). Kettunen asserts, (Eur J Clin Pharmacol, 2018), “Among persons with AD, antidepressants are used for treatment of BPSD…their effectiveness in this indication is modest.” Casey states, (Pharmacy & Therapeutics, 2015), “Antidepressants…are widely used in dementia for depressed mood, anxiety, agitation, and apathy.” Bui recommends, (Cochrane for Clinicians, American Family Practice, 2012), “…antidepressants should be used [in patients with dementia] only if all other nonpharmacologic interventions for neuropsychiatric symptoms are unsuccessful.” Herein, we examine the effect of the CIPCM program on antidepressant usage and the Behavioral and Psychological Symptoms of Dementia (BPSD) as measured with the BEHAVE‐AD‐FW.

Method

Investigators blinded to treatment group assignment reviewed subject charts (N=20), for antidepressant usage, and BEHAVE‐AD‐FW total and category F scores, which measure tearfulness and depressed mood. Costs of antidepressant usage, and BEHAVE‐AD‐FW total, and category F scores for each group were compared.

Result

There were no significant differences in antidepressant usage or BEHAVE‐AD‐FW total or category F scores between groups at baseline. At all study visits, 50% of subjects in each group took antidepressants. At week 28, community physicians prescribed CI‐PCM subjects less or the same dose of antidepressants, and prescribed comparator subjects the same or greater doses, and additional antidepressants. BEHAVE‐AD‐FW category F scores for UCC comparators were persistently elevated and worsened by week 28, whereas, CI‐PCM group scores improved to zero, indicating no depressive symptoms.

Conclusion

For CI‐PCM subjects, total BPSD symptomatology declined significantly (p<0.05), antidepressant usage declined, and tearfulness and depressed mood resolved, by week 28. In contrast, UCC subjects increased antidepressant usage, paid 4.42 times more for antidepressants, and had worsening of behavioral disturbances and depressive symptoms. CI‐PCM is an effective nonpharmacologic intervention that reduces antidepressant usage in advanced AD persons with BPSD.
PET differences between cognitively unimpaired stable and declining subtypes: Multiple approaches show higher amyloid and tau among those with sub‐clinical cognitive decline
Authors: Koscik Rebecca L. , Jonaitis Erin M. , Betthauser Tobey J. , Hermann Bruce P. , Clark Lindsay R. , Mueller Kimberly D. , Du Lianlian , Birdsill Alex C. , Chin Nathaniel A. , Christian Bradley T. , Johnson Sterling C.
Published: December 2020

Background

Biomarker‐related cognitive decline begins well before mild cognitive impairment (MCI), yet detecting subclinical decline is challenging. The presence of differences in AD biomarkers between cognitively unimpaired stable and declining subtypes (CU‐S and CU‐D) might indicate validity evidence for CU‐D criteria. This study examines whether brain amyloid and tau biomarkers differed across concurrent determinations of CU‐S, CU‐D and MCI/Dementia statuses using consensus conference and algorithm‐based cognitive statuses.

Method

WRAP participants with >=3 Preclinical Alzheimer’s Cognitive Composite (PACC3) scores, free of dementia at baseline PACC3, and >=1 positron emission tomography (PET) [C‐11]Pittsburgh Compound B (PiB) scan were included (n=269); n=215 also had [F‐18]MK‐6240 tau scans. The mean(sd) age at last cognitive assessment was 67.0(6); PET PiB and MK scans occurred within means of 1.6(2) and .8(1.1) years of cognitive assessment. Cognitive statuses of CU‐S, CU‐D, and MCI/Dementia were assigned via consensus conference review. Six algorithm‐based cognitive status indicators were also examined (3 PACC3 composite‐based and 3 based on combinations of individual tests; for all, CU‐D range = centiles [4, 16), or ∼1 to 1.75 SD below expected; see Table 1). We compared continuous Global PiB DVR and MK‐6240 regional SUVR outcomes across cognitive statuses using analysis of variance and proportions PiB+ (Global PiB DVR>1.2) across cognitive statuses using Fisher’s exact tests. Significant omnibus tests (p<.05) were followed with pairwise comparisons.

