Mechanisms of anesthesia-induced loss of consciousness remain poorly understood. Resting-state functional magnetic resonance imaging allows investigating whole-brain connectivity changes during pharmacological modulation of the level of consciousness.Low-frequency spontaneous blood oxygen level-dependent fluctuations were measured in 19 healthy volunteers during wakefulness, mild sedation, deep sedation with clinical unconsciousness, and subsequent recovery of consciousness.Propofol-induced decrease in consciousness linearly correlates with decreased corticocortical and thalamocortical connectivity in frontoparietal networks (i.e., default- and executive-control networks). Furthermore, during propofol-induced unconsciousness, a negative correlation was identified between thalamic and cortical activity in these networks. Finally, negative correlations between default network and lateral frontoparietal cortices activity, present during wakefulness, decreased proportionally to propofol-induced loss of consciousness. In contrast, connectivity was globally preserved in low-level sensory cortices, (i.e., in auditory and visual networks across sedation stages). This was paired with preserved thalamocortical connectivity in these networks. Rather, waning of consciousness was associated with a loss of cross-modal interactions between visual and auditory networks.Our results shed light on the functional significance of spontaneous brain activity fluctuations observed in functional magnetic resonance imaging. They suggest that propofol-induced unconsciousness could be linked to a breakdown of cerebral temporal architecture that modifies both within- and between-network connectivity and thus prevents communication between low-level sensory and higher-order frontoparietal cortices, thought to be necessary for perception of external stimuli. They emphasize the importance of thalamocortical connectivity in higher-order cognitive brain networks in the genesis of conscious perception.
Aggregation of α-synuclein is a hallmark for several neurodegenerative diseases including Dementia with Lewy bodies (DLB), Parkinson's Disease (PD), and multiple systems atrophy. Here we report a family with a history of synucleinopathy. The index case (61 y/o, APOE3/4) developed DLB by the age of 59, while his father (APOE3/3) died of DLB at the age of 75 (age of onset at 70). Two controls (paternal aunts of the proband, both APOE3/3) remain cognitively healthy at ages 77 and 73, respectively. Given the extensive familial history, we undertook a search for putative, pathogenic variants driving the underlying synucleinopathy. Visual hallucinations and cognitive decline with prominent parkinsonism were documented for the index case at the Stanford Center for Memory Disorders. One of the aunts was confirmed to be a healthy control following a research-based clinical and neuropsychological evaluations. The other aunt underwent a phone interview with a clinical dementia rating of 0. DNA of living subjects were collected from saliva samples, while the father's DNA was brain derived. Whole exome sequencing (WES) was performed on the Illumina HiSeq2000 platform. Raw data were analyzed with BWA (read mapping) and GATK (variant calling) software packages. Variants present in father-son pair and not carried by the two healthy aunts were selected for further investigation. These filtered variants were screened against 4449 controls aged 80 and up (1802 males, 2647 females) from the Alzheimer's Disease Sequencing Project. Variants not found in any controls were annotated using the Ensembl Variant Effect Predictor toolkit. Two variants remained after the filtering process—a missense variant on ZNF679 (NM_153363.2, 4:p.Ser253Leu) and a missense variant on CTD-3214H19.16 (ENSP00000469811.1:p.Ala128Thr). The father-son pair are heterozygous for each variant. Presence of these two variants in the father-son pair, combined with their absence in the two family controls and nearly 4,500 controls suggest that they are candidate pathogenic variants underlying the synucleinopathy in this family. Additional analysis of this family is underway, with WES being performed on a third paternal aunt (age 75) to further validate our findings . Pedigree of the family with an extensive history of synucleinopathy. Subjects with known APOE status have whole exome sequencing data available and were included in the analysis. Two cases of PD and three cases of dementia were reported by family members for generation I. DLB subjects are heterozygous for both c.380G>A CTD-3214H19.16 and c.758C>T ZNF679. Filtering scheme used for the discovery of possible putative, pathogenic variants.
Measurement of the spatial distribution of Tau pathology is critical for early diagnosis and disease monitoring. We sought to investigate a novel Tau PET ligand, 18F-PI2620, in aging and throughout the spectrum of Alzheimer's disease (AD). Seventeen participants within known Amyloid status (via CSF or Amyloid PET) underwent Tau PET scanning with 18F-PI2620 on a GE PET-MRI scanner: ten older clinically normal (CN) individuals (five Amyloid- CN, mean age=72.6±4.0; and five Amyloid+ CN, mean age=72.2±6.8), six clinically impaired patients on the AD trajectory (mean age=65.0±8.2; three Amyloid+ Mild Cognitive Impairment and three Amyloid+ AD dementia), as well as one Amyloid- patient with Dementia with Lewy Bodies (DLB). Standardized uptake value ratios were computed 60-90 minutes post-injection and normalized to the inferior cerebellum. We examined target regions known to show high Tau uptake in AD (entorhinal cortex, hippocampus, amygdala, inferior temporal cortex, precuneus, and lateral parietal cortex). Group differences (Amyloid- CN vs. Amyloid+ CN vs. Amyloid+ Impaired) in regional Tau were assessed with Wilcoxon signed-rank tests, whereas associations between continuous CSF measures (Aβ42 and pTau) with regional Tau within the CN group were assessed with Spearman's Rank correlation coefficients. Compared to Amyloid- CN, Amyloid+ CN showed greater PI2620 uptake in entorhinal cortex, hippocampus, and amygdala (p-values<0.032). The Amyloid+ Impaired group showed elevated Tau in all regions compared to Amyloid- CN (p-values<0.008), as well as elevated Tau in inferior temporal cortex (p= 0.016), precuneus (p<0.001), and lateral parietal cortex (p<0.001) compared to the Amyloid+ CN group (Figure 1). Within the CN group, continuous levels of CSF Aβ42 were negatively associated with elevated Tau PET in entorhinal cortext (p=0.026), hippocampus (p=0.004), and amygdala (p=0.007). CSF pTau was not related to any regional Tau PET value (Figure 2). The Amyloid- DLB case did not show evidence of uptake in any Tau PET region.
