Patient Polypharmacy use Following a Multi-Disciplinary Dementia Care Program in a Memory Clinic: A Retrospective Cohort Study.

Introduction: Dementia increases the risk of polypharmacy. Timely detection and optimal care can stabilize or delay the progression of dementia symptoms, which may in turn reduce polypharmacy. We aimed to evaluate the change in polypharmacy use among memory clinic patients living with dementia who participated in a dementia care program compared to those who did not. We hypothesized that patients in the dementia care program would reduce their use of polypharmacy compared to those who were not in standard care. Methods: We retrospectively analyzed data extracted from electronic medical records from a university memory clinic. Data from a total of 381 patients were included in the study: 107 in the program and 274 matched patients in standard care. We used adjusted odds ratios to assess the association between enrollment in the program and polypharmacy use at follow-up (five or more concurrent medications), controlling for baseline polypharmacy use and stratified polypharmacy use by prescription and over-the-counter (OTC). Results: The two groups did not differ in the use of five or more overall and prescription medications at follow-up, controlling for the use of five or more of the respective medications at baseline and covariates. Being in the program was associated with a three-fold lower odds of using five or more OTC medications at follow-up (adjusted odds ratio = 0.30; p <0.001; 95% Confidence interval = 0.15-0.58) after controlling for using five or more OTC medications at baseline and covariates. Conclusions: Dementia care may reduce polypharmacy of OTC medications, potentially reducing risky drug-drug interactions. More research is needed to infer causality and understand how to reduce prescription medication polypharmacy.

FUS G559A Mutation in a Patient with a Frontotemporal Dementia-Motor Neuron Disease Compatible Syndrome: A Case Report.

Fused in sarcoma (FUS) mutations cause frontotemporal dementia (FTD) and motor neuron disease (MND). Here, we describe a 43-year-old man with progressive behavioral and cognitive change, myelopathy, clinical and electrophysiologic evidence of MND, and a FUS variant of unknown significance (VUS). This VUS, a heterozygous G559A transition (Gly187Ser), was previously reported in a patient with sporadic MND and affects important FUS biophysical properties. While this rare variant's presence in a second patient with a related neurodegenerative syndrome does not establish pathogenicity, it raises the question of whether its association with our patient is coincidental and increases the possibility that FUS G559A is pathogenic.

Illustrated Neuropathologic Diagnosis of Alzheimer's Disease.

As of 2022, the prevalence of Alzheimer's disease (AD) among individuals aged 65 and older is estimated to be 6.2 million in the United States. This figure is predicted to grow to 13.8 million by 2060. An accurate assessment of neuropathologic changes represents a critical step in understanding the underlying mechanisms in AD. The current method for assessing postmortem Alzheimer's disease neuropathologic change follows version 11 of the National Alzheimer's Coordinating Center (NACC) coding guidebook. Ambiguity regarding steps in the ABC scoring method can lead to increased time or inaccuracy in staging AD. We present a concise overview of how this postmortem diagnosis is made and relate it to the evolving understanding of antemortem AD biomarkers.

Primary Care Provider Preferences on Dementia Training: A Qualitative Study.

BACKGROUND: Dementia has no cure, but interventions can stabilize the progression of cognitive, functional, and behavioral symptoms. Primary care providers (PCPs) are vital for the early detection, and long-term management of these diseases, given their gatekeeping role in the healthcare system. However, PCPs rarely implement evidence-based dementia care due to time limitations and knowledge about diagnosis and treatment. Training PCPs may help address these barriers. OBJECTIVE: We explored the preferences of PCPs for dementia care training programs. METHODS: We conducted qualitative interviews with 23 PCPs recruited nationally via snowball sampling. We conducted remote interviews and organized the transcripts for qualitative review to identify codes and themes, using thematic analysis methods. RESULTS: PCP preferences varied regarding many aspects of ADRD training. Preferences varied regarding how to best increase PCP participation in training, and what content and materials were needed to help them and the families they serve. We also found differences regarding the duration and timing of training, and the modality of training sessions (remote versus in-person). CONCLUSION: The recommendations arising from these interviews have the potential to inform the development and refinement of dementia training programs to optimize their implementation and success.

Acceptability and Preliminary Effectiveness of a Remote Dementia Educational Training Among Primary Care Providers and Health Navigators.

