Depth- and curvature-based quantitative susceptibility mapping analyses of cortical iron in Alzheimer's disease.

In addition to amyloid beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been associated with elevated iron in deep gray matter nuclei using quantitative susceptibility mapping (QSM). However, only a few studies have examined cortical iron, using more macroscopic approaches that cannot assess layer-specific differences. Here, we conducted column-based QSM analyses to assess whether AD-related increases in cortical iron vary in relation to layer-specific differences in the type and density of neurons. We obtained global and regional measures of positive (iron) and negative (myelin, protein aggregation) susceptibility from 22 adults with AD and 22 demographically matched healthy controls. Depth-wise analyses indicated that global susceptibility increased from the pial surface to the gray/white matter boundary, with a larger slope for positive susceptibility in the left hemisphere for adults with AD than controls. Curvature-based analyses indicated larger global susceptibility for adults with AD versus controls; the right hemisphere versus left; and gyri versus sulci. Region-of-interest analyses identified similar depth- and curvature-specific group differences, especially for temporo-parietal regions. Finding that iron accumulates in a topographically heterogenous manner across the cortical mantle may help explain the profound cognitive deterioration that differentiates AD from the slowing of general motor processes in healthy aging.

Neuropsychiatric Comorbidities and Psychotropic Medication Use in Medicare Beneficiaries With Dementia by Sex and Race.

BACKGROUND: Neuropsychiatric symptoms affect the majority of dementia patients. Past studies report high rates of potentially inappropriate prescribing of psychotropic medications in this population. We investigate differences in neuropsychiatric diagnoses and psychotropic medication prescribing in a local US cohort by sex and race. METHODS: We utilize Medicare claims and prescription fill records in a cohort of 100% Medicare North and South Carolina beneficiaries ages 50 and above for the year 2017 with a dementia diagnosis. We identify dementia and quantify diagnosis of anxiety, depression and psychosis using validated coding algorithms. We search Medicare claims for antianxiety, antidepressant and antipsychotic medications to determine prescriptions filled. RESULTS: Anxiety and depression were diagnosed at higher rates in White patients; psychosis at higher rates in Black patients. (P < .001) Females were diagnosed with anxiety, depression and psychosis at higher rates than males (P < .001) and filled more antianxiety and antidepressant medications than males. (P < .001) Black and Other race patients filled more antipsychotic medications for anxiety, depression and psychosis than White patients. (P < .001) Antidepressants were prescribed at higher rates than antianxiety or antipsychotic medications across all patients and diagnoses. Of patients with no neuropsychiatric diagnosis, 11.4% were prescribed an antianxiety medication, 22.8% prescribed an antidepressant and 7.6% prescribed an antipsychotic. CONCLUSIONS: The high fill rate of antianxiety (benzodiazepine) medications in dementia patients, especially females is a concern. Patients are prescribed psychotropic medications at high rates. This practice may represent potentially inappropriate prescribing. Patient/caregiver education with innovative community outreach and care delivery models may help decrease medication use.

Identifying vulnerable brain networks associated with Alzheimer's disease risk.

The selective vulnerability of brain networks in individuals at risk for Alzheimer's disease (AD) may help differentiate pathological from normal aging at asymptomatic stages, allowing the implementation of more effective interventions. We used a sample of 72 people across the age span, enriched for the APOE4 genotype to reveal vulnerable networks associated with a composite AD risk factor including age, genotype, and sex. Sparse canonical correlation analysis (CCA) revealed a high weight associated with genotype, and subgraphs involving the cuneus, temporal, cingulate cortices, and cerebellum. Adding cognitive metrics to the risk factor revealed the highest cumulative degree of connectivity for the pericalcarine cortex, insula, banks of the superior sulcus, and the cerebellum. To enable scaling up our approach, we extended tensor network principal component analysis, introducing CCA components. We developed sparse regression predictive models with errors of 17% for genotype, 24% for family risk factor for AD, and 5 years for age. Age prediction in groups including cognitively impaired subjects revealed regions not found using only normal subjects, i.e. middle and transverse temporal, paracentral and superior banks of temporal sulcus, as well as the amygdala and parahippocampal gyrus. These modeling approaches represent stepping stones towards single subject prediction.

