Clinical Dementia Rating Score Research Articles

A Combined Index Using the Mini-Mental State Examination and Lawton Index to Discriminate Between Clinical Dementia Rating Scores of 0.5 and 1

A Combined Index Using the Mini-Mental State Examination and Lawton Index to Discriminate Between Clinical Dementia Rating Scores of 0.5 and 1

Association between elevated blood-brain barrier permeability and the risk of progressive cognitive decline: A longitudinal study

BackgroundThe breakdown of the blood-brain barrier (BBB) is intricately linked to the onset and advancement of cognitive impairment and dementia. This investigation explores the correlation between blood-brain barrier permeability, assessed through the cerebrospinal fluid/serum albumin ratio (QAlb), in a clinical cohort and the evolution of cognitive decline. MethodsThis prospective observational cohort study included 295 participants. Cognitive decline progression was characterized by an escalation in the overall deterioration scale and/or clinical dementia rating scores. The investigation delves into the correlation between blood-brain barrier permeability and the advancement of cognitive impairment among patients. ResultsThe APOE 4 allele and diabetes mellitus among individuals exhibited increased BBB permeability (P < 0.05). Moreover, AD patients exhibited the highest QAlb levels, signifying elevated BBB permeability compared to individuals with MCI and SCD (P < 0.05). After mean 17 months following up, 117 patients (51.31 %) were identified as experiencing cognitive decline progression, and we found that only AD diagnosis, CDR, and QAlb (All P < 0.05) were significant predictors of cognitive decline progression. ConclusionOur study emphasizes the clinical relevance of QAlb in detecting individuals with an elevated risk of cognitive decline. It suggests that heightened BBB permeability could contribute to clinical deterioration and serves as a plausible therapeutic target.

Brain Age Is Associated with Cognitive Outcomes of Cholinesterase Inhibitor Treatment in Patients with Mild Cognitive Impairment.

The effect of cholinesterase inhibitor (ChEI) on mild cognitive impairment (MCI) is controversial. Brain age has been shown to predict Alzheimer's disease conversion from MCI. The study aimed to show that brain age is related to cognitive outcomes of ChEI treatment in MCI. Brain MRI, the Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) scores were retrospectively retrieved from a ChEI treatment database. Patients who presented baseline CDR of 0.5 and received ChEI treatment for at least 2 years were selected. Patients with stationary or improved cognition as verified by the CDR and MMSE were categorized to the ChEI-responsive group, and those with worsened cognition were assigned to the ChEI-unresponsive group. A gray matter brain age model was built with a machine learning algorithm by training T1-weighted MRI data of 362 healthy participants. The model was applied to each patient to compute predicted age difference (PAD), i.e. the difference between brain age and chronological age. The PADs were compared between the two groups. 58 patients were found to fit the ChEI-responsive criteria in the patient data, and 58 matched patients that fit the ChEI-unresponsive criteria were compared. ChEI-unresponsive patients showed significantly larger PAD than ChEI-responsive patients (8.44±8.78 years versus 3.87±9.02 years, p = 0.0067). Gray matter brain age is associated with cognitive outcomes after 2 years of ChEI treatment in patients with the CDR of 0.5. It might facilitate the clinical trials of novel therapeutics for MCI.

Characterization of African-American Super-Agers in the National Alzheimer's Coordinating Center cohort.

"Super-agers" are adults aged ≥80 with cognitive performance similar to persons two to three decades younger. Characteristics such as larger hippocampal volume, APOE-ε4 allele absence, higher educational attainment, female sex, and lifelong cognitive stimulation are associated with cognitive performance compatible with super-aging. These findings are based on predominantly white research samples. Limited data are available on African-American super-agers. To fill this gap, we explored potential factors associated with super-aging in older African-American adults. Data from African-American participants aged ≥80 in the National Alzheimer's Coordinating Center (NACC) dataset were analyzed. Using global Clinical Dementia Rating (CDR) scores, participants were first categorized as impaired (score ≥0.5) or non-impaired/normal cognition (NC) (score = 0). From the NC group, super-agers were identified using NACC-data-driven cutoffs. Participants were considered super-agers if their memory performance was similar to persons aged 50-60 with NC, and their performance on other domains was within one standard deviation of the mean for persons aged ≥80. We examined group characteristics (NC, super-ager, impaired) using chi-square and ANOVA with pairwise comparisons. Multinomial logistic regression, adjusted for sex and education, evaluated correlates of super-ager group assignment. Data for 1285 African-American participants aged ≥80 were analyzed. We identified 24.7% (n = 316) NC, 4.8% (n = 61) super-agers, and 70.6% (n = 905) impaired. Super-agers were mostly female and more educated, had similar vascular comorbidities as the other groups, and had less sleep disorders, depression, and alcohol use. After adjusting for sex and education, super-ager group assignment was associated with less sleep disorders, less depression, and moderate alcohol use. Participants with controlled vascular risk, mental health, alcohol use, and sleep disorders tended to be in the super-ager group. These factors may be important focus areas in clinical practice to support cognitive resilience with aging in older African-American adults.

