Arterial stiffness mediates the association between age and processing speed at low levels of microvascular function in humans across the adult lifespan.

The function of micro- and macrovessels within the peripheral vasculature has been identified as a target for the investigation of potential cardiovascular-based promoters of cognitive decline. However, little remains known regarding the interaction of the micro- and macrovasculature as it relates to cognitive function, especially in cognitively healthy individuals. Therefore, our purpose was to unravel peripheral factors that contribute to the association between age and processing speed. Ninety-nine individuals (51 men, 48 women) across the adult life span (19-81 yr) were used for analysis. Arterial stiffness was quantified as carotid-femoral pulse-wave velocity (cfPWV) and near-infrared spectroscopy assessed maximal tissue oxygenation (Sto2max) following a period of ischemia. Processing speed was evaluated with Trail Making Test (TMT) Parts A and B. Measures of central (cPP) and peripheral pulse pressure (pPP) were also collected. Moderated mediation analyses were conducted to determine contributions to the age and processing speed relation, and first-order partial correlations were used to assess associations while controlling for the linear effects of age. A P ≤ 0.05 was considered statistically significant. At low levels of Sto2max, there was a significant positive (b = 1.92; P = 0.005) effect of cfPWV on time to completion on TMT part A. In addition, cPP (P = 0.028) and pPP (P = 0.027) remained significantly related to part A when controlling for age. These results suggested that the peripheral microvasculature may be a valuable target for delaying cognitive decline, especially in currently cognitively healthy individuals. Furthermore, we reinforced current evidence that pulse pressure is a key endpoint for trials aimed at preventing or delaying the onset of cognitive decline.NEW & NOTEWORTHY Arterial stiffness partially mediates the association between age and processing speed in the presence of low microvascular function, as demarcated by maximum tissue oxygenation following ischemia. Central and peripheral pulse pressure remained associated with processing speed even after controlling for age. Our findings were derived from a sample that was determined to be cognitively healthy, which highlights the potential for these outcomes to be considered during trials aimed at the prevention of cognitive decline.

Neurocognitive and psychiatric outcomes associated with postacute COVID-19 infection without severe medical complication: a meta-analysis.

BACKGROUND: Cognitive symptoms are often reported by those with a history of COVID-19 infection. No comprehensive meta-analysis of neurocognitive outcomes related to COVID-19 exists despite the influx of studies after the COVID-19 pandemic. This study meta-analysed observational research comparing cross-sectional neurocognitive outcomes in adults with COVID-19 (without severe medical/psychiatric comorbidity) to healthy controls (HCs) or norm-referenced data. METHODS: Data were extracted from 54 studies published between January 2020 and June 2023. Hedges' g was used to index effect sizes, which were pooled using random-effects modelling. Moderating variables were investigated using meta-regression and subgroup analyses. RESULTS: Omnibus meta-analysis of 696 effect sizes extracted across 54 studies (COVID-19 n=6676, HC/norm-reference n=12 986; average time since infection=~6 months) yielded a small but significant effect indicating patients with COVID-19 performed slightly worse than HCs on cognitive measures (g=-0.36; 95% CI=-0.45 to -0.28), with high heterogeneity (Q=242.30, p<0.001, τ=0.26). Significant within-domain effects was yielded by cognitive screener (g=-0.55; 95% CI=-0.75 to -0.36), processing speed (g=-0.44; 95% CI=-0.57 to -0.32), global cognition (g=-0.40; 95% CI=-0.71 to -0.09), simple/complex attention (g=-0.38; 95% CI=-0.46 to -0.29), learning/memory (g=-0.34; 95% CI=-0.46 to -0.22), language (g=-0.34; 95% CI=-0.45 to -0.24) and executive function (g=-0.32; 95% CI=-0.43 to -0.21); but not motor (g=-0.40; 95% CI=-0.89 to 0.10), visuospatial/construction (g=-0.09; 95% CI=-0.23 to 0.05) and orientation (g=-0.02; 95% CI=-0.17 to 0.14). COVID-19 samples with elevated depression, anxiety, fatigue and disease severity yielded larger effects. CONCLUSION: Mild cognitive deficits are associated with COVID-19 infection, especially as detected by cognitive screeners and processing speed tasks. We failed to observe clinically meaningful cognitive impairments (as measured by standard neuropsychological instruments) in people with COVID-19 without severe medical or psychiatric comorbidities.