ASSESSMENT OF RETINAL MICROVASCULAR ALTERATIONS IN INDIVIDUALS WITH AMNESTIC AND NONAMNESTIC MILD COGNITIVE IMPAIRMENT USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To assess retinal microvascular alterations in individuals with amnestic mild cognitive impairment (MCI) and nonamnestic MCI. METHODS: One hundred twelve eyes of 59 amnestic MCI participants, 32 eyes of 17 nonamnestic MCI participants, and 111 eyes of 56 controls with normal cognition were included. Optical coherence tomography angiography vessel density and perfusion density in the Early Treatment Diabetic Retinopathy Study 3-mm circle and ring were assessed. Retinal thickness parameters including retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, central subfield thickness, and subfoveal choroidal thickness were also analyzed. Multivariable generalized estimating equations were used for statistical analysis. RESULTS: Perfusion density in the 3-mm inner ring was significantly lower in amnestic MCI patients when compared with nonamnestic MCI participants (0.29 ± 0.03 vs. 0.34 ± 0.09, P = 0.025) and controls with normal cognition (0.29 ± 0.03 vs. 0.39 ± 0.02, P < 0.001), after adjustment for age and sex as covariates. Vessel density, retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, central subfield thickness, and subfoveal choroidal thickness did not differ among or between diagnostic groups. CONCLUSION: Perfusion density was significantly reduced in individuals with amnestic MCI, compared with those with nonamnestic MCI and controls with normal cognition.

Advances in Pharmacotherapy of Late-Life Depression.

This paper reviews recent research on late-life depression (LLD) pharmacotherapy, focusing on updated information for monotherapy and augmentation treatments. We then review new research on moderators of clinical response and how to use the information for improved efficacy. RECENT FINDINGS: A recent review shows that sertraline, paroxetine, and duloxetine were superior to placebo for the treatment of LLD. There is concern that paroxetine could have adverse outcomes in the geriatric population due to anticholinergic properties; however, studies show no increases in mortality, dementia risk, or cognitive measures. Among newer antidepressants, vortioxetine has demonstrated efficacy in LLD, quetiapine has demonstrated efficacy especially for patients with sleep disturbances, and aripiprazole augmentation for treatment resistance in LLD was found to be safe and effective. Researchers have also been identifying moderators of LLD that can guide treatment. Researchers are learning how to associate moderators, neuroanatomical models, and antidepressant response. SSRI/SNRIs remain first-line treatment for LLD. Aripiprazole is an effective and safe augmentation for treatment resistance. Studies are identifying actionable moderators that can increase treatment response.

Peripapillary Optical Coherence Tomography Angiography in Alzheimer's Disease, Mild Cognitive Impairment, and Normal Cognition.

OBJECTIVE: This study aimed to identify peripapillary microvascular changes in Alzheimer's disease (AD) and mild cognitive impairment (MCI). PATIENTS AND METHODS: In this prospective study, 66 eyes of 36 subjects with AD, 119 eyes of 63 with MCI, and 513 eyes of 265 controls with normal cognition were enrolled. Peripapillary capillary perfusion density (CPD), capillary flux index (CFI), and retinal nerve fiber layer (RNFL) thickness were determined. RESULTS: Average CPD differed significantly between all three groups (P = 0.001), being significantly greater in AD vs controls (0.446 ± 0.015 vs 0.439 ± 0.017, P = 0.001) and MCI vs controls (0.443 ± 0.020 vs 0.439 ± 0.017, P = 0.007) but not AD vs MCI (P = 0.69). CFI and average RNFL thickness did not significantly differ among groups (all P > 0.05). CONCLUSION: Peripapillary CPD is increased in eyes with AD or MCI compared to controls despite similar RNFL thickness. [Ophthalmic Surg Lasers Imaging Retina 2024;55:78-84.].

Differences in Retinal and Choroidal Microvasculature and Structure in Dementia With Lewy Bodies Compared With Normal Cognition.

