The impact of the cost-of-living crisis on population health in the UK: rapid evidence review.

BACKGROUND: In the UK, unique and unforeseen factors, including COVID-19, Brexit, and Ukraine-Russia war, have resulted in an unprecedented cost of living crisis, creating a second health emergency. We present, one of the first rapid reviews with the aim of examining the impact of this current crisis, at a population level. We reviewed published literature, as well as grey literature, examining a broad range of physical and mental impacts on health in the short, mid, and long term, identifying those most at risk, impacts on system partners, including emergency services and the third sector, as well as mitigation strategies. METHODS: We conducted a rapid review by searching PubMed, Embase, MEDLINE, and HMIC (2020 to 2023). We searched for grey literature on Google and hand-searched the reports of relevant public health organisations. We included interventional and observational studies that reported outcomes of interventions aimed at mitigating against the impacts of cost of living at a population level. RESULTS: We found that the strongest evidence was for the impact of cold and mouldy homes on respiratory-related infections and respiratory conditions. Those at an increased risk were young children (0-4 years), the elderly (aged 75 and over), as well as those already vulnerable, including those with long-term multimorbidity. Further short-term impacts include an increased risk of physical pain including musculoskeletal and chest pain, and increased risk of enteric infections and malnutrition. In the mid-term, we could see increases in hypertension, transient ischaemic attacks, and myocardial infarctions, and respiratory illnesses. In the long term we could see an increase in mortality and morbidity rates from respiratory and cardiovascular disease, as well as increase rates of suicide and self-harm and infectious disease outcomes. Changes in behaviour are likely particularly around changes in food buying patterns and the ability to heat a home. System partners are also impacted, with voluntary sectors seeing fewer volunteers, an increase in petty crime and theft, alternative heating appliances causing fires, and an increase in burns and burn-related admissions. To mitigate against these impacts, support should be provided, to the most vulnerable, to help increase disposable income, reduce energy bills, and encourage home improvements linked with energy efficiency. Stronger links to bridge voluntary, community, charity and faith groups are needed to help provide additional aid and support. CONCLUSION: Although the CoL crisis affects the entire population, the impacts are exacerbated in those that are most vulnerable, particularly young children, single parents, multigenerational families. More can be done at a community and societal level to support the most vulnerable, and those living with long-term multimorbidity. This review consolidates the current evidence on the impacts of the cost of living crisis and may enable decision makers to target limited resources more effectively.

Influence of factors commonly known to be associated with health inequalities on antibiotic use in high-income countries: a systematic scoping review.

INTRODUCTION: Inappropriate antibiotic use contributes to antimicrobial resistance. High-income countries have high rates of antibiotic use, with a prevalence of health inequalities amongst populations. OBJECTIVES: To understand the influence of factors commonly known to be associated with health inequalities on antibiotic use in high-income countries. METHODS: Factors commonly known to be associated with health inequalities were defined as protected characteristics under UK's Equality Act (age, disability, gender reassignment, marriage and civil partnership, pregnancy and maternity, race/ethnicity, religion or belief, sex, sexual orientation), socioeconomic characteristics (income, insurance, employment status, deprivation, education), geography (urban versus rural, region) and vulnerable groups. The study followed PRISMA-ScR and, PRISMA-E statements. RESULTS: Fifty-eight of 402 identified studies met inclusion criteria. Fifty of those papers (86%) included one or more protected characteristics, 37 (64%) socioeconomic characteristics, 21 (36%) geography and 6 (10%) vulnerable groups. Adults in older age groups, especially those in residential care, had the highest antibiotic use. The influence of race or ethnicity and antibiotic use was particular to country context. Areas of high deprivation had higher antibiotic use compared with areas of no or low deprivation, and geographical variation existed within countries. When faced with health system barriers, migrants relied on alternative routes of antibiotic supply other than prescription. RECOMMENDATIONS FOR FUTURE RESEARCH: To investigate how factors and wider social determinants of health interplay and impact antibiotic use, using frameworks/approaches to reduce health inequalities such as England's Core20PLUS approach. Antimicrobial stewardship initiatives should equip healthcare professionals to review patients at the highest risk of antibiotic use.

