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Background: The APOE4 allele is a genetic risk factor for developing late-onset Alzheimer’s disease (AD). Previous work by our group revealed that female APOE4 homozygotes with Lewy body (LB) pathology were more likely to experience psychosis compared to female APOE4 non-carriers, whereas in males there was no APOE4 dose-dependent significant effect. The objective of this study was to refine our previous findings by adjusting for covariates and determining the probability of an APOE4 sex-mediated effect on psychosis. Methods: Neuropathologically confirmed AD patients with LB pathology (n = 491) and without LB pathology (n = 716) were extracted from the National Alzheimer’s Coordinating Center (NACC). Patients were classified as psychotic if they scored positively for delusions and/or hallucinations on the Neuropsychiatric Inventory. Analysis consisted of a preliminary unadjusted binary logistic regression and a Generalized Additive binary logistic regression Model (GAM) to predict the relationship between APOE4 status and sex on the presence of psychosis in both cohorts, adjusting for age, education and MMSE. Results: In the cohort with LB pathology, female APOE4 homozygotes were significantly more likely to experience psychosis compared to female APOE4 non-carriers (OR = 4.15, 95%CI [1.21, 14.2], p = 0.023). Female heterozygotes were also more likely to experience psychosis compared to female APOE4 non-carriers, but to a lesser extent (OR = 2.37, 95%CI [1.01, 5.59], p = 0.048). There was no significant difference in males with LB pathology or in any sex in the cohort without LB pathology. Conclusions: Sex and zygosity influence the effect of APOE4 on psychosis in neuropathologically confirmed AD patients, with the effect being limited to females with LB pathology.

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Background: This study examines the relationship between delusional severity in cognitively impaired adults with automatically computed volume and texture biomarkers from the Normal Appearing Brain Matter (NABM) in FLAIR MRI. Methods: Patients with mild cognitive impairment (MCI, n = 24) and Alzheimer’s Disease (AD, n = 18) with delusions of varying severities based on Neuropsychiatric Inventory-Questionnaire (NPI-Q) (1—mild, 2—moderate, 3—severe) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed for this task. The NABM region, which is gray matter (GM) and white matter (WM) combined, was automatically segmented in FLAIR MRI volumes with intensity standardization and thresholding. Three imaging biomarkers were computed from this region, including NABM volume and two texture markers called “Integrity” and “Damage”. Together, these imaging biomarkers quantify structural changes in brain volume, microstructural integrity and tissue damage. Multivariable regression was used to investigate relationships between imaging biomarkers and delusional severities (1, 2 and 3). Sex, age, education, APOE4 and baseline cerebrospinal fluid (CSF) tau were included as co-variates. Results: Biomarkers were extracted from a total of 42 participants with longitudinal time points representing 164 imaging volumes. Significant associations were found for all three NABM biomarkers between delusion level 3 and level 1. Integrity was also sensitive enough to show differences between delusion level 1 and delusion level 2. A significant specified interaction was noted with severe delusions (level 3) and CSF tau for all imaging biomarkers (p < 0.01). APOE4 homozygotes were also significantly related to the biomarkers. Conclusion: Cognitively impaired older adults with more severe delusions have greater global brain disease burden in the WM and GM combined (NABM) as measured using FLAIR MRI. Relative to patients with mild delusions, tissue degeneration in the NABM was more pronounced in subjects with higher delusional symptoms, with a significant association with CSF tau. Future studies are required to establish potential tau-associated mechanisms of increased delusional severity.