Purpose: To evaluate the retinal and choroidal microvasculature and structure in individuals with dementia with Lewy bodies (DLB) compared with controls with normal cognition using optical coherence tomography (OCT) and OCT angiography (OCTA). Methods: An institutional review board-approved cross-sectional comparison of patients with DLB and cognitively normal controls was performed. The Cirrus HD-OCT 5000 with AngioPlex (Carl Zeiss Meditec) was used to obtain OCT and OCTA images. Results: Thirty-four eyes of 18 patients with DLB and 85 eyes of 48 cognitively normal patients were analyzed. The average capillary perfusion density (CPD) was higher in the DLB group than in the control group (P = .005). The average capillary flux index (CFI) and ganglion cell inner-plexiform layer (GC-IPL) thickness were lower in the DLB group than in the control group (P = .016 and P = .040, respectively). Conclusions: Patients with DLB had an increased peripapillary CPD, decreased peripapillary CFI, and attenuated GC-IPL thickness compared with those with normal cognition.

Racial Disparities in Low-Value Care in the Last Year of Life for Medicare Beneficiaries With Neurodegenerative Disease.

Background and Objectives: There are racial disparities in health care services received by patients with neurodegenerative diseases, but little is known about disparities in the last year of life, specifically in high-value and low-value care utilization. This study evaluated racial disparities in the utilization of high-value and low-value care in the last year of life among Medicare beneficiaries with dementia or Parkinson disease. Methods: This was a retrospective, population-based cohort analysis using data from North and South Carolina fee-for-service Medicare claims between 2013 and 2017. We created a decedent cohort of beneficiaries aged 50 years or older at diagnosis with dementia or Parkinson disease. Specific low-value utilization outcomes were selected from the Choosing Wisely initiative, including cancer screening, peripheral artery stenting, and feeding tube placement in the last year of life. Low-value outcomes included hospitalization, emergency department visits, neuroimaging services, and number of days receiving skilled nursing. High-value outcomes included receipt of occupational and physical therapy, hospice care, and medications indicated for dementia and/or Parkinson disease. Results: Among 70,650 decedents, 13,753 were Black, 55,765 were White, 93.1% had dementia, and 7.7% had Parkinson disease. Adjusting for age, sex, Medicaid dual enrollment status, rural vs urban location, state (NC and SC), and comorbidities, Black decedents were more likely to receive low-value care including colorectal cancer screening (adjusted hazard ratio [aHR] 1.46 [1.32-1.61]), peripheral artery stenting (aHR 1.72 [1.43-2.08]), and feeding tube placement (aHR 2.96 [2.70-3.24]) and less likely to receive physical therapy (aHR 0.73 [0.64-0.85)], dementia medications (aHR 0.90 [0.86-0.95]), or Parkinson disease medications (aHR 0.88 [0.75-1.02]) within the last year of life. Black decedents were more likely to be hospitalized (aHR 1.28 [1.25-1.32]), more likely to be admitted to skilled nursing (aHR 1.09 [1.05-1.13]), and less likely to be admitted to hospice (aHR 0.82 [0.79-0.85]) than White decedents. Discussion: We found racial disparities in care utilization among patients with neurodegenerative disease in the last year of life, such that Black decedents were more likely to receive specific low-value care services and less likely to receive high-value supportive care than White decedents, even after adjusting for health status and socioeconomic factors.

Intrasession Repeatability of OCT Angiography Parameters in Neurodegenerative Disease.

Purpose: To assess the intrasession repeatability of macular OCT angiography (OCTA) parameters in Alzheimer's disease (AD), mild cognitive impairment (MCI), Parkinson's disease (PD), and normal cognition (NC). Design: Cross sectional study. Subjects: Patients with a clinical diagnosis of AD, PD, MCI, or NC were imaged. Images with poor quality and of those with diabetes mellitus, glaucoma, or vitreoretinal disease were excluded from analysis. Methods Intervention or Testing: All participants were imaged using the Zeiss Cirrus HD-5000 with AngioPlex (Carl Zeiss Meditec, Software Version 11.0.0.29946) and repeat OCTA images were obtained for both eyes. Perfusion density (PFD), vessel density (VD), and Foveal avascular zone (FAZ) area were measured from 3 × 3 mm and 6 × 6 mm OCTA images centered on the fovea using an ETDRS grid overlay. Main Outcome Measures: Intraclass correlation coefficients were used to quantify repeatability of PFD, VD, and FAZ area measurements obtained from imaging. Results: 3 × 3 mm scans of 22 AD, 40 MCI, 21 PD, and 26 NC participants and 6 × 6 mm scans of 29 AD, 44 MCI, 29 PD, and 30 NC participants were analyzed. Repeatability values ranged from 0.64 (0.49-0.82) for 6 × 6 mm PFD in AD participants to 0.87 (0.67-0.92) for 3 × 3 mm PFD in AD participants. No significant differences were observed in repeatability between NC participants and those with neurodegenerative disease. Conclusions: Overall, similar OCTA repeatability was observed between NC participants and those with neurodegeneration. Regardless of diagnostic group, macular OCTA metrics demonstrated moderate to good repeatability. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

