bluuebunny/crossref_metadata_2025 huggingface dataset:
TGF344‐AD rats exhibit cognitive reserve despite continual Aβ and tau accumulation
Authors: Morrone Christopher D. , Lai Aaron Y. , Hill Mary E. , McLaurin JoAnne
Published: December 2020

Background

Patient to patient variability in Alzheimer’s disease progression complicates treatment efficacy. Furthermore, the presence of Aβ pathology does not always indicate cognitive impairments. Epidemiological evidence of cognitive reserve suggests some individuals exhibit enhanced neuronal and behavioural resilience, protecting against neurodegeneration and cognitive decline. However, Alzheimer’s disease models typically exhibit a correlation between accumulation of pathology and behavioural impairments, making cognitive reserve difficult to investigate preclinically.

Method

TgF344‐AD rats recapitulate the amyloid cascade with a long‐term accumulation of Aβ and tau pathology leading to significant neurodegeneration and behavioural impairments. TgF344‐AD rats were assessed for cognitive and neuropathological alterations compared to age‐matched non‐transgenic littermates, across disease progression at 4, 6, 9, 12 and 15 months of age. Latency to escape and complexity of search strategies utilized in the Barnes maze spatial and reversal phases were assessed to determine learning, long‐term memory, and executive function. Neuropathological assessment included GABAergic and total neuronal counts, and quantification of Aβ and tau pathology.

Result

TgF344‐AD rats demonstrate deficits in spatial memory and executive function beginning at 6 months which are not exacerbated at 9 or 12 months, but are at 15 months of age. GABAergic and total neuronal counts in the hippocampus and entorhinal cortex of TgF344‐AD rats exhibit a similar trend, with deficits not progressing between 9 and 12 months of age. Conversely, Aβ and tau pathology accumulate continually across disease progression. Non‐transgenic rats exhibit slight, yet consistent age‐related decline in cognitive and neuronal measures.

Conclusion

Disease‐bearing TgF344‐AD rats exhibit cognitive reserve before robust cognitive decline at 15 months, despite consistent increases in Aβ and tau deposition. Maintenance, and in certain hippocampal subregions a recovery, of neuronal loss at 12 months support this observation, and suggest the involvement of compensatory mechanisms such as hippocampal neurogenesis. Understanding the mechanisms underlying cognitive reserve in Alzheimer’s disease will help explain patient variability in disease progression and elucidate novel regenerative therapeutic targets.
Cognitively defined subtypes of Alzheimer's disease
Authors: Crane Paul K. ,   for the ADNI Psychometrics Study Group
Published: December 2020

Background

We have developed a framework for using cognitive test results at Alzheimer’s disease (AD) diagnosis to categorize people into AD subgroups. We have shown that risk factors and genetic variant associations vary across subgroups. We also showed differences in gray matter volume (GMV) using voxel‐based p‐values. Here we present new findings with beta coefficient maps and a movie showing regional atrophy associated with greater global atrophy.

Method

We use data from the first ADNI study visit with AD for 624 amyloid positive patients, and the first visit for 119 amyloid negative cognitively normal controls (CN). We generated voxel‐wise gray matter (GM) W‐scores as (actual GM‐expected GM)/SD. Expected GM is based on voxel‐wise regressions in CN in SPM12 with age, sex, ICV, and field strength. SD is the voxel‐specific SD of residuals from the regression analyses. We obtained global W‐scores as the number of voxels with W<‐1.65. We generated beta‐coefficient maps from SPM, controlling for global W‐score, age, sex, ICV, and field strength. We obtained regional W‐scores using the Desikan‐Killiany cortical parcellation atlas and performed regression analyses predicting regional W‐scores as a function of total W‐score as a continuous predictor, and present the results as a movie for each region.

Result

There were 267 people with no prominent differences across domains (AD‐No Domain), 189 with AD‐Memory, 14 AD‐Executive, 46 AD‐Language, 85 AD‐Visuospatial, and 23 AD‐multiple domains. Groups did not differ with respect to sex, years of education, handedness, or proportion who were non‐Hispanic white. Mean age at diagnosis ranged from 73 (AD‐Visuospatial and controls) to 77 (AD‐Language; omnibus p = 0.015) Compared to other groups, the AD‐Memory group consistently had greater GMV loss in medial temporal lobes (Figure 1). Each of the other groups had substantial areas of cortex with greater GMV loss than the AD‐Memory group (Figure 2). Regions associated with more global atrophy varied substantially across groups (Figure 3: this is a still of coordinated movies for each subgroup).

Conclusion

Cognitively defined AD subgroups differ in patterns of GMV in regions that make sense with the cognitive phenotype.
Progressive dysexecutive syndrome due to Alzheimer’s disease: A description of 55 cases and comparisons to other clinical AD phenotypes
Authors: Townley Ryan A , Graff‐Radford Jonathan , Mantyh William G. , Botha Hugo , Polsinelli Angelina J. , Przybelski Scott A. , Machulda Mary M. , Senjem Matthew L. , Murray Melissa E. , Reichard Ross R. , Savica Rodolfo , Boeve Bradley F. , Drubach Daniel A. , Josephs Keith A. , Knopman David S. , Lowe Val J. , Jack Clifford R. , Petersen Ronald C. , Jones David T.
Published: December 2020

Background

We report a group of individuals presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions and positive biomarkers for Alzheimer’s pathophysiology.

