Removing outliers from the normative database improves regional atrophy detection in single-subject voxel-based morphometry.

PURPOSE: Single-subject voxel-based morphometry (VBM) compares an individual T1-weighted MRI to a sample of normal MRI in a normative database (NDB) to detect regional atrophy. Outliers in the NDB might result in reduced sensitivity of VBM. The primary aim of the current study was to propose a method for outlier removal ("NDB cleaning") and to test its impact on the performance of VBM for detection of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: T1-weighted MRI of 81 patients with biomarker-confirmed AD (n = 51) or FTLD (n = 30) and 37 healthy subjects with simultaneous FDG-PET/MRI were included as test dataset. Two different NDBs were used: a scanner-specific NDB (37 healthy controls from the test dataset) and a non-scanner-specific NDB comprising 164 normal T1-weighted MRI from 164 different MRI scanners. Three different quality metrics based on leave-one-out testing of the scans in the NDB were implemented. A scan was removed if it was an outlier with respect to one or more quality metrics. VBM maps generated with and without NDB cleaning were assessed visually for the presence of AD or FTLD. RESULTS: Specificity of visual interpretation of the VBM maps for detection of AD or FTLD was 100% in all settings. Sensitivity was increased by NDB cleaning with both NDBs. The effect was statistically significant for the multiple-scanner NDB (from 0.47 [95%-CI 0.36-0.58] to 0.61 [0.49-0.71]). CONCLUSION: NDB cleaning has the potential to improve the sensitivity of VBM for the detection of AD or FTLD without increasing the risk of false positive findings.

Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy.

BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).

Amino acid PET vs. RANO MRI for prediction of overall survival in patients with recurrent high grade glioma under bevacizumab therapy.

PURPOSE: To summarize evidence on the comparative value of amino acid (AA) PET and conventional MRI for prediction of overall survival (OS) in patients with recurrent high grade glioma (rHGG) under bevacizumab therapy. METHODS: Medical databases were screened for studies with individual data on OS, follow-up MRI, and PET findings in the same patient. MRI images were assessed according to the RANO criteria. A receiver operating characteristic curve analysis was used to predict OS at 9 months. RESULTS: Five studies with a total of 72 patients were included. Median OS was significantly lower in the PET-positive than in the PET-negative group. PET findings predicted OS with a pooled sensitivity and specificity of 76% and 71%, respectively. Corresponding values for MRI were 32% and 82%. Area under the curve and sensitivity were significantly higher for PET than for MRI. CONCLUSION: For monitoring of patients with rHGG under bevacizumab therapy, AA-PET should be preferred over RANO MRI.

Similarity between structural and proxy estimates of brain connectivity.

Functional magnetic resonance and diffusion weighted imaging have so far made a major contribution to delineation of the brain connectome at the macroscale. While functional connectivity (FC) was shown to be related to structural connectivity (SC) to a certain degree, their spatial overlap is unknown. Even less clear are relations of SC with estimates of connectivity from inter-subject covariance of regional F18-fluorodeoxyglucose uptake (FDGcov) and grey matter volume (GMVcov). Here, we asked to what extent SC underlies three proxy estimates of brain connectivity: FC, FDGcov and GMVcov. Simultaneous PET/MR acquisitions were performed in 56 healthy middle-aged individuals. Similarity between four networks was assessed using Spearman correlation and convergence ratio (CR), a measure of spatial overlap. Spearman correlation coefficient was 0.27 for SC-FC, 0.40 for SC-FDGcov, and 0.15 for SC-GMVcov. Mean CRs were 51% for SC-FC, 48% for SC-FDGcov, and 37% for SC-GMVcov. These results proved to be reproducible and robust against image processing steps. In sum, we found a relevant similarity of SC with FC and FDGcov, while GMVcov consistently showed the weakest similarity. These findings indicate that white matter tracts underlie FDGcov to a similar degree as FC, supporting FDGcov as estimate of functional brain connectivity.

Theranostics in Neurooncology: Heading Toward New Horizons.

