Higher Risk Of Clinical Progression Research Articles

Impaired glymphatic function as a biomarker for subjective cognitive decline: An exploratory dual cohort study.

Subjective cognitive decline (SCD) has been recognized as a potential risk stage for progression to Alzheimer's disease (AD), while glymphatic dysfunction is considered an important characteristic of AD. We hypothesize that glymphatic dysfunction occurs during the SCD stage, aiming to discover potential biomarkers for SCD. Participants from two independent studies, Sino Longitudinal Study on Cognitive Decline (SILCODE, n=654) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=650), representing different ethnicities and disease stages, were included to assess glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Abnormal glymphatic function occurs during the SCD stage, with the ALPS index demonstrating excellent classification performance for SCD and normal controls (area under the receiver operating characteristic curve [AUC]SILCODE=0.816, AUCADNI=0.797). Lower ALPS index indicates higher risk of cognitive progression, which is negatively correlated with Subjective Cognitive Decline Questionnaire 9 scores and amyloid positron emission tomography burden. Our study suggests the ALPS index has the potential to serve as a biomarker for SCD. Glymphatic function characterized by the analysis along the perivascular space (ALPS) index becomes abnormal in subjective cognitive decline (SCD), the earliest symptomatic manifestation and preclinical stage of Alzheimer's disease (AD). The ALPS index demonstrates excellent classification performance for SCD and normal controls in the East Asian and Western cohorts. Participants with a lower ALPS index show a higher risk of clinical progression. The ALPS index is closely associated with serval cognitive scales and amyloid beta burden.

Characterization of Treatment Resistance and Viral Kinetics in the Setting of Single-Active Versus Dual-Active Monoclonal Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2.

Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs. Participants were nonhospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S-gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant. Study participants receiving single- or dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared with single-active mAb treatment, treatment with dual-active mAbs led to faster viral load decline at study days 3 (P < .001) and 7 (P < .01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than with placebo (2.6% vs 0%; P < .001) and were more frequently detected in the setting of single-active compared with dual-active mAb treatment (7.3% vs 1.1%; P < .01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death. Compared with single-active mAb therapy, dual-active mAbs led to similar clinical outcomes but significantly faster viral load decline and a lower risk of emergent resistance.

Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status

AbstractBackgroundSelf‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.MethodWe used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.ResultBoth self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p&lt;.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p&lt;.001] (Figure 1D).ConclusionLongitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.

Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status

AbstractBackgroundSelf‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.MethodWe used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.ResultsBoth self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p&lt;.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p&lt;.001] (Figure 1D).ConclusionLongitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.

Predictors of progression from subjective cognitive decline to objective cognitive impairment: A systematic review and meta-analysis of longitudinal studies

BackgroundSubjective cognitive decline is one of the first symptoms of dementia. With increasing awareness of brain health and a rising prevalence of dementia, a growing number of individuals seek medical assistance for purely subjective cognitive decline. However, only individuals with specific characteristics tend to experience clinical progression. ObjectivesThis study aims to summarize the predictors of objective cognitive impairment in individuals with subjective cognitive decline and to identify those at higher risk of clinical progression. DesignSystematic review and meta-analysis. MethodsWe systematically searched 11 electronic databases from inception to February 1, 2023, for longitudinal studies investigating factors associated with the clinical progression of subjective cognitive decline. Effect sizes were pooled using fixed-effects and random-effects models. Leveraging the results of the meta-analysis, we developed two risk prediction models for objective cognitive impairment. ResultsForty-six cohort studies were included in the systematic review, of which 28 met the meta-analysis criteria. Fifteen predictors were identified, including 4 biomarkers (amyloid β deposition, lower Hulstaert Formula scores, apolipoprotein e4, and hippocampus atrophy), four epidemiological factors (older age at baseline, impaired instrumental activity of daily living, depression, and anxiety), and seven neuropsychological factors (participants in clinical settings, older age at onset, stable symptom, concerns, cognitive decline confirmed by informant, severe symptoms, and poor performance on Trail Making Test B). Based on the meta-analysis results, we developed two risk prediction models. The first model (Model1) incorporates epidemiological and neuropsychological factors, distinguishing individuals with low and medium risk. The second model (Model2) includes additional biomarkers to enhance predictive performance and identify individuals at high risk. ConclusionsThis study provides a comprehensive characterization of individuals undergoing clinical progression from subjective cognitive decline to mild cognitive impairment or dementia. The developed models support the prediction of progression risk in both memory clinic and community settings, aiding in the early identification of individuals at risk of disease conversion and facilitating the translation of evidence into clinical practice. RegistrationThe systematic review and meta-analysis have been registered in PROSPERO (CRD 42023392476). Tweetable abstractFactors for predicting progression from subjective cognitive decline to objective cognitive impairment: evidence from longitudinal studies.