Method

In this retrospective review, we report on 55 participants with a clinically defined progressive dysexecutive syndrome with 18F‐fluorodeoxyglucose‐positron emission tomography (FDG) and AD biomarker positivity. A subset of these individuals enrolled in our ADRC were compared to other phenotypic variants of AD.

Result

Sixty‐two percent were female with a mean of 15.2 years of education. Mean age of symptom onset was 53.8 while mean age at diagnosis was 57.2 years. Multi‐domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently and severely affected. The frontal and/or parietal regions demonstrate clear hypometabolism on positron emission tomography in all cases. Genetic testing for autosomal dominant genes was negative in all 8 participants tested and at least one APOE ε4 allele was present in 14/26. EEG was abnormal in 14/17 cases. CSF and neuroimaging biomarkers (PIB‐PET and Tau‐PET) were consistent with Alzheimer’s disease pathophysiology, although CSF p‐tau was normal in 24% of cases. In two participants that came to autopsy, the hippocampus was relatively spared compared to frontal and parietal cortex. Participants presenting with a progressive dysexecutive syndrome and evidence of AD pathology are labeled dAD. Comparing FDG in dAD relative to other AD phenotypes revealed unique areas of relatively greater hypometabolism in parieto‐frontal cortex and relative sparing of medial temporal (vs typical AD), visual (vs PCA), and left temporal (vs lvPPA) (Figure 1). Controlling for age did not alter patterns of regional differences. This demonstrates regional variability related to clinical phenotype not accountable by variation in age, duration, stage, or severity (Figure 2).

Conclusion

A progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype. This clinical presentation can be due to Alzheimer’s disease but is not specific for any single etiology (non‐AD cases of progressive dysexecutive syndrome will be discussed). Prominent impairment of executive task performance, young‐age of onset, normal CSF p‐tau, and relative preservation of the hippocampus were commonly encountered in this case series of dAD.
How ‘atypical’ is the neuroimaging signature of Alzheimer’s atypical variants? MRI and PET imaging of posterior cortical atrophy and logopenic variant of primary progressive aphasia
Authors: Joie Renaud La , Damasceno Pablo F. , Visani Adrienne , Iaccarino Leonardo , Strom Amelia , Edwards Lauren , Gorno‐Tempini Marilu , Jagust William J. , Miller Bruce L. , Raj Ashish , Rabinovici Gil D.
Published: December 2020

Background

Alzheimer’s disease clinical expression is highly heterogeneous: cognitive and anatomical variations exist on a multi‐axis spectrum with well‐described variants like posterior cortical atrophy (PCA) or logopenic variant of primary progressive aphasia (lvPPA) representing extreme phenotypes of so‐called “atypical” AD. Here, we provide an overview of our investigations of PCA and lvPPA using structural MRI and amyloid/tau‐PET imaging, emphasizing both the differences and the similarities between these phenotypes and more typical presentations of AD.

Method

We investigated 97 amyloid‐positive patients with a clinical diagnosis of AD (MCI or dementia stage), including 18 patients with PCA and 19 with lvPPA; the remaining patients are referred to as typical (tAD; Table 1). Patients received 3‐tesla MRI and PET with [11C]PIB and [18F]Flortaucipir. Standardized Uptake Value Ratio (SUVR) images were created using specific reference regions. Mean SUVR or cortical thickness values were extracted from 72 FreeSurfer regions, and cortical asymmetry indices were calculated.

Result

Atypical variants tended to be younger and less likely to carry APOE4 than tAD (Table1). Global amyloid burden did not vary across phenotypes or with any clinical measure (Figure 1A). The cortical distribution of PIB was widespread and only showed minor differences between variants (Figure 2A). In contrast, global Flortaucipir‐SUVR was higher in atypical groups compared to tAD, and was lower in older patients across phenotypes (Figure 1A). Flortaucipir was consistently elevated in temporo‐parietal regions but also showed strong between‐variant regional differences (Figure 2B) that mirrored differences in cortical volume (Figure 3B). Flortaucipir and MRI asymmetries were strongly inter‐related and very common across all AD phenotypes rather than specific to atypical variants (Figure 3). However, asymmetry was systematic in lvPPA (84‐95% left‐predominant, 5% right‐predominant) and PCA (33% left‐predominant, 66% right‐predominant)

Conclusion

Atypical phenotypes share various features with tAD: i) widespread cortical amyloid deposition, ii) tau pathology in the temporo‐parietal areas, iii) higher tau burden associated with earlier disease onset, iv) a strong negative relationship between tau and local cortical volume. The main between‐phenotype differences were related to the distribution of tau and associated atrophy that were more left‐predominant and perisylvian in lvPPA, and more occipital and asymmetric in PCA.
Raising awareness of clinical trials in dementia: A national survey testing concept designs tailored to African American caregivers and individuals at risk
Authors: Massett Holly A , McGowan Melissa , Han Sae H , Watson Jennifer , Emmerson Karen , Burns Adam , Robinson Candice Watkins , Hummel Allyson , Silverberg Nina , Elliott Cerise L , Donley Grayson , Bernard Marie A
Published: December 2020

Background

Low enrollment of African Americans into clinical trials for Alzheimer’s Disease (AD) and related dementias (ADRD) is partly a result of too few researchers offering trial opportunities and inadequate information that is culturally relevant. The National Institute on Aging (NIA) sought to develop a culturally acceptable/effective toolkit of AD/ADRD clinical trial (CT) outreach materials for community health professionals to use with African American audiences. This abstract presents the results of a national online survey testing several AD/ADRD concept designs with adults/caregivers to guide the toolkit’s development.