The X chromosome has remained enigmatic in Alzheimer's disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.
Behavioral variant frontotemporal dementia (bvFTD) disrupts our most human social and emotional functions. Early in the disease, patients show focal anterior cingulate cortex (ACC) and orbital frontoinsula (FI) degeneration, accentuated in the right hemisphere. The ACC and FI, though sometimes considered ancient in phylogeny, feature a large bipolar projection neuron, the von Economo neuron (VEN), which is found only in humans, apes, and selected whales—all large-brained mammals with complex social structures. In contrast to bvFTD, Alzheimer disease (AD) often spares social functioning, and the ACC and FI, until late in its course, damaging instead a posterior hippocampal-cingulo-temporal-parietal network involved in episodic memory retrieval. These divergent patterns of functional and regional impairment remain mysterious despite extensive molecular-level characterization of bvFTD and AD. In this report, we further develop the hypothesis that VENs drive the regional vulnerability pattern seen in bvFTD, citing recent evidence from functional imaging in healthy humans, and also structural imaging and quantitative neuropathology data from bvFTD and AD. Our most recent findings suggest that bvFTD and AD target distinct, anticorrelated intrinsic connectivity networks and that bvFTD-related VEN injury occurs throughout the ACC-FI network. We suggest that the regional and neuronal vulnerability patterns seen in bvFTD and AD underlie the divergent impact of these disorders on recently evolved social-emotional functions.
Abstract Background APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aβ+) remains unclear. Methods We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aβ-, 1323 Aβ+) and tau PET data were available for a subset of 447 participants (55 Aβ-, 392 Aβ+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE 4 effects on regional tau were examined in 220 Aβ + CU and mild cognitive impairment (MCI) participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results APOE 2 and APOE 4 were associated with lower and higher amyloid positivity rates, respectively. Among Aβ+ CU, e2 and e4 were associated with reduced (−12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE 2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE 4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aβ+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE 4 patterns were confirmed in Aβ+ ADNI participants. Conclusions APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aβ+ individuals.
Identifying genetic risk factors underpinning different aspects of Alzheimer's disease has the potential to provide important insights into pathogenesis. Moving away from simple case-control definitions, there is considerable interest in using quantitative endophenotypes, such as those derived from imaging as outcome measures. Previous genome-wide association studies of imaging-derived biomarkers in sporadic late-onset Alzheimer's disease focused only on phenotypes derived from single imaging modalities. In contrast, we computed a novel multi-modal neuroimaging phenotype comprising cortical amyloid burden and bilateral hippocampal volume. Both imaging biomarkers were used as input to a disease progression modelling algorithm, which estimates the biomarkers' long-term evolution curves from population-based longitudinal data. Among other parameters, the algorithm computes the shift in time required to optimally align a subjects' biomarker trajectories with these population curves. This time shift serves as a disease progression score and it was used as a quantitative trait in a discovery genome-wide association study with n = 944 subjects from the Alzheimer's Disease Neuroimaging Initiative database diagnosed as Alzheimer's disease, mild cognitive impairment or healthy at the time of imaging. We identified a genome-wide significant locus implicating LCORL (rs6850306, chromosome 4; P = 1.03 × 10-8). The top variant rs6850306 was found to act as an expression quantitative trait locus for LCORL in brain tissue. The clinical role of rs6850306 in conversion from healthy ageing to mild cognitive impairment or Alzheimer's disease was further validated in an independent cohort comprising healthy, older subjects from the National Alzheimer's Coordinating Center database. Specifically, possession of a minor allele at rs6850306 was protective against conversion from mild cognitive impairment to Alzheimer's disease in the National Alzheimer's Coordinating Center cohort (hazard ratio = 0.593, 95% confidence interval = 0.387-0.907, n = 911, PBonf = 0.032), in keeping with the negative direction of effect reported in the genome-wide association study (βdisease progression score = -0.07 ± 0.01). The implicated locus is linked to genes with known connections to Alzheimer's disease pathophysiology and other neurodegenerative diseases. Using multimodal imaging phenotypes in association studies may assist in unveiling the genetic drivers of the onset and progression of complex diseases.
Abstract Background Many Alzheimer’s disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery. Methods Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases). Results Modeling variable AD risk across age results in 5–10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3 , and TAOK2 genes. Conclusion Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.
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