Neuropsychological Functioning in Primary Dystonia: Updated and Expanded Multidomain Meta-Analysis.

BACKGROUND: Primary dystonia is conventionally considered as a motor disorder, though an emerging literature reports associated cognitive dysfunction. OBJECTIVES: Here, we conducted meta-analyses on studies comparing clinical measures of cognition in persons with primary dystonia and healthy controls (HCs). METHODS: We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO (January 2000-October 2020). Analyses were modeled under random effects. We used Hedge's g as a bias-corrected estimate of effect size, where negative values indicate lower performance in dystonia versus controls. Between-study heterogeneity and bias were primarily assessed with Cochran's Q, I2 , and Egger's regression. RESULTS: From 866 initial results, 20 studies met criteria for analysis (dystonia n = 739, controls n = 643; 254 effect sizes extracted). Meta-analysis showed a significant combined effect size of primary dystonia across all studies (g = -0.56, P < 0.001), with low heterogeneity (Q = 25.26, P = 0.15, I2  = 24.78). Within-domain effects of primary dystonia were motor speed = -0.84, nonmotor speed = -0.83, global cognition = -0.65, language = -0.54, executive functioning = -0.53, learning/memory = -0.46, visuospatial/construction = -0.44, and simple/complex attention = -0.37 (P-values <0.01). High heterogeneity was observed in the motor/nonmotor speed and learning/memory domains. There was no evidence of publication bias. Moderator analyses were mostly negative but possibly underpowered. Blepharospasm samples showed worse performance than other focal/cervical dystonias. Those with inherited (ie, genetic) disease etiology demonstrated worse performance than acquired. CONCLUSIONS: Dystonia patients consistently demonstrated lower performances on neuropsychological tests versus HCs. Effect sizes were generally moderate in strength, clustering around -0.50 SD units. Within the speed domain, results suggested cognitive slowing beyond effects from motor symptoms. Overall, findings indicate dystonia patients experience multidomain cognitive difficulties, as detected by neuropsychological tests. © 2022 International Parkinson and Movement Disorder Society.

Great balls of fire: activation and signalling of inflammatory caspases.

Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.

Structural analysis reveals a pyruvate-binding activator site in the Agrobacterium tumefaciens ADP-glucose pyrophosphorylase.

The pathways for biosynthesis of glycogen in bacteria and starch in plants are evolutionarily and biochemically related. They are regulated primarily by ADP-glucose pyrophosphorylase, which evolved to satisfy metabolic requirements of a particular organism. Despite the importance of these two pathways, little is known about the mechanism that controls pyrophosphorylase activity or the location of its allosteric sites. Here, we report pyruvate-bound crystal structures of ADP-glucose pyrophosphorylase from the bacterium Agrobacterium tumefaciens, identifying a previously elusive activator site for the enzyme. We found that the tetrameric enzyme binds two molecules of pyruvate in a planar conformation. Each binding site is located in a crevice between the C-terminal domains of two subunits where they stack via a distinct ß-helix region. Pyruvate interacts with the side chain of Lys-43 and with the peptide backbone of Ser-328 and Gly-329 from both subunits. These structural insights led to the design of two variants with altered regulatory properties. In one variant (K43A), the allosteric effect was absent, whereas in the other (G329D), the introduced Asp mimicked the presence of pyruvate. The latter generated an enzyme that was preactivated and insensitive to further activation by pyruvate. Our study furnishes a deeper understanding of how glycogen biosynthesis is regulated in bacteria and the mechanism by which transgenic plants increased their starch production. These insights will facilitate rational approaches to enzyme engineering for starch production in crops of agricultural interest and will promote further study of allosteric signal transmission and molecular evolution in this important enzyme family.

CD5 positive B-ALL, a uniquely aggressive subcategory of B-ALL? A case report and brief review of the literature.

CD5 antigen expression in B-cell acute lymphoblastic leukemia (B-ALL) is exceptionally rare. There are six detailed case reports in the literature, with only 16 cases described. Case series analyzing the frequency of aberrant B-ALL immunophenotypes suggest that this variant may occur in as little as 2-4.5% of all B-ALL cases, with one series having no CD5+ positive cases. Herein we report a case of CD5+ B-ALL in a 15-year-old female, and review the previously reported cases. As limited information is available, more data from prospective clinical trials are required to determine whether CD5 positivity portends a poorer prognosis.