The effect of plasma cortisol on hippocampal atrophy and clinical progression in mild cognitive impairment.

Both elevated cortisol and hippocampal volume have been linked to an increased risk for the development of Alzheimer's disease (AD). This longitudinal study assessed the effects of plasma cortisol on hippocampal atrophy and clinical progression rates in patients with mild cognitive impairment (MCI). Patients with amnestic MCI (n=304) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on availability of baseline plasma cortisol and hippocampal volume measures, assessed at baseline and during follow-ups. We investigated associations between plasma cortisol, hippocampal volume, and risk of clinical progression to AD over a study period of up to 100 months (mean follow-up time 36.8 months) using linear mixed models, Cox proportional hazards models, and Kaplan-Meier estimators. Plasma cortisol predicted greater hippocampal atrophy, such that participants with higher cortisol showed faster decline in hippocampal volume over time (interaction: β=-0.15, p=0.004). Small hippocampal volume predicted a higher risk of clinical progression to AD (haard ratio [HR]=2.15; confidence in terval [CI], 1.64-2.80; p<0.001). A similar effect was not found for cortisol (HR=1.206; CI, 0.82-1.37; p=0.670) and there was no statistical evidence for an interaction between hippocampal volume and cortisol on clinical progression (HR=0.81; CI, 0.57-0.17; p=0.260). Our findings suggest that higher cortisol predicts higher hippocampal atrophy, which in turn is a risk factor for progression to AD. Regulation of the hypothalamic-pituitary-adrenal axis through stress-reducing lifestyle interventions might be a protective factor against hippocampal degeneration at the prodromal stage of AD.

Spatial navigation is associated with subcortical alterations and progression risk in subjective cognitive decline

BackgroundSubjective cognitive decline (SCD) may serve as a symptomatic indicator for preclinical Alzheimer’s disease; however, SCD is a heterogeneous entity regarding clinical progression. We aimed to investigate whether spatial navigation could reveal subcortical structural alterations and the risk of progression to objective cognitive impairment in SCD individuals.MethodsOne hundred and eighty participants were enrolled: those with SCD (n = 80), normal controls (NCs, n = 77), and mild cognitive impairment (MCI, n = 23). SCD participants were further divided into the SCD-good (G-SCD, n = 40) group and the SCD-bad (B-SCD, n = 40) group according to their spatial navigation performance. Volumes of subcortical structures were calculated and compared among the four groups, including basal forebrain, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens. Topological properties of the subcortical structural covariance network were also calculated. With an interval of 1.5 years ± 12 months of follow-up, the progression rate to MCI was compared between the G-SCD and B-SCD groups.ResultsVolumes of the basal forebrain, the right hippocampus, and their respective subfields differed significantly among the four groups (p < 0.05, false discovery rate corrected). The B-SCD group showed lower volumes in the basal forebrain than the G-SCD group, especially in the Ch4p and Ch4a-i subfields. Furthermore, the structural covariance network of the basal forebrain and right hippocampal subfields showed that the B-SCD group had a larger Lambda than the G-SCD group, which suggested weakened network integration in the B-SCD group. At follow-up, the B-SCD group had a significantly higher conversion rate to MCI than the G-SCD group.ConclusionCompared to SCD participants with good spatial navigation performance, SCD participants with bad performance showed lower volumes in the basal forebrain, a reorganized structural covariance network of subcortical nuclei, and an increased risk of progression to MCI. Our findings indicated that spatial navigation may have great potential to identify SCD subjects at higher risk of clinical progression, which may contribute to making more precise clinical decisions for SCD individuals who seek medical help.

Outcomes after biochemical or clinical progression in patients with multiple myeloma.