A blood biomarker test for brain amyloid impacts the clinical evaluation of cognitive impairment.

OBJECTIVE: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. METHODS: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. RESULTS: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). INTERPRETATION: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

Retinal Vascular Changes in Alzheimer's Dementia and Mild Cognitive Impairment: A Pilot Study Using Ultra-Widefield Imaging.

Purpose: Retinal microvascular abnormalities measured on retinal images are a potential source of prognostic biomarkers of vascular changes in the neurodegenerating brain. We assessed the presence of these abnormalities in Alzheimer's dementia and mild cognitive impairment (MCI) using ultra-widefield (UWF) retinal imaging. Methods: UWF images from 103 participants (28 with Alzheimer's dementia, 30 with MCI, and 45 with normal cognition) underwent analysis to quantify measures of retinal vascular branching complexity, width, and tortuosity. Results: Participants with Alzheimer's dementia displayed increased vessel branching in the midperipheral retina and increased arteriolar thinning. Participants with MCI displayed increased rates of arteriolar and venular thinning and a trend for decreased vessel branching. Conclusions: Statistically significant differences in the retinal vasculature in peripheral regions of the retina were observed among the distinct cognitive stages. However, larger studies are required to establish the clinical importance of our findings. UWF imaging may be a promising modality to assess a larger view of the retinal vasculature to uncover retinal changes in Alzheimer's disease. Translational Relevance: This pilot work reports an investigation into which retinal vasculature measurements may be useful surrogate measures of cognitive decline, as well as technical developments (e.g., measurement standardization), that are first required to establish their recommended use and translational potential.

Retinal and Choroidal Changes in Men Compared with Women with Alzheimer's Disease: A Case-Control Study.

Purpose: To evaluate differences in the retinal microvasculature and structure and choroidal structure among men and women with Alzheimer's disease (AD) compared with age-matched cognitively normal male and female controls. Design: Case-control study of participants ≥ 50 years of age. Participants: A total of 202 eyes of 139 subjects (101 cases and 101 controls). Methods: All participants and controls underwent OCT and OCT angiography (OCTA), and parameters of subjects with AD were compared with those of cognitively normal controls. Main Outcome Measures: The foveal avascular zone (FAZ) area, vessel density (VD), and perfusion density (PD) in the superficial capillary plexus within the 3- and 6-mm circle and ring using Early Treatment Diabetic Retinopathy Study (ETDRS) grid overlay on OCTA; central subfield thickness (CST), retinal nerve fiber layer (RNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, and choroidal vascularity index (CVI) on OCT. Results: No significant sex differences in VD or PD were found in the AD or control cohorts; however, there were greater differences in VD and PD among AD female participants than AD male participants compared with their respective controls. The CST and FAZ area were not different between male and female AD participants. Among controls, men had a thicker CST (P < 0.001) and smaller FAZ area (P = 0.003) compared with women. The RNFL thickness, GCIPL thickness, and CVI were similar among male and female AD participants and controls. Conclusions: There may be a loss of the physiologic sex-related differences in retinal structure and microvasculature in those with AD compared with controls. Further studies are needed to elucidate the pathophysiological basis for these findings.

Repeatability of Peripapillary OCT Angiography in Neurodegenerative Disease.