Result

Table 1 shows cognitive statuses by determination method. All omnibus tests comparing biomarkers across CU‐S, CU‐D and MCI groups were significant. CU‐D had higher proportion PiB+ than CU‐S for 4 of 7 methods (Figure 1). CU‐D differed from CU‐S on average Global PiB DVR (5 methods; Figure 2), MK‐6240 entorhinal cortex SUVR (6 methods, Figure 3), and MK‐6240 hippocampus SUVR (6 methods, Figure 4).

Conclusion

Reaching a clinical diagnosis of Alzheimer’s or other dementia is the culmination of years of brain changes and initially subtle cognitive decline. The observed increased PET amyloid and tau pathology among cognitively unimpaired‐declining participants, particularly in cognitive status determination methods using longitudinal patterns, suggest CU‐D criteria can be sensitive to preclinical changes. Detecting subclinical cognitive decline may improve opportunity for early intervention that could ultimately delay clinical impairment.
Patterns of brain atrophy in dysexecutive amnestic mild cognitive impairment raise confidence about prodromal AD dementia
Authors: Junquera Fernández Almudena , García Estefanía , Parra Mario A. , Fernández Guinea Sara
Published: December 2020

Background

Prediction models aimed at detecting risk of progression from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) dementia increase their accuracy when impaired executive functions enter the analysis. This suggests that impaired executive functions in MCI are likely linked to the prodromal stages of AD dementia. Neuroimaging assessment of such patients would allow exploring if they show AD related patterns of brain atrophy. We hypothesized that AD sensitive brain regions would show discrimination between dysexecutive amnestic MCI (maMIC) and healthy controls.

Method

We analysed 32 healthy controls and 23 MCI patients. Patients were divided in single domain amnestic MCI, multidomain amnestic MCI (i.e., with the dysexecutive component), and non‐amnestic MCI. Brain volume data entered regression models to analyse which brain regions predict group membership (control vs maMCI). Stepwise lineal regression model was then conducted to identify the brain regions with better prediction power.

Results

Four variables were able to predict group membership in simple lineal regression models: entorhinal cortex, lingual gyrus and parahippocampal gyrus in the left hemisphere and fusiform gyrus in the right hemisphere. The entorhinal cortex provided the most accurate model (F(1, 42) = 14.19, p=0.001, R2=0.24). Linear regression models were run with performance on executive function tasks including tests of switching, planning, verbal fluency and working memory. The most accurate model returned Letters and Numbers and categories fluency (F(2, 44) = 21.35, p=0.000, R2=0.48) suggesting that working memory and category generation are the functions contributing to the dysexecutive profiles observed in maMCI patients.

Conclusion

Dysexecutive profiles in multidomain amnestic MCI together with neuroimaging volumetric analysis increase the probability of identifying the prodromal stages of AD dementia.
Could intelligency be a proxy for cognitive resilience in the elderly?
Authors: Pires Lívia Rabelo , Ávila Rafaela , Costa Mônica Vieira , Dias Bruna Fugêncio , Bertola Laiss , Bicalho Maria Aparecida
Published: December 2020

Background

Resilience is a concept related to individual diferences between functionality/cognition and clinical situations associated to aging. In Brazil, elderlies commonly have low educational level and, years of schooling , is not necessarily associated to learning. In this context, we hypothesize that inteligency could be a potencial proxy of cognitive resilience. The aim of this study was to evaluate if inteligency could act as a measure of cognitive resilience, explaining individual variation between expected cognitive profile and its performance.

Method

We conducted a cross sectional study, enrolling 60 elderlies, 29 without functional and Cognitive Impairment (CG) and 31 with Mild Cognitive Impairment (MCI). To evaluate inteligency we applied WASI, Mattis scale for general cognition and, Frontal Assessment Battery (FAB) for executive functions. Participants were submitted to the same study protocol, including a geriatrician evaluation and neuropsychological assessment. We applied Mann‐Whitney and chi‐square to compare the groups. Pearson correlation coefficient and multivariate analysis were employed to compare samples. Linear regression analysis with control of independent variables age, sex and years of schooling and, the outcomes Mattis and FAB were applied to verify cognitive discrepancy. The intelligency quociente (IQ) was analyzed as a cognitive discrepancy predictor by regression analysis.