Apathy in Lewy body disease and its effects on functional impairment over time.

Apathy strongly affects function in Alzheimer's disease and frontotemporal dementia, however its effect on function in Lewy Body Disease (LBD) has not been well-described. This study aims to (1) examine the prevalence and persistence of apathy in a large, national cohort of well-characterized patients with LBD, and (2) estimate the effect of apathy on function over time. Study included 676 participants with mild cognitive impairment (MCI) or dementia in the National Alzheimer's Coordinating Center Uniform Data Set. Participants were followed for an average of 3.4 ± 1.7 years and consistently had a primary diagnosis of LBD. Apathy was defined by clinician judgment, categorized into four mutually exclusive profiles: (1) never apathetic across all visits, (2) at least one but <50% of visits with apathy (intermittent apathy), (3) ≥50% but not all visits with apathy (persistent apathy), and (4) always apathy across all visits. Dementia severity was measured by baseline Clinical Dementia Rating score. Parkinsonism was defined by the presence of bradykinesia, resting tremor, rigidity, gait, and postural instability. Functional impairment was assessed using the Functional Assessment Questionnaire (FAQ). Baseline characteristics of the sample were: average age = 72.9 ± 6.9, years of education = 15.6 ± 3.4, Mini Mental State Exam (MMSE) = 24.4 ± 5.4, Geriatric Depression Scale (GDS) = 3.8 ± 3.2, FAQ = 12.0 ± 9.1. 78.8% were male and 89% were non-Hispanic white. Prevalence of apathy increased from 54.4% at baseline to 65.5% in year 4. 77% of participants had apathy at some point during follow-up. Independent of cognitive status and parkinsonian features, FAQ was significantly higher in participants with intermittent/persistent and always apathetic than never apathetic. Annual rate of decline in FAQ was faster in participants who were always apathetic than never apathy. In this large national longitudinal cohort of LBD patients with cognitive impairment, apathy was strongly associated with greater functional impairment at baseline and faster rate of decline over time. The magnitude of these effects were clinically important and were observed beyond the effects on function from participants' cognitive status and parkinsonism, highlighting the importance of specifically assessing for apathy in LBD.

Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson’s disease and dementia with Lewy bodies

Regional differences in synaptic degeneration may underlie differences in clinical presentation and neuropathological disease progression in Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Here, we mapped and quantified synaptic degeneration in cortical brain regions in PD, PD with dementia (PDD) and DLB, and assessed whether regional differences in synaptic loss are linked to axonal degeneration and neuropathological burden. We included a total of 47 brain donors, 9 PD, 12 PDD, 6 DLB and 20 non-neurological controls. Synaptophysin+ and SV2A+ puncta were quantified in eight cortical regions using a high throughput microscopy approach. Neurofilament light chain (NfL) immunoreactivity, Lewy body (LB) density, phosphorylated-tau and amyloid-β load were also quantified. Group differences in synaptic density, and associations with neuropathological markers and Clinical Dementia Rating (CDR) scores, were investigated using linear mixed models. We found significantly decreased synaptophysin and SV2A densities in the cortex of PD, PDD and DLB cases compared to controls. Specifically, synaptic density was decreased in cortical regions affected at Braak α-synuclein stage 5 in PD (middle temporal gyrus, anterior cingulate and insula), and was additionally decreased in cortical regions affected at Braak α-synuclein stage 4 in PDD and DLB compared to controls (entorhinal cortex, parahippocampal gyrus and fusiform gyrus). Synaptic loss associated with higher NfL immunoreactivity and LB density. Global synaptophysin loss associated with longer disease duration and higher CDR scores. Synaptic neurodegeneration occurred in temporal, cingulate and insular cortices in PD, as well as in parahippocampal regions in PDD and DLB. In addition, synaptic loss was linked to axonal damage and severe α-synuclein burden. These results, together with the association between synaptic loss and disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical differences between PD and PDD/DLB. Our results might provide useful information for the interpretation of synaptic biomarkers in vivo.