Purpose: To assess the repeatability of peripapillary OCT angiography (OCTA) in those with Alzheimer disease (AD), mild cognitive impairment (MCI), Parkinson disease (PD), or normal cognition. Design: Cross-sectional. Participants: Patients with a clinical diagnosis of AD, MCI, PD, or normal cognition were imaged. Those with glaucoma, diabetes mellitus, vitreoretinal pathology, and poor-quality images were excluded. Methods: Each eligible eye of each participant underwent 2 OCTA 4.5 × 4.5-mm peripapillary scans in a single session using a Zeiss Cirrus HD-OCT 5000 with AngioPlex (Carl Zeiss Meditec). The Zeiss software (v11.0.0.29946) quantified measures of perfusion in the radial peripapillary capillary (RPC) plexus in 4 sectors (superior, nasal, inferior, temporal). The average of these sectors was calculated and reported. Main Outcome Measures: Radial peripapillary capillary plexus perfusion was quantified using 2 parameters: capillary perfusion density (CPD) and capillary flux index (CFI). Intraclass correlation coefficients (ICCs) were used to quantify repeatability. For subjects who had both eyes included, the average values of each scan pair were used to assess interocular symmetry of CPD and CFI. Results: Of 374 eyes, 46 were from participants who had AD, 85 were from participants who had MCI, 87 were from participants who had PD, and 156 were from participants who had normal cognition. Capillary perfusion density ICC in AD = 0.88 (95% confidence interval [CI], 0.79-0.93), MCI = 0.95 (0.92-0.96), PD = 0.91 (0.87-0.94), and controls = 0.90 (0.87-0.93). Capillary flux index ICC in AD = 0.82 (0.70-0.90), MCI = 0.87 (0.80-0.91), PD = 0.91 (0.87-0.94) and controls = 0.85 (0.79-0.89). There were no significant differences in interocular variation in average CPD and CFI in AD, MCI, or PD (all P > 0.05). Isolated interocular sectoral CPD differences were noted in AD (nasal, P = 0.049; temporal, P = 0.024), PD (nasal, P = 0.036), and controls (nasal, P = 0.016). Interocular differences in CFI in the superior sector in MCI (P = 0.028) and in average CFI for controls (P = 0.035) were observed. Conclusions: Peripapillary OCTA repeatability in AD, MCI, and PD is good-excellent and similar to those with normal cognition. Insignificant interocular asymmetry in peripapillary OCTA suggests neurodegeneration may proceed uniformly; future studies may reveal the appropriateness of single-eye imaging.

Discharge Plans for Geriatric Inpatients with Delirium: A Plan to Stop Antipsychotics?

BACKGROUND: Studies show inpatient geriatric patients with reversible conditions like delirium may continue on antipsychotic medications without clear indications after hospital discharge. We conducted this study to determine how often geriatric patients were discharged on a newly started antipsychotic during admission with a plan for discontinuation of the antipsychotic documented in the discharge summary. DESIGN: We conducted retrospective chart review identifying geriatric inpatients in our health system started on a new antipsychotic during admission. In patients discharged from the hospital on a new antipsychotic, we examined the discharge summary for a discontinuation treatment plan. RESULTS: Of 487 patients started on a new antipsychotic, 147 (30.2%) were discharged on the antipsychotic. Of those, 121 (82.3%) had a diagnosis of delirium. Discharge summaries of 15 (12.4%) patients discharged on an antipsychotic with a diagnosis of delirium included instructions for discontinuation of the antipsychotic. Of those patients discharged with instructions for discontinuation, 12 (80%) received a psychiatric or geriatric medicine consult. CONCLUSION: In our health system, the majority of geriatric patients with delirium, discharged on a new antipsychotic had no instructions outlined to outpatient providers for discontinuation management. Further interventions could target increasing antipsychotic guidance at transitions of care.

Re-emergence of posttraumatic stress disorder nightmares with nursing home admission: treatment with prazosin.

Seniors with a history of emotional trauma decades earlier can experience a recurrence of posttraumatic stress disorder symptoms when transitioning to a nursing home. We present the case of an 86-year-old male Holocaust survivor admitted to a nursing home for physical therapy and rehabilitation 6 weeks after the death of his wife; the patient was expressing a persistent death wish. Despite the multiple risk factors for depression, his distress was specifically related to the reemergence of nightly posttraumatic nightmares. Over the course of 1 week of treatment with 1 mg prazosin at bedtime, his nightmares and his death wish completely resolved. He achieved his rehabilitation goals and was discharged to a community setting. This report highlights the importance of considering posttraumatic stress disorder in nursing home residents with a history of emotional trauma, and understanding how to address these symptoms pharmacologically and nonpharmacologically.