The APOE4 allele is a significant genetic risk factor for Alzheimer's disease (AD). Prior work from our group suggests that among neuropathologically verified AD patients, homozygous APOE4 status increases psychosis risk in females compared to heterozygotes, non-carriers, and males but only in the presence of Lewy Body (LB) pathology. This study examines the effects of APOE4 carrier status (homozygous, heterozygous, or non-carrier) and sex on the visual hallucinations relative to auditory hallucinations and delusions in AD. We hypothesize that female-specific findings will be greater in visual hallucinations compared to auditory hallucinations and delusions given they are a proxy of LB pathology. Patient data was extracted from the NACC database. The sample was limited to patients with an etiologic diagnosis of AD. Psychosis was defined based on Neuropsychiatric Inventory subscores for delusions and hallucinations. We analyzed data separately for female APOE4 homozygotes, heterozygotes and non-carriers as well as male APOE4 homozygotes, heterozygotes and non-carriers using a binary logistic regression. Covariates, including age, education, Montreal Cognitive Assessment (MoCA) scores, and Mini-Mental State Examination (MMSE) scores, were controlled for in all analyses. When pooling males and females together, APOE4 homozygotes had a significantly greater likelihood of auditory hallucinations compared to heterozygotes and delusions compared to non-carriers (p < .05). When comparing female APOE4 homozygotes relative to female heterozygotes and non-carriers, homozygous individuals displayed a greater likelihood of hallucinations compared to non-carriers (p < 0.05). Among males there were significant differences in hallucinations overall, visual and auditory among homozygotes relative to heterozygotes and no differences with non-carriers (p < .05). Findings suggest that APOE4 homozygosity increases psychosis risk among males relative to heterozygotes and females relative to non-carriers, with effects being limited to hallucinations. Pooled analyses in both sexes showed effects of APOE4 mainly in delusions and auditory hallucinations. This data suggests the sex effects of APOE4 may be stronger for hallucinations relative to delusions though further studies in larger samples are needed to corroborate this finding. It should also be noted that these analyses did not adjust for LB pathology.

Neuropsychiatric symptoms (NPS) are prevalent in individuals with Alzheimer's disease (AD), impacting disease progression and patient quality of life. AD pathology (amyloid and tau) and related TDP-43 neuropathology may contribute to NPS. The National Alzheimer's Coordinating Center (NACC) database was used to explore the relationship between NPS and AD, TDP-43 neuropathology and clinical diagnosis. A total of 1391 participants from the NACC database were included in the analysis, with data available on NPS (NPI-Q domains), clinical diagnosis (normal cognition, impaired-not-MCI, MCI, and dementia) and neuropathology. Logistic and linear regression models assessed associations between NPS presence or absence, severity and interactions involving clinical diagnosis and AD and TDP-43 neuropathology, including their co-occurrence. Age, sex, education, cognitive scores, and APOE e4 status were adjusted for in all models. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to quantify the effects. The regression models for several NPS domains were statistically significant with clinical diagnosis being the most consistent across domains (Table 1). The clinical diagnosis and neuropathology were significantly associated with apathy (OR = 2.80, 95% CI [2.13, 3.66], p < .001; OR = 1.74, 95% CI [1.09, 2.80], p = .021, respectively) and delusions (OR = 2.71, 95% CI [1.44, 5.09], p = .002; OR = 3.12, 95% CI [1.14, 8.54], p = .026, respectively). Interaction effects were also observed for apathy (OR = 0.88, 95% CI [0.77, 1.00], p = .049) and delusions (OR = 0.75, 95% CI [0.58, 0.98], p = .038). Clinical diagnosis also influenced NPS severity in nighttime behaviors (β = 1.14, 95% CI [0.02, 0.26], p = .018) and apathy (β = 0.16, 95% CI [0.01, 0.32], p = .039). Age, sex, education, cognitive scores, and APOE e4 status had domain-specific effects. The findings highlight the role of clinical diagnosis on NPS across domains, with AD and TDP-43 neuropathology and demographic factors exerting domain-specific effects, most notably in delusions and apathy. Interaction effects between neuropathology and clinical diagnosis were only seen in apathy, suggesting that pathology and clinical diagnosis may have independent effects on NPS. Future research is warranted to examine these effects longitudinally.