A unique phenotype of T-cell acute lymphoblastic leukemia in a patient with GATA2 haploinsufficiency.

Germline or acquired mutations involving the GATA-binding protein gene (GATA2) have been linked to a variety of clinical conditions. In addition, patients harboring GATA2 mutations have a striking predisposition to develop myeloid malignancies, such as myelodysplastic syndrome or acute myeloid leukemia, but not acute lymphoblastic leukemia (ALL). We report here a unique occurrence of early T-cell precursor ALL in a young child with GATA2 haploinsufficiency.

Guilt after placement questionnaire: a new instrument to assess caregiver emotional functioning following nursing home placement.

OBJECTIVE: Guilt is a core feature of dementia caregivers' experiences following placement. This study describes and validates a new assessment tool for monitoring caregiver adjustment after placement. METHODS: Forty-six items addressing ambivalence and guilt about placement were tested with 170 dementia caregivers (M age = 56.79, SD = 13.19; 69.4% female; 54.7% adult child). RESULTS: Using principal axis factor analysis, 10 items were retained that showed acceptable internal consistency (Cronbach's alpha of 0.92). Construct validity was established in a subset of the sample (n = 53) with measures of depression (r = 0.53), burden (r = 0.48), conflict with staff (r = 0.47), and well-being (r = -0.30). CONCLUSIONS: This scale may be used to identify caregivers at risk for adjustment problems following placement and to monitor adjustment over time.

On the stability of nucleoside diphosphate glucose metabolites: implications for studies of plant carbohydrate metabolism.

Nucleoside diphosphate sugars (NDP-sugars) are the substrates for biosynthesis of oligo- and polysaccharides, such as starch and cellulose, and are also required for biosynthesis of nucleotides, ascorbic acid, several cofactors, glycoproteins and many secondary metabolites. A controversial study that questions the generally accepted pathway of ADP-glucose and starch synthesis in plants is based, in part, on claims that NDP-sugars are unstable at alkaline pH in the presence of Mg2+ and that this instability can lead to unreliable results from in vitro assays of enzyme activities. If substantiated, this claim would have far-reaching implications for many published studies that report on the activities of NDP-sugar metabolizing enzymes. To resolve this controversy, we investigated the stability of UDP- and ADP-glucose using biophysical, namely nuclear magnetic resonance (NMR), and highly specific enzymatic methods. Results obtained with both techniques indicate that NDP-sugars are not as unstable as previously suggested. Moreover, their calculated in vitro half-lives are significantly higher than estimates of their in planta turnover times. This indicates that the physico-chemical stability of NDP-sugars has little impact on their concentrations in vivo and that NDP-sugar levels are determined primarily by the relative rates of enzymatic synthesis and consumption. Our results refute one of the main arguments for the controversial pathway of starch synthesis from imported ADP-glucose produced by sucrose synthase in the cytosol.

P300 Event-Related Potentials Differentiate Better Performing Individuals With Traumatic Brain Injury: A Preliminary Study of Semantic Processing.

OBJECTIVE: To measure the effect of traumatic brain injury on the cognitive processing of words, as measured by the P300, in a semantic categorization task. PARTICIPANTS: Eight adults with a history of moderate to severe traumatic brain injury and 8 age- and gender-matched controls. DESIGN: A pilot study measuring cognitive event-related potentials in response to word pairs that were either in same or different semantic categories. MAIN MEASURES: The P300 (P3b) component of the auditory event-related potential and neuropsychological assessment. RESULTS: Two patterns of P300 amplitude related to brain injury were observed. Participants with poorer performance on neuropsychological tests exhibited reduced P300 amplitude as compared to controls but showed the typical P300 parietal scalp distribution. In contrast, better performing participants demonstrated robust P300 amplitude but a substantially altered scalp distribution, characterized by the recruitment of anterior brain regions in addition to parietal activation. CONCLUSIONS: The recruitment of frontal areas after traumatic brain injury may represent compensatory neural mechanisms utilized to successfully maximize task performance. The P300 in a semantic processing paradigm may be a sensitive marker of neural plasticity that could be used to improve functional outcomes in cognitive remediation paradigms.

