Porphyria cutanea tarda in Scotland: underlying associations and treatment approaches.

BACKGROUND: Despite its rarity, porphyria cutanea tarda (PCT) is globally recognized as the most common form of cutaneous porphyria. This study aims to review the underlying associations and treatment of PCT in Scotland. METHODS: We retrospectively reviewed data on 27 patients diagnosed with PCT between 1987 and 2022 at the Scottish Cutaneous Porphyria Service. RESULTS: Males slightly predominated (66.7%). The mean ± standard deviation (SD) age at diagnosis was 55.6 ± 12.5 years. Common associated factors were heavy alcohol intake (88.5%), genetic hemochromatosis (72%), smoking (45.5%), and hepatitis C virus infection (16%). Most had multiple associated factors (70.4%). Patients with genetic hemochromatosis with the C282Y genotype exhibited higher median transferrin saturation (69.5 vs. 35, P = 0.004) and ferritin levels (observed in males only) (1175 vs. 339; P = 0.014) than those with the H636D genotype. Most (52%) received combination therapy of venesection and antimalarials, followed by venesection monotherapy (32%) and antimalarial monotherapy (16%). Overall, 95.2% achieved biochemical improvement. Median time to improvement was 7, 5, and 9 months with venesection, antimalarial, and combined treatments, respectively (P = 0.173). Biochemical remission was achieved in 50% of patients. Remission occurred in 2/4 of patients with antimalarial monotherapy (median time 19 months) and 9/13 patients with combined treatment (median time 26 months). Biochemical relapse was found in three patients, all of whom received combination therapy. CONCLUSION: Excess alcohol intake and genetic hemochromatosis were the most common underlying associations with PCT in our Scottish cohort. Treatment for PCT should be individualized, and long-term follow-up is needed to monitor for disease relapse.

Associations of brain morphology with cortical proteins of cognitive resilience.

In a recent proteome-wide study, we identified several candidate proteins for drug discovery whose cortical abundance was associated with cognitive resilience to late-life brain pathologies. This study examines the extent to which these proteins are associated with the brain structures of cognitive resilience in decedents from the Religious Orders Study and Memory and Aging Project. Six proteins were associated with brain morphometric characteristics related to higher resilience (i.e., larger anterior and medial temporal lobe volumes), and five were associated with morphometric characteristics related to lower resilience (i.e., enlarged ventricles). Two synaptic proteins, RPH3A and CPLX1, remained inversely associated with the lower resilience signature, after further controlling for 10 neuropathologic indices. These findings suggest preserved brain structure in periventricular regions as a potential mechanism by which RPH3A and CPLX1 are associated with cognitive resilience. Further work is needed to elucidate other mechanisms by which targeting these proteins can circumvent the effects of pathology on individuals at risk for cognitive decline.

Volumetric brain correlates of gait associated with cognitive decline in community-dwelling older adults.

Objective: To determine the extent to which the regional brain volumes associated with slow gait speed can inform subsequent cognitive decline in older adults from the Rush Memory and Aging Project. Approach: We utilized deformation-based morphometry (DBM) in a whole-brain exploratory approach to identify the regional brain volumes associated with gait speed assessed over a short distance during an in-home assessment. We created deformation scores to summarize the gait-associated regions and entered the scores into a series of longitudinal mixed effects models to determine the extent to which deformation predicted change in cognition over time, controlling for associations between gait and cognition. Results: In 438 older adults (81 ± 7; 76% female), DBM revealed that slower gait speed was associated with smaller volumes across frontal white matter, temporal grey matter, and subcortical areas and larger volumes in the ventricles during the same testing cycle. When a subset was followed over multiple (5 ± 2) years, slower gait speed was also associated with annual declines in global cognition, executive functioning, and memory abilities. Several of the gait-related brain structures were associated with these declines in cognition; however, larger ventricles and smaller medial temporal lobe volumes proved most robust and attenuated the association between slow gait and cognitive decline. Conclusion: Regional brain volumes in the ventricles and temporal lobe associated with both slow gait speed and faster cognitive decline have potential to improve risk stratification for cognitive decline in older adults.

Multi-region brain transcriptomes uncover two subtypes of aging individuals with differences in Alzheimer risk and the impact of APOEε4.