Method

An online national panel survey was conducted with African American adults who: 1) had a family history of AD/ADRD (n=206); 2) had no family history of AD/ADRD (n=204); and, 3) were caregivers of persons with AD/ADRD (n=206). Respondents reported their AD/ADRD and CT knowledge/attitudes/intentions; they reviewed four concept designs and indicated preferences/likelihood of each concept to impact five variables (visit website, interest in trials, attention, believability, salience). Concepts featured messages that tested well in focus groups.

Result

Caregivers and those at‐risk self‐reported higher familiarity with AD/ADRD signs/symptoms than those with no family history; all groups self‐reported limited understanding of CTs. Two concepts ranked highest among all participants: emphasizing helping future generations and noting that AD/ADRD affects races differently. Most caregivers (61‐87%) and at‐risk participants (46‐89%) gave favorable scores for all impact variables across all concepts, indicating they found most concepts motivating and acceptable. Those with no family history provided lower impact scores (39‐78%). After viewing all concepts: all groups significantly increased (p<.05) their “interest in participating in clinical trials”; and, the at‐risk and no‐history groups were significantly more likely to disagree with “there is nothing I can do to reduce my risk of [AD]”.

Conclusion

This research identifies effective AD/ADRD ad concepts that are culturally tailored and acceptable to African Americans nationally, and addresses a known obstacle to recruitment. The combination of the messages/images successfully increased interest in CTs as an option to address AD/ADRD. Using these findings, NIA developed and offers an outreach toolkit to assist community health professionals who do not otherwise have resources to develop their own materials.
Evaluation of 18F‐JNJ‐067 as a tau tracer
Authors: Baker Suzanne L. , Provost Karine , Thomas Wesley P. , Whitman A. J. , Janabi Mustafa , Schmidt Mark E. , Timmers Maarten , Kolb Hartmuth C. , Rabinovici Gil D. , Jagust William J.
Published: December 2020

Background

Current tau PET tracers have obvious shortcomings. 18F‐JNJ‐64326067 (18F‐JNJ‐067) is a new tau tracer that binds to aggregated tau in Alzheimer’s Disease (AD) brain tissue with Ki=2.4nM. Our objective was to evaluate 18F‐JNJ‐067 in individuals with AD (N=3), Mild Cognitive Impairment (MCI, N=3), Progressive Supranuclear Palsy (PSP, N=2) and healthy controls (HC, N=4).

Method

Following a 50‐70min 11C‐PIB PET scan (Siemens Biograph PET/CT), 12 subjects underwent 90 min dynamic PET scan after 18F‐JNJ‐067 injection. MPRAGEs were acquired on a Siemens 3T and segmented using FreeSurfer. Time activity and SUVR curves were viewed for commentary on steady state. Logan DVR quantification was calculated from 35‐90min (k2ref=0.025 min‐1 derived from SRTM2 analysis) using inferior cerebellar gray as a reference region. Data quantification was done in native space; images were warped to template space for visualization.

Result

Subject information is shown in figure 1; all AD and MCI subjects were PIB positive with MMSE scores from 18‐30, all PSP and HCs were PIB negative. Steady state was not reached in ROIs with high levels of tracer retention within 90 minutes (SUVR curves shown in figure 2). Figure 1 shows native space DVR quantification for ROIs. ADs had 18F‐JNJ‐067 binding in typical AD regions, one MCI had elevated binding, the others showed low binding (DVR images in figure 3). HCs showed no binding in entorhinal cortex, and had elevated signal in basal ganglia, midbrain, superior cerebellar gray, and white matter but no binding in the choroid plexus or meninges (figure 4). MMSE was correlated with Braak I/II (r2=0.80), Braak III/IV (r2=0.73) and Braak V/VI (r2=0.50) ROIs.

Conclusion

18F‐JNJ‐067 shows relatively slow pharmacokinetics in brain regions with high target density, has low levels of probable off‐target binding in the basal ganglia and white matter but not elsewhere, and low entorhinal signal in HCs and MCIs. Binding in AD patients reflects a typical pattern of tau distribution seen with other tracers, and MCI patients are intermediate. Braak ROIs are significantly correlated to MMSE. These data suggest that 18F‐JNJ‐067 is suitable for investigation of the AD continuum.
Changes in cardiac structure over 25 years are associated with lower midlife cognition: The CARDIA study
Authors: Rouch Laure , Hoang Tina D , Xia Feng , Sidney Stephen , Lima Joao , Yaffe Kristine
Published: December 2020

Background

Cardiovascular risk factors are associated with worse cognition, yet less is known about the impact of cardiac structure and function and their adverse effects on the brain possibly from decreased perfusion. The few studies included older patients with cardiovascular disease and relied on single echocardiographic assessment.