Almost all patients with multiple myeloma (MM) eventually relapse, either asymptomatically or with end-organ damage. However, it remains unclear whether initiating therapy at the time of biochemical progression (BP) improves the outcomes compared with initiating therapy at the clinical progression (CP) stage. Here, we retrospectively assessed 1347 patients with relapsed MM. Most progressions were BP (60.4%); 39.6% had CP. The most prevalent symptoms at relapse were new or evolving bone disease (80.9%), anemia (38.0%), and renal failure (12.7%). Patients with BP had longer median time from second-line treatment to the next treatment compared with patients who had CP (17.0 vs 9.6 months; P< .001) as well as longer median overall survival from first relapse (59.4 vs 26.2 months; P< .001). Male sex (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.02-2.18; P= .04), plasma cell labeling index ≥2% (OR, 1.58; 95% CI, 1.02-2.45; P= .04), and extramedullary disease at diagnosis (OR, 1.84; 95% CI, 1.08-3.13; P= .03) were associated with higher risk of CP, whereas very good partial remission or better had decreased risk of CP (OR, 0.62; 95% CI, 0.43-0.91; P= .02). To conclude, patients with CP have inferior postprogression outcomes compared with patients who have BP. Patients with deeper response to first-line therapy are less likely to develop CP. The presence of a specific CRAB (C, hypercalcemia; R, renal failure; A, anemia; B, bone disease) symptom at diagnosis predicts for the development of similar CRAB symptoms at relapse.

Neuropsychiatric symptoms in patients with possible vascular cognitive impairment, does sex matter?

Neuropsychiatric symptoms (NPS) are common in patients with vascular cognitive impairment (VCI). We aimed to establish sex differences in the manifestation of NPS in memory clinic patients with possible VCI and identify which NPS are determinants of clinical progression in women and men separately. We included 718 memory clinic patients (age 68±8; 45% women) with cognitive complaints and vascular brain lesions on MRI (i.e. possible VCI). NPS were measured using the 12-item Neuropsychiatric Inventory. Clinical progression after two years (women 18%, men 14%) was defined as increase in CDR ≥1 or institutionalization (available n=589 without advanced dementia at baseline). The association between NPS and clinical progression was assessed with Cox proportional hazard models stratified by sex, adjusted for age and clinical diagnosis and in a second model additionally for manifestations of vascular brain lesions. Men more often presented with agitation (29% versus 17%, p<.05) and irritability (58% versus 45%, p<.05), the other 10 NPS (delusions, hallucinations, depression, anxiety, euphoria, apathy, disinhibition, aberrant motor behavior, nighttime disturbances and appetite & eating abnormalities) did not differ between sexes. In women the presence of apathy (HR 2.1[1.1;4.3]) was associated with higher risk of clinical progression. In men the presence of depression (HR 2.7[1.4;5.1]) and aberrant motor behavior (HR 2.1[1.1;3.8]) were associated with increased risk of clinical progression. Manifestations of NPS in patients with possible VCI differ by sex. Different NPS are associated with future clinical progression in men and women. Management strategies of NPS could benefit from sex-specific approaches.

Outcomes Following Biochemical or Clinical Progression in Patients with Multiple Myeloma

Outcomes Following Biochemical or Clinical Progression in Patients with Multiple Myeloma

Determinants of loss to care and risk of clinical progression in PLWH who are re-engaged in care after a temporary loss

The risk of developing AIDS is elevated not only among those with a late HIV diagnosis but also among those lost to care (LTC). The aims were to address the risk of becoming LTC and of clinical progression in LTC patients who re-enter care. Patients were defined as LTC if they had no visit for ≥ 18 months. Of these, persons with subsequent visits were defined as re-engaged in care (RIC). Factors associated with becoming LTC and RIC were investigated. The risk of disease progression was estimated by comparing RIC with patients continuously followed. Over 11,285 individuals included, 3962 became LTC, and of these, 1062 were RIC. Older age, presentation with AIDS and with higher HIV-RNA were associated with a reduced risk of LTC. In contrast, lower education level, irregular job, being an immigrant and injecting-drug user were associated with an increased LTC probability. Moreover, RIC with HIV-RNA > 200 copies/mL at the re-entry had a higher risk of clinical progression, while those with HIV-RNA ≤ 200 copies/mL had a higher risk of only non-AIDS progression. Patients re-entering care after being LTC appeared to be at higher risk of clinical progression than those continuously in care. Active strategies for re-engagement in care should be promoted.