The heterogeneity of the older population suggests the existence of subsets of individuals which share certain brain molecular features and respond differently to risk factors for Alzheimer's disease, but this population structure remains poorly defined. Here, we performed an unsupervised clustering of individuals with multi-region brain transcriptomes to assess whether a broader approach, simultaneously considering data from multiple regions involved in cognition would uncover such subsets. We implemented a canonical correlation-based analysis in a Discovery cohort of 459 participants from two longitudinal studies of cognitive aging that have RNA sequence profiles in three brain regions. 690 additional participants that have data in only one or two of these regions were used in the Replication effort. These clustering analyses identified two meta-clusters, MC-1 and MC-2. The two sets of participants differ primarily in their trajectories of cognitive decline, with MC-2 having a delay of 3 years to the median age of incident dementia. This is due, in part, to a greater impact of tau pathology on neuronal chromatin architecture and to broader brain changes including greater loss of white matter integrity in MC-1. Further evidence of biological differences includes a significantly larger impact of APOEε4 risk on cognitive decline in MC-1. These findings suggest that our proposed population structure captures an aspect of the more distributed molecular state of the aging brain that either enhances the effect of risk factors in MC-1 or of protective effects in MC-2. These observations may inform the design of therapeutic development efforts and of trials as both become increasingly more targeted molecularly. One Sentence Summary: There are two types of aging brains, with one being more vulnerable to APOEε4 and subsequent neuronal dysfunction and cognitive loss.

Frequency and Underlying Pathology of Pure Vascular Cognitive Impairment.

Importance: It is not clear how common pure vascular cognitive impairment (VCI) is in the absence of Alzheimer disease (AD) and/or other neurodegenerative pathologies. Objective: To identify participants without AD and other neurodegenerative pathologies and determine the extent to which cerebrovascular disease pathologies were associated with cognitive impairment. Design, Setting, and Participants: This clinical pathological study included participants from 2 ongoing community-based cohorts that began enrollment in 1994 and 1997. Prior to death, participants were observed for a mean (SD) of 8.4 (5.3) years with annual assessments. From 2096 participants who died, 1799 (85.8%) underwent autopsy and 1767 had complete postmortem pathological examination data at the time of data analyses. To identify participants without neurodegenerative pathologies, we categorized them in 3 subgroups. A vascular subgroup was composed of participants without significant levels of neurodegenerative brain pathologies. A neurodegenerative subgroup was composed of participants without significant levels of cerebrovascular disease pathologies. A mixed subgroup was composed of the rest of the participants. Data were analyzed from May 2021 to July 2022. Exposures: Brain pathology indices obtained by postmortem pathological assessments. Main Outcomes and Measures: The primary outcome was cognitive impairment defined by presence of mild cognitive impairment or dementia. The secondary outcome was cognition assessed by 19 neuropsychological tests. Results: Of 1767 included participants, 1189 (67.3%) were women, and the mean (SD) age at death was 89.4 (6.6) years. In the vascular subgroup (n = 369), cognitive impairment was present in 156 participants (42.3%) and was associated with cerebrovascular disease pathologies (macroinfarcts: odds ratio [OR], 2.05; 95% CI, 1.49-2.82; P < .001; arteriolosclerosis in basal ganglia: OR, 1.35; 95% CI, 1.04-1.76; P = .03) but not AD or other neurodegenerative pathologies, an indication of pure VCI. In mixed-effects models including all the pathologies, only macroinfarcts were associated with a faster cognitive decline rate (estimate, -0.019; SE, 0.005; P < .001) in the vascular subgroup. Further analyses identified macroinfarcts in the frontal white matter to be associated with faster cognitive decline rate when macroinfarcts of cortical and subcortical brain regions were examined in a single model. Conclusions and Relevance: In this study, pure VCI was not rare. Macroinfarcts, specifically in frontal white matter, were the main cerebrovascular disease pathologies associated with cognitive decline in pure VCI.

Insights into proton pump inhibitor-induced photosensitivity: An observational study in a tertiary photobiology service.

BACKGROUND: Proton pump inhibitors (PPIs) are extensively prescribed but may cause photosensitivity and drug-induced lupus erythematosus (DILE), which can be overlooked as the drug may have been taken for years prior to presentation. METHODS: We reviewed the clinical and investigation findings of patients diagnosed with PPI-induced photosensitivity, diagnosed through the Scottish Photobiology Service. RESULTS: We report 11 patients with median age of onset 61-years and mean duration of PPI ingestion of 5-years [DILE (n = 6), phototoxicity (n = 3) and drug-induced solar urticaria through a lupus mechanism (n = 2)]. Five had Anti-Ro antibodies (three also ANA positive). Predominantly UVA and visible light photosensitivity was observed on phototesting. DISCUSSION: PPIs are a reversible cause of photosensitivity and DILE. Time to onset from drug initiation to symptoms can be prolonged, so clinicians should have a high index of suspicion in those taking PPIs. Most are diagnosed through clinical assessment and lupus serology, with phototesting indicated if there is diagnostic uncertainty.