Method

We included 2256 subjects from the CARDIA (Coronary Artery Risk Development in Young Adults) study (60% women, 44% black). Echocardiograms were repeated at Years 5, 25, 30 (mean age 30, 50, 55 years, respectively) to assess cardiac structure: left ventricular mass (LVMi), left atrial volume (LAVi) and systolic function: left ventricular ejection fraction (LVEF). Diastolic function was assessed at Year 25 as the ratio of early peak mitral velocity (E)/early peak mitral annular velocity (e’). Five cognitive domains were assessed at Year 30: verbal memory [Rey Auditory Verbal Learning Test (RAVLT)], category and letter fluency, processing speed [Digit Symbol Substitution Test (DSST)], executive function [Stroop] and global cognition [Montreal Cognitive Assessment MoCA]. We investigated the association of (1) 25‐year change and (2) Year 25 cardiac structure and function on midlife cognition using linear regressions.

Result

Over 25 years, LVMi and LAVi increased with mean change (SD) of 5.7 g/m² (21.7) and 9.6 mL/m² (7.4) while LVEF decreased by mean (SD) change of 1.5% (9.0). After adjustment for demographics and education, abnormal cardiac structure assessed by greater 25‐year increase (≥ 1‐SD) in LVMi was associated with lower cognition on most tests: RAVLT (6.2 vs. 6.8, p<0.001), DSST (59.7 vs. 61.7, p=0.02), Stroop (29.0 vs. 27.2, p=0.01) and MoCA (19.1 vs 19.7, p=0.001). Similarly, greater 25‐year increase in LAVi was associated with lower MoCA (19.8 vs. 20.3, p=0.04). Further adjustment for hypertension, diabetes and smoking reported similar findings. 25‐year decrease in LVEF was not associated with cognition. In addition, higher Year 25 LVMi, LAVi and E/e’ ratio were significantly associated with worse cognition on most cognitive tests.

Conclusion

Midlife cardiac structure and its change from early to middle adulthood are associated with lower midlife cognition. Moreover, midlife diastolic but not systolic function is linked to cognition. Our results provide novel information linking cardiac structure and function to cognition.
A single dose of melatonin fails to reduce brain damage following cardiac I/R injury
Authors: Apaijai Nattayaporn , Singhanat Kodchanan , Jaiwongkam Thidarat , Kerdphoo Sasiwan , Chattipakorn Nipon , Chattipakorn Siriporn C.
Published: December 2020

Background

Cardiac ischemia/reperfusion (I/R) injury caused the detrimental effects not only to the heart but also to the brain. We previously reported that cardiac I/R injury led to blood brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and microglial hyperactivation, resulting in amyloid beta (Aβ) aggregation. Pretreatment with melatonin showed a neuroprotective effect against cerebral I/R injury. However, the effects of melatonin on the brain pathologies following cardiac I/R injury have never been investigated. Therefore, we hypothesize that melatonin treatment at various time points of cardiac I/R including pretreatment, during cardiac ischemia, and at the onset of reperfusion attenuate brain damages via decreasing inflammation, mitochondrial dysfunction, and Alzheimer’s proteins levels in rats with cardiac I/R injury.

Method

Male Wistar rats (n=45) were subjected to either sham operation (n=5) or cardiac I/R injury (30 min of cardiac ischemia, followed by 120 min of reperfusion). Rats were divided into 4 groups (n=10/group) including 1) vehicle (normal saline solution), 2) Pretreatment with melatonin, 3) Melatonin treatment during cardiac ischemia (15 min after ischemia), and 4) Melatonin treatment at the onset of reperfusion. Melatonin was administered at the dose of 10 mg/kg via intravenous injection. At the end of reperfusion, brains were rapidly removed, and brain tissue was used to determine brain mitochondrial function, microglial morphology, BBB and Alzheimer’s protein expression.

Result

Cardiac I/R led to brain inflammation as indicated by increasing the number of activated microglia and reducing number of resident microglia. Moreover, brain mitochondrial dysfunction was observed after cardiac I/R as indicated by increasing mitochondrial oxidative stress, mitochondrial membrane depolarization and mitochondrial swelling. Our results also showed that Aβ/APP and p‐Tau/Tau were increased after cardiac I/R, together with a reduction of occludin protein levels. These data suggested that cardiac I/R led to brain damages. Treatment with melatonin at all time points did not affect the number of activated and resident microglia, brain mitochondrial function, Alzheimer’s related proteins, or BBB protein after cardiac I/R, when compared with vehicle group (Figure 1).

Conclusion

A single dose of melatonin administration failed to reduce brain damage following cardiac I/R injury.
Meta‐analysis of mouse transcriptomic studies supports a context‐dependent astrocyte reaction in acute CNS injury versus neurodegeneration
Authors: Das Sudeshna , Li Zhaozhi , Noori Ayush , Hyman Bradley T. , Serrano‐Pozo Alberto
Published: December 2020

Background

Neuronal damage in both acute central nervous system (CNS) injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction, which has traditionally been depicted with GFAP immunohistochemistry. However, whether and how the nature of the CNS insult —acute versus chronic — influences the astrocyte response is unknown. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, in addition to a shared “pan‐reactive” signature common to both types of conditions.

Method

We performed a meta‐analysis of 15 publicly available astrocyte transcriptomic datasets from acute injury (n=6) and chronic neurodegeneration (n=9) mouse models. We identified a pan‐reactive, acute injury‐ and chronic neurodegeneration‐specific signatures, with both up‐regulated (UP) and down‐regulated (DOWN) genes.