The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration.

The Myogenic Regulatory Factors (MRFs) Myf5, MyoD, myogenin and MRF4 are members of the basic helix-loop-helix family of transcription factors that control the determination and differentiation of skeletal muscle cells during embryogenesis and postnatal myogenesis. The dynamics of their temporal and spatial expression as well as their biochemical properties have allowed the identification of a precise and hierarchical relationship between the four MRFs. This relationship establishes the myogenic lineage as well as the maintenance of the terminal myogenic phenotype. The application of genome-wide technologies has provided important new information as to how the MRFs function to activate muscle gene expression. Application of combined functional genomics technologies along with single cell lineage tracing strategies will allow a deeper understanding of the mechanisms mediating myogenic determination, cell differentiation and muscle regeneration.

Absence of hyperplasia in Gasp-1 overexpressing mice is dependent on myostatin up-regulation.

BACKGROUND/AIMS: Overexpression of Gasp-1, an inhibitor of myostatin, leads to a hypermuscular phenotype due to hypertrophy rather than hyperplasia in mice. However to date, the cellular and molecular mechanisms underlying this phenotype are not investigated. METHODS: Skeletal muscles of overexpressing Gasp-1 mice, called Tg(Gasp-1) mice, were analyzed by histological methods. Satellite cell-derived myoblasts from these mice were used to investigate the molecular mechanisms. RESULTS: We demonstrated that hypertrophy in Tg(Gasp-1) mice was related to a myonuclear accretion during the first 3 postnatal weeks and an activation of the pro-hypertrophic Akt/mTORC/p70S6K signaling. In accordance with these results, we showed that overexpressing Gasp-1 primary myoblasts proliferated faster and myonuclei average per myotube was increased during differentiation. Molecular analysis revealed that Gasp-1 overexpression resulted in increased myostatin expression related to its auto-regulation. Despite its inhibition, myostatin led to Pax7 deregulation through its non-canonical Erk1/2 signaling pathway. Consistent with this, inhibition of Erk1/2 signaling pathway as well as neutralization of secreted myostatin rescue the Pax7 expression in overexpressing Gasp-1 myoblasts. CONCLUSION: Our study shows that myostatin is able to act independently of its canonical pathway to regulate the Pax7 expression. Altogether, our results indicate that myostatin could regulate muscle development despite its protein inhibition.

Setdb1 protects genome integrity in murine muscle stem cells to allow for regenerative myogenesis and inflammation.

The histone H3 lysine 9 methyltransferase SETDB1 controls transcriptional repression to direct stem cell fate. Here, we show that Setdb1 expression by adult muscle stem cells (MuSCs) is required for skeletal muscle regeneration. We find that SETDB1 represses the expression of endogenous retroviruses (ERVs) in MuSCs. ERV de-repression in Setdb1-null MuSCs prevents their amplification following exit from quiescence and promotes cell death. Multi-omics profiling shows that chromatin decompaction at ERV loci activates the DNA-sensing cGAS-STING pathway, entailing cytokine expression by Setdb1-null MuSCs. This is followed by aberrant infiltration of inflammatory cells, including pathological macrophages. The ensuing histiocytosis is accompanied by myofiber necrosis, which, in addition to progressive MuSCs depletion, completely abolishes tissue repair. In contrast, loss of Setdb1 in fibro-adipogenic progenitors (FAPs) does not impact immune cells. In conclusion, genome maintenance by SETDB1 in an adult somatic stem cell is necessary for both its regenerative potential and adequate reparative inflammation.

Criteria to achieve safe antimicrobial intravenous-to-oral switch in hospitalised adult populations: a systematic rapid review.