Dividing attention during the Timed Up and Go enhances associations of several subtask performances with MCI and cognition.

We tested the hypothesis that dividing attention would strengthen the ability to detect mild cognitive impairment (MCI) and specific cognitive abilities from Timed Up and Go (TUG) performance in the community setting. While wearing a belt-worn sensor, 757 dementia-free older adults completed TUG during two conditions, with and without a concurrent verbal serial subtraction task. We segmented TUG into its four subtasks (i.e., walking, turning, and two postural transitions), and extracted 18 measures that were summarized into nine validated sensor metrics. Participants also underwent a detailed cognitive assessment during the same visit. We then employed a series of regression models to determine the combinations of subtask sensor metrics most strongly associated with MCI and specific cognitive abilities for each condition. We also compared subtask performances with and without dividing attention to determine whether the costs of divided attention were associated with cognition. While slower TUG walking and turning were associated with higher odds of MCI under normal conditions, these and other subtask associations became more strongly linked to MCI when TUG was performed under divided attention. Walking and turns were also most strongly associated with executive function and attention, particularly under divided attention. These differential associations with cognition were mirrored by performance costs. However, since several TUG subtasks were more strongly associated with MCI and cognitive abilities when performed under divided attention, future work is needed to determine how instrumented dual-task TUG testing can more accurately estimate risk for late-life cognitive impairment in older adults.

Inferring protein expression changes from mRNA in Alzheimer's dementia using deep neural networks.

Identifying the molecular systems and proteins that modify the progression of Alzheimer's disease and related dementias (ADRD) is central to drug target selection. However, discordance between mRNA and protein abundance, and the scarcity of proteomic data, has limited our ability to advance candidate targets that are mainly based on gene expression. Therefore, by using a deep neural network that predicts protein abundance from mRNA expression, here we attempt to track the early protein drivers of ADRD. Specifically, by applying the clei2block deep learning model to 1192 brain RNA-seq samples, we identify protein modules and disease-associated expression changes that were not directly observed at the mRNA level. Moreover, pseudo-temporal trajectory inference based on the predicted proteome became more closely correlated with cognitive decline and hippocampal atrophy compared to RNA-based trajectories. This suggests that the predicted changes in protein expression could provide a better molecular representation of ADRD progression. Furthermore, overlaying clinical traits on protein pseudotime trajectory identifies protein modules altered before cognitive impairment. These results demonstrate how our method can be used to identify potential early protein drivers and possible drug targets for treating and/or preventing ADRD.

Phototherapy for atopic eczema.