Biomarkers of chronic inflammation and cognitive decline: A prospective observational study.

We sought to determine whether the biomarkers of chronic inflammation predict cognitive decline in a prospective observational study. We measured baseline serum soluble urokinase plasminogen activator receptor (suPAR) and high sensitivity C-reactive protein (hs-CRP) levels in 282 participants of the University of Michigan Memory and Aging Project. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and the Clinical Dementia Rating (CDR) scale for up to five time points. SuPAR and hs-CRP levels were not significantly higher in participants with mild cognitive impairment (n=97) or dementia (n=59), compared to those with normal cognitive function (n=126). Overall, 14% of participants experienced significant cognitive decline over the study period. The change in MoCA or CDR scores over time did not differ significantly according to baseline suPAR or hs-CRP levels. Chronic systemic inflammation, as measured by serum suPAR or hs-CRP levels, is unlikely to contribute significantly to cognitive decline.

Experience Related to Acceptance of Illness among People with Early-Stage Dementia: A Phenomenological Study

Purpose: This study aims to describe the structure of the experience related to acceptance of illness among people with early-stage dementia (PWED).Methods: Participants were six people who had Alzheimer’s disease or vascular dementia. Their clinical dementia rating scores were 0.5 or 1. Data were collected from individual in-depth interviews. The collected qualitative data were analyzed based on Giorgi’s descriptive phenomenological method.Results: The five constituents and eight sub-constituents were derived from the experience related to acceptance of illness among PWED; ‘Facing the changed me’, ‘Facing changes in roles and relationships with others’, ‘Conflict between recognizing and denying dementia in daily life’, ‘Perceiving the limits and accepting dementia’, and ‘Reconstructing daily life for the prolongation of the current health status’.Conclusion: This study contributes to the expansion of the in-depth understanding of the experience related to acceptance of illness among PWED. The results of the study will be helpful as basic data for community health nurses to develop interventions to improve acceptance of illness of PWED.

Care needs assessment of older adults with dementia in a semi-rural district in Vietnam: A community-based cross-sectional study.

The increasing needs of people living with dementia (PLWD) in Vietnam present an enormous public health challenge. Vietnam is an understudied country, and little is known regarding the overall unmet needs of caregivers or the demographic risk factors associated with unmet caregiving needs. This study aimed to determine the burden of unmet care needs of community-dwelling PLWD and identify sociodemographic risks associated with unmet care needs. A cross-sectional study in a rural area facing urbanisation in Hanoi, Vietnam recruited PWLD-caregiver dyads with multistage sampling. We utilised the Camberwell Assessment of Need for the Elderly (CANE) instrument to evaluate care needs across four domains. Caregivers rated PLWD needs, with higher scores indicating greater unmet needs. The Mann-Whitney test was employed for comparing two groups, while the Kruskal-Wallis test was used for comparisons involving more than two groups in the analysis, and a P-value of less than 0.05 was considered statistically significant. Among 90 PLWD participating in the study, the overall mean care needs score was 11.6 ± 4.3, with only 16.2% of PLWD having their care needs met. Environmental and physical needs were more frequently met than psychological or social needs. Only 48.0% and 43.9% of environmental and physical needs were met respectively, and a meagre 20.9% and 23.6% for psychological and social needs. Unmet care needs were more frequent for PWLD who were female, single or divorced, had lower monthly household income, or who were in more advanced stages of dementia, as indicated by Clinical Dementia Rating scores ≥1. Unmet needs for PWLD are common. Increased caregiver education, resources, and services in Vietnam are urgently required to improve the quality of life for this population.

Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine signaling via the ubiquitously expressed adenosine receptors; however, adenosine A1 and A2A receptor (A1R and A2AR) mRNA expression is poorly understood in specific cell subtypes in the frontal cortical brain regions implicated in this disorder. In this study, we assayed A1R and A2AR mRNA expression via qPCR in enriched populations of pyramidal neurons, which were isolated from postmortem anterior cingulate cortex (ACC) tissue from schizophrenia (n = 20) and control (n = 20) subjects using laser microdissection (LMD). A1R expression was significantly increased in female schizophrenia subjects compared to female control subjects (t(13) = -4.008, p = 0.001). A1R expression was also significantly decreased in female control subjects compared to male control subjects, suggesting sex differences in basal A1R expression (t(17) = 2.137, p = 0.047). A significant, positive association was found between dementia severity (clinical dementia rating (CDR) scores) and A2AR mRNA expression (Spearman's r = 0.424, p = 0.009). A2AR mRNA expression was significantly increased in unmedicated schizophrenia subjects, suggesting that A2AR expression may be normalized by chronic antipsychotic treatment (F(1,14) = 9.259, p = 0.009). Together, these results provide novel insights into the neuronal expression of adenosine receptors in the ACC in schizophrenia and suggest that receptor expression changes may be sex-dependent and associated with cognitive decline in these subjects.

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment

Recent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. To determine the safety and efficacy of cilostazol in mild cognitive impairment. The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. ClinicalTrials.gov Identifier: NCT02491268.

Amyloid‐Beta PET Synthesis from Structural MRI: A Potential Alternative Method for Alzheimer’s Disease Screening

AbstractBackgroundAmyloid‐beta and structural brain atrophy are known to be hallmarks of Alzheimer’s Disease (AD), and can be quantified with Positron Emission Tomography (PET) and structural Magnetic Resonance (MRI), respectively. PET scans use radiotracers that binds to amyloid‐beta molecules, whereas MRI measures changes in structural morphology. PET scans are difficult to perform due to cost (∼$5000/scan), invasiveness, and ionizing radiation exposure, making them inaccessible for screening early‐onset AD. Conversely, MRI is a cheaper (∼$500/scan), non‐invasive, and free from ionizing radiation technique, however, it cannot provide molecular information obtained from PET. There is a known relationship between amyloid‐beta and brain atrophy, hence, amyloid‐beta PET images might be synthesized from structural MRI using image translation, which is an advanced form of machine learning.MethodAn image translation algorithm was developed using the Open Access Series of Imaging Studies (OASIS‐3) dataset that provides 929 subjects with pairs of T1‐weighted MRI and amyloid‐beta PET images, where 609 are cognitively normal (CN) and 489 at different stages of cognitive decline based on Clinical Dementia Rating scores. The image translation algorithm implemented with Conditional Generative Adversarial Networks, shown in Figure 1, was trained with 550 pairs with 156 axial slices each of amyloid‐beta and MRI images. Eight models where generated with different parameters to assess their impact in the generalization quality, then compared in a sample of 334 subjects using Structural Similarity Index (SSIM) and Peak Signal‐to‐Noise Ratio (PSNR).ResultFigure 2, compares the models performance based on SSIM and PSNR, where the best performing model generates synthetic PET images with a high degree of similarity with the real ones in Figure 3.ConclusionAn image translation pipeline was implemented and explored by changing parameters that can affect the model performance, the developed models are robust against the different parameters that were changed and it demonstrates that amyloid‐beta PET images can be synthesized from structural MRI, reducing cost, invasiveness and increasing availability. Such a method could enable non‐invasive screening of early onset AD.