Therapeutic approaches to brain tumors remain a challenge, with considerable limitations regarding delivery of drugs. There has been renewed and increasing interest in translating the popular theranostic approach well known from prostate and neuroendocrine cancer to neurooncology. Although far from perfect, some of these approaches show encouraging preliminary results, such as for meningioma and leptomeningeal spread of certain pediatric brain tumors. In brain metastases and gliomas, clinical results have failed to impress. Perspectives on these theranostic approaches regarding meningiomas, brain metastases, gliomas, and common pediatric brain tumors will be discussed. For each tumor entity, the general context, an overview of the literature, and future perspectives will be provided. Ongoing studies will be discussed in the supplemental materials. As most theranostic agents are unlikely to cross the blood-brain barrier, the delivery of these agents will be dependent on the successful development and clinical implementation of techniques enhancing permeability and retention. Moreover, the international community should strive toward sufficiently large and randomized studies to generate high-level evidence on theranostic approaches with radioligand therapies for central nervous system tumors.

An energy costly architecture of neuromodulators for human brain evolution and cognition.

In comparison to other species, the human brain exhibits one of the highest energy demands relative to body metabolism. It remains unclear whether this heightened energy demand uniformly supports an enlarged brain or if specific signaling mechanisms necessitate greater energy. We hypothesized that the regional distribution of energy demands will reveal signaling strategies that have contributed to human cognitive development. We measured the energy distribution within the brain functional connectome using multimodal brain imaging and found that signaling pathways in evolutionarily expanded regions have up to 67% higher energetic costs than those in sensory-motor regions. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an up-regulation of signaling at G-protein-coupled receptors in energy-demanding regions. Our findings indicate that neuromodulator activity is predominantly involved in cognitive functions, such as reading or memory processing. This study suggests that an up-regulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer disease.

Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer Disease (AD). Given their essential role in neural communication, disruptions to these hubs have profound implications for overall brain network integrity and functionality. Hub disruption, or targeted impairment of functional connectivity at the hubs, is recognized in AD patients. Computational models paired with evidence from animal experiments hint at a mechanistic explanation, suggesting that these hubs may be preferentially targeted in neurodegeneration, due to their high neuronal activity levels-a phenomenon termed "activity-dependent degeneration". Yet, two critical issues were unresolved. First, past research hasn't definitively shown whether hub regions face a higher likelihood of impairment (targeted attack) compared to other regions or if impairment likelihood is uniformly distributed (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We applied a refined hub disruption index to determine the presence of targeted attacks in AD. Furthermore, we explored potential evidence for activity-dependent degeneration by evaluating if hub vulnerability is better explained by global connectivity or connectivity variations across functional systems, as well as comparing its timing relative to amyloid beta deposition in the brain. Our unique cohort of participants with autosomal dominant Alzheimer Disease (ADAD) allowed us to probe into the preclinical stages of AD to determine the hub disruption timeline in relation to expected symptom emergence. Our findings reveal a hub disruption pattern in ADAD aligned with targeted attacks, detectable even in pre-clinical stages. Notably, the disruption's severity amplified alongside symptomatic progression. Moreover, since excessive local neuronal activity has been shown to increase amyloid deposition and high connectivity regions show high level of neuronal activity, our observation that hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in Aß PET cortical markers is consistent with the activity-dependent degeneration model. Intriguingly, these disruptions were discernible 8 years before the expected age of symptom onset. Taken together, our findings not only align with the targeted attack on hubs model but also suggest that activity-dependent degeneration might be the cause of hub vulnerability. This deepened understanding could be instrumental in refining diagnostic techniques and developing targeted therapeutic strategies for AD in the future.

T1 and FLAIR signal intensities are related to tau pathology in dominantly inherited Alzheimer disease.

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (µ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-µ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-µ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.

Imaging the WHO 2021 Brain Tumor Classification: Fully Automated Analysis of Imaging Features of Newly Diagnosed Gliomas.