CSF AD‐like profile in SCD, pre‐MCI and MCI subjects: Application of the A/T/N classification model in a retrospective cohort from a memory clinic

AbstractBackgroundSubtle deficits not fulfilling Mild Cognitive Impairment (MCI) can be associated with pathophysiological AD biomarkers positivity and higher risk of clinical progression (Parnetti et al., 2019). Several attempts have been carried out in order to characterize neuropsychological features and Alzheimer’s disease (AD) biomarkers in pre‐MCI populations (Chipi et al., 2019). We aimed to explore, by applying the A/T/(N) classification scheme (Jack et al., 2018), the prevalence of cerebrospinal fluid (CSF) AD‐like profile (A+/T+) in a cohort of subjective cognitive decline (SCD), pre‐MCI and MCI subjects.MethodSeventy‐six consecutive patients (34 M; 42F; mean age: 68.7 years; mean education: 10.7 years), referred to our Memory Clinic from 2016 to 2019, were defined as SCD (n.11) (Jessen et al., 2014), pre‐MCI (n. 28) (Duara et al., 2011) and MCI (n.37) (Albert et al., 2011) by means of an advance neuropsychological battery and underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, total tau, phospho‐tau). According to the cut‐off used in our lab, we considered Aβ42/40 ratio &lt;0.069 as A+, phospho‐tau &gt;70 pg/mL as T+, total tau &gt; 400 pg/mL as N+.ResultNo differences were found in age, gender and education among groups. AD‐like CSF profile (A+T+) was found in 10.7% of pre‐MCI and in 54.1% of MCI (p&lt;0.001). None of SCD subjects showed AD‐like profile. Prevalence of A+ was found in 9.1% of SCD and 35.7% of pre‐MCI, compared to 73% of MCI (SCD vs MCI: p&lt;0.001; pre‐MCI vs MCI: p=0.0049).ConclusionConsistent proportion (10.7%) of subjects with subtle cognitive deficits not fulfilling MCI (pre‐MCI) in our cohort showed evidence of AD‐like profile, while none of SCD resulted A+/T+. Amyloidosis was detectable in both SCD and pre‐MCI subjects. Accordingly, pre‐MCI with evidence of AD‐like biomarkers may be considered as the earliest clinical manifestation of AD, and may represent an important target for treatment with disease‐modifying drugs.

Nutritional Status Is Associated With Clinical Progression in Alzheimer's Disease: The NUDAD Project.

In cognitively normal adults, nutritional parameters are related to cognitive decline and incidence of dementia. Studies on the role of nutrition in predementia stages subjective cognitive decline and mild cognitive impairment, and mild stages of Alzheimer's disease (AD) dementia in a clinical setting are lacking. In the absence of a curative treatment, this evidence is important for targeting nutritional factors to potentially prevent or delay further cognitive decline. Our aim is to investigate associations of nutritional parameters with clinical progression in patients ranging from those who are cognitively normal to those who have AD dementia. Longitudinal. Memory clinic, 551 patients (219 with subjective cognitive decline, 135 with mild cognitive impairment, and 197 with AD dementia), mean age 64±8years. We assessed body mass index, fat-free mass, Mini-Nutritional Assessment, and dietary intake with the Dutch Healthy Diet food frequency questionnaire and the 238-item healthy life in an urban setting (HELIUS) food frequency questionnaire at baseline. Cox proportional hazard models were used to evaluate associations of nutritional parameters with clinical progression. Additional analyses were restricted to patients who were amyloid positive. We observed clinical progression in 170 patients (31%) over 2.2±0.9years. Poorer Mini-Nutritional Assessment score [hazard ratio (95% confidence interval) 1.39 (1.18-1.64)], lower body mass index [1.15 (0.96-1.38)], lower fat-free mass [1.40 (0.93-2.10)], and a less healthy dietary pattern [1.22 (1.01-1.48)] were associated with a higher risk of clinical progression. Similar effect sizes were found in patients who were amyloid positive. Poorer nutritional status and a less healthy dietary pattern are associated with a higher risk of clinical progression. This study provides support for investigating whether improving nutritional status can alter the clinical trajectory of AD.

Inflammatory biomarkers, endogenous analgesia and gait characteristics in those with moderate medial compartment knee osteoarthritis who experience increased pain after 30 minutes of continuous walking

Purpose: Walking is recommended for those with knee osteoarthritis (OA) to improve pain; however, numerous reports of increased pain after walking exist following short durations of activity. The purpose of this study was to quantify the concurrent response of inflammatory biomarkers, endogenous analgesia and gait biomechanics to 30 minutes of physical activity across individuals with varied pain responses. The hypothesis was that those with medial compartment knee OA who self-reported an increase in pain following a 30-min walk would have a greater increase in inflammatory biomarkers, less increase in endogenous analgesia and a gait pattern consistent with a higher risk of clinical progression based on knee adduction moment (KAM) magnitude and dynamic knee flexion moment (KFM) unloading features compared to OA participants with no increase in pain and asymptomatic controls (ASYM).