High‐density lipoprotein particle size distribution among patients with Alzheimer’s disease, mild cognitive impairment, and age‐matched controls

AbstractBackgroundHigh‐density lipoproteins (HDL) are protective against several chronic diseases, including Alzheimer’s disease (AD). The size distribution of HDL particles is one of the determining factors of HDL function since HDL of various sizes subgroups play unique roles. Yet not much is known about HDL particle size distribution in the context of AD.MethodIn this study negative‐stained transmission electron microscopy (NS‐TEM) was used to explore the particle size distribution of isolated HDL samples from 194 subjects with AD (n = 71), mild cognitive impairment (MCI, n = 40), or no cognitive impairment (n = 83). HDL particles were isolated using density‐adjusted ultracentrifugation followed by size exclusion chromatography and analyzed by NS‐TEM followed by image analysis using the software ImageJ. Individual particle diameter data were obtained, grouped into different size‐based categories and the relative abundances of each subgroup were compared among diagnostic groups and across clinical parameters.ResultPatients with AD and MCI had a significantly higher percentage of 7‐8 nm HDL particles and a lower percentage of 9‐10 nm, 12‐13 nm, and 13‐14 nm particles. Body mass index, clinical dementia rating score, and white matter hyperintensity volume were positively correlated with the percentage of 7‐8 nm particles and negatively correlated with the percentage of 9‐10 nm particles, whereas executive score, semantic memory score, and verbal memory score were negatively correlated with the percentage of 7‐8 nm particles, and positively correlated with the percentage of 9‐10 nm particles.ConclusionThese findings show that specific alterations in HDL particle size distribution in patients with AD and MCI are linked with measures of cognitive function and may be a promising direction for the discovery of new biomarkers and therapeutic targets in AD.

Tau PET: utility as a biomarker for chronic traumatic encephalopathy

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by tau deposition in the depths of the sulci associated with exposure to repetitive head impacts (RHI). It is a post‐mortem diagnosis. We previously reported a frontotemporal predominant tau 18F‐MK6240 PET pattern resembling the distribution of CTE in a retired Australian Rules Football player in the context of a moderate amyloid‐beta plaque burden.1 This study aimed to investigate the utility of 18F‐MK6240 PET as a potential biomarker for CTE in contact sports players with exposure to RHI (sRHI).MethodsRHI (n = 33) and age‐matched healthy controls (HC) (n = 32) completed amyloid (18F‐NAV4694) and tau (18F‐MK6240) PET scans. Amyloid PET was quantified in Centiloids. 18F‐MK240 standardized uptake value ratios (SUVRs) were generated for the dorsolateral prefrontal cortex and composite regions of interest (ROI) (frontal; mesial temporal; temporoparietal).ResultFor sRHI, the primary contact sport was Australian Rules Football (n = 17), boxing/kickboxing/martial arts (n = 11), rugby (n = 4) and soccer (n = 1), with 36.4% participating at a professional level. sRHI had a mean age of 54.2 (±9.2) (vs HC 53.0±9.5, p = 0.61), and 94% were male (vs HC 78%, p = 0.08). sRHI did not differ from HC in years of education (p = 0.46) but had more impaired MMSE (28.1±1.9 vs 29.3±0.8, p = 0.006, d = ‐0.80) and Clinical Dementia Rating scores (0.21±0.3 vs 0±0, p&lt;0.001, d = 1.25). sRHI and HC did not differ in mean Centiloid values (2.9±8.4 vs 3.0±8.2). sRHI and HC did not differ in 18F‐MK6240 SUVR in the regions examined, and no differences were observed between professional and amateur sRHI.ConclusionContact sports players with exposure to repetitive head impacts did not differ from age‐matched healthy controls on 18F‐MK6240 SUVR in frontal, mesial temporal, and temporoparietal brain regions. Study limitations include the small sample size, heterogeneity in sports type and highest level of participation, and participants with relatively mild cognitive and functional impairments. Additionally, while 18F‐MK6240 has high affinity for 3R/4R tau in Alzheimer’s disease, its affinity in CTE, particularly important at early stages, remains unclear.

P26: Self-reported health-related quality of life for people with dementia in long-term care facilities in Taiwan: a nationwide survey