Result

The number of UP/DOWN genes for each signature was: 67/21 for pan‐reactive, 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan‐reactive‐UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (i.e. Gfap, Vim), plus extracellular matrix (i.e. Cd44, Lgals1, Lgals3, Timp1), and immune response genes (i.e. C3, Serping1, Fas, Stat1, Stat2, Stat3). The acute injury‐UP signature was enriched in protein synthesis and degradation (both ubiquitin‐proteasome and autophagy systems), and anti‐oxidant defense genes, whereas the acute injury‐DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which were transcriptional repressors. The chronic neurodegeneration‐UP signature was further enriched in astrocyte‐secreted extracellular matrix proteins (Lama4, Cyr61, Thbs4), while the DOWN set included genes such as Agl (glycogenolysis), S1pr1 (immune modulation) and Sod2 (antioxidant).

Conclusion

We conclude that acute and chronic injuries to the CNS are associated with distinct astrocyte gene expression programs beyond their common astrocyte reaction signature.
Reduction of neurogranin immunostaining in the hippocampus of post‐mortem brain of Alzheimer’s disease
Authors: Vontell Regina T. , Davis David A. , Barreda Ayled , Blennow Kaj , Zetterberg Henrik , Gultekin Sakir Humayun , DeKosky Steve , Scott William K. , Sun Xiaoyan ,   Brain Endowment Bank
Published: December 2020

Background

Neurogranin (Ng) is a post‐synaptic protein involved in formation of long‐term potential. It plays an important role in learning and memory. The concentration of Ng is increased in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), and CSF Ng is considered to be a biomarker for synaptic dysfunction in AD. In contrast, the expression of Ng protein in the human brain and its association with AD pathology are less well studied.

Method

Using immunohistochemical detection methods, we investigated the protein expression of Ng, beta‐amyloid (Aβ) and hyperphosphorylated tau (AT8) in the post‐mortem hippocampus from four AD patients and four normal controls (NC). We quantitively compared the number of Ng positively stained cells in the hippocampal sub‐regions (dentate gyrus, CA3, CA2 and CA1) in post‐mortem donors with intermediate AD (i.e., Braak stage III‐IV) to NC (Braak 0) using Image Pro Premier automated image analysis software. The data was normalized to the number of Ng cells/mm2 and analyzed using a one‐way ANOVA. The AT8 and Aβ were scored using a scale that ranged from 0‐3; based on the number of immunopositive structures identified per mm2. The Ng data was correlated to the AT8 and Aβ using the Pearson’s correlation.

Result

We showed that Ng was localized mainly in neuronal cell soma and dendritic processes of the hippocampus of AD and NC donors. On average there was a 30% reduction (p<0.05) of Ng immunopositive neurons in the dentate gyrus, CA2 and CA1 hippocampal sub‐regions in cases of AD compared to that of NC. Ng positive cells did not significantly change in the CA3 hippocampal region in cases with AD when compared to NC. In cases with AD the reduction of Ng immunostaining was correlated with increased AT8 immunopositive neurofibrillary tangles (r=‐ 0.80; p<0.05), but not with Aβ plaques.

Conclusion

Loss of Ng immunostaining in CA1, CA2 and dentate gyrus confirms that synaptic damage in AD is a region‐specific event. The mechanism underlying such regional synaptic damage and the changes in Ng expression will be key in understanding the selective vulnerability of brain regions and systems to AD.
BeYOND: Biomarkers in younger‐onset neurocognitive disorders — The first 50 participants
Authors: Loi Samantha M. , Eratne Dhamidhu , Waterfang Mark , Kelso Wendy , Farrand Sarah , Goh Anita M.Y. , Chadunow Carolyn , Ravenfar Parsa Seyed , Watson Rosie , Evans Andrew H. , Vidaurre Lesley , Velakoulis Dennis
Published: December 2020

Background

There are currently 28000 people in Australia with younger‐onset dementia (YOD). A recent review of younger‐onset dementia cohorts (Loi SM et al. submitted) suggested that there needs to be more detailed study in this heterogenous group in order to glean more clinically relevant information. For example, our group (Eratne D et al. 2020) investigated the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain in a group of people with a range of psychiatric and neurodegenerative disorders and reported that NfL could distinguish between these two broad disorders, demonstrating the benefits in studying a large range of YODs. BeYOND (Biomarkers in younger‐onset neurocognitive disorders) was established as a longitudinal cohort of younger people presenting with neurocognitive symptoms to a clinical diagnostic service, with the aim of identifying clinical and investigational biomarkers which can inform diagnostic and psychosocial outcomes in a clinically heterogenous population.

Method

Patients are prospectively recruited during their index presentation to Neuropsychiatry, Royal Melbourne Hospital, Australia. Neuropsychiatry is a tertiary specialist service which provides diagnostic work‐up for patients with cognitive, psychiatric and neurological symptoms. The diagnostic process includes baseline and 18 month assessments of clinical and diagnostic outcomes including CSF and blood biomarkers, cognition, neuroimaging and psychosocial (including caregiver).