History of loss of consciousness with mild traumatic brain injury affects PTSD symptom presentation in treatment-seeking Iraq/Afghanistan veterans.

OBJECTIVE: This study was conducted (1) to examine differences in post-traumatic stress disorder (PTSD) symptoms, perceived quality-of-life (QoL) and post-concussive symptoms (PCS) among veterans who experienced deployment-related mild traumatic brain injuries (mTBIs) with or without loss of consciousness (LOC) and (2) to test the additive role of PCS on QOL. DESIGN: Two hundred and twelve Iraq/Afghanistan veterans who were admitted to a residential programme for PTSD were assessed shortly following intake. A MANCOVA was conducted to examine QoL, PTSD symptom domains and PCS across the No LOC and LOC groups. Multivariate regression models were conducted to examine whether prevalence of PCS might be uniquely linked with veterans' QoL (physical, psychological and social). RESULTS: When controlling for combat exposure (CE), LOC status was uniquely linked with avoidance symptomatology, Psychological QoL and PCS; LOC status was not significantly linked with other domains of PTSD or QoL. When controlling for CE and PTSD, PCS was similarly linked with QoL in the psychological domain, but not Physical or Social QoL. CONCLUSION/IMPLICATIONS: LOC associated with a mTBI may contribute to behavioural avoidance and poorer psychological well-being among veterans seeking treatment for PTSD. In addition, PCS associated with mTBI may diminish Psychological QoL for veterans seeking treatment for PTSD.

So how special is special K? A systematic review and meta-analysis of ketamine for PTSD RCTs.

Background: PTSD is a significant mental health problem worldwide. Current evidence-based interventions suffer various limitations. Ketamine is a novel agent that is hoped to be incrementally better than extant interventions.Objective: Several randomized control trials (RCTs) of ketamine interventions for PTSD have now been published. We sought to systematically review and meta-analyse results from these trials to evaluate preliminary evidence for ketamine's incremental benefit above-and-beyond control interventions in PTSD treatment.Results: Omnibus findings from 52 effect sizes extracted across six studies (n = 221) yielded a small advantage for ketamine over control conditions at reducing PTSD symptoms (g = 0.27, 95% CI = 0.03, 0.51). However, bias-correction estimates attenuated this effect (adjusted g = 0.20, 95%, CI = -0.08, 0.48). Bias estimates indicated smaller studies reported larger effect sizes favouring ketamine. The only consistent timepoint assessed across RCTs was 24-hours post-initial infusion. Effects at 24-hours post-initial infusion suggest ketamine has a small relative advantage over controls (g = 0.35, 95% CI = 0.06, 0.64). Post-hoc analyses at 24-hours post-initial infusion indicated that ketamine was significantly better than passive controls (g = 0.44, 95% CI = 0.03, 0.85), but not active controls (g = 0.24, 95% CI = -0.30, 0.78). Comparisons one-week into intervention suggested no meaningful group differences (g = 0.24, 95% CI = 0.00, 0.48). No significant differences were evident for RCTs that examined effects two-weeks post initial infusion (g = 0.17, 95% CI = -0.10, 0.44).Conclusions: Altogether, ketamine-for-PTSD RCTs reveal a nominal initial therapeutic advantage relative to controls. However, bias and heterogeneity appear problematic. While rapid acting effects were observed, all control agents (including saline) also evidenced rapid acting effects. We argue blind penetration to be a serious concern, and that placebo is the likely mechanism behind reported therapeutic effects.

We systematically reviewed and meta-analysed all randomized control trials of ketamine intervention for PTSD.While ketamine was associated with a reduction in symptoms, the effect was generally not stronger than control conditions.By two-weeks post-initial infusion, no meaningful differences are evident between ketamine and controls.

Various modalities of resistance exercise promote similar acute cognitive improvements and hemodynamic increases in young, healthy adults.