Background:Quality of life is an essential outcome parameter in geriatric research; however, research to date offers mixed evidence about the factors associated with health-related quality of life (HRQOL) among people with dementia (PWDs). We aimed to identify factors relating to HRQOL among PWDs living in long-term care (LTC) facilities.Methods:A total of 299 from 1,607 registered long-term care facilities were randomly selected in every administrative region of Taiwan. A cross-sectional two-phase survey, which included the demographic data, comorbidities, EuroQol-5 dimensions-5 levels (EQ-5D-5L), mini-mental state examination (MMSE) score, clinical dementia rating scores (CDR), behavioral and psychological symptoms of dementia, and activities of daily living (ADL) of PWDs, was then conducted from 2019 to 2020.Results:A total of 1,313 PWDs who self-completed EQ-5D-5L were enrolled in this analysis with a mean age of 76.43 ± 12.7 years. The mean utility and visual analogue scale (VAS) scores of EQ-5D-5L were 0.10 (standard deviation, SD = 0.48) and 66.57 (SD = 20.67), respectively. Multivariate linear regression analysis showed that higher scores in ADL, instrumental ADL, and lower CDR sum scores were associated with higher EQ-5D-5L utility scores. Higher ADL scores and higher MMSE scores were associated with higher scores in an EQ-5D-5L-VAS. More depressive symptoms were related to both lower utility score and lower EQ-5D-5L-VAS score.Conclusion:Findings highlight the importance to recognize and to treat depression to maintain HRQOL of PWDs in LTC facilities. Longitudinal studies are needed to better understand the long-term changes in HRQOL of PWDs.

Tau PET: utility as a biomarker for chronic traumatic encephalopathy

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by tau deposition in the depths of the sulci associated with exposure to repetitive head impacts (RHI). It is a post‐mortem diagnosis. We previously reported a frontotemporal predominant tau 18F‐MK6240 PET pattern resembling the distribution of CTE in a retired Australian Rules Football player in the context of a moderate amyloid‐beta plaque burden.1 This study aimed to investigate the utility of 18F‐MK6240 PET as a potential biomarker for CTE in contact sports players with exposure to RHI (sRHI).MethodsRHI (n = 33) and age‐matched healthy controls (HC) (n = 32) completed amyloid (18F‐NAV4694) and tau (18F‐MK6240) PET scans. Amyloid PET was quantified in Centiloids. 18F‐MK240 standardized uptake value ratios (SUVRs) were generated for the dorsolateral prefrontal cortex and composite regions of interest (ROI) (frontal; mesial temporal; temporoparietal).ResultFor sRHI, the primary contact sport was Australian Rules Football (n = 17), boxing/kickboxing/martial arts (n = 11), rugby (n = 4) and soccer (n = 1), with 36.4% participating at a professional level. sRHI had a mean age of 54.2 (±9.2) (vs HC 53.0±9.5, p = 0.61), and 94% were male (vs HC 78%, p = 0.08). sRHI did not differ from HC in years of education (p = 0.46) but had more impaired MMSE (28.1±1.9 vs 29.3±0.8, p = 0.006, d = ‐0.80) and Clinical Dementia Rating scores (0.21±0.3 vs 0±0, p&lt;0.001, d = 1.25). sRHI and HC did not differ in mean Centiloid values (2.9±8.4 vs 3.0±8.2). sRHI and HC did not differ in 18F‐MK6240 SUVR in the regions examined, and no differences were observed between professional and amateur sRHI.ConclusionContact sports players with exposure to repetitive head impacts did not differ from age‐matched healthy controls on 18F‐MK6240 SUVR in frontal, mesial temporal, and temporoparietal brain regions. Study limitations include the small sample size, heterogeneity in sports type and highest level of participation, and participants with relatively mild cognitive and functional impairments. Additionally, while 18F‐MK6240 has high affinity for 3R/4R tau in Alzheimer’s disease, its affinity in CTE, particularly important at early stages, remains unclear.

Prevalence of Mild cognitive impairment (MCI) in a rural Indian population and its association with hypertension, diabetes and depression

