Secondary prevention of Alzheimer\u2019s dementia: neuroimaging contributions

Chapter 11 - Cingulate role in Tourette syndrome

Hybrid PET-MRI Applications in Movement Disorders.

Establishing the in vivo diagnosis of Alzheimer’s disease (AD) or other dementias relies on clinical criteria; however, the accuracy of these criteria can be limited. The diagnostic accuracy is 77% for a clinical diagnosis of AD, even among experts. We performed a review through PubMed of articles related to specific diagnostic modalities, including APOE genotyping, cerebrospinal fluid (CSF) testing, fludeoxyglucose F 18 positron emission tomography (PET), amyloid PET, tau PET, computed tomography (CT), single-photon emission CT, magnetic resonance imaging (MRI), and B12 and thyroid-stimulating hormone screening, to determine the specificity and sensitivity of each test used in the clinical diagnosis of AD. We added a novel immunomagnetic reduction assay that provides ultrasensitivity for analyzing the levels of plasma tau and beta amyloid 42 (Aβ42). The sensitivity and specificity of the current diagnostic approach (structural CT or MRI with screening labs) remain low for clinical detection of AD and are primarily used to exclude other conditions. Because of limited diagnostic capabilities, physicians do not feel comfortable or skilled in rendering a clinical diagnosis of AD. Compounding this problem is the fact that inexpensive, minimally invasive diagnostic tests do not yet exist. Biomarkers (obtained through CSF testing or PET imaging), which are not routinely incorporated in clinical practice, correlate well with pathologic changes. While PET is particularly costly and difficult to assess, CSF measures of tau and beta amyloid are not costly, and these tests may be worthwhile when the tiered approach proposed here warrants further testing. There is a need for developing bloodborne biomarkers that can aid in the clinical diagnosis of AD. Here we present a streamlined questionnaire-enriched, biomarker-enriched approach that is more cost-effective than the current diagnosis of exclusion and is designed to increase clinical confidence for a diagnosis of dementia due to AD.

BackgroundHyperphosphorylated tau isoforms (p‐tau) in cerebrospinal fluid (CSF) and plasma represent promising measures to monitor Alzheimer disease (AD) pathological changes. Brain amyloid deposition precedes tau aggregation and associated clinical decline by two decades. Several CSF and plasma p‐tau isoforms have been described as potential surrogates for tau Positron Emission Tomography (PET) imaging, but p‐tau isoforms have a strong association with amyloid PET, and increase without tau pathology. In this study, we investigated the relationship between multiple CSF p‐tau isoforms and brain imaging measures in the Knight ADRC cohort.MethodWe analyzed 10 p‐tau isoforms by mass spectrometry in 1932 CSF samples (1173 participants). Associated data includes 1250 amyloid PET and 442 tau PET scans, as well as CSF Aβ42/Aβ40 by immunoassay for all samples. We measured phosphorylation occupancies (ptau/tau) at T111, T153, T175, T181, S199, S202, T205, S208, T217 and T231, together with corresponding p‐tau and tau concentrations. We compared the accuracy of CSF p‐tau isoforms in predicting amyloid PET and tau PET status stratified according to amyloid PET, tau PET and/or Clinical Dementia Rating (CDR) status.ResultsPT217/T217 best‐predicted abnormal amyloid PET (AUROC=0.980) or CSF Aβ42/Aβ40 (AUC=0.954). PT217/T217 predicted brain amyloidosis in asymptomatic and symptomatic participants with similar accuracy (AUC=0.979 and 0.986 respectively) and was correlated with amyloid PET centiloid and CSF Aβ42/Aβ40 (Spearman R=0.73 and ‐0.76, p<0.0001). Notably, the correlation between pT217/T217 and amyloid PET centiloid was higher in amyloid PET(+)/tau PET(‐) compared to amyloid PET(+)/tau‐PET(+) (R=0.77, p<0.0001 versus 0.16, p=0.007). PT205/T205 and pT217/T217 better predicted tau PET positivity in amyloid PET(+)positive participants (AUC=0.908 and 0.866). These markers were also associated with tau PET signal in tau PET(+) participants (R=0.53 and 0.55 p<0.0001). Other p‐tau isoforms also predicted amyloidosis, except for T175, S199, S202 and T205. Only pT205/T205 and pT217/T217 were correlated with tau‐PET in tau PET(+) participants.ConclusionThese results suggest that tau hyperphosphorylation, notably at T217, is more strongly associated with brain amyloid burden than tau deposition in tau PET(‐) individuals. After tau PET becomes positive, p‐tau217 and p‐tau205 are correlated with tau burden. Soluble p‐tau are markers of both amyloid and tau aggregation in the AD brain.