Results

To date, 50 participants have been recruited (17 females, mean age 55). Thirty of had a dementia diagnosis (including Alzheimer’s dementia, frontotemporal dementia and Huntington’s disease), with the remainder having a psychiatric disorder (including depression and schizophrenia) as principle diagnosis. All participants have had clinical, neuropsychology and imaging. Eleven have had a lumbar puncture. Twenty participants have had a research blood panel for genetic analysis)and 12 had quantitative susceptibility mapping imaging.

Conclusion

The diagnosis of neurodegenerative disorders in younger people can be difficult and is often associated with diagnostic delays (Draper B et al. 2016). The BeYOND study aims to longitudinally assess younger patients with suspected neurodegenerative disease in order to improve diagnostic and psychosocial outcomes for this population. References: Loi SM et al. J Neuropsychiatry Clin Neuroscience. Submitted 23/1/2020. Eratne D et al. ANZJP. 54 (1): 57‐67. 2020. Draper B et al. Int J Geriatr Psychiatry. 31 (11): 1217‐1224. 2016.
Cognitive complaints and objective cognitive impairment in Sichuan community residents
Authors: Wang Ziqi , Dong LI , Yao Dezhong , Yang Jie , Han Ying
Published: December 2020

Background

Little knowledge was known about cognitive complaints (CC) and objective cognitive impairment (OCI) in the western China.

Method

To investigate the prevalence of CC and OCI in Sichuan province.

Result

A total of 308 community‐based individuals (128 male and 180 female, aged 40–91 years) were enrolled in this study. We investigated the information on demographics, medical conditions, mental health questionnaires, subjective cognitive complain and objective cognitive performance tested by comprehensive neuropsychological batteries were analyzed.

Conclusion

For CC, the total prevalence was 88.64%, and memory was 79.22%, language was 46.23%, executive function 39.60%, attention was 46.20% and other domains were 41.03%. For OCI, the total prevalence was 95.10%, and memory was 89.08%, language was 58.03%, and executive function 54.44%.
The imprint of sex on the heterogeneity of Alzheimer's disease sex differences in advanced Alzheimer’s disease: A clinical‐pathological study
Authors: Zea‐Sevilla María Ascensión , Uceda‐Heras Alicia , Rabano Alberto
Published: December 2020

Background

Alzheimer's disease(AD) displays both clinical and pathological heterogeneity, and the effects of sex difference on various neuropathological, functional and epidemiological aspects of AD are currently under study. The existence of sex‐specific clinical‐pathological phenotypes is still unknown, but the accumulated evidence indicates specific patterns as well as clinical‐pathological differences suggesting that sex is a crucial variable in the heterogeneity of the disease. Hippocampal sclerosis (HS) is characterized by selective neuronal loss and gliosis of the CA 1 region of the hippocampus and the subiculum associated with age and multiple pathologies such as AD, and has recently been included in Limbic‐predominant aging‐related TDP‐43 encepahalopathy (LATE). The aim of this study is to know if AD patients with HS show sex‐specific difference both at a neuropathological and a clinical level.

Method

A full postmortem neuropathological study was performed on 126 consecutive brains from a clinicopathologic cohort of institutionalized dementia patients (Vallecas Alzheimer’s Center Study), mean age at death(87.3 ± 6.6), sex ratio(79.4% females), with a predominant primary diagnosis of Alzheimer’s disease(77.6%).HS was defined based on morphologic criteria including pre‐HS changes defined by our group.

Result

69.79 % of AD patients displayed HS(women 83.58%, male 16.41%).Clinical disease onset was earlier in men 72.93 ± 9.3 vs 77.19 ± 6.57 (p < 0.05). In women, the presence of HS is associated with a later disease onset 78.67 ± 6.03 vs 75.05 ± 6.40 (p = 0.05), a later age at exitus 90.44 ± 5.33 vs 84.95 ± 6.62 (p < 0.05) and a longer survival time 11.78±3.85 vs 9.45 ± 4.69 (p < 0.05). In men, these variables also differed between HS+ and HS‐ subjects, but did not reach statistical significance. APOE4 was not associated with HS in any sex group.

Conclusion

In our study, the difference in the age of disease onset, age of exitus and survival time in the presence of HS is linked to sex. Sex is an important factor in the phenotypic heterogeneity of AD, and male sex predominates in earlier onset AD with hippocampal preservation while later onset and limbic‐predominant disease is higher in women. In this axis of phenotypic variability, HS is a determinant factor. These disease phenotypes may be relevant to a "precision medicine" approach and should be considered in the development of therapeutic strategies and clinical trials for AD.
Does decline in cardiovascular risk factor levels also have an impact on the age‐specific cognitive function of older adults over time? A comparison of a repeated cross‐sectional panel study in the same population over 14 years
Authors: Johnsen Bente , Schirmer Henrik , Martinatyte Ieva , Strand Bjørn Heine
Published: December 2020

Background

Research suggests that cardiovascular risk factors have an impact on cognitive function and development of dementia. We lack evidence that cognitive function is actually improving in the population, as the risk factors decrease. We aim to see if the dementia‐free population of Tromsø has improved cognition over time and if so which changes are associated with improved cognition.