Result

60 individuals were selected, aged 76.8 ± 5.80 years, 75% female and 4.6 ± 3.42 years of schooling. There were no diferences between groups considering age, schooling and IQ, Mattis and FAB. In CG, we observed correlation between age and IQ and Mattis; and, schooling and IQ and Mattis. For MCI, there were correlation between age and Mattis; schooling and Mattis; IQ and FAB; and, Mattis and FAB. The regression model showed the higher the intelligence level, the greater the positive discrepancy in general cognition (Mattis) (Figure 1). The result of analysis carried out between IQ and discrepancy in executive functions (FAB) showed the higher the IQ, the greater the positive discrepancy in executive functions (Figure 2).

Conclusion

Our results suggest IQ can be measure of discrepancy in general cognition and executive functions. It can be a good proxy of cognitive reserve.
Plasma phospholipid fatty acids, cognitive function, and risk of dementia among older adults
Authors: Koch Manja , Furtado Jeremy D. , DeKosky Steven T. , Fitzpatrick Annette L. , Lopez Oscar L. , Kuller Lewis H. , Mukamal Kenneth J. , Jensen Majken K.
Published: December 2020

Background

Plasma phospholipids are biomarkers of dietary fat intake and metabolism which have been linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to adjudicated dementia risk and cognitive decline.

Method

We measured plasma phospholipids in a case‐cohort study nested within the Ginkgo Evaluation of Memory Study. We included 911 randomly selected participants and 498 participants who developed dementia during a mean [SD] of 5.0 [1.8] years of follow‐up. We measured individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by gas chromatography with flame ionization detection. These were evaluated in association with the Modified Mini‐Mental State Examination (3MSE) scores at baseline and neurologist‐adjudicated risks of all‐cause dementia and Alzheimer’s disease (AD), adjusting for sociodemographic and clinical characteristics.

Result

When compared with saturated fatty acids (SFA), we found no associations of total mono‐unsaturated (MUFA), polyunsaturated (PUFA), or trans‐fatty acids (TFA) with risk of dementia or AD. However, higher docosahexaenoic acid was associated with a lower risk of dementia (hazard ratio 0.80 per 1% of docosahexaenoic acid instead of SFA; 95% confidence interval: 0.71‐0.91). Similarly, higher PUFA was associated with 0.04 point higher 3MSE score at baseline (per 1% PUFA instead of SFA; 95% confidence interval: 0.01, 0.08) signifying better cognitive function.

Conclusions

Although we did not find strong associations of mono‐unsaturated or TFA with risk of dementia or AD when compared with SFA, replacement with PUFA was associated with better baseline cognitive function, and replacement with the marine n‐3 fatty acid docosahexaenoic acid was associated with lower risk of dementia. This prospective study highlights the potential of dietary improvement to prevent dementia.
Sex differences in the association between education in adulthood and late‐life cognition in the Kaiser Health Aging and Diverse Life Experiences (KHANDLE) Study
Authors: Gilsanz Paola , Mayeda Elizabeth Rose , Eng Chloe W , Glymour M Maria , Peterson Rachel , George Kristen M , Quesenberry Charles P , Mungas Dan M , DeCarli Charles , Whitmer Rachel A
Published: December 2020

Background

While education is strongly associated with late‐life cognitive level, it is unclear how education after young adulthood is associated with late‐life cognition. This study examines the association between adult education and overall and domain specific cognition in a diverse sample allowing for possible differences in associations by sex. This is important to consider given recent increases in educational opportunities for women.

Method

The Kaiser Healthy Aging and Diverse Life Experiences Study (KHANDLE) enrolled Kaiser Permanente Northern California members age 65+ who completed a Multiphasic Health Checkup (MHC) conducted from 1964‐1996. Among 1,363 KHANDLE participants who reported education attainment at an MHC before age 25, education in adulthood was a binary variable reflecting reporting higher levels of education during KHANDLE interviews than at their first MHC visit after age 25. Executive function, semantic memory and verbal episodic memory were captured through the Spanish and English Neuropsychological Assessment Scales (SENAS) during KHANDLE baseline interviews and z‐standardized. Linear regressions estimated the association between education in adulthood and domain‐specific late‐life cognition adjusting for age at MHC, age at KHANDLE, sex, race/ethnicity, and educational attainment at MHC. Stratified models and interaction terms tested for possible sex differences in associations.

