Street Pharmacology: Toxico-Dermatology of Injection Drug Use.

Street medicine is a point-of-care, mobile approach that services the needs of unhoused individuals who are otherwise unable to access medical care in traditional settings. The prevalence of injection drug use combines with the pipeline of illicit substances, to produce a constellation of severe, potentially life-threatening dermatological disorders unique to this population. This review applies principles of clinical pharmacology to clarify the mechanisms underlying the dermatological toxicity of xylazine, desomorphine, and 3,4-methylenedioxymethamphetamine (MDMA).

Biomarkers.

Background: Inexpensive, non-invasive tests may improve the identification of persons at increased risk for cognitive decline and dementia. We compared impairment in odor identification and global cognition with neuro-imaging biomarkers to predict cognitive decline and dementia in the population-based Mayo Clinic Study of Aging (MCSA).

Method: At the 2008 assessment, 647 participants who were ≥ 55 years old with at least one follow-up had the following procedures: modified Blessed Information-Memory-Concentration Test (BIMCT), 12-item Brief Smell Identification Test (BSIT), brain magnetic resonance imaging (MRI), and Positron Emission Tomography (PET) amyloid imaging with 11C-Pittsburgh compound B (11C-PiB).

Biomarkers.

Background: In prior work we identified cortical resilience proteins associated with the linear trajectories of cognitive decline independent of the effects of neuropathology. Some of these proteins were associated with slower and some with faster cognitive decline. We tested the hypothesis that the temporal onset and duration of effects of cortical resilience proteins associated with cognitive trajectories may vary in aging adults.

Biomarkers.

Background: Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and other neurodegenerative diseases (NDD) develop over an extended preclinical period, sharing common risk factors and underlying pathophysiological mechanisms. Plasma proteins, including Amyloid-beta peptides (Aβ) and Tau isoforms, facilitate differential diagnosis of NDD in their earliest stages, allowing for timely delivery of targeted interventions. Blood-based biomarkers may also serve as a reliable means of monitoring disease progression and evaluating the effectiveness of individualized interventions across the spectrum of disease.

Biomarkers.

Background: Alzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early-mid 50s) and in those with autosomal dominant mutations (ADAD, 40-50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD.

Biomarkers.

Background: Motoric Cognitive Risk (MCR) syndrome is a predementia syndrome characterized by slow gait and subjective cognitive concerns. Individuals with MCR are at high risk of transitioning to both Alzheimer's disease (AD) and vascular dementia. With chronological age, the incidence of MCR increases and MCR cases exhibit a higher prevalence of age-associated diseases.

Biomarkers.

Background: The hippocampus and its subfields in the human brain play a pivotal role in forming new memories and spatial navigation. The automated assessment of the hippocampus and its subfields are useful tools for the early diagnosis of Alzheimer's disease and other neurodegenerative diseases such as primary age-related tauopathy, Lewy body dementia, limbic-predominant age-related TDP-43 encephalopathy (LATE), and frontotemporal lobar Dementia. Postmortem brain magnetic resonance imaging plays a crucial role in neuroscience and clinical research, providing valuable insights into the structural and pathological features of the brain after death.

Biomarkers.

Background: Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Its underlying mechanisms remain elusive and specific mechanism-based drugs are lacking.

Method: We integrated more than 2,800 CSF and 4,600 plasma pQTL, derived from the largest proteomic studies so far (SOMAscan 7k and 4k; in up to 35,559 individuals), and the two most prevalent MRI-markers of cSVD (MRI-cSVD, white matter hyperintensities and perivascular spaces burden; in up to 48,454 individuals) in a Mendelian Randomization (MR) framework to identify causal and druggable targets for cSVD.

Biomarkers.

Background: Cardiovascular disease and dementia often co-exist at advanced stages. Yet, midlife longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health are scarce. We aimed to determine the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis and cardiovascular risk factors in middle-aged asymptomatic individuals.

Biomarkers.

Background: Cognitive impairment is one of the most frequently reported post-acute sequelae of COVID-19, yet the pathophysiology underpinning this symptom remains unknown. We aimed to explore the correlation of blood markers of inflammation, BBB disruption and neurodegeneration with MRI volume measurements in COVID-19 patients with and without cognitive impairment, and among patients with no prior history of COVID-19.

Method: We conducted a prospective study of COVID-19 patients (COV+; laboratory verified SARS-CoV-2 infection) and non-COVID-19 controls (COV-; no history of SARS-CoV-2 infection and negative SARS-CoV-2 nucleocapsid antibody).

Biomarkers.

Background: By age 40 years, adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology and progress to dementia in their 60s. Despite minimal systemic vascular risk factors, individuals with DS have MRI evidence of cerebrovascular injury that progresses with AD severity, suggesting an intrinsic vascular component to DS-AD that may interact with neuroinflammatory processes to promote tau pathology and cognitive decline. In the current study we examined whether cerebrovascular disease (CVD) burden and inflammation/astrocytosis independently and interactively were associated with incident diagnosis among adults with DS.

Criteria for identifying and evaluating locations that could potentially host the Cosmic Explorer observatories.

Cosmic Explorer is a next-generation ground-based gravitational-wave observatory that is being designed in the 2020s and is envisioned to begin operations in the 2030s together with the Einstein Telescope in Europe. The Cosmic Explorer concept currently consists of two widely separated L-shaped observatories in the United States, one with 40 km-long arms and the other with 20 km-long arms. This order of magnitude increase in scale with respect to the LIGO-Virgo-KAGRA observatories will, together with technological improvements, deliver an order of magnitude greater astronomical reach, allowing access to gravitational waves from remnants of the first stars and opening a wide discovery aperture to the novel and unknown.

