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Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11 C-labelled Pittsburgh Compound B-PET and structural MRI. 18 F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB 50-70 cerebellar grey reference and FDG 30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18 F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18 F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18 F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease., Competing Interests: Y.L., E.T., B.G., and G.W. report no conflict of interest relevant to this manuscript. J.J.L.-G.’s research is supported by NIH-NIA (K01AG073526), the Alzheimer’s Association (AARFD-21-851415, SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes-Jewish Hospital and the McDonnell Academy. T.L.S.B., MD, PhD, has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. T.L.S.B. participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen and F. Hoffmann-La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. J.C.M., MD, is the Friedman Distinguished Professor of Neurology, Director, Knight ADRC; Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Carlos Cruchaga, PhD, receives research support from Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Cruchaga is a member of the advisory board of Vivid Genetics, Halia Therapeutics and Adx Healthcare. G.S.D.’s research is supported by NIH (K23AG064029, U01AG057195 and U19AG032438), the Alzheimer’s Association and the Chan Zuckerberg Initiative. He serves as a consultant for Parabon NanoLabs, Inc., as a Topic Editor (Dementia) for DynaMed (EBSCO), and as the clinical director of the Anti-NMDA Receptor Encephalitis Foundation, Inc. (Canada; uncompensated). He is the co-project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media, Inc., and Continuing Education, Inc. He owns stock in ANI Pharmaceuticals. R.J.B., MD, is the director and principal investigator of the DIAN and DIAN-TU-001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN-TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman-La Roche, Ltd. and Avid Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN-TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech, United Neuroscience. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi). He has been an invited speaker and consultant for AC Immune, F. Hoffman La Roche, Ltd. and Janssen and a consultant for Amgen and Eisai. J.L., MD, reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH and is an inventor in a patent ‘Pharmaceutical Composition and Methods of Use’ (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. L.I. is currently a full-time employee of Eli Lilly and Company/Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. G.D.R., MD, receives research support from NIA P30-AG062422, U01 AG057195, R35 AG072362, R56-AG075744, NINDS R21-NS120629, Alzheimer’s Association ZEN-21-848216, American College of Radiology, Rainwater Charitable Foundation, Shenandoah Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging, GE HealthCare and Genentech. He has served as a consultant for Alector, Eli Lilly, Genentech, GE HealthCare, Roche, Johnson & Johnson and Merck. He serves as an associate editor for JAMA Neurology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t -tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline ( P = 0.006) and 46.1% versus 25.4% at last visit ( P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency ( P < 0.001), Trail Making Test Part B ( P < 0.001) and digit span ( P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points ( P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels ( P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design., Competing Interests: J.J.L.-G.’s research is supported by NIH-NIA (K01AG073526), the Alzheimer’s Association (AARFD-21-851415 and SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes-Jewish Hospital and the McDonnell Academy. A.M.F., PhD, is the Biomarker Core Leader of the DIAN-TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR and Otsuka Pharmaceuticals. T.L.S.B., MD, PhD, has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. T.L.S.B. participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen and F. Hoffmann-La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. J.C.M., MD, is the Friedman Distinguished Professor of Neurology, Director, Knight ADRC, Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. A.J.A., PhD, has served as a consultant for Biogen Inc and H. Lundbeck HS. J.H., PhD, is a paid consultant for F. Hoffmann-La Roche, Ltd., Takeda, and Lundbeck and is on the Data Safety and Monitoring Board for Eisai. J.L., MD, reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH and is an inventor in a patent ‘Pharmaceutical Composition and Methods of Use’ (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. L.I. is currently a full-time employee of Eli Lilly and Company/Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. G.D.R., MD, receives research support from NIA P30-AG062422, U01-AG057195, R35 AG072362, R56-AG075744, NINDS R21-NS120629, Alzheimer’s Association ZEN-21-848216, American College of Radiology, Rainwater Charitable Foundation, Shenandoah Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging, GE Healthcare and Genentech. He has served as a consultant for Alector, Eli Lilly, Genentech, GE Healthcare, Roche, Johnson & Johnson and Merck. He serves as associate editor for JAMA Neurology. All other authors report no conflict of interest relevant to this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Acquired brain injury (ABI) commonly causes cognitive dysfunction that needs to be assessed and treated to maximize rehabilitation outcomes. Research suggests that music, emotion, and cognition are intimately linked, and that music can contribute to the assessment and treatment of cognitive functions of adults who have suffered from ABI. To this date, no standardized music based assessment tool exists to identify and measure cognitive functioning and mood states of Spanish-speaking persons with ABI at treatment intake and over time. The objective of this study was to develop such a scale and determine its psychometric properties in terms of internal consistency, reliability, and concurrent validity. The "Evaluación de la Cognición Musical para Adultos con Lesión Cerebral Adquirida" (in English "Music Based Assessment for Cognitive Functions of Adults with Acquired Brain Injury - ECMUS") was developed and tested at a neurorehabilitation institute in Argentina. Twenty-four healthy adults and 20 adults with ABI were recruited and assessed with the ECMUS. Despite the limited number of participants, this preliminary psychometric examination shows promising results. The tool has an acceptable internal consistency, excellent test-retest and inter-rater reliability, and, depending on the subscale, weak to strong correlations to related, nonmusical constructs. Overall, this pilot study opens the possibility to further explore the inclusion of music in assessment procedures of Spanish-speaking individuals with ABI in rehabilitation settings. It is clinically derived and emphasizes evidence-based contributions of the field of music therapy to interdisciplinary assessment and treatment in rehabilitation settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Music Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer's disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer's disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer's Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer's disease using data of the National Alzheimer's Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: We measured frequency and epidemiologic, clinical, and hematochemical variables associated with respiratory tract infections (RTIs) in foreign-born and national patients hospitalized with fever with a history of international travel, and compared the final diagnosis of RTI with the presence of a respiratory syndrome (RS) at presentation., Methods: A prospective, multicenter, observational study was conducted at tertiary care hospitals in Northern Italy from September 1998 to December 2000., Results: A final diagnosis of RTI was obtained in 40 cases (7.8%), 27 (67.5%) with lower RTI and 13 (32.5%) with upper RTI. The most common RTIs were pneumonia (35%) and pulmonary tuberculosis (15%). A white blood cell count > or = 10,000 and an erythrocyte sedimentation rate > or = 20 mm/h were independently associated with a final diagnosis of RTI; onset of symptoms at > or = 16 days and > or = 75% neutrophils were independently associated with lower RTI. An RS was identified in 51 (9.9%) of 515 travelers. Sensitivity, specificity, and positive and negative predictive values of a diagnosis of RS for a final diagnosis of RTI were 67.5%, 94.9%, 52.9%, and 97.2%, respectively., Conclusions: Pneumonia and pulmonary tuberculosis were frequent among foreign-born and national travelers with fever admitted to a tertiary care hospital. Half of the pneumonia cases did not present with an RS at first clinical examination.