Discordant amyloid-\u03b2 PET and CSF biomarkers and its clinical consequences

BackgroundIn vivo, high cerebral amyloid-β load has been associated with (i) reduced concentrations of Aβ42 in cerebrospinal fluid and (ii) increased retention using amyloid-β positron emission tomography. Although these two amyloid-β biomarkers generally show good correspondence, ~ 10–20% of cases have discordant results. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories.MethodsWe included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer’s dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ε4 status, CSF tau, and clinical and neuropsychological progression.ResultsWe found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ε4 (28%, 55%, 70%, Z = − 10.6, P < 0.001), CSF total tau (25%, 45%, 78%, Z = − 13.7, P < 0.001), and phosphorylated tau (28%, 43%, 80%, Z = − 13.7, P < 0.001) positivity. In patients without dementia, linear mixed models showed that Mini-Mental State Examination and memory composite scores did not differ between concordant-negative (β [SE] − 0.13[0.08], P = 0.09) and discordant (β 0.08[0.15], P = 0.15) patients (Pinteraction = 0.19), while these scores declined in concordant-positive (β − 0.75[0.08] patients (Pinteraction < 0.001). In patients with dementia, longitudinal cognitive scores were not affected by amyloid-β biomarker concordance or discordance. Clinical progression rates from SCD to MCI or dementia (P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive.ConclusionsDiscordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ε4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.

Preserved immune functionality and high CMV-specific T-cell responses in HIV-infected individuals with poor CD4+ T-cell immune recovery

Poor CD4+ T-cell recovery after cART has been associated with skewed T-cell maturation, inflammation and immunosenescence; however, T-cell functionality in those individuals has not been fully characterized. In the present study, we assessed T-cell function by assessing cytokine production after polyclonal, CMV and HIV stimulations of T-cells from ART-suppressed HIV-infected individuals with CD4+ T-cell counts >350 cells/μL (immunoconcordants) or <350 cells/μL (immunodiscordants). A group of HIV-uninfected individuals were also included as controls. Since CMV co-infection significantly affected T-cell maturation and polyfunctionality, only CMV+ individuals were analyzed. Despite their reduced and skewed CD4+ T-cell compartment, immunodiscordant individuals showed preserved polyclonal and HIV-specific responses. However, CMV response in immunodiscordant participants was significantly different from immunoconcordant or HIV-seronegative individuals. In immunodiscordant subjects, the magnitude of IFN-γ+ CD8+ and IL-2+ CD4+ T-cells in response to CMV was higher and differently associated with the CD4+ T-cell maturation profile., showing an increased frequency of naïve, central memory and EMRA CMV-specific CD4+ T-cells. In conclusion, CD4+ and CD8+ T-cell polyfunctionality was not reduced in immunodiscordant individuals, although heightened CMV-specific immune responses, likely related to subclinical CMV reactivations, may be contributing to the skewed T-cell maturation and the higher risk of clinical progression observed in those individuals.

PD-L1 Expression and CD8+ T-cell Infiltrate are Associated with Clinical Progression in Patients with Node-positive Prostate Cancer

Prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy are at higher risk of tumor recurrence and receive immediate androgen deprivation therapy (ADT). While approximately 30% of these patients do not experience recurrence, others experience disease recurrence despite ADT, and currently no biomarkers can accurately identify them. We analyzed tumors from 51 patients with node-positive prostate cancer using immunohistochemistry to investigate whether expression of the immune checkpoint ligand PD-L1 by tumor cells or the density of CD8+ or CD20+ cells are associated with clinical progression. Patients with at least 1% PD-L1+ tumor cells had shorter metastasis-free survival than those with PD-L1− tumors (p=0.008, log-rank test). Univariate Cox regression showed that patients with PD-L1+ tumors had almost four times the risk of experiencing distant metastases than those with PD-L1− tumors (hazard ratio 3.90). In addition, we found that PD-L1 expression was significantly associated with CD8+ T-cell density, but not with CD20+ B-cell density. While these results need to be confirmed in larger studies, they show that PD-L1 and CD8 may be used as biomarkers for node-positive patients at high risk of progression. The study also provides a rationale for selecting patients with node-positive PCa who might benefit the most from adjuvant immunotherapies. Patient summaryNone of the available biomarkers can identify node-positive prostate cancer that will recur after surgery. We found that expression of PD-L1 by tumor cells and a high density of CD8+ T cells in tumor are associated with a higher risk of clinical progression in men with node-positive prostate cancer.