Biomarkers.

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. To address this, Accelerating Medicines Partnership in AD (AMP-AD) aimed to promote inclusivity in multi-omics AD research, to unravel unique molecular signatures and pathways. The study aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial groups.

Biomarkers.

Background: Cerebral amyloid angiopathy (CAA) has been recognized as one of the morphologic hallmarks of Alzheimer disease (AD). The development of new AD drugs has brought unforeseen challenges that manifest as amyloid-related imaging abnormalities (ARIA) appearing as vasogenic edema/effusion (ARIA-E) and cerebral microhemorrhage/hemosiderosis (ARIA-H). The prominence of CAA pathology in aged squirrel monkeys (SQMs), a New World non-human primate model, underlines the importance of advancing this unique species for use in AD and dementia research.

Biomarkers.

Background: Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer's disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, around the same time as amyloid and tau, but the regional rates of accumulation within individuals are unknown.

Method: Adults with DS from the multisite Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n=78; age=50±6; 40% women) have two timepoints of T2 FLAIR MRI (1.

Biomarkers.

Background: Diffusion weighted imaging (DWI) of brain white matter is better at predicting future cognitive decline and medial temporal lobe atrophy than cerebrospinal fluid biomarkers in subjective cognitive decline (SCD). However, few studies have investigated gray matter DWI in SCD, despite the importance of regional gray matter changes as a biomarker for Alzheimer's Disease and related dementias.

Method: 316 cognitively normal participants from Cam-CAN (123 SCD) older than 55 were included in the analysis.

Biomarkers.

Background: High glycemic levels, indexed by hemoglobin A1c (HbA1c), heighten risk for Alzheimer's Disease and Related Dementias (ADRD). Previous studies suggest that high HbA1c and low socioeconomic status (SES) may be associated with MRI markers of ADRD risk, including lower cortical thickness and greater white matter hyperintensities (WMH). The weathering hypothesis suggests that the stress of low SES accelerates and exacerbates physiological deterioration, leading to worsening health outcomes.

Biomarkers.

Background: Plasma glial fibrillary acidic protein (GFAP) is associated with amyloid-β (Aβ) and tau, but their causal relationships remain unclear. We used Mendelian randomization (MR; using genetic causal anchors to avoid reverse causation) to clarify the causal relationship between plasma/brain GFAP, Aβ, and tau.

Methods: Study participants are from two independent datasets: the Harvard Aging Brain Study (HABS) and the Religious Orders Study/the Rush Memory and Aging Project (ROSMAP) (Table 1).

Biomarkers.

Background: Widely used neuropsychological test instruments are notoriously biased across the demographics of age, sex/gender, education, language and culture. This includes verbal memory tests that elicit speech such as the paragraph recall or list-learning memory tests. Language tests are similarly biased, including the Boston Diagnostic Aphasia Examination Cookie Theft Test (CTT) that has been used to elicit both written and spoken responses for decades.

Biomarkers.

Background: The unique lesion of chronic traumatic encephalopathy (CTE) is the perivascular deposition of hyperphosphorylated tau at the depth of the cortical sulci. The distribution and molecular composition of p-tau is distinct from Alzheimer's disease (AD), but differential diagnostic challenges remain. Understanding disease differences in regional density of p-tau will inform differential diagnosis and interpretation of in vivo biomarkers.

Biomarkers.

Background: Early detection of dementia and cognitive impairment is recommended for persons 65 years and older during wellness primary care visits. The importance of early detection has increased with the availability of new treatments for early Alzheimer's disease (AD). However, there is no clear approach for early detection in primary care.

Biomarkers.

Background: Moderate alcohol use may be associated with brain and cognitive benefits compared to heavy alcohol use. However, results have varied. We hypothesized that the relationship between alcohol use and cognition is mediated by neurodegenerative and cerebrovascular measures in a diverse middle-aged sample of non-alcohol dependent community-dwelling adults in Northern Manhattan.

Biomarkers.

Background: Identifying individuals' levels of tau PET pathology could prove to be beneficial in clinical settings, given that emerging therapies aimed reducing Aβ seem to be most effective in these individuals. Here, we present the cases of four patients who visited the memory clinic at the University of Pittsburgh Medical Center between June and December 2023 and underwent both Aβ and tau-PET scans.

Method: These individuals had standard clinical and cognitive outcomes, typical blood tests order in patients with memory impairment, MRI, and, as part of the HEAD study, PET PIB Aβ and two tau PET tracers (MK6240 and Flortaucipir).

Biomarkers.

Background: Digital neuropsychological assessment easily captures behavior previously not obtainable by traditional pencil-and-paper tests. Verbal serial list learning tests are commonly used to assess for putative neurogenerative syndromes. Recognition test performance is often expressed compiling simple 'yes/ no' responses, but fail to assess process metrics such as the latency to respond to individual recognition test items.

Biomarkers.

Background: Neuroinflammatory processes, assessed by cytokines such as interleukins, are implicated in vascular disease and amyloid-β (Aβ) burden. White matter hyperintensities (WMH), markers of small vessel cerebrovascular disease, are associated with memory impairment and Alzheimer's disease (AD)-related cortical atrophy. Here, we used structural equation modeling (SEM) to test whether inflammatory markers are related to markers of AD pathology and neurodegeneration through their impact on WMH.