Method

The Tromsø Study is an ongoing large, prospective population based cohort study. Cognitive measures was included from 2001 and repeated in 2008 and 2015. Only participants in the ages of 60‐88 were included. A total of 5173 women and 4341 men did at least one cognitive test during these three waves. Age groups were stratified to 60‐66 years, 66‐73 years, 74‐80 years and 80‐88 years. The cognitive tests were Word test 1 (12‐word immediate recall), Word test 2 (recognition), Digit‐Symbol Coding and Tapping test.All participants also filled out an extensive questionnaire, had blood samples and anthropomorphic measures taken.Difference between screenings in all cognitive tests were analysed in Stata using sex specific linear regression. The results were then adjusted for age, education, blood pressure, smoking, hypercholesterolemia, previous heart attack, previous stroke, diabetes, depression, activity levels, alcohol consumption and BMI. The explanatory variables were tested to see how much they accounted for a change in the beta coefficient when added.

Result

The cognitive tests show a significant improvement in cognitive function in age specific groups in 2015, compared to 2001. This improvement is present in all age groups. (p < 0,001 for all age groups) The factors that contribute most to the improvement is alcohol consumption (15,2 % men, 20 % women), increased education (44,7 % men and 39,5 % women) and physical activity (10,7 % men and 12,8 % women). Other cardiovascular risk factors had little to no impact.

Conclusion

Cognitive function improves in older adults consistently in four cognitive tests covering different aspects of neuropsychological functioning. Improvement in education, alcohol consumption and physical activity is the factors contributing most to this change. Improvement in traditional cardiovascular factors contribute little or nothing the improvement in cognitive function.
Are existing dementia risk prediction models reliable?
Authors: Goerdten Jantje , Čukić Iva , Danso Samuel O , Carriere Isabelle , Terrera Graciela Muniz
Published: December 2020

Background

Numerous dementia risk prediction models have been developed in the past, however only a few are recommended for clinical use (Stephan et al., 2015; Tang et al., 2015). This might be due to methodological limitations that hamper their reliability and accuracy. Here we summarize and critically discuss the employed methodological approaches to develop dementia risk prediction models.

Method

We systematically reviewed the literature from March 2014 to September 2018 for publications presenting a dementia risk prediction model.

Result

In total 137 publications were included in the qualitative synthesis. Three analytical techniques are commonly used: machine learning, logistic regression and Cox regression. Additionally, we identified three major methodological weaknesses: (1) overreliance on one data source, (2) poor verification of statistical assumptions of Cox and logistic regression and (3) lack of validation.

Conclusion

Inaccurate application of analytical techniques can cause false identification of high‐risk groups and biased prognoses (Abrahamowicz et al.,1997; Exalto et al., 2014). Hence, we recommend the use and collection of larger and more diverse samples. Furthermore, the assumptions should be tested thoroughly, and actions taken if derivations are detected. Improved practice in data analysis and innovative data designs may improve dementia risk scores. References: (1) Abrahamowicz, M., du Berger, R., & Grover, S. A. (1997). Flexible modeling of the effects of serum cholesterol on coronary heart disease mortality. Am J Epidemiol, 145(8), 714‐729. (2) Exalto, L. G., Quesenberry, C. P., Barnes, D., Kivipelto, M., Biessels, G. J., & Whitmer, R. A. (2014). Midlife risk score for the prediction of dementia four decades later. Alzheimers Dement, 10(5), 562‐570. doi:10.1016/j.jalz.2013.05.1772. (3) Stephan, B. C., Tzourio, C., Auriacombe, S., Amieva, H., Dufouil, C., Alperovitch, A., & Kurth, T. (2015). Usefulness of data from magnetic resonance imaging to improve prediction of dementia: population based cohort study. BMJ, 350, h2863. doi:10.1136/bmj.h2863. (4) Tang, E. Y., Harrison, S. L., Errington, L., Gordon, M. F., Visser, P. J., Novak, G., Stephan, B. C. (2015). Current Developments in Dementia Risk Prediction Modelling: An Updated Systematic Review. PLoS One, 10(9), e0136181. doi:10.1371/journal.pone.0136181.
Physical fitness and cognitive performance in non‐demented elderly subjects
Authors: Adler Georg , Marczak Agnies
Published: December 2020

Background

Poor physical fitness is a well‐known risk factor for cognitive impairment. Physical fitness is closely correlated with age and physical morbidity. We studied, whether the correlation between poor physical fitness and cognitive impairment can be ascertained when these variables are controlled.

Method

The data of 135 non‐demented participants of a dementia prevention program, who were aged between 50 and 60 years, were evaluated (mean age: 55.3 years). Physical fitness was examined using the Step Test (ST) for cardiorespiratory fitness and the Chair Stand Test (CST) for motor fitness. We compared subjective memory disorders, cognitive blackouts (checklist for cognitive blackouts, CKB) and objective cognitive performance between people with low and normal physical fitness.

Result

The participants with low cardiorespiratory fitness (ST) were more concerned with their memory and they reported cognitive blackouts more frequently. They also had a lower orientation score and a lower MMSE score. The participants with low motor fitness (CST) also reported memory loss and cognitive blackouts more frequently and had lower scores in orientation, language, praxia as well as in higher cortical functions. Lower cardiorespiratory fitness was found more frequently in men and in participants with a history of high blood pressure. The participants with lower motor fitness had a higher BMI and a larger hip size.

