👤 Jack W Lipton

BackgroundInterpreting blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) in a multicultural cohort is complicated by inconsistent evidence on racial differences. Kidney function, which varies by race and influences biomarker levels, is often overlooked, potentially contributing to these inconsistencies.ObjectiveTo characterize racial differences in plasma levels of ADRD biomarkers after adjusting for comorbidities and assessed the impact of estimated glomerular filtration rate (eGFR) adjustment using either race-specific or race-neutral equations.MethodsData from the Einstein Aging Study, a multicultural cohort of older adults, included plasma biomarkers (Aβ Show less

The purpose of this study was to estimate the prevalence and number of cerebral microbleeds (CMBs) in a Hispanic and Latino cohort from various self-identified backgrounds and test associations with age, vascular risk factors, APOE (apolipoprotein E), and cognitive function. The 3T brain magnetic resonance imaging exams were obtained on SOL-INCA-MRI (Study of Latinos-Investigation of Neurocognitive Aging-MRI) magnetic resonance imaging study participants, a community-based study. CMB number was counted and categorized as: (1) any CMB, (2) lobar only, (3) deep only, (4) mixed, (5) deep+mixed, and (6) lobar+mixed. We examined whether prevalence of CMBs varied by age, sex, education, Hispanic background, cardiovascular risk factors (hypertension, diabetes, Framingham Risk Score), APOE genotype, and cognition. A total of 2455 participants were included who were 63.0±8.4 years of age, 67.9% women, and 62.2% high school education or higher. CMBs prevalence was 11.7% (8.3% lobar only, 2.0% deep only, 1.4% mixed locations). After adjusting for age, sex, and education, a high Framingham Risk Score was associated with the presence of CMBs of all types, except lobar only. Prevalent stroke/transient ischemic attack was associated with higher likelihood of deep-only CMBs. For participants with cognitive impairment, the adjusted prevalence of mixed CMBs (2.2% versus 1.1%, High vascular risk scores, self-reported history of stroke/transient ischemic attack, and cognitive status were associated with a higher likelihood of CMBs, especially in deep regions. Show less

Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes. Show less

Blood-based biomarkers hold promise as a minimally invasive tool for identifying early signs of Alzheimer's disease pathology and neurodegeneration. We investigated associations between plasma biomarkers of amyloid-beta, tau, neuroaxonal injury, and glial activation with cognitive performance among community-dwelling Hispanic/Latino adults in the United States. We analyzed cross-sectional data from 5730 adults aged 50 years and older (unweighted; mean [SD], 63.5 [8.2] years) in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA; 2016-2018). Plasma concentrations of amyloid-beta (Aβ Here we show higher ln(pTau-181) and ln(NfL) are associated with lower global cognitive performance (b Plasma biomarkers related to Alzheimer's disease pathophysiology and broader neurodegenerative processes are associated with cognitive performance among Hispanic/Latino adults. These findings highlight the potential utility of blood-based biomarkers for identifying early cognitive vulnerability in this population. Show less

Pacemakers and implantable cardioverter defibrillators are commonly encountered in clinical practice, and entails special consideration when magnetic resonance imaging (MRI) is required. It is estimated that 50-75% of patients with cardiac implantable electronic devices (CIED) will have an indication for MRI during their lifetime. Radiologists may want to recommend MRI or may be consulted about the need to perform MRI in a patient with a CIED, at which point they may need to approve or at least provide guidance as to whether MRI may be performed safely. Even in situations where final clearance will not be provided by the radiologist, he or she can provide valuable information by reviewing radiographs and determining (a) whether a device is MRI-conditional and MRI may ultimately be permitted, (b) is not MRI-conditional and MRI using the standard workflow will therefore not be approved, or (c) when additional information will clearly be required. CIED identification and verification of leads can be accomplished through review of the medical record and/or evaluation of a chest radiograph. In patients with MRI-conditional CIEDs (as well as with legacy CIEDs in those institutions that perform MRI of these patients), specific imaging protocols must be adhered to in order to prevent death or injury to the patient or damage to the device. In this update, we provide details regarding the above topics and provide an algorithm for integrating this information into a clinical workflow to efficiently triage patients with CIEDs who are being considered for MRI. Show less