Result

Women were more likely than men to have ≤ HS at their MCH (33% vs 20%; chi‐square p‐value=<0.0001) and to receive additional education during adulthood (37% vs 27%; chi‐square p‐value=<0.0001). Among recipients of adult education, 50% had ≤ HS at their MCH and at the KHANDLE interview 25% completed HS or trade school, 18% completed college, and 24% completed graduate school. Education during adulthood was associated with executive function (β=0.18, 95% CI: 0.07, 0.28) but not semantic memory (β=0.09, 95% CI: ‐0.02, 0.19) nor verbal episodic memory (β=0.06, 95% CI: ‐0.05, 0.18). The association between adulthood education and executive function was stronger among women than men (women: β=0.19, 95% CI: 0.06, 0.32; men β=0.12, 95% CI: ‐0.07, 0.32; executive function*female interaction term p‐value=0.04).

Conclusion

Education during adulthood was associated with better executive function among women. Additional research is needed to assess if education during adulthood is associated with cognition and cognitive decline in late‐life.
High frequency of progranulin mutations in Caribbean Hispanic families with dementia
Authors: Vardarajan Badri N. , Reyes‐Dumeyer Dolly , Piriz Angel , Medrano Martin , Lantigua Rafael , Mayeux Richard
Published: December 2020

Background

Progranulin (GRN) mutations cause frontotemporal dementia (FTD) and have been implicated in causing a variety of clinical neuro‐degenerative syndromes, including Alzheimer’s disease (AD) but it is hypothesized that these presentations all result from TDP‐43 pathology. We estimated the frequency of GRN mutations in multiplex families with dementia in the Dominican Republic and in New York.

Methods

We analyzed GRN mutations from whole genome sequencing data in 1941 individuals from 307 multiplex Caribbean Hispanic families with dementia. We prioritized rare (MAF<0.05 in GnomAD exomes and genomes) GRN variants annotated as having moderate‐high functional effect. Identified variants were cross‐referenced with FTD mutations found in Orphanet, MedGen, SNOMED and OMIM databases. GRN mutation carriers further were assessed for clinical and behavioral symptoms.

Results

We identified 27 rare, moderate‐high impact variants in GRN in the Caribbean Hispanic families. Six mutations (rs63750723, rs368705304, rs63750479, rs63750412, rs63751294, rs25647) were previously reported as associated with FTD and were found with MAF<0.05 in the GnomAD genomes. 92 individuals (4.7%) from 45 families carried at least one of the six previously reported GRN variants. Of these 47 (51 %) were initially thought to have Alzheimer’s Disease with an average age at onset of 77.8 (±8.93) and the remaining 46 were unaffected (average age of last healthy exam= 65.05 (±8.4)). Aggression and psychosis were frequently observed behavioral symptoms in the demented patients consistent with FTD phenotype.

Conclusions

In this study we observed a higher than expected frequency of damaging GRN mutations in families multiply affected by dementia. The majority of demented individuals were thought to have Alzheimer’s disease initially. Further analyses of phenotype‐genotype correlations should provide insight into impact of GRN mutations among Caribbean Hispanics.
Vascular cognitive impairment due to dilated perivascular spaces in putamen: Connections with the ventrolateral prefrontal cortex and neurological deficits
Authors: Canella Marcelo , de Oliveira Souza Natalia Vasconcellos , Bertolucci Paulo Henrique Ferreira , de Oliveira Fabricio Ferreira
Published: December 2020

Background

Anatomical studies in animals have described multiple striatal circuits and suggested that sub‐components of the striatum project to distinct cortical areas. Researchers that reconstructed tracts of the left and right putamen have shown ipsilateral projections to the primary motor area, primary somatosensory area, supplementary motor area, premotor area, cerebellum, thalamus and prefrontal cortex (specifically to the ventrolateral prefrontal cortex). The ventrolateral prefrontal cortex appears to have a specific role in spatial processing and memory retrieval.