BACKGROUND: The fifth version of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) in 2021 brought substantial changes. Driven by the enhanced implementation of molecular characterization, some diagnoses were adapted while others were newly introduced. How these changes are reflected in imaging features remains scarcely investigated. MATERIALS AND METHODS: We retrospectively analyzed 226 treatment-naive primary brain tumor patients from our institution who received extensive molecular characterization by epigenome-wide methylation microarray and were diagnosed according to the 2021 WHO brain tumor classification. From multimodal preoperative 3T MRI scans, we extracted imaging metrics via a fully automated, AI-based image segmentation and processing pipeline. Subsequently, we examined differences in imaging features between the three main glioma entities (glioblastoma, astrocytoma, and oligodendroglioma) and particularly investigated new entities such as astrocytoma, WHO grade 4. RESULTS: Our results confirm prior studies that found significantly higher median CBV (p = 0.00003, ANOVA) and lower median ADC in contrast-enhancing areas of glioblastomas, compared to astrocytomas and oligodendrogliomas (p = 0.41333, ANOVA). Interestingly, molecularly defined glioblastoma, which usually does not contain contrast-enhancing areas, also shows significantly higher CBV values in the non-enhancing tumor than common glioblastoma and astrocytoma grade 4 (p = 0.01309, ANOVA). CONCLUSIONS: This work provides extensive insights into the imaging features of gliomas in light of the new 2021 WHO CNS tumor classification. Advanced imaging shows promise in visualizing tumor biology and improving the diagnosis of brain tumor patients.

Longitudinal Relationships of White Matter Hyperintensities and Alzheimer Disease Biomarkers Across the Adult Life Span.

BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMH) correlate with Alzheimer disease (AD) biomarkers cross-sectionally and modulate AD pathogenesis. Longitudinal changes have been reported for AD biomarkers, including concentrations of CSF ß-amyloid (Aß) 42, Aß40, total tau and phosphorylated tau181, standardized uptake value ratio from the molecular imaging of cerebral fibrillar Aß with PET using [11C] Pittsburgh Compound-B, MRI-based hippocampal volume, and cortical thickness. Correlations between established AD biomarkers and the longitudinal change for WMH have not been fully evaluated, especially among cognitively normal individuals across the adult life span. METHODS: We jointly analyzed the longitudinal data of WMH volume and each of the established AD biomarkers and cognition from 371 cognitively normal individuals whose baseline age spanned from 19.6 to 88.20 years from 4 longitudinal studies of aging and AD. A 2-stage algorithm was applied to identify the inflection point of baseline age whereby older participants had an accelerated longitudinal change in WMH volume, in comparison with the younger participants. The longitudinal correlations between WMH volume and AD biomarkers were estimated from the bivariate linear mixed-effects models. RESULTS: A longitudinal increase in WMH volume was associated with a longitudinal increase in PET amyloid uptake and a decrease in MRI hippocampal volume, cortical thickness, and cognition. The inflection point of baseline age in WMH volume was identified at 60.46 (95% CI 56.43-64.49) years, with the annual increase for the older participants (83.12 [SE = 10.19] mm3 per year) more than 13 times faster (p < 0.0001) than that for the younger participants (6.35 [SE = 5.63] mm3 per year). Accelerated rates of change among the older participants were similarly observed in almost all the AD biomarkers. Longitudinal correlations of WMH volume with MRI, PET amyloid biomarkers, and cognition seemed to be numerically stronger for the younger participants, but not significantly different from those for the older participants. Carrying APOE ε4 alleles did not alter the longitudinal correlations between WMH and AD biomarkers. DISCUSSION: Longitudinal increases in WMH volume started to accelerate around a baseline age of 60.46 years and correlated with the longitudinal change in PET amyloid uptake, MRI structural outcomes, and cognition.

Elecsys Cerebrospinal Fluid Immunoassays Accurately Detect Alzheimer's Disease Regardless of Concomitant Small Vessel Disease.

