Increasing incidence of dementia in the oldest old: evidence and implications

The oldest old are the fastest growing segment of the US population but accurate estimates of the incidence of dementia in this age group have been elusive. Corrada and colleagues present data on the 5-year age-specific rates of dementia incidence in persons 90 years and older from The 90+ Study. Their findings show a continued exponential increase in dementia incidence after age 90 that mirrors the increase observed in persons aged 65 to 90, with a doubling every 5.5 years. This contrasts with previous smaller studies reporting a slowing of the increase in incidence after age 90. If confirmed, the continued increase, rather than a plateau, in the incidence of dementia in the oldest old has implications for proper healthcare planning. Strategies for prevention and treatment will require more information regarding risk factors and the etiopathogenesis of dementia in the oldest old

Paleomythologies: The Spiritual Persuasion of Evolution

A current rise in so-called “caveman” diets, books, exercise regimes and other trends demonstrates a cultural attempt to reclaim idealized prehistoric conditions for the modern human. In a rhetorical analysis of texts from this modern paleo culture, we identify what we call a “paleomyth” and illustrate how such lifestyle trends not only offer truncated understandings of evolutionary science, but more importantly how they offer a mythological narrative for paleo believers

Timing of Moderate Level Prenatal Alcohol Exposure Influences Gene Expression of Sensory Processing Behavior in Rhesus Monkeys

Sensory processing disorder, characterized by over- or under-responsivity to non-noxious environmental stimuli, is a common but poorly understood disorder. We examined the role of prenatal alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and striatal dopamine (DA) function on behavioral measures of sensory responsivity to repeated non-noxious sensory stimuli in macaque monkeys. Results indicated that early gestation alcohol exposure induced behavioral under-responsivity to environmental stimuli in monkeys carrying the short (s) rh5-HTTLPR allele compared to both early-exposed monkeys homozygous for the long (l) allele and monkeys from middle-to-late exposed pregnancies and controls, regardless of genotype. Moreover, prenatal timing of alcohol exposure altered the relationship between sensory scores and DA D2R availability. In early-exposed monkeys, a positive relationship was shown between sensory scores and DA D2R availability, with low or blunted DA function associated with under-responsive sensory function. The opposite pattern was found for the middle-to-late gestation alcohol-exposed group. These findings raise questions about how the timing of prenatal perturbation and genotype contributes to effects on neural processing and possibly alters neural connections

Ex vivo MRI facilitates localization of cerebral microbleeds of different ages during neuropathology assessment

Cerebral microbleeds (CMBs) identified by in vivo magnetic resonance imaging (MRI) of brains of older persons may have clinical relevance due to their association with cognitive impairment and other adverse neurologic outcomes, but are often not detected in routine neuropathology evaluations. In this study, the utility of ex vivo MRI in the neuropathological identification, localization, and frequency of CMBs was investigated. The study included 3 community dwelling elders with Alzheimer’s dementia, and mild to severe small vessel disease (SVD). Ex vivo MRI was performed on the fixed hemisphere to identify CMBs, blinded to the neuropathology diagnoses. The hemibrains were then sliced at 1 cm intervals and 2, 1 or 0 microhemorrhages (MH) were detected on the cut surfaces of brain slabs using the routine neuropathology protocol. Ex vivo imaging detected 15, 14 and 9 possible CMBs in cases 1, 2 and 3, respectively. To obtain histological confirmation of the CMBs detected by ex vivo MRI, the 1 cm brain slabs were dissected further and MHs or areas corresponding to the CMBs detected by ex vivo MRI were blocked and serially sectioned at 6 µm intervals. Macroscopic examination followed by microscopy post ex vivo MRI resulted in detection of 35 MHs and therefore, about 12 times as many MHs were detected compared to routine neuropathology assessment without ex vivo MRI. While microscopy identified previously unrecognized chronic MHs, it also showed that MHs were acute or subacute and therefore may represent perimortem events. Ex vivo MRI detected CMBs not otherwise identified on routine neuropathological examination of brains of older persons and histologic evaluation of the CMBs is necessary to determine the age and clinical relevance of each hemorrhage

Polygenic risk associated with Alzheimer’s disease and other traits influences genes involved in T cell signaling and activation

IntroductionT cells, known for their ability to respond to an enormous variety of pathogens and other insults, are increasingly recognized as important mediators of pathology in neurodegeneration and other diseases. T cell gene expression phenotypes can be regulated by disease-associated genetic variants. Many complex diseases are better represented by polygenic risk than by individual variants.MethodsWe first compute a polygenic risk score (PRS) for Alzheimer’s disease (AD) using genomic sequencing data from a cohort of Alzheimer’s disease (AD) patients and age-matched controls, and validate the AD PRS against clinical metrics in our cohort. We then calculate the PRS for several autoimmune disease, neurological disorder, and immune function traits, and correlate these PRSs with T cell gene expression data from our cohort. We compare PRS-associated genes across traits and four T cell subtypes.ResultsSeveral genes and biological pathways associated with the PRS for these traits relate to key T cell functions. The PRS-associated gene signature generally correlates positively for traits within a particular category (autoimmune disease, neurological disease, immune function) with the exception of stroke. The trait-associated gene expression signature for autoimmune disease traits was polarized towards CD4+ T cell subtypes.DiscussionOur findings show that polygenic risk for complex disease and immune function traits can have varying effects on T cell gene expression trends. Several PRS-associated genes are potential candidates for therapeutic modulation in T cells, and could be tested in in vitro applications using cells from patients bearing high or low polygenic risk for AD or other conditions

Multiple Gene Variants Linked to Alzheimer\u27s-Type Clinical Dementia via GWAS are Also Associated with Non-Alzheimer\u27s Neuropathologic Entities

The classic pathologic hallmarks of Alzheimer’s disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer’s disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as ADrelated were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P \u3c 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies

Hyperbaric oxygen treatment in autism spectrum disorders

Traditionally, hyperbaric oxygen treatment (HBOT) is indicated in several clinical disorders include decompression sickness, healing of problem wounds and arterial gas embolism. However, some investigators have used HBOT to treat individuals with autism spectrum disorders (ASD). A number of individuals with ASD possess certain physiological abnormalities that HBOT might ameliorate, including cerebral hypoperfusion, inflammation, mitochondrial dysfunction and oxidative stress. Studies of children with ASD have found positive changes in physiology and/or behavior from HBOT. For example, several studies have reported that HBOT improved cerebral perfusion, decreased markers of inflammation and did not worsen oxidative stress markers in children with ASD. Most studies of HBOT in children with ASD examined changes in behaviors and reported improvements in several behavioral domains although many of these studies were not controlled. Although the two trials employing a control group reported conflicting results, a recent systematic review noted several important distinctions between these trials. In the reviewed studies, HBOT had minimal adverse effects and was well tolerated. Studies which used a higher frequency of HBOT sessions (e.g., 10 sessions per week as opposed to 5 sessions per week) generally reported more significant improvements. Many of the studies had limitations which may have contributed to inconsistent findings across studies, including the use of many different standardized and non-standardized instruments, making it difficult to directly compare the results of studies or to know if there are specific areas of behavior in which HBOT is most effective. The variability in results between studies could also have been due to certain subgroups of children with ASD responding differently to HBOT. Most of the reviewed studies relied on changes in behavioral measurements, which may lag behind physiological changes. Additional studies enrolling children with ASD who have certain physiological abnormalities (such as inflammation, cerebral hypoperfusion, and mitochondrial dysfunction) and which measure changes in these physiological parameters would be helpful in further defining the effects of HBOT in ASD