BACKGROUND: Optimal care can improve lives of families with dementia but remains under-implemented. Most healthcare professional training is in person, time-intensive, and does not focus on key aspects such as early detection, and cultural competency. OBJECTIVE: We explored the acceptability and preliminary effectiveness of a training, The Dementia Update Course, which addressed these issues. We hypothesized that the training would lead to increased levels of perceived dementia care competency among key healthcare workers, namely primary care providers (PCPs) and health navigators (HNs). METHODS: We conducted pre-post training assessments among 22 PCPs and 32 HNs. The 6.5-h training was remote, and included didactic lectures, case discussion techniques, and materials on dementia detection and care. Outcomes included two 5-point Likert scales on acceptability, eleven on perceived dementia care competency, and the three subscales of the General Practitioners Confidence and Attitude Scale for Dementia. We used paired samples t-tests to assess the mean differences in all preliminary effectiveness outcomes. RESULTS: The training included 28.6% of PCPs and 15.6% of HNs that self-identified as non-White or Latino and 45.5% of PCPs and 21.9% of HNs who served in rural areas. PCPs (84.2%) and HNs (91.7%) reported a high likelihood to recommend the training and high satisfaction. Most preliminary effectiveness outcomes analyzed among PCPs (11/14) and all among HNs (8/8) experienced an improvement from pre- to post-training (p < 0.05). CONCLUSION: A relatively brief, remote, and inclusive dementia training was associated with high levels of acceptability and improvements in perceived dementia care competency among PCPs and HNs.

Relationship of fasting glucose and longitudinal Alzheimer's disease imaging markers.

INTRODUCTION: Fasting glucose increases with age and is linked to modifiable Alzheimer's disease risk factors such as cardiovascular disease and Type 2 diabetes (T2D). METHODS: We leveraged available biospecimens and neuroimaging measures collected during the Alzheimer's Prevention Through Exercise (APEx) trial (n = 105) to examine the longitudinal relationship between change in blood glucose metabolism and change in regional cerebral amyloid deposition and gray and white matter (WM) neurodegeneration in older adults over 1 year of follow-up. RESULTS: Individuals with improving fasting glucose (n = 61) exhibited less atrophy and regional amyloid accumulation compared to those whose fasting glucose worsened over 1 year (n = 44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus and inferior parietal cortex, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by apolipoprotein E ε4 carrier status. DISCUSSION: Dysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine whether treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.

Alzheimer's disease clinical trial update 2019-2021.

The current clinical trial landscape targeting Alzheimer's disease (AD) is reviewed in the context of studies completed from 2019 to 2021. This review focuses on available data for observational and phase II/III clinical trial results, which will have the most impact on the field. ClinicalTrials.gov, the United States (US) comprehensive federal registry, was queried to identify completed trials. There are currently 226 interventional clinical trials and 51 observational studies completed, suspended, terminated, or withdrawn within our selected time frame. This review reveals that the role of biomarkers is expanding and although many lessons have been learned, many challenges remain when targeting disease modification of AD through amyloid and tau. In addition, to halt or slow clinical progression of AD, new clinical and observational trials are focusing on prevention as well as the role of more diverse biological processes known to influence AD pathology.

Posterior cortical atrophy phenotypic heterogeneity revealed by decoding 18F-FDG-PET.

Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer's disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45-72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values ('eigenbrains' or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.

Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer's: A 1-year randomized controlled trial.

BACKGROUND: Our goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer's-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging. METHODS AND FINDINGS: This 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 underactive older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n = 79) or subthreshold (n = 38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control. CONCLUSIONS: Aerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects. TRIAL REGISTRATION: NCT02000583; ClinicalTrials.gov.

Progressive dysexecutive syndrome due to Alzheimer's disease: a description of 55 cases and comparison to other phenotypes.

We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer's pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer's disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18F-fluorodeoxyglucose-positron emission tomography and Alzheimer's disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as 'memory problems' but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE ε4 allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer's disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic (n = 110), visual (n = 18) and language (n = 7) predominate clinical phenotypes of Alzheimer's disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer's disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation.

Longitudinal clinical, neuropsychological, and neuroimaging characterization of a kindred with a 12-octapeptide repeat insertion in PRNP: the next generation.

BACKGROUND: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. METHOD: Clinical, neuropsychological, and neuroimaging characterization of a kindred. RESULTS: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. CONCLUSIONS AND RELEVANCE: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.

Comparison of the Short Test of Mental Status and the Montreal Cognitive Assessment Across the Cognitive Spectrum.