BACKGROUND: Differentiating dementia due to small vessel disease (SVD) from dementia due to Alzheimer's disease (AD) with concomitant SVD is challenging in clinical practice. Accurate and early diagnosis of AD is critical to delivering stratified patient care. OBJECTIVE: We characterized the results of Elecsys® cerebrospinal fluid (CSF) immunoassays (Roche Diagnostics International Ltd) in patients with early AD, diagnosed using core clinical criteria, with varying extent of SVD. METHODS: Frozen CSF samples (n = 84) were measured using Elecsys ß-Amyloid(1-42) (Aß42), Phospho-Tau (181P) (pTau181), and Total-Tau (tTau) CSF immunoassays, adapted for use on the cobas® e 411 analyzer (Roche Diagnostics International Ltd), and a robust prototype ß-Amyloid(1-40) (Aß40) CSF immunoassay. SVD was assessed by extent of white matter hyperintensities (WMH) using the lesion segmentation tool. Interrelations between WMH, biomarkers, fluorodeoxyglucose F18-positron emission tomography (FDG-PET), and other parameters (including age and Mini-Mental State examinations [MMSE]) were assessed using Spearman's correlation, sensitivity/specificity, and logistic/linear regression analyses. RESULTS: The extent of WMH showed significant correlation with Aß42/Aß40 ratio (Rho=-0.250; p = 0.040), tTau (Rho = 0.292; p = 0.016), tTau/Aß42 ratio (Rho = 0.247; p = 0.042), age (Rho = 0.373; p = 0.002), and MMSE (Rho=-0.410; p = 0.001). Sensitivity/specificity point estimates for Elecsys CSF immunoassays versus FDG-PET positivity for underlying AD pathophysiology were mostly comparable or greater in patients with high versus low WMH. WMH were not a significant predictor and did not interact with CSF biomarker positivity but modified the association between pTau181 and tTau. CONCLUSION: Elecsys CSF immunoassays detect AD pathophysiology regardless of concomitant SVD and may help to identify patients with early dementia with underlying AD pathophysiology.

Adjustment for the Age- and Gender-Related Metabolic Changes Improves the Differential Diagnosis of Parkinsonism.

Age and gender are the important factors for brain metabolic declines in both normal aging and neurodegeneration, and the confounding effects may influence early and differential diagnosis of neurodegenerative diseases based on the [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET). We aimed to explore the potential of the adjustment of age- and gender-related confounding factors on [18F]FDG PET images in differentiation of Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supra-nuclear palsy (PSP). Eight hundred and seventy-seven clinically definitely diagnosed Parkinsonian patients from a benchmark Huashan Parkinsonian PET imaging database were included. An age- and gender-adjusted Z (AGAZ) score was established based on the gender-specific longitudinal metabolic changes on healthy subjects. AGAZ scores and standardized uptake value ratio (SUVR) values were quantified at regional-level and support vector machine-based error-correcting output codes method was applied for classification. Additional references of the classifications based on metabolic pattern scores were included. The feature-based AGAZ score showed the best performance in classification (accuracy for PD, MSA, PSP: 93.1%, 96.3%, 94.8%). In both genders, the AGAZ score consistently achieved the best efficiency, and the improvements compared to the conventional SUVR value for PD, MSA, and PSP mainly laid in specificity (Male: 5.7%; Female: 11.1%), sensitivity (Male: 7.2%; Female: 7.3%), and sensitivity (Male: 7.3%; Female: 17.2%). Female patients benefited more from the adjustment on [18F]FDG PET in MSA and PSP groups (absolute net reclassification index, p < 0.001). Collectively, the adjustment of age- and gender-related confounding factors may improve the differential diagnosis of Parkinsonism. Particularly, the diagnosis of female Parkinsonian population has the best improvement from this correction. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00079-6.

Brain connectomics: time for a molecular imaging perspective?

In the past two decades brain connectomics has evolved into a major concept in neuroscience. However, the current perspective on brain connectivity and how it underpins brain function relies mainly on the hemodynamic signal of functional magnetic resonance imaging (MRI). Molecular imaging provides unique information inaccessible to MRI-based and electrophysiological techniques. Thus, positron emission tomography (PET) has been successfully applied to measure neural activity, neurotransmission, and proteinopathies in normal and pathological cognition. Here, we position molecular imaging within the brain connectivity framework from the perspective of timeliness, validity, reproducibility, and resolution. We encourage the neuroscientific community to take an integrative approach whereby MRI-based, electrophysiological techniques, and molecular imaging contribute to our understanding of the brain connectome.

Pattern and implications of neurological examination findings in autosomal dominant Alzheimer disease.

INTRODUCTION: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. METHODS: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. RESULTS: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. DISCUSSION: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

Negative symptoms, striatal dopamine and model-free reward decision-making in schizophrenia.

Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free reward predictions on decision-making ('reward prediction influence', RPI) underlie negative symptoms. We focused on psychotic remission, because psychotic symptoms might confound reward-based decision-making. Moreover, we hypothesized that impaired model-based/model-free RPIs depend on alterations of both associative striatum dopamine synthesis and storage (DSS) and executive functioning. Both factors influence RPI in healthy subjects and are typically impaired in schizophrenia. Twenty-five patients with schizophrenia with pronounced negative symptoms during psychotic remission and 24 healthy controls were included in the study. Negative symptom severity was measured by the Positive and Negative Syndrome Scale negative subscale, model-based/model-free RPI by the two-stage decision task, associative striatum DSS by 18F-DOPA positron emission tomography and executive functioning by the symbol coding task. Model-free RPI was selectively reduced in patients and associated with negative symptom severity as well as with reduced associative striatum DSS (in patients only) and executive functions (both in patients and controls). In contrast, model-based RPI was not altered in patients. Results provide evidence for impaired model-free reward prediction influence as a mechanism for negative symptoms in schizophrenia as well as for reduced associative striatum dopamine and executive dysfunction as relevant factors. Data suggest potential treatment targets for patients with schizophrenia and pronounced negative symptoms.

Utility of Amino Acid PET in the Differential Diagnosis of Recurrent Brain Metastases and Treatment-Related Changes: A Meta-analysis.

Amino acid PET is an established method to assist differential diagnosis of therapy-related changes versus recurrence in gliomas. However, its diagnostic value in brain metastases is yet to be determined. The goal of this study was to summarize evidence on the diagnostic utility of amino acid PET in recurrent brain metastases. Methods: The medical databases MEDLINE, EMBASE, and the Cochrane Library were screened for English-language studies with at least 10 patients who had undergone first-line treatment including radiotherapy and in whom a final diagnosis had been determined by histologic examination or imaging and clinical follow-up. Pooled estimates with 95% CIs were calculated. Heterogeneity was assessed using I2 statistics. Results: Following the above criteria, 12 studies with the tracers methyl-[11C]-methionine (n = 6), O-(2-[18F]fluoroethyl)-l-tyrosine (n = 3), methyl-[11C]-methionine and O-(2-[18F]fluoroethyl)-l-tyrosine (n = 1), and 6-[18F]fluoro-L-dopa (n = 2), with a total of 547 lesions in 397 patients, were included. Pooled sensitivity and specificity were 82% (95% CI, 76-86) and 84% (95% CI, 79-88), respectively. Pooled positive and negative predictive values were 84% (95% CI, 77-90) and 83% (95% CI, 77-88), respectively. Positive and negative likelihood ratios, and diagnostic odds ratio were 3.8 (95% CI 3.0-4.8), 0.3 (95% CI 0.2-0.3), and 16.7 (95% CI 10.8-25.9), respectively. Heterogeneity was overall low. Conclusion: The present meta-analysis indicates a good accuracy of amino acid PET in the differential diagnosis of recurrent brain metastases. In particular, specificity of 84% suggests that amino acid PET may reduce the number of invasive procedures and overtreatment in patients with treatment-related changes. This study provides class IIa evidence on the utility of amino acid PET in the differential diagnosis of recurrent brain metastases.

Herpes simplex virus alters Alzheimer's disease biomarkers - A hypothesis paper.

INTRODUCTION: Human herpes simplex virus 1 (HSV1) is discussed to induce amyloid-ß (Aß) accumulation and neurofibrillary tangles of hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) in cell culture and animal models. Aß appears to be virostatic. We investigated the association between intrathecal antibodies against HSV or cytomegalovirus (CMV) and cerebrospinal fluid (CSF) AD biomarkers. METHODS: Aß42 /Aß40 ratio, pTau, and tTau were measured in CSF of 117 patients with early AD positive for amyloid pathology (A+) and 30 healthy controls (A-). CSF-to-serum anti-HSV1/2-IgG antibody indices (AI-IgGHSV1/2 ) and CMV (AI-IgGCMV ) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Exclusively in HSV1-seropositive AD, pTau was positively and significantly predicted by AI-IgGHSV1/2 and negatively by the Aß42 /Aß40 ratio in both univariate and multivariate regression analyses. Furthermore, a significant and negative interaction between the AI-IgGHSV1/2 and Aß42 /Aß40 ratio on pTau was found. DISCUSSION: The results support the hypothesis that HSV infection contributes to AD. HIGHLIGHTS: HSV antibody index is positively associated with tau pathology in patients with AD. HSV antibody index is negatively associated with cerebral FDG metabolism. Amyloid modulates the association of HSV antibody index with CSF-pTau. HSV in AD offers a pathophysiological model connecting tau and amyloid.