Conclusion

Poor physical fitness is correlated with subjective memory disorders and cognitive blackouts as well as with minor objective cognitive impairments, even when controlling for age and physical morbidity.
New model giving insight in group of 256,000 people living with dementia in the Netherlands
Authors: van den Pol Henri
Published: December 2020

Background

Vektis has the complete dataset about health care claims in the Netherlands. By using the health care claims we are able to give a factual insight in how many people in the Netherlands live with dementia and what kind of health care they use. By establishing the group living with dementia in the Netherlands we can give factual numbers about prevalence, incidence and healthcare consumption. We can do this on each required level: age, gender, region, living situation and so on.

Method

Vektis has data about all the healthcare claims in the Netherlands. i.e.: General practitioner and all other kinds of primary healthcare, hospital care, mental healthcare to nursing homes and home care. Vektis receives data from all the health insurance companies in the Netherlands. Based on this data we can provide, a complete picture of the healthcare used while ensuring anonymity. To establish the group of people having dementia we investigate which healthcare claims are related to dementia and if they can be used to include someone in the group of people having dementia. For the criteria see table 1. The model is discussed with experts and validated with international reviews on the prevalence of dementia, see figure 1 and 2.

Result

Using the above criteria we establish a total group of 256.000 people living with dementia during the year 2017. Based upon this model Vektis has delivered several reports to support healthcare providers, healthcare insurance companies, towns, patient federations and other healthcare parties in improving the dementia care in the Netherlands.

Conclusion

In this study we created an almost complete view on the group of people living with dementia in the Netherlands. This makes it possible to give insights in the integral healthcare of people living with dementia at every required level, intersection or slide. Next steps are forecasting and dashboards for regional partnerships.
Insulin resistance accounts for metabolic syndrome‐related alterations in brain structure
Authors: Lu Ran , Aziz N Ahmad , Diers Kersten , Stoecker Tony , Reuter Martin , Breteler Monique MB
Published: December 2020

Background

Metabolic syndrome (MetS) is a major public health burden worldwide and associated with brain abnormalities. Although insulin resistance is considered a pivotal feature of MetS, its role in the pathogenesis of MetS‐related brain alterations in the general population is unclear. Therefore, we aimed to 1) assess the relation of metabolic syndrome (MetS) and insulin resistance with brain structure, and 2) determine to what extent the effects of MetS on brain structure are due to insulin resistance.

Methods

We used cross‐sectional data from 973 participants (43.4% male, mean age 52.5 years) of the Rhineland Study, an ongoing population‐based cohort study. MetS was defined in accordance with the revised criteria of the National Cholesterol Education Program Adult Treatment Panel III. Insulin resistance was assessed through fasting serum insulin and the homeostatic model assessment of insulin resistance. Cortical reconstruction and volumetric segmentation were obtained from high‐resolution brain images at 3 Tesla. The relation between metabolic measures and brain structural features was assessed through (generalized) linear models.

Results

MetS and insulin resistance were both associated with smaller cortical gray matter volume and mean cortical thickness, but not with white matter or subcortical gray matter volume. Vertex‐based brain morphometry showed that MetS and insulin resistance were related to brain structure in a similar spatial pattern, with the largest effect sizes observed in the precentral cortex, transverse and superior temporal cortex, and the cuneus and its neighboring regions. There was no independent effect of MetS on cortical gray matter when additionally adjusted for insulin resistance.

Conclusion

MetS and insulin resistance are associated with cortical gray matter thinning, especially in regions involved in motor regulation and auditory and visual processing, with insulin resistance largely accounting for MetS‐related changes in brain structure.
Living at home with dementia and incontinence: A qualitative analysis of patient, family carer and health care professionals’ perspectives
Authors: Murphy Catherine , Laine Christine , Fader Mandy
Published: December 2020

Background

People with dementia are more likely than other people of the same age to experience bladder or bowel incontinence. This can be distressing and difficult to manage for both the person with dementia and family carers, potentially contributing to the breakdown of care at home. The aim of this work was to understand the range of problems that people face and their opinions on what could be done to better manage these problems and enable people to get on with their daily lives.

Methods

Using a semi‐structured topic guide, participants were interviewed about their experiences and views on the problems associated with living at home with both dementia and incontinence and the support that people would like to receive. People with dementia and family carers were invited via www.joindementiaresearch.nihr.ac.uk, dementia cafes and their nurses (dementia or continence specialists). Healthcare professionals (dementia care and continence care specialists) were invited via their employer. The interviews were transcribed and constant comparison techniques were used to interpret the data.

Results

45 people (27 family carers, 2 people with dementia and 16 healthcare professionals) took part. Many carers found coping with incontinence to be the most challenging part of their caring experience. They reported feeling unsupported, lacking information and expert advice, plus continence management product provision was often found to be inadequate. Dementia nurses reported little knowledge of continence care and continence nurses had not received any dementia specific training. When continence problems develop, carers generally rely on continence information from peers or product manufacturers. Many said they had initially viewed incontinence problems as a “red line” beyond which they would no longer be able to provide care. For some, this was the case, but others adapted to providing continence support. Many carers reported a distressing period of trial and error when learning how to manage with new onset continence issues.

Conclusion

Far more could be done to help support people to live well with the combination of dementia and incontinence. Currently there is little or no support or expertise available. There were two urgent priorities: Better information/advice and appropriate product provision.