AbstractBackgroundMild cognitive impairment (MCI) is a transitional phase between normal cognitive ageing and dementia. The prevalence of MCI in rural populations is an understudied area. Risk factors such as hypertension, diabetes, and depression are more prevalent in rural areas, which can contribute to the development of MCI (Longfei et al, 2020). The purpose of this study is to find out the prevalence of MCI amongst a rural cohort and to study the relationship between MCI and hypertension, diabetes and depression.MethodCross sectional analysis on the subset of data taken from ongoing longitudinal study on dementia named Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) (Sundarakumar et al, 2020), which has a target of 10000 participants. MCI was diagnosed in the subject whose Clinical Dementia Rating (CDR) score was 0.5, as per the NIA‐AA (National Institute on Aging‐Alzheimer’s Association) criteria, 2011. Presence of hypertension and diabetes were collected through a structured clinical questionnaire. Depression was assessed using the Geriatric Depression Scale 30 (GDS‐30) and a score above 9 was considered as depression. Chi‐square analysis(χ2) was used to study the association between MCI and hypertension, diabetes and depression.ResultA total of 3789 participants were examined amongst which 293 had a CDR score of 0.5, indicating presence of MCI in 7.7% of the study group. Prevalence of depression in non‐MCI and MCI subjects was 14.91% and 30.73% respectively and depression was found to be significantly associated with MCI(χ2 =24.522, p&lt; 0.001). Hypertension was seen in 13.83% of non‐MCI subjects and in 17.76% of subjects with MCI. Diabetes was seen in 16.93% of non‐MCI subjects and in 18.25% of subjects with MCI. Both hypertension (χ2 =2.086, p = 0.149) and diabetes (χ2=0.195, p = 0.659) were not significantly associated with MCI.ConclusionDepression was significantly associated with MCI. It is known that late onset depression, which is diagnosed above the age of 50, may be a predisposing factor for dementia in later life. Our results may indicate this relationship between depression and cognitive impairment. However, further longitudinal studies are necessary to evaluate causal relationship.

Parietal‐temporal structural network reorganization is associated with pathological load and axonal damage in Alzheimer’s disease: a post‐mortem MRI and pathology study.

AbstractBackgroundThe characteristic spatial pattern of Aβ and p‐tau distribution suggests that pathology spreads from brain regions exhibiting pathology to interconnected regions through large‐scale axonal networks. Advances in MRI and graph theory have made it possible to study brain network organization. The current study aims to assess whether local proteinopathy and/or axonal degeneration contributes to regionally altered network measures of integration and segregation in clinically‐defined and pathologically‐confirmed Alzheimer’s disease (AD) and control brain donors.MethodPostmortem In‐situ 3T‐MRI (3DT1 and DTI) data were collected for 25 AD (6F/19M, 66y±11y) and 14 control (7F/7M, 72y±8y) brain donors. Following probabilistic tractography and structural network reconstruction, graph theoretical measures of integration (eigenvector centrality) and segregation (clustering coefficient) were calculated. After autopsy, the middle frontal gyrus (MFG), middle temporal gyrus (MTG), precuneus and middle hippocampus were immunostained for amyloid‐beta (Aβ), phosphorylated tau (p‐tau) and neurofilament light (NfL), and quantitative area% load was determined. Clinical Dementia Rating (CDR) scores were obtained from clinical records. Group differences were assessed with linear models and regional associations with Spearman and Pearson correlations, corrected for age, gender, and postmortem delay.ResultIn AD, no differences were observed in Aβ, p‐tau and NfL load among the selected neocortical regions, the hippocampus had lower Aβ and NfL load. Compared to controls, the AD group showed lower integration (p = 0.078) of the MTG, associated with higher CDR scores (r = ‐0.50;p = 0.035), more p‐tau pathology (r = ‐0.61;p = 0.002) and axonal damage (r = ‐0.64;p = 0.001). Furthermore, higher segregation (p = 0.006) of the MTG was observed and associated with higher p‐tau burden (r = 0.51;p = 0.015). In contrast, the precuneus showed higher integration (p = 0.038) and lower segregation (p = 0.023) in AD compared to controls, associated with less axonal damage (r = ‐0.44;p = 0.036) and less p‐tau pathology (r = 0.46;r = 0.033) respectively. No effects were found for the MFG and hippocampus.ConclusionIn AD decedents, a reorganization of the structural network is observed, predominantly in the parietal‐temporal region; while the temporal region is more disconnected, the parietal region is more strongly connected. Our work furthermore shows that this network (dis)integration is driven by p‐tau pathology and axonal damage, and associates with cognitive outcome.