OBJECTIVES: This rapid review aimed to assess and collate intravenous-to-oral switch (IVOS) criteria from the literature to achieve safe and effective antimicrobial IVOS in the hospital inpatient adult population. DESIGN: The rapid review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. DATA SOURCES: OVID Embase and Medline databases. ELIGIBILITY CRITERIA: Articles of adult populations published globally between 2017 and 2021 were included. DATA EXTRACTION AND SYNTHESIS: An Excel spreadsheet was designed with specific column headings. IVOS criteria from UK hospital IVOS policies informed the framework synthesis. RESULTS: IVOS criteria from 45/164 (27%) local IVOS policies were categorised into a five-section framework: (1) timing of IV antimicrobial review, (2) clinical signs and symptoms, (3) infection markers, (4) enteral route and (5) infection exclusions. The literature search identified 477 papers, of which 16 were included. The most common timing for review was 48-72 hours from initiation of intravenous antimicrobial (n=5, 30%). Nine studies (56%) stated clinical signs and symptoms must be improving. Temperature was the most frequently mentioned infection marker (n=14, 88%). Endocarditis had the highest mention as an infection exclusion (n=12, 75%). Overall, 33 IVOS criteria were identified to go forward into the Delphi process. CONCLUSION: Through the rapid review, 33 IVOS criteria were collated and presented within five distinct and comprehensive sections. The literature highlighted the possibility of reviewing IVOS before 48-72 hours and of presenting heart rate, blood pressure and respiratory rate as a combination early warning score criterion. The criteria identified can serve as a starting point of IVOS criteria review for any institution globally, as no country or region limits were applied. Further research is required to achieve consensus on IVOS criteria from healthcare professionals that manage patients with infections. PROSPERO REGISTRATION NUMBER: CRD42022320343.

Ubiquitous Gasp1 overexpression in mice leads mainly to a hypermuscular phenotype.

BACKGROUND: Myostatin, a member of the TGFß superfamily, is well known as a potent and specific negative regulator of muscle growth. Targeting the myostatin signalling pathway may offer promising therapeutic strategies for the treatment of muscle-wasting disorders. In the last decade, various myostatin-binding proteins have been identified to be able to inhibit myostatin activity. One of these is GASP1 (Growth and Differentiation Factor-Associated Serum Protein-1), a protein containing a follistatin domain as well as multiple domains associated with protease inhibitors. Despite in vitro data, remarkably little is known about in vivo functions of Gasp1. To further address the role of GASP1 during mouse development and in adulthood, we generated a gain-of-function transgenic mouse model that overexpresses Gasp1 under transcriptional control of the human cytomegalovirus immediate-early promoter/enhancer. RESULTS: Overexpression of Gasp1 led to an increase in muscle mass observed not before day 15 of postnatal life. The surGasp1 transgenic mice did not display any other gross abnormality. Histological and morphometric analysis of surGasp1 rectus femoris muscles revealed an increase in myofiber size without a corresponding increase in myofiber number. Fiber-type distribution was unaltered. Interestingly, we do not detect a change in total fat mass and lean mass. These results differ from those for myostatin knockout mice, transgenic mice overexpressing the myostatin propeptide or follistatin which exhibit both muscle hypertrophy and hyperplasia, and show minimal fat deposition. CONCLUSIONS: Altogether, our data give new insight into the in vivo functions of Gasp1. As an extracellular regulatory factor in the myostatin signalling pathway, additional studies on GASP1 and its homolog GASP2 are required to elucidate the crosstalk between the different intrinsic inhibitors of the myostatin.

Murine GASP-1 N-glycosylation is not essential for its activity on C2C12 myogenic cells but alters its secretion.

BACKGROUND/AIMS: Growth and differentiation factor-associated serum protein-1 (GASP-1) is a secreted protein known to be capable of binding and inhibiting the activity of several TGF-beta family members, including myostatin. The present study was designed to characterize murine GASP-1 post-translational modifications and to determine their influence on the biological activity of GASP-1. METHODS: We describe herein the site-directed mutagenesis of single N-glycosylation sites and combinations of them in 4 mutants of murine GASP-1. RESULTS: In vitro and in vivo analysis revealed that GASP-1 is a glycoprotein containing 2 N-glycans and several mucin-type O-glycans. Treatments by the recombinant murine GASP-1 protein enhance C2C12 proliferation and differentiation by inhibition of the myostatin pathway. The loss of N-glycans leads to a decrease in protein secretion rate but does not affect its ability to activate myogenesis. CONCLUSION: Analysis of structure-function relationships of murine GASP-1 provides insights into the involvement of the carbohydrate moiety of mGASP-1 on its biological activity.