The aim was to examine the effects of modalities of acute resistance exercise (RE) on cognition and hemodynamics including internal carotid artery (ICA) blood flow (BF). Twenty adults completed familiarization and experimental visits. One-repetition maximum (1RM) for bilateral leg extension was quantified, and baseline executive functioning was determined from three run-in visits. Subsequent visits included three randomized, volume-equated, acute exercise bouts of 30 %1RM+blood flow restriction (BFR), 30 %1RM, and 70 %1RM. Both 30 %1RM trials completed four sets of exercise (1 × 30, 3 × 15), and the 70 %1RM condition completed four sets of 8 repetitions. BFR was induced with 40 % of the pressure to occlude the femoral arteries. 11 min following each exercise, participants completed the Stroop and Shifting Attention Tests. Baseline and post-exercise values were used to calculate change scores. The resulting mean change scores were evaluated with mixed factorial ANOVAs. A p≤0.05 was considered significant. All measured outcome variables increased in response to exercise. The ANOVAs for cognitive scores indicated no significant (p>0.05) interactions. For cognitive flexibility and executive function index, there were main effects of Sex. Change scores of the females were significantly greater than the males for cognitive flexibility (7.6 ± 5.9 vs. -2.6 ± 8.4 au; p=0.007) and executive function index (7.4 ± 4.6 vs. -2.5 ± 6.5 au; p=0.001). For ICA BF, there was no significant interaction or any main effect. The females exhibited a smaller exercise-induced increase in blood pressure compared to the males (17.7 ± 5.9 vs. 11.0 ± 4.1 mmHg; p=0.010). Each RE modality yielded acute improvements in cognition, but only for females. There were no cognitive improvements related to BFR such that each RE bout yielded similar results.

Neuropsychological Function in Migraine Headaches: An Expanded Comprehensive Multidomain Meta-Analysis

BACKGROUND AND OBJECTIVES: A sizable literature has studied neuropsychologic function in persons with migraine (PwM), but despite this, few quantitative syntheses exist. These focused on circumscribed areas of the literature. In this study, we conducted an expanded comprehensive meta-analysis comparing performance on clinical measures of neuropsychological function both within and across domains, between samples of PwM and healthy controls (HCs). METHODS: For this Meta-analyses Of Observational Studies in Epidemiology-compliant meta-analysis, a unified search strategy was applied to OneSearch (a comprehensive collection of electronic databases) to identify peer-reviewed original research published across all years up until August 1, 2023. Using random-effects modeling, we examined aggregated effect sizes (Hedges' g), between-study heterogeneity (Cochran Q and I2), moderating variables (meta-regression and subgroup analyses), and publication bias (Egger regression intercept and Duval and Tweedie Trim-and-Fill procedure). Study bias was also coded using the NIH Study Quality Assessment Tools. RESULTS: Omnibus meta-analysis from the 58 studies included (PwM n = 5,452, HC n = 16,647; 612 effect sizes extracted) indicated lower overall cognitive performance in PwM vs HCs (g = -0.37; 95% CI -0.47 to -0.28; p < 0.001), and high between-study heterogeneity (Q = 311.25, I2 = 81.69). Significant domain-specific negative effects were observed in global cognition (g = -0.46, p < 0.001), executive function (g = -0.45, p < 0.001), processing speed (g = -0.42, p < 0.001), visuospatial/construction (g = -0.39, p = 0.006), simple/complex attention (g = -0.38, p < 0.001), learning/memory (g = -0.25, p < 0.001), and language (g = -0.24, p < 0.001). Orientation (p = 0.146), motor (p = 0.102), and intelligence (p = 0.899) were not significant. Moderator analyses indicated that age (particularly younger HCs), samples drawn from health care facility settings (e.g., tertiary headache centers) vs community-based populations, and higher attack duration were associated with larger (negative) effects and accounted for a significant proportion of between-study heterogeneity in effects. Notably, PwM without aura yielded stronger (negative) effects (omnibus g = -0.37) vs those with aura (omnibus g = -0.10), though aura status did not account for heterogeneity observed between studies. DISCUSSION: Relative to HCs, PwM demonstrate worse neurocognition, as detected by neuropsychological tests, especially on cognitive screeners and tests within executive functioning and processing speed domains. Effects were generally small to moderate in magnitude and evident only in clinic (vs community) samples. Aura was not meaningfully associated with neurocognitive impairment.

A Randomized, Placebo-Controlled Clinical Trial of a Novel Dietary Supplement on Standardized CNS Vital Signs Cognitive Performance Parameters in Adults.