OBJECTIVE: To compare the Short Test of Mental Status (STMS) with the Montreal Cognitive Assessment (MoCA) for predicting and detecting mild cognitive impairment (MCI). PARTICIPANTS AND METHODS: Participants from the community-based Mayo Clinic Study of Aging (MCSA) (November 24, 2010, through May 19, 2012) and an academic referral Alzheimer's Disease Research Center (ADRC) (March 16, 2015, through September 5, 2018) were analyzed. All participants were evaluated using a standardized neuropsychological battery, and a multidisciplinary consensus diagnosis was assigned. The MCSA and ADRC samples included 313 and 106 stable cognitively normal (CN) participants, 72 and 8 CN participants at baseline who developed incident MCI or dementia, 114 and 96 participants with prevalent MCI, and 25 and 132 participants with dementia, respectively. RESULTS: There were no statistically significant differences between the 2 tests in 6 of 7 diagnostic comparisons across academic referral and community populations. The STMS had a better area under the curve (0.90; 95% CI, 0.87-0.93) for differentiating prevalent MCI from CN participants in the MCSA cohort compared with the MoCA cohort (0.85; 95% CI, 0.81-0.89; P=.01). In addition, 53% of the stable CN participants (222 of 419) scored less than 26 on the MoCA, with specificity of 47% for diagnosing prevalent MCI. CONCLUSION: We provide evidence that the STMS performs similarly to the MoCA in a variety of settings and neurodegenerative syndromes. These results suggest that the current recommended MoCA cutoff score may be overly sensitive, consistent with previous studies. We also provide a conversion table for comparing the 2 cognitive tests.

Amyloid- and tau-PET imaging in a familial prion kindred.

OBJECTIVE: To study the in vivo binding properties of 18F-AV-1451 (tau-PET) and Pittsburgh compound B (PiB-PET) in a unique kindred with a familial prion disorder known to produce amyloid plaques composed of prion protein alongside Alzheimer disease (AD)-like tau tangles. METHODS: A case series of 4 symptomatic family members with the 12-octapeptide repeat insertion in the PRNP gene were imaged with 3T MRI, PiB-PET, and tau-PET in their fourth decade of life. RESULTS: There was significant neocortical uptake of the tau-PET tracer in all 4 familial prion cases. However, PiB-PET images did not demonstrate abnormally elevated signal in neocortical or cerebellar regions for any of the patients. CONCLUSIONS: In vivo detection of molecular hallmarks of neurodegenerative diseases will be a prerequisite to well-conducted therapeutic trials. Understanding the in vivo behavior of these PET biomarkers in the setting of various neurodegenerative processes is imperative to their proper use in such trials and for research studies focused on the basic neurobiology of neurodegeneration. This study supports the high specificity of neocortical 18F-AV-1451 binding to AD-like tau and the lack of PiB binding to PrP plaques. It is uncertain how early in the disease course tau pathology appears in the brains of individuals who carry this PRNP gene mutation or how it evolves throughout the disease course, but future longitudinal 18F-AV-1451 imaging of symptomatic and asymptomatic individuals in this kindred will help address these uncertainties.

18F-FDG PET-CT pattern in idiopathic normal pressure hydrocephalus.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is an important and treatable cause of neurologic impairment. Diagnosis is complicated due to symptoms overlapping with other age related disorders. The pathophysiology underlying iNPH is not well understood. We explored FDG-PET abnormalities in iNPH patients in order to determine if FDG-PET may serve as a biomarker to differentiate iNPH from common neurodegenerative disorders. Methods: We retrospectively compared 18F-FDG PET-CT imaging patterns from seven iNPH patients (mean age 74 ±â€¯6 years) to age and sex matched controls, as well as patients diagnosed with clinical Alzheimer's disease dementia (AD), Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD), and behavioral variant frontotemporal dementia (bvFTD). Partial volume corrected and uncorrected images were reviewed separately. Results: Patients with iNPH, when compared to controls, AD, DLB/PDD, and bvFTD, had significant regional hypometabolism in the dorsal striatum, involving the caudate and putamen bilaterally. These results remained highly significant after partial volume correction. Conclusions: In this study, we report a FDG-PET pattern of hypometabolism in iNPH involving the caudate and putamen with preserved cortical metabolism. This pattern may differentiate iNPH from degenerative diseases and has the potential to serve as a biomarker for iNPH in future studies. These findings also further our understanding of the pathophysiology underlying the iNPH clinical presentation.

Heterozygous genotype at codon 129 correlates with prolonged disease course in Heidenhain variant sporadic CJD: case report.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains.

Propofol Frenzy: Clinical Spectrum in 3 Patients.

Postsedation neuroexcitation is sometimes attributed to intravenous injection of the sedative-hypnotic drug propofol. The movements associated with these events have strongly suggested convulsive activity, but they rarely have been comprehensively evaluated. We present video recordings of 3 healthy young patients who underwent elective surgery under conscious sedation and emerged from sedation with transient but repetitive violent motor activity and impaired consciousness. These manifestations required considerable mobilization of multiple health care workers to protect the patient from inflicting harm. All patients received propofol, and all fully recovered without adverse sequelae. We postulate that these movements are propofol related. Importantly, we found no evidence of seizures clinically or electrographically.