Method

Case report and analyses of MR Images (T1, T2 and Flair) of a patient presenting with vascular cognitive impairment due to dilated perivascular spaces in putamen bilaterally.

Result

Male patient, 81 years‐old, right‐handed, with four years of formal education and high cerebrovascular risk. His cognitive complaints began twelve years ago, and worsened in the last two years (losing personal belongings inside his own house, sometimes forgetting names of well‐known persons, with word finding difficulties). He denied impairment in activities of daily living, was able to organize his home budget, take his medications and go to the market alone. Now, he is physically and intellectually active (walking, reading newspapers, and talking about Philosophy), and still drives cars. His CDR score is 0.5, and his MMSE score is 29 (with 3 points in evoked memory). Word List Memory Task (Immediate Recall):4/5/8 (intrusion of "vessel" in the first two lists); Evocation:6 (intrusion of "vessel"); Recognition:10; Verbal Fluency (Animals):20; Verbal Fluency (Fruits):9. MR (10/15/2018): mild supratentorial microangiopathy; encephalomalacia/gliosis in the vermis and the left cerebellar hemisphere; Fasekas = 1 / Scheltens = 1 (bilaterally); bilateral supratentorial dilated perivascular spaces, particularly in the putamen.

Conclusion

Our patient does not have dementia, regardless of more than ten years of cognitive impairment. Bilateral dilated perivascular spaces in the putamen may cause deficits in memory retrieval and spatial processing. Neuropsychological evaluations must consider specific areas of brain injury. Our patient has impaired memory retrieval (with false memories verified by constant intrusions in the Word List Memory Task), and the high occurrence of losing personal belongings inside his house can be due to difficulties in spatial processing (mental map of positions of items in space).
Association of late‐onset dementia risk scores and Alzheimer’s disease pathology status in preclinical older adults
Authors: Udeh‐Momoh Chinedu T. , Zheng Bang , Price Geraint J. , Watermeyer Tam J. , Jager Celeste A. , Su Bowen , Giannakopoulou Parthenia , Saad Ziad , Fogle Michael , Robb Catherine , Ford Jamie , Ritchie Craig W. , Baker David , Novak Gerald P. , Ahmadi‐Abhari Sara , Middleton Lefkos T.
Published: December 2020

Background

Dementia risk scores (DRS) for the prediction of Alzheimer’s disease (AD) have the potential to identify at‐risk individuals for secondary prevention trials. To date, risk scores have focused primarily on predicting dementia symptoms rather than AD histopathology. Prediction of biological disease status could inform more precise targeting of at‐risk populations for prevention strategies.

In this study, we compare the predictive value of three late‐life DRSs, namely the revised CAIDE (younger and older old) and the Reitz DRS (Reitz et al. 2010). Capacity for distinguishing pathogenic amyloid‐beta status and relation to multi‐domain cognitive performance was explored.

Methods

1378 cognitively‐unimpaired participants aged 60‐85 years from the UK Cognitive Health in Ageing Register: Investigational, Observational, and Trial Studies in Dementia Research: Prospective Readiness cOhort (CHARIOT‐PRO) Sub‐study had cerebral amyloid load dichotomized as positive vs negative. The predictive value of the Reitz and CAIDE risk scores for determining amyloid status were tested in separate logistic regression models. Associations of the risk scores with global and multi‐domain cognitive performance (assessed via the RBANS) were further evaluated. Finally, the contributions of individual components of the risk scores on amyloid status and cognitive performance were tested in multiple logistic and linear regression models.

Results

19.3% of the participants were amyloid‐positive. The Reitz and CAIDE young‐old (age<75) scores were higher in the amyloid positive versus negative group (median(IQR): 20 (10) vs 15 (11), 1 (2) vs 0 (2) respectively; P<0.05). Higher Reitz and CAIDE younger‐old scores were associated with increased risk of amyloid positivity (OR=1.05 (1.03‐1.08) and 1.17 (1.03‐1.34) respectively; P<0.05). Reitz score alone was negatively correlated with global cognition, memory and visuospatial indices (r ranges from ‐0.10 to ‐0.14; P<0.05). The potential contributing factors for predicting amyloid status were age, ApoE‐e4, and ethnicity; while diabetes and education predicted cognitive performance. In contrast, nil associations of CAIDE older‐old (age≥75) score with amyloid status or cognitive performance were noted (P>0.05).