BACKGROUND: Atopic eczema (AE), also known as atopic dermatitis, is a chronic inflammatory skin condition that causes significant burden. Phototherapy is sometimes used to treat AE when topical treatments, such as corticosteroids, are insufficient or poorly tolerated. OBJECTIVES: To assess the effects of phototherapy for treating AE. SEARCH METHODS: We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and ClinicalTrials.gov to January 2021. SELECTION CRITERIA: We included randomised controlled trials in adults or children with any subtype or severity of clinically diagnosed AE. Eligible comparisons were any type of phototherapy versus other forms of phototherapy or any other treatment, including placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. For key findings, we used RoB 2.0 to assess bias, and GRADE to assess certainty of the evidence. Primary outcomes were physician-assessed signs and patient-reported symptoms. Secondary outcomes were Investigator Global Assessment (IGA), health-related quality of life (HRQoL), safety (measured as withdrawals due to adverse events), and long-term control. MAIN RESULTS: We included 32 trials with 1219 randomised participants, aged 5 to 83 years (mean: 28 years), with an equal number of males and females. Participants were recruited mainly from secondary care dermatology clinics, and study duration was, on average, 13 weeks (range: 10 days to one year). We assessed risk of bias for all key outcomes as having some concerns or high risk, due to missing data, inappropriate analysis, or insufficient information to assess selective reporting. Assessed interventions included: narrowband ultraviolet B (NB-UVB; 13 trials), ultraviolet A1 (UVA1; 6 trials), broadband ultraviolet B (BB-UVB; 5 trials), ultraviolet AB (UVAB; 2 trials), psoralen plus ultraviolet A (PUVA; 2 trials), ultraviolet A (UVA; 1 trial), unspecified ultraviolet B (UVB; 1 trial), full spectrum light (1 trial), Saalmann selective ultraviolet phototherapy (SUP) cabin (1 trial), saltwater bath plus UVB (balneophototherapy; 1 trial), and excimer laser (1 trial). Comparators included placebo, no treatment, another phototherapy, topical treatment, or alternative doses of the same treatment. Results for key comparisons are summarised (for scales, lower scores are better): NB-UVB versus placebo/no treatment There may be a larger reduction in physician-assessed signs with NB-UVB compared to placebo after 12 weeks of treatment (mean difference (MD) -9.4, 95% confidence interval (CI) -3.62 to -15.18; 1 trial, 41 participants; scale: 0 to 90). Two trials reported little difference between NB-UVB and no treatment (37 participants, four to six weeks of treatment); another reported improved signs with NB-UVB versus no treatment (11 participants, nine weeks of treatment). NB-UVB may increase the number of people reporting reduced itch after 12 weeks of treatment compared to placebo (risk ratio (RR) 1.72, 95% CI 1.10 to 2.69; 1 trial, 40 participants). Another trial reported very little difference in itch severity with NB-UVB (25 participants, four weeks of treatment). The number of participants with moderate to greater global improvement may be higher with NB-UVB than placebo after 12 weeks of treatment (RR 2.81, 95% CI 1.10 to 7.17; 1 trial, 41 participants). NB-UVB may not affect rates of withdrawal due to adverse events. No withdrawals were reported in one trial of NB-UVB versus placebo (18 participants, nine weeks of treatment). In two trials of NB-UVB versus no treatment, each reported one withdrawal per group (71 participants, 8 to 12 weeks of treatment). We judged that all reported outcomes were supported with low-certainty evidence, due to risk of bias and imprecision. No trials reported HRQoL. NB-UVB versus UVA1 We judged the evidence for NB-UVB compared to UVA1 to be very low certainty for all outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician-assessed signs after six weeks (MD -2.00, 95% CI -8.41 to 4.41; 1 trial, 46 participants; scale: 0 to 108), or patient-reported itch after six weeks (MD 0.3, 95% CI -1.07 to 1.67; 1 trial, 46 participants; scale: 0 to 10). Two split-body trials (20 participants, 40 sides) also measured these outcomes, using different scales at seven to eight weeks; they reported lower scores with NB-UVB. One trial reported HRQoL at six weeks (MD 2.9, 95% CI -9.57 to 15.37; 1 trial, 46 participants; scale: 30 to 150). One split-body trial reported no withdrawals due to adverse events over 12 weeks (13 participants). No trials reported IGA. NB-UVB versus PUVA We judged the evidence for NB-UVB compared to PUVA (8-methoxypsoralen in bath plus UVA) to be very low certainty for all reported outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician-assessed signs after six weeks (64.1% reduction with NB-UVB versus 65.7% reduction with PUVA; 1 trial, 10 participants, 20 sides). There was no evidence of a difference in marked improvement or complete remission after six weeks (odds ratio (OR) 1.00, 95% CI 0.13 to 7.89; 1 trial, 9/10 participants with both treatments). One split-body trial reported no withdrawals due to adverse events in 10 participants over six weeks. The trials did not report patient-reported symptoms or HRQoL. UVA1 versus PUVA There was very low-certainty evidence, due to serious risk of bias and imprecision, that PUVA (oral 5-methoxypsoralen plus UVA) reduced physician-assessed signs more than UVA1 after three weeks (MD 11.3, 95% CI -0.21 to 22.81; 1 trial, 40 participants; scale: 0 to 103). The trial did not report patient-reported symptoms, IGA, HRQoL, or withdrawals due to adverse events. There were no eligible trials for the key comparisons of UVA1 or PUVA compared with no treatment. Adverse events Reported adverse events included low rates of phototoxic reaction, severe irritation, UV burn, bacterial superinfection, disease exacerbation, and eczema herpeticum. AUTHORS' CONCLUSIONS: Compared to placebo or no treatment, NB-UVB may improve physician-rated signs, patient-reported symptoms, and IGA after 12 weeks, without a difference in withdrawal due to adverse events. Evidence for UVA1 compared to NB-UVB or PUVA, and NB-UVB compared to PUVA was very low certainty. More information is needed on the safety and effectiveness of all aspects of phototherapy for treating AE.