GLI3 regulates muscle stem cell entry into GAlert and self-renewal.

Satellite cells are required for the growth, maintenance, and regeneration of skeletal muscle. Quiescent satellite cells possess a primary cilium, a structure that regulates the processing of the GLI family of transcription factors. Here we find that GLI3 processing by the primary cilium plays a critical role for satellite cell function. GLI3 is required to maintain satellite cells in a G0 dormant state. Strikingly, satellite cells lacking GLI3 enter the GAlert state in the absence of injury. Furthermore, GLI3 depletion stimulates expansion of the stem cell pool. As a result, satellite cells lacking GLI3 display rapid cell-cycle entry, increased proliferation and augmented self-renewal, and markedly enhanced regenerative capacity. At the molecular level, we establish that the loss of GLI3 induces mTORC1 signaling activation. Therefore, our results provide a mechanism by which GLI3 controls mTORC1 signaling, consequently regulating muscle stem cell activation and fate.

Acetylation of PAX7 controls muscle stem cell self-renewal and differentiation potential in mice.

Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. Here we report the identification of two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD +, are identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis leads to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirms that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Therefore, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue.

Brain structure changes visualized in early- and late-onset blind subjects.

We examined 3D patterns of volume differences in the brain associated with blindness, in subjects grouped according to early and late onset. Using tensor-based morphometry, we mapped volume reductions and gains in 16 early-onset (EB) and 16 late-onset (LB) blind adults (onset <5 and >14 years old, respectively) relative to 16 matched sighted controls. Each subject's structural MRI was fluidly registered to a common template. Anatomical differences between groups were mapped based on statistical analysis of the resulting deformation fields revealing profound deficits in primary and secondary visual cortices for both blind groups. Regions outside the occipital lobe showed significant hypertrophy, suggesting widespread compensatory adaptations. EBs but not LBs showed deficits in the splenium and the isthmus. Gains in the non-occipital white matter were more widespread in the EBs. These differences may reflect regional alterations in late neurodevelopmental processes, such as myelination, that continue into adulthood.

3D mapping of brain differences in native signing congenitally and prelingually deaf subjects.

In the prelingual and congenital deaf, functional reorganization is known to occur throughout brain regions normally associated with hearing. However, the anatomical correlates of these changes are not yet well understood. Here, we perform the first tensor-based morphometric analysis of voxel-wise volumetric differences in native signing prelingual and congenitally deaf subjects when compared with hearing controls. We obtained T1-weighted scans for 14 native signing prelingual and congenitally deaf subjects and 16 age- and gender-matched controls. We used linear and fluid registration to align each image to a common template. Using the voxel-wise determinant of the Jacobian of the fluid deformation, significant volume increases, of up to 20%, were found in frontal lobe white matter regions including Broca's area, and adjacent regions involved in motor control and language production. A similar analysis was performed on hand-traced corpora callosa. A strong trend for group differences was found in the area of the splenium considered to carry fibers connecting the temporal (and occipital) lobes. These anatomical differences may reflect experience-mediated developmental differences in myelination and cortical maturation associated with prolonged monomodal sensory deprivation.

Mouse WIF1 Is Only Modified with O-Fucose in Its EGF-like Domain III Despite Two Evolutionarily Conserved Consensus Sites.