The choroid plexus (CP), located in the brain's lateral ventricles, plays a vital role in brain homeostasis by clearing cellular/molecular waste. Alzheimer's disease (AD) progression is associated with accumulation of toxic byproducts (hyperphosphorylated Tau & amyloid-beta) due to impaired cellular/molecular clearance . While CP abnormalities are presumably involved, this has yet to be established. It is thus of substantial clinical interest to identify CP alterations that are indicative of AD pathology burden. We aim to examine CP morphology (volume), as a marker of function, in pathologically-confirmed AD and hypothesize that CP-Volume increases with greater AD-pathology to compensate for the impaired/reduced clearance. Structural T1-weighted magnetic resonance imaging (sMRI) from 312 patients with pathological workup were analyzed from the National Alzheimer's Consortium Centre dataset (Table 1). Patients were grouped based on pathological staging of accumulated tau (Thal staging) and amyloid (Braak staging): Normal (Thal 0-2, Braak 0-2), Pre-AD (Thal 1-5, Braak 0-2), Mild-AD (Thal 1-5, Braak 3-4), and Severe-AD (Thal 1-5, Braak 5-6). sMRI underwent automatic segmentation followed by estimation of bilateral CP-Volumes which were normalized to estimated total intracranial volume. Bayesian multilevel regression was performed by modelling normalized CP-Volume as a function of pathological status, controlling for age, sex and time between sMRI acquisition and death. Group differences in CP-Volume were reported in terms of magnitude of effect (i.e.median), probability of direction and 95% highest density interval (HDI), contrasting between normal and pathology-confirmed groups. There was a high probability (>0.9) of greater CP-Volume (Table 2) in the path-confirmed AD groups compared to normal (Figure 1). The magnitude of effect increased with pathological burden, with mild (1.78×10 cm , [7.11×10 , 2.84×10 ]) and severe-AD (1.75×10 cm , [9.77×10 , 2.55×10 ]) having the largest effect. Given existing evidence that impaired clearance is related to AD-pathology, and CP's involvement in clearance, our findings suggest we can detect morphological changes (via CP-Volume changes) related to these processes. This warrants further investigation longitudinally and supports the feasibility of sMRI in assessing CP as a correlate of pathological burden.

Objectives To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). Methods 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function. Results At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1–2%, 90%HDI [−0.01%: −0.001%], probability of direction (PD) = 90–99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [−5.17%: 43.2%], PD = 91.7%). Conclusions Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI.

Background The APOE ε4 allele (ApoE4) is a known genetic risk factor for developing Alzheimer’s disease (AD). Previous work by our group demonstrated that female ApoE4 homozygotes with Lewy body (LB) pathology were significantly more likely to experience psychosis compared to female ApoE4 non‐carriers, whereas there was no dose‐dependent difference found in males (Valcic et al., 2022). The objective of this study was to examine LB pathology presence and severity in males and females across ApoE4 status, with a particular interest in female ApoE4 homozygotes. Method Demographics, APOE genotype, and LB pathology data was collected in individuals with neuropathologically‐confirmed AD (n=1,234) from the National Alzheimer’s Coordinating Center (NACC). Bayesian Multilevel Regression was used to predict the probability of LB pathology presence in males and females across ApoE4 status (0, 1, 2 ε4 alleles). An Ordinal Regression was used to examine the relationship between LB pathology severity (brainstem‐predominant (mild), limbic or amygdala‐predominant (moderate), neocortical‐predominant (severe)) and ApoE4 status, stratifying by sex. Result While males had a higher probability of exhibiting LB pathology compared to females, after stratifying by ApoE4 status, female ApoE4 homozygotes showed the highest probability of LB pathology at a 91.1% Highest Density Interval (91.1%HDI[0.12: 0.95]) across both sexes. Within females, ApoE4 homozygotes showed a significantly higher probability of having moderate to severe LB pathology relative to other groups (p =.02). Within males, there was no significant relationship between ApoE4 status and LB pathology severity. Conclusion This study revealed that sex and zygosity modulate the effect of ApoE4 on presence of LB pathology and LB severity in neuropathologically‐confirmed AD patients. Specifically, female ApoE4 homozygotes had the highest probability of having LB pathology, as well as greater LB pathology severity. Future work should explore the association between LB pathology severity and psychosis while stratifying for sex and ApoE4 status. Reference: Valcic, M., Khoury, M. A., Kim, J., Fornazzari, L., Churchill, N. W., Ismail, Z., De Luca, V., Tsuang, D., Schweizer, T.A., Munoz, D.G, & Fischer, C. E. (2022). Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically‐Confirmed Alzheimer’s Disease Cohort. Brain Sciences, 12(9), 1266.