The role of intravesical prostatic protrusion (IPP) in the evaluation and treatment of bladder outlet obstruction (BOO).

Intravesical prostatic protrusion (IPP) may be an underutilized modality for the assessment of bladder outlet obstruction (BOO). Pressure flow studies or urodynamics have long been the gold standard for the evaluation of lower urinary tract symptoms (LUTS) in men but are invasive, time-consuming and costly. Potentially, IPP may be a useful adjunct prior to performing urodynamics. Measurement of IPP is taken in the sagittal view, using the transabdominal ultrasound. It is the vertical height from the tip of the protrusion to the base of the prostate. This technique was previously described. We reviewed previous publications that studied the accuracy, positive predictive value and clinical use of IPP. In addition, we noted the comments regarding the challenges of using this technique. IPP has been shown to have a positive predictive value of 72% for BOO. It has been calculated to have an area under curve (AUC) value of 0.71 and 0.84 in some stuies. Clinically, it may be used to predict the outcome of a trial without catheter following acute retention of urine. Patients with higher IPP grade were noted to have a higher risk of clinical progression. Studies have also shown that men with higher IPP are poorer responders to medical treatment such as α-blockers. Compared to other modalities, the advantage of IPP in assessing BOO may be its easy applicability and non-invasive nature. Therefore, there is a consideration for a larger role of IPP in bedside assessment and management of BOO in daily practice. Neurourol. Urodynam. 35:535-537, 2016. © 2015 Wiley Periodicals, Inc.

Intravesical prostatic protrusion predicts clinical progression of benign prostatic enlargement in patients receiving medical treatment

To assess intravesical prostatic protrusion (IPP) as a novel predictor of clinical progression in patients with benign prostatic enlargement (BPE). All patients attending the outpatient clinic at our institution who were being treated for lower urinary tract symptoms (LUTS) secondary to BPE between January 1997 and December 2003 were recruited into the study. International Prostate Symptom Score (IPSS) scores, uroflowmetry parameters, post-void residual urine volume (PVR), IPP and serum prostate-specific antigen (PSA) were collected. IPP was classified into Grade 1, 2 or 3. Patients were stratified to different treatment options including watchful waiting, alpha blockers or 5-alpha reductase inhibitors. Those who developed high post-void residual urine volume (>100 mL), acute urinary retention or a deterioration of at least 4 points in IPSS score were considered to have disease progression. Using the Grade 1 IPP group as a reference, the odds ratio for clinical progression of Grade 2 and Grade 3 IPP were calculated by using multivariate analysis. A total of 259 patients with a mean age of 63 years (range 50-90 years) and mean follow-up time of 32 months were available for analysis. Fifty-two patients were found to have clinical progression. Odds ratio for progression of a Grade 2 IPP was 5.1 (95% confidence interval [CI] 1.6-16.2) and that of a Grade 3 IPP was 10.4 (95% CI 3.3-33.4). A higher IPP grade is associated with a higher risk of clinical progression in BPE. IPP is a useful non-invasive predictor for clinical progression in BPE.

Metodología diagnostica ante la recidiva bioquímica después de prostatectomía radical

Prostate cancer is one of the main health problems of the male population. Radical prostatectomy has demonstrated to have an excellent long-term cure rate. Nevertheless, globally, a 25% of the operated patients will suffer a PSA increase over 15 years of follow-up. Generally, the PSA value associated with a higher risk of clinical progression, that may be established as the cut point for biochemical recurrence is 0.4 ng/ ml. Once biochemical recurrence is diagnosed, the most important clinical data is to determine if clinical recurrence is going to be local or systemic, because it will determine treatment. Main parameters helping to differentiate between one and another are: time interval to PSA increase, PSA velocity, PSA doubling time (PSA-DT), pathologic stage and specimen's Gleason's score. The possibilities of treatment of biochemical failure after radical prostatectomy are under debate. Nevertheless, it is currently considered that patients with biochemical recurrence without radiological evidence of distant metastases are ideal candidates for local treatment with radiotherapy.