The Wnt Inhibitory Factor 1 (Wif1), known to inhibit Wnt signaling pathways, is composed of a WIF domain and five EGF-like domains (EGF-LDs) involved in protein interactions. Despite the presence of a potential O-fucosylation site in its EGF-LDs III and V, the O-fucose sites occupancy has never been demonstrated for WIF1. In this study, a phylogenetic analysis on the distribution, conservation and evolution of Wif1 proteins was performed, as well as biochemical approaches focusing on O-fucosylation sites occupancy of recombinant mouse WIF1. In the monophyletic group of gnathostomes, we showed that the consensus sequence for O-fucose modification by Pofut1 is highly conserved in Wif1 EGF-LD III while it was more divergent in EGF-LD V. Using click chemistry and mass spectrometry, we demonstrated that mouse WIF1 was only modified with a non-extended O-fucose on its EGF-LD III. In addition, a decreased amount of mouse WIF1 in the secretome of CHO cells was observed when the O-fucosylation site in EGF-LD III was mutated. Based on sequence comparison and automated protein modeling, we suggest that the absence of O-fucose on EGF-LD V of WIF1 in mouse and probably in most gnathostomes, could be related to EGF-LD V inability to interact with POFUT1.

The effectiveness of smoking cessation, alcohol reduction, diet and physical activity interventions in changing behaviours during pregnancy: A systematic review of systematic reviews.

BACKGROUND: Pregnancy is a teachable moment for behaviour change. Multiple guidelines target pregnant women for behavioural intervention. This systematic review of systematic reviews reports the effectiveness of interventions delivered during pregnancy on changing women's behaviour across multiple behavioural domains. METHODS: Fourteen databases were searched for systematic reviews published from 2008, reporting interventions delivered during pregnancy targeting smoking, alcohol, diet or physical activity as outcomes. Data on behaviour change related to these behaviours are reported here. Quality was assessed using the JBI critical appraisal tool for umbrella reviews. Consistency in intervention effectiveness and gaps in the evidence-base are described. RESULTS: Searches identified 24,388 results; 109 were systematic reviews of behaviour change interventions delivered in pregnancy, and 36 reported behavioural outcomes. All smoking and alcohol reviews identified reported maternal behaviours as outcomes (n = 16 and 4 respectively), whereas only 16 out of 89 diet and/or physical activity reviews reported these behaviours. Most reviews were high quality (67%) and interventions were predominantly set in high-income countries. Overall, there was consistent evidence for improving healthy diet behaviours related to increasing fruit and vegetable consumption and decreasing carbohydrate intake, and fairly consistent evidence for increase in some measures of physical activity (METs and VO2 max) and for reductions in fat intake and smoking during pregnancy. There was a lack of consistent evidence across reviews reporting energy, protein, fibre, or micronutrient intakes; smoking cessation, abstinence or relapse; any alcohol behaviours. CONCLUSIONS: The most consistent review evidence is for interventions improving dietary behaviours during pregnancy compared with other behaviours, although the majority of diet reviews prioritised reporting health-related outcomes over behavioural outcomes. Heterogeneity between reported behaviour outcomes limits ability to pool data in meta-analysis and more consistent reporting is needed. Limited data are available for alcohol interventions in pregnancy or interventions in low- or middle-income-countries, which are priority areas for future research.

Mapping the regional influence of genetics on brain structure variability--a tensor-based morphometry study.

Genetic and environmental factors influence brain structure and function profoundly. The search for heritable anatomical features and their influencing genes would be accelerated with detailed 3D maps showing the degree to which brain morphometry is genetically determined. As part of an MRI study that will scan 1150 twins, we applied Tensor-Based Morphometry to compute morphometric differences in 23 pairs of identical twins and 23 pairs of same-sex fraternal twins (mean age: 23.8+/-1.8 SD years). All 92 twins' 3D brain MRI scans were nonlinearly registered to a common space using a Riemannian fluid-based warping approach to compute volumetric differences across subjects. A multi-template method was used to improve volume quantification. Vector fields driving each subject's anatomy onto the common template were analyzed to create maps of local volumetric excesses and deficits relative to the standard template. Using a new structural equation modeling method, we computed the voxelwise proportion of variance in volumes attributable to additive (A) or dominant (D) genetic factors versus shared environmental (C) or unique environmental factors (E). The method was also applied to various anatomical regions of interest (ROIs). As hypothesized, the overall volumes of the brain, basal ganglia, thalamus, and each lobe were under strong genetic control; local white matter volumes were mostly controlled by common environment. After adjusting for individual differences in overall brain scale, genetic influences were still relatively high in the corpus callosum and in early-maturing brain regions such as the occipital lobes, while environmental influences were greater in frontal brain regions that have a more protracted maturational time-course.