Conclusions

The risk scores tested revealed differential predictive abilities in relation to amyloid pathology status and late‐life cognitive performance. Risk composites focusing on identified genetic and metabolic factors may be useful for more precise participant selection in targeted prevention and risk‐reduction trials.
Defining Alzheimer’s disease subtypes using polygenic risk scores integrated with genomic and brain transcriptomic profiles
Authors: Hu Junming , Chung Jaeyoon , Panitch Rebecca , Zhu Congcong , Beecham Gary W. , Mez Jesse , Farrer Lindsay A. , Stein Thor D. , Crane Paul K. , Jun Gyungah R.
Published: December 2020

Background

In light of the complex etiology of Alzheimer’s disease (AD), classifying AD patients into clinical subtypes is important for precision medicine. We tested whether polygenic risk scores (PRSs) combined with brain expression profiles in AD patients are correlated with clinically defined AD subtypes.

Methods

We generated 143 co‐expressed gene networks (modules) using RNA sequencing (RNA‐Seq) data derived from 64 autopsied AD brains from the Framingham Heart Study and Boston University Alzheimer’s Disease Center. These modules were validated using brain RNA‐seq data from participants with AD in the Religious Orders Study and Memory and Aging Project (n = 363) and the Mayo Clinic Study of Aging (n = 82). Fourteen AD‐related modules were selected by enrichment analysis using the significant genes (P < 0.001) identified in a genome‐wide association study for neuropathological traits (Beecham, 2015) and then characterized by brain cell‐type specific expression profiles. We computed polygenic risk scores of the AD‐associated genes within each module (module‐based PRSs) using the estimates from Beecham et al. in the 449 AD patients of the Alzheimer’s Disease Neuroimaging Initiative. Next, we examined correlations of the 14 module‐based PRSs with (1) scores for 9 different cognitive tests and six cognitively‐defined AD subtypes including memory, language, visuospatial, executive, multi, or no domains (Mukherjee, 2018).

Results

Eleven of the 14 AD‐related modules were significantly enriched (P < 0.05) for specific brain cell types including four in neurons (best P = 6.8 × 10−104), four in astrocytes (best P = 5.2 × 10−76), two in endothelial cells (best P = 9.9 × 10−87), and one in microglia (P = 1.7 × 10−129). The most significant correlation between the PRSs from the 14 modules and clinical phenotypes was found with an astrocyte‐specific module and language‐related cognitive functions (correlation r2>0.2; P = 6.7 × 10−3), and this module contained 8 AD genes (best gene: DOCK1, P = 3.4 × 10−5). The individual PRSs of the astrocyte‐module were significantly higher in the language‐specific AD patients compared with in other five subtypes (best P = 0.01 from comparison with AD patients in the no domain group).

Conclusion

These findings illustrate for the first time that genetic risk scores integrated with system biology may define clinical subtypes of AD. Our findings will facilitate genome‐guided precision medicine efforts in prevention and treatment of AD.
Arterial stiffness acts synergistically with APOE genotype and amyloid status to predict cognitive impairment in non‐demented elderly
Authors: Smirnov Denis S. , Bangen Katherine J. , Galasko Doug R. , Brewer James B. , Salmon David P.
Published: December 2020

Background

Vascular disease is a known contributor to cognitive impairment in the elderly, often associated with impairments in Executive Functions. Aortic‐femoral Pulse Wave Velocity (PWV) measures have been proposed as a non‐invasive measure of vascular risk. However, the predictive value for cognitive decline and interactions with amyloid biomarkers have received limited study.