Background The choroid plexus (CP), located in the brain's lateral ventricles, plays a vital role in brain homeostasis by clearing cellular/molecular waste. Alzheimer's disease (AD) progression is associated with accumulation of toxic byproducts (hyperphosphorylated Tau & amyloid‐beta) due to impaired cellular/molecular clearance1. While CP abnormalities are presumably involved, this has yet to be established. It is thus of substantial clinical interest to identify CP alterations that are indicative of AD pathology burden. We aim to examine CP morphology (volume), as a marker of function, in pathologically‐confirmed AD and hypothesize that CP‐Volume increases with greater AD‐pathology to compensate for the impaired/reduced clearance. Methods Structural T1‐weighted magnetic resonance imaging (sMRI) from 312 patients with pathological workup were analyzed from the National Alzheimer's Consortium Centre dataset (Table 1). Patients were grouped based on pathological staging of accumulated tau (Thal staging) and amyloid (Braak staging): Normal (Thal 0‐2, Braak 0‐2), Pre‐AD (Thal 1‐5, Braak 0‐2), Mild‐AD (Thal 1‐5, Braak 3‐4), and Severe‐AD (Thal 1‐5, Braak 5‐6). sMRI underwent automatic segmentation followed by estimation of bilateral CP‐Volumes which were normalized to estimated total intracranial volume. Bayesian multilevel regression was performed by modelling normalized CP‐Volume as a function of pathological status, controlling for age, sex and time between sMRI acquisition and death. Group differences in CP‐Volume were reported in terms of magnitude of effect (i.e.median), probability of direction and 95% highest density interval (HDI), contrasting between normal and pathology‐confirmed groups. Results There was a high probability (>0.9) of greater CP‐Volume (Table 2) in the path‐confirmed AD groups compared to normal (Figure 1). The magnitude of effect increased with pathological burden, with mild (1.78×10−4 cm3, [7.11×10−5, 2.84×10−4]) and severe‐AD (1.75×10−4 cm3, [9.77×10−5, 2.55×10−4]) having the largest effect. Conclusions Given existing evidence that impaired clearance is related to AD‐pathology, and CP's involvement in clearance, our findings suggest we can detect morphological changes (via CP‐Volume changes) related to these processes. This warrants further investigation longitudinally and supports the feasibility of sMRI in assessing CP as a correlate of pathological burden.

Background The APOE4 allele is a significant genetic risk factor for Alzheimer's disease (AD). Prior work from our group suggests that among neuropathologically verified AD patients, homozygous APOE4 status increases psychosis risk in females compared to heterozygotes, non‐carriers, and males but only in the presence of Lewy Body (LB) pathology. This study examines the effects of APOE4 carrier status (homozygous, heterozygous, or non‐carrier) and sex on the visual hallucinations relative to auditory hallucinations and delusions in AD. We hypothesize that female‐specific findings will be greater in visual hallucinations compared to auditory hallucinations and delusions given they are a proxy of LB pathology. Method Patient data was extracted from the NACC database. The sample was limited to patients with an etiologic diagnosis of AD. Psychosis was defined based on Neuropsychiatric Inventory subscores for delusions and hallucinations. We analyzed data separately for female APOE4 homozygotes, heterozygotes and non‐carriers as well as male APOE4 homozygotes, heterozygotes and non‐carriers using a binary logistic regression. Covariates, including age, education, Montreal Cognitive Assessment (MoCA) scores, and Mini‐Mental State Examination (MMSE) scores, were controlled for in all analyses. Result When pooling males and females together, APOE4 homozygotes had a significantly greater likelihood of auditory hallucinations compared to heterozygotes and delusions compared to non‐carriers (p < .05). When comparing female APOE4 homozygotes relative to female heterozygotes and non‐carriers, homozygous individuals displayed a greater likelihood of hallucinations compared to non‐carriers (p < 0.05). Among males there were significant differences in hallucinations overall, visual and auditory among homozygotes relative to heterozygotes and no differences with non‐carriers (p < .05). Conclusion Findings suggest that APOE4 homozygosity increases psychosis risk among males relative to heterozygotes and females relative to non‐carriers, with effects being limited to hallucinations. Pooled analyses in both sexes showed effects of APOE4 mainly in delusions and auditory hallucinations. This data suggests the sex effects of APOE4 may be stronger for hallucinations relative to delusions though further studies in larger samples are needed to corroborate this finding. It should also be noted that these analyses did not adjust for LB pathology.