Mapping brain abnormalities in boys with autism.

Children with autism spectrum disorder (ASD) exhibit characteristic cognitive and behavioral differences, but no systematic pattern of neuroanatomical differences has been consistently found. Recent neurodevelopmental models posit an abnormal early surge in subcortical white matter growth in at least some autistic children, perhaps normalizing by adulthood, but other studies report subcortical white matter deficits. To investigate the profile of these alterations in 3D, we mapped brain volumetric differences using a relatively new method, tensor-based morphometry. 3D T1-weighted brain MRIs of 24 male children with ASD (age: 9.5 years +/- 3.2 SD) and 26 age-matched healthy controls (age: 10.3 +/- 2.4 SD) were fluidly registered to match a common anatomical template. Autistic children had significantly enlarged frontal lobes (by 3.6% on the left and 5.1% on the right), and all other lobes of the brain were enlarged significantly, or at trend level. By analyzing the applied deformations statistically point-by-point, we detected significant gray matter volume deficits in bilateral parietal, left temporal and left occipital lobes (P = 0.038, corrected), trend-level cerebral white matter volume excesses, and volume deficits in the cerebellar vermis, adjacent to volume excesses in other cerebellar regions. This profile of excesses and deficits in adjacent regions may (1) indicate impaired neuronal connectivity, resulting from aberrant myelination and/or an inflammatory process, and (2) help to understand inconsistent findings of regional brain tissue excesses and deficits in autism.

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions. Inhibiting EGFR causes a substantial shift from asymmetric to symmetric division modes, whereas EGF treatment increases asymmetric divisions. EGFR activation acts through Aurka to orient mitotic centrosomes, and inhibiting Aurka blocks EGF stimulation-induced asymmetric division. In vivo EGF treatment markedly activates asymmetric divisions of dystrophin-deficient satellite cells in mdx mice, increasing progenitor numbers, enhancing regeneration, and restoring muscle strength. Therefore, activating an EGFR-dependent polarity pathway promotes functional rescue of dystrophin-deficient satellite cells and enhances muscle force generation.

MLL1 is required for PAX7 expression and satellite cell self-renewal in mice.

PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mll1-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.

3D characterization of brain atrophy in Alzheimer's disease and mild cognitive impairment using tensor-based morphometry.

Tensor-based morphometry (TBM) creates three-dimensional maps of disease-related differences in brain structure, based on nonlinearly registering brain MRI scans to a common image template. Using two different TBM designs (averaging individual differences versus aligning group average templates), we compared the anatomical distribution of brain atrophy in 40 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with amnestic mild cognitive impairment (aMCI), a condition conferring increased risk for AD. We created an unbiased geometrical average image template for each of the three groups, which were matched for sex and age (mean age: 76.1 years+/-7.7 SD). We warped each individual brain image (N=120) to the control group average template to create Jacobian maps, which show the local expansion or compression factor at each point in the image, reflecting individual volumetric differences. Statistical maps of group differences revealed widespread medial temporal and limbic atrophy in AD, with a lesser, more restricted distribution in MCI. Atrophy and CSF space expansion both correlated strongly with Mini-Mental State Exam (MMSE) scores and Clinical Dementia Rating (CDR). Using cumulative p-value plots, we investigated how detection sensitivity was influenced by the sample size, the choice of search region (whole brain, temporal lobe, hippocampus), the initial linear registration method (9- versus 12-parameter), and the type of TBM design. In the future, TBM may help to (1) identify factors that resist or accelerate the disease process, and (2) measure disease burden in treatment trials.