Methods

PWV was assessed in 129 non‐demented participants (108 cognitively normal and 21 mild cognitive impairment [MCI]) who underwent comprehensive medical and neuropsychological evaluation at the Shiley‐Marcos UCSD ADRC. PCA‐derived Domain Z‐Scores (relative to robust normal controls) were generated, representing Memory, Language, Visuospatial, Executive Functions, and Attention. Linear models examined if PWV significantly predicted each Domain Score and global cognition (the Mattis Dementia Rating Scale (DRS) total score), adjusting for age, sex, and education. In a subanalysis, history of hypertension, hypercholesterolemia, diabetes, stoke/TIA, CVD, atrial fibrillation, and current smoking status were each added to the model. Next, presence of an APOE ε4 allele was added and allowed to interact with PWV. Amyloid status was determined using CSF AB42/40 ratios in a subset of participants (n = 93), and its interaction with PWV was similarly tested.

Results

After adjusting for demographics, PWV predicted DRS scores (B=‐0.47, p=0.01), Memory Domain Scores (B=‐0.11, p=0.02), and Executive Domain Scores (B=‐0.10, p = 0.04, Figure 1). The pattern of results did not change when history of vascular risk factors was added to the models. When restricting to only cognitively normal participants, PWV significantly predicted only Executive Domain Scores (B=‐0.08, p = 0.03). Presence of an APOE e4 allele showed a significant interaction with PWV in predicting Memory (B=‐0.18, p=0.03, Figure 2). In the subsample with CSF data, the Memory Domain Score was predicted by the interaction of PWV with amyloid status (B = ‐0.30, p = 4.2x10‐4, Figure 3).

Conclusions

Arterial Stiffness measured through aortic‐femoral PWV is a predictor of cognitive impairment, especially in the Memory and Executive Function domains, and interacts with markers of Alzheimer’s disease (APOE and amyloid status), such that a stronger relationship is found in the amyloid/ε4 positive population.
Longitudinal change in CSF biomarkers, especially NPTX2, in non‐demented elderly predicts cognitive decline and conversion to dementia
Authors: Galasko Doug R. , Smirnov Denis S. , Salmon David P. ,   Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: December 2020

Background

We have previously shown that markers of synaptic dysfunction (e.g. NPTX2) measured cross‐sectionally in CSF improve prediction of current cognitive status and future cognitive decline above and beyond amyloid (i.e., Aβ1‐42) alone (Galasko et al, 2019). Here we assess if longitudinal change in these and other candidate CSF biomarkers (NPTX2, VGF, SCG2, CMGA, FAPBH), with total tau (T‐Tau), correlate with cognitive decline and predict conversion to dementia.

Methods

Longitudinal CSF samples collected over 4 years from 193 non‐demented elderly from ADNI (81 NC, 45 EMCI, 67 MCI, age = 72.6±7, 45% Female, MMSE = 28.4±1.7) were analyzed by mass spectrometry for absolute concentration of NPTX2, VGF, SCG2, CMGA, and FAPBH. Elecsys data for Aβ1‐42 and T‐Tau were also available. All biomarker values were log transformed. Rates of change (Δ) were calculated from regression on age. Linear mixed effects models assessed the ability of the slope of each marker over the same time period to predict the rate of longitudinal cognitive decline on the cognitive tests of the ADNI cognitive battery, adjusted for age, sex, education, baseline cognitive performance, and baseline CSF Aβ1‐42 levels. Cox Proportional Hazard models were fit for progression to dementia (CDR >= 1.0), adjusting for the same covariates.

Results

Although the candidate markers were all highly intercorrelated (r= .42‐.95), their change over time was differentially associated with amyloid status (Figure 1) and to longitudinal decline on cognitive test score and functional measures (Table 1, e.g. Figure 2). Slopes of NPTX2 (p=0.0008), SCG2 (p=0.03), CMGA (p=0.04) and VGF (p=0.01) each predicted conversion to dementia (Table 2, e.g. Figure 3) and MMSE decline. Change in T‐tau only predicted MMSE decline.

Conclusions

Longitudinal change of candidate markers, especially NPTX2, has utility for predicting degree of prodromal/early cognitive decline and transition to dementia, beyond the ability of amyloid alone or change in CSF T‐tau. Thus, these candidate CSF biomarkers may have utility as indicators of cognitive impairment and predictors of cognitive decline.