Objective: To test the effectiveness of a novel dietary supplement as a support for cognitive function in healthy younger and older adults Design: A double-blind, randomized, placebo-controlled trial of the dietary supplement, Braini® in two age cohorts with 60 participants: 31 healthy younger adults (18-30 years) and 29 healthy older adults (55-80 years). Intervention: A 28-day intervention of a dietary supplement (active or placebo) taken daily with cognitive assessment using CNS Vital Signs computer-based testing at day 0 and 28. Participants were asked to fill out a daily survey regarding compliance with supplement protocol, changes in health, adherence to the protocol, and reported side effects. CNS Vital Signs provides aged normed aggregated outcome measures for Processing Speed, Psychomotor Speed, Reaction Time, Cognitive Flexibility, Executive Function, and Motor Speed. Results: Significant improvements in performance were found for two CNS Vital Signs domains, Cognitive Flexibility (p = 0.048), and Executive Function (p = 0.025) in the treated younger adults (n = 12) compared with the placebo group (n = 19) at day 28 compared with baseline. The Shifting Attention Test Reaction Time (SAT-RT), a measure of shifting attention correct response reaction time, showed significant improvement at 28 days in those taking Braini in both younger (p = 0.004) and older adult cohorts (p = 0.05) with an average improvement over the control subjects of 44%. No serious side effects were reported. Conclusions: The dietary formulation, Braini, safely and significantly improved cognitive flexibility and executive function in younger adults and trended positively in older adults in this study that was stopped prematurely due to pandemic restrictions. Scores on SAT-RT significantly improved in both younger and older adults. Further studies are needed to confirm that Braini reliably improves cognitive function in additional CNS domains in healthy adults. Clinical Trial Registration: Clinicaltrials.gov under registration number: NCT04025255.

Examining Relationships between Cognitive Flexibility, Exercise Perceptions, and Cardiovascular Disease Risk Factors.

Adults do not engage in enough physical activity. Investigating cognitive and physiological factors related to improving this behavior-and reducing health risks-remains a public health priority. Our objective was to assess whether cognitive flexibility influenced perceptions and choice of exercise programs and whether flexibility was associated with cardiovascular disease (CVD) risk factors. Independent sample groups of college-aged adults (18-24 yrs) participated in two studies. Data were collected on individuals' degree of cognitive flexibility (both self-reported and objectively measured), perceptions and choice of exercise programs, and health status markers known to be associated with CVD (vascular function, muscular strength, and body composition). Vascular function was assessed with a near-infrared spectroscopy device, strength was defined as handgrip, and body composition was estimated via digital circumferences. Self-reported flexibility reliably predicted individuals' choice of exercise program and perceptions of effort required for success on an exercise program. The relationships among CVD risk factors and objectively measured cognitive flexibility were not significant, demonstrating that identifying a healthy individual's degree of performance-based cognitive flexibility does not predict health status. Furthermore, although greater self-reported trait flexibility (rigidity) is known to predict higher (lower) likelihood of physical activity, this finding should not be extrapolated to also assume that flexibility (rigidity), as measured by objective cognitive tests, is associated with reduced CVD risk in healthy adults. We posit a rationale for how understanding cognitive flexibility and rigidity can play an impactful role in improving adherence to exercise prescriptions targeted to reducing risks.

Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications.

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Examining an Alternative Scoring Procedure for a Clinical Working Memory Measure.

The Digit Span test is a widely used working memory measure. However, when using standardized scoring procedures, previous studies have demonstrated inconsistent relationships between Digit Span subtests and working memory measures frequently used in cognitive psychology experiments. Partial scoring involves awarding credit for all digits recalled in the correct serial location, whereas traditional scoring involves only awarding credit for a trial if all digits are recalled in the correct serial location. The current study compared the traditional all-or-nothing scoring method and the partial scoring method on Digit Span with other working memory measures and with measures of general fluid intelligence. The results showed that when differences were found, partial scoring was associated with stronger relationships with Digit Span Backwards but weaker relationships with Digit Span Forward and Sequencing compared with traditional scoring. These results support previous findings identifying differences between the Digit Span subtests and the utility of examining traditional scoring procedures.