Electronic stimulation devices are implanted in various locations in the body to decrease pain, modulate nerve function, or stimulate various end organs. The authors describe these devices using a craniocaudal approach, first describing deep brain stimulation (DBS) devices and ending with sacral nerve stimulation (SNS) devices. The radiology-relevant background information for each device and its imaging appearance are also described. These devices have a common design theme and include the following components: Show less

To perform a systematic review and meta-analysis to quantitatively assess functional magnetic resonance (MR) imaging lateralization of language function in comparison with the Wada test. This study was determined to be exempt from review by the institutional review board. A systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A structured Medline search was conducted to identify all studies that compared functional MR imaging with the Wada test for determining hemispheric language dominance prior to brain surgery. Studies meeting predetermined inclusion criteria were selected independently by two radiologists who also assessed their quality using the Quality Assessment of Diagnostic Accuracy Studies tool. Language dominance was classified as typical (left hemispheric language dominance) or atypical (right hemispheric language dominance or bilateral language representation) for each patient. A meta-analysis was then performed by using a bivariate random-effects model to derive estimates of sensitivity and specificity, with Wada as the standard of reference. Subgroup analyses were also performed to compare the different functional MR imaging techniques utilized by the studies. Twenty-three studies, comprising 442 patients, met inclusion criteria. The sensitivity and specificity of functional MR imaging for atypical language dominance (compared with the Wada test) were 83.5% (95% confidence interval: 80.2%, 86.7%) and 88.1% (95% confidence interval: 87.0%, 89.2%), respectively. Functional MR imaging provides an excellent, noninvasive alternative for language lateralization and should be considered for the initial preoperative assessment of hemispheric language dominance. Further research may help determine which functional MR methods are most accurate for specific patient populations. Show less

Polyunsaturated fatty acids (PUFA), a lipid family comprised of omega-3 (n-3) and n-6 fatty acids, are a critical component of cellular membranes, and recent in vitro studies have found that antipsychotic medications up-regulate genes responsible for PUFA biosynthesis. To evaluate this effect in vivo, rats were treated with risperidone (1.5, 3, 6mg/kg/day), paliperidone (1.5, 3, 6mg/kg/day), olanzapine (2.5, 5, 10mg/kg/day), quetiapine (5, 10, 20mg/kg/day), haloperidol (1, 3mg/kg/day) or vehicle through their drinking water for 40day. Effects on liver Fads1, Fads2, Elovl2, and Elovl5 mRNA expression, plasma indices of n-3 (plasma 22:6/18:3 and 20:5/18:3 ratios) and n-6 (plasma 20:4/18:2 and 20:3/18:2 ratios) biosynthesis, and peripheral (erythrocyte, heart) and central (frontal cortex) membrane PUFA composition were determined. Only risperidone and its metabolite paliperidone significantly and selectively up-regulated liver delta-6 desaturase (Fads2) mRNA expression, and robustly increased plasma indices of n-3 and n-6 fatty acid biosynthesis. In risperidone- and paliperidone-treated rats, plasma indices of n-3 and n-6 fatty acid biosynthesis were all positively correlated with liver Fads2 mRNA expression, but not Fads1, Elovl2, or Elovl5 mRNA expression. All antipsychotics at specific doses increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3) composition, and all except quetiapine increased arachidonic acid (AA, 20:4n-6) composition. Risperidone, paliperidone, and olanzapine increased heart DHA and AA composition, and no antipsychotic altered frontal cortex DHA or AA composition. These in vivo data demonstrate that augmentation of PUFA biosynthesis is not common to all antipsychotic medications, and that risperidone and paliperidone uniquely increase delta-6 desaturase (Fads2) mRNA expression and most robustly increase PUFA biosynthesis and peripheral membrane composition. Show less

Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians (n = 213), their offspring (n = 216), and an age-matched Ashkenazi control group (n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the -641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) (p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the -641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable -641C homozygote (p < 0.0001). Homozygosity for the APOC3 -641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans. Show less