Physical activity, brain tissue microstructure, and cognition in older adults.

OBJECTIVE: To test whether postmortem MRI captures brain tissue characteristics that mediate the association between physical activity and cognition in older adults. METHODS: Participants (N = 318) were older adults from the Rush Memory and Aging Project who wore a device to quantify physical activity and also underwent detailed cognitive and motor testing. Following death, cerebral hemispheres underwent MRI to quantify the transverse relaxation rate R2, a metric related to tissue microstructure. For analyses, we reduced the dimensionality of the R2 maps from approximately 500,000 voxels to 30 components using spatial independent component analysis (ICA). Via path analysis, we examined whether these R2 components attenuated the association between physical activity and cognition, controlling for motor abilities and indices of common brain pathologies. RESULTS: Two of the 30 R2 components were associated with both total daily physical activity and global cognition assessed proximate to death. We visualized these components by highlighting the clusters of voxels whose R2 values contributed most strongly to each. One of these spatial signatures spanned periventricular white matter and hippocampus, while the other encompassed white matter of the occipital lobe. These two R2 components partially mediated the association between physical activity and cognition, accounting for 12.7% of the relationship (p = .01). This mediation remained evident after controlling for motor abilities and neurodegenerative and vascular brain pathologies. CONCLUSION: The association between physically activity and cognition in older adults is partially accounted for by MRI-based signatures of brain tissue microstructure. Further studies are needed to elucidate the molecular mechanisms underlying this pathway.

The "cognitive clock": A novel indicator of brain health.

INTRODUCTION: We identified a "cognitive clock," a novel indicator of brain health that provides person-specific estimates of cognitive age, and tested the hypothesis that cognitive age is a better predictor of brain health than chronological age in two independent datasets. METHODS: The initial analyses were based on 1057 participants from the Rush Memory and Aging Project and the Religious Orders Study who began without impairment and underwent cognitive assessments up to 24 years. A shape invariant model characterized the latent pattern of cognitive decline, conceptualized here as the "cognitive clock," and yielded person-specific estimates of cognitive age. Survival analyses examined cognitive versus chronological age for predicting Alzheimer's disease dementia, mild cognitive impairment and mortality, and regression analyses examined associations of cognitive versus chronological age with neuropathology and brain atrophy. Finally, we applied the cognitive clock to an independent validation sample of 2592 participants from the Chicago Health and Aging Project, a biracial population-based study, to confirm the predictive utility of cognitive age. RESULTS: The "cognitive clock" showed that cognition remained stable until a cognitive age of about 80, then declined moderately until 90, then declined precipitously. In the initial dataset, cognitive age was a better predictor of dementia, mild cognitive impairment and mortality than chronological age, and was more strongly associated with neuropathology and brain atrophy. Application of the cognitive clock to the independent validation sample provided further support for the utility of cognitive age as a strong prognostic indicator of adverse outcomes. DISCUSSION: Cognitive age is a robust prognostic indicator of adverse health outcomes and may serve as a useful biomarker in aging research.

To what degree is late life cognitive decline driven by age-related neuropathologies?

The ageing brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease, infarcts, and Lewy bodies, account for ∼40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline [e.g. limbic predominant age-related TDP-43 encephalopathy (LATE-NC), hippocampal sclerosis, other cerebrovascular conditions]. We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. Deceased participants (n = 1164) from two longitudinal clinical-pathological studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathological examinations provided 11 pathological indices, including markers of Alzheimer's disease, non- Alzheimer's disease neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathological indices with global cognitive decline, and random change point models examined the relation of the pathological indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, P < 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, P < 0.001). When considered separately, 10 of 11 pathological indices were associated with faster decline and accounted for between 2% and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathological indices together accounted for 43% of the variation in decline; Alzheimer's disease-related indices accounted for 30-36% of the variation, non-Alzheimer's disease neurodegenerative indices 4-10%, and cerebrovascular indices 3-8%. Finally, the 11 pathological indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive ageing and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.

Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity.

INTRODUCTION: Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS). METHODS: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS. RESULTS: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity. CONCLUSION: Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.