Predicting clinical decline over 36 months with a memory‐based digital biomarker

AbstractBackgroundWord‐list recall tests are routinely employed in clinical practice for dementia screening. Process scoring and latent modeling of these tests, where underlying neurocognitive mechanisms are exploited, have shown potential to enhance test accuracy without requiring test redesign. We examined Embic’s digital biomarker M, a measure of recall derived from multinomial processing trees and hierarchical Bayesian computational methods, as a predictor of conversion to mild cognitive impairment (MCI) and Alzheimer’s disease (AD), and of increase in Clinical Dementia Rating (CDR) score.MethodsSecondary data analyses were carried out from ADNI data. M was computed from Rey’s AVLT data, and compared to standard AVLT clinical metrics (total and delayed recall). We conducted logistic regression analyses with diagnosis at 36 months (normal vs. MCI + AD) as outcome; all 169 participants were classified as normal at baseline, and 13 of these progressed to a clinical diagnosis (see Table 1). We controlled for baseline age, gender and years of education; and ran separate analyses with other metrics to avoid multicollinearity. We then repeated the same analytical framework with CDR scores (stable at 0 vs. increased to 0.5 or 1) at 36 months as outcome: stable participants were 141, and 24 increased (see Table 2). Covariates and predictors were the same as in the previous analysis.Results M predicted conversion to MCI or AD after three years (FDR‐corrected p value = 0.048), while neither AVLT total nor delayed recall did. Performance metrics showed that M generated 92% accuracy, or probability of yielding a correct classification, and 100% specificity, or no false positives (Figure 1). Analogously, M, but not standard AVLT metrics, also predicted a CDR increase after three years (FDR‐corrected p value = 0.003), with high accuracy (84%), specificity (96%), and precision (80%), or positive predictive value (Figure 2). Sensitivity analyses with ordinal regression broadly confirmed these findings.ConclusionsThese results indicate Embic’s digital biomarker M outperforms some of AVLT’s traditional metrics in identifying individuals who will progress to MCI and AD after three years, from a healthy baseline.

Identifying Optimal Blood Tau Epitopes for the Detection of Alzheimer’s Disease Neuropathology: An Immunoprecipitation Mass Spectrometry and Autopsy Study

AbstractBackgroundPlasma‐to‐autopsy studies are essential for validation of plasma biomarkers for the detection of Alzheimer’s disease (AD). Few such studies have been done and those that exist have had limited or no comparison of the different tau epitopes. This plasma‐to‐autopsy study is the first to use immunoprecipitation mass spectrometry (IP‐MS) to compare the accuracy of eight different plasma tau epitopes (six p‐tau, two total tau) in predicting autopsy‐confirmed AD.MethodThe sample included 123 participants from the Boston University Alzheimer’s Disease Research Center who had an available antemortem plasma sample and donated their brain for neuropathological examination. Plasma samples proximate to death were analyzed for six different plasma p‐tau (181+199+202+205+217+231) and two total tau (t‐tau) epitopes (195‐205, 212‐221) simultaneously using IP‐MS. NIA‐Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma epitope and autopsy‐confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Analyses were repeated stratified by Clinical Dementia Rating (CDR) score (i.e., &lt;1 and ≥1) at the time of blood draw. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications.Result Table 1 shows sample characteristics. Sixty‐nine of the 123 (56.1%) brain donors had autopsy‐confirmed AD and the average interval between blood draw and death was ∼5 years. Table 2 summarizes logistic regressions and Figure 1 displays ROC curves. Plasma p‐tau217 (AUC = 89.8), p‐tau231 (AUC = 83.4), and p‐tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non‐AD brain donors. Among those with CDR≥1, p‐tau217, p‐tau231, and p‐tau205 had outstanding discrimination and all other epitopes had excellent discrimination. Among those with CDR&lt;1, p‐tau217 (AUC = 86.3) and p‐tau231 (AUC = 80.6) still had excellent discrimination accuracy; p‐tau181, p‐tau205, and t‐tau195‐209 had acceptable discrimination. Furthermore, p‐tau217, p‐tau205 and p‐tau231 were the tau species that showed higher ORs with both CERAD (ORp‐tau217 = 15.29, ORp‐tau205 = 5.05 and ORp‐tau231 = 3.86) and Braak staging (ORp‐tau217 = 14.29, ORp‐tau205 = 5.27 and ORp‐tau231 = 4.02).ConclusionPlasma levels of p‐tau217, p‐tau231, and p‐tau205 showed the best discrimination accuracy for AD confirmed neuropathology in both mild and severe cognitive impairment.