Neuroimaging studies have demonstrated that irritable bowel syndrome (IBS)—a relapsing functional bowel disorder—presents with disrupted brain connections. However, little is known about the alterations of interhemispheric functional connectivity and underlying structural connectivity in IBS. This study combined resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) to investigate changes in interhemispheric coordination in IBS patients. Resting-state functional and structural magnetic resonance images were acquired from 65 IBS patients and 67 healthy controls (HCs; matched for age, sex and educational level). Interhemispheric voxel-mirrored homotopic connectivity (VMHC) was calculated and compared between groups. Homotopic regions showing abnormal VMHC in patients were targeted as regions of interest (ROIs) for analysis of DTI tractography. The fractional anisotropy (FA), fiber number and fiber length were compared between groups. Statistical analysis was also performed by including anxiety and depression as covariates to evaluate their effect. A Pearson correlation analysis between abnormal interhemispheric connectivity and clinical indices of IBS patients was performed. Compared to HCs, IBS patients had higher interhemispheric functional connectivity between bilateral thalami, cuneus, posterior cingulate cortices (PCC), lingual gyri and inferior occipital/cerebellum lobes, as well as lower interhemispheric functional connectivity between bilateral ventral anterior cingulate cortices (vACC) and inferior parietal lobules (IPL). The inclusion of anxiety and depression as covariates abolished VMHC difference in vACC. Microstructural features of white matter tracts connecting functionally abnormal regions did not reveal any differences between the groups. VMHC values in vACC negatively correlated with the quality of life (QOL) scores of patients. In conclusion, this study provides preliminary evidence of the disrupted functional coordination rather than anatomic coordination between interhemispheric regions within the cortex-thalamus circuit in IBS patients, which could partly account for the enhanced visceral information processing and impaired endogenous pain or emotion inhibition associated with IBS.

Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease. To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+). This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022. Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined. The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin. This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioral changes, language abnormality, as well as executive function deficits and motor impairment. In about 30–50% of FTLD patients, an autosomal dominant pattern of inheritance was found with major mutations in the MAPT, GRN, and the C9orf72 repeat expansion. These mutations could lead to neurodegenerative pathology years before clinical symptoms onset. With potential disease-modifying treatments that are under development, non-invasive biomarkers that help determine the early brain changes in presymptomatic FTLD patients will be critical for tracking disease progression and enrolling the right participants into the clinical trials at the right time during the disease course. In recent years, there is increasing evidence that a number of imaging biomarkers show the abnormalities during the presymptomatic stage. Imaging biomarkers of presymptomatic familial FTLD may provide insight into the underlying neurodegenerative process years before symptom onset. Structural magnetic resonance imaging (MRI) has demonstrated cortical degeneration with a mutation-specific neurodegeneration pattern years before onset of clinical symptoms in presymptomatic familial FTLD mutation carriers. In addition, diffusion tensor imaging (DTI) has shown the loss of white matter microstructural integrity in the presymptomatic stage of familial FTLD. Furthermore, proton magnetic resonance spectroscopy (1H MRS), which provides a non-invasive measurement of brain biochemistry, has identified early neurochemical abnormalities in presymptomatic MAPT mutation carriers. Positron emission tomography (PET) imaging with [18F]-fluorodeoxyglucose (FDG) has demonstrated the glucose hypometabolism in the presymptomatic stage of familial FTLD. Also, a novel PET ligand, 18F-AV-1451, has been used in this group to evaluate tau deposition in the brain. Promising imaging biomarkers for presymptomatic familial FTLD have been identified and assessed for specificity and sensitivity for accurate prediction of symptom onset and tracking disease progression during the presymptomatic stage when clinical measures are not useful. Furthermore, identifying imaging biomarkers for the presymptomatic stage is important for the design of disease-modifying trials. We review the recent progress in imaging biomarkers of the presymptomatic phase of familial FTLD and discuss the imaging techniques and analysis methods, with a focus on the potential implication of these imaging techniques and their utility in specific mutation types.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

OP0169 Assessment of Lupus Nephritis Disease Activity Using Non-Contrast MRI: A Pilot Study

To compare diagnostic accuracy of T2-weighted magnetic resonance (MR) imaging with that of multiparametric (MP) MR imaging combining T2-weighted imaging with diffusion-weighted (DW) MR imaging, dynamic contrast material-enhanced (DCE) MR imaging, or both in the detection of locally recurrent prostate cancer (PCa) after radiation therapy (RT). This retrospective HIPAA-compliant study was approved by the institutional review board; informed consent was waived. Fifty-three men (median age, 70 years) suspected of having post-RT recurrence of PCa underwent MP MR imaging, including DW and DCE sequences, within 6 months after biopsy. Two readers independently evaluated the likelihood of PCa with a five-point scale for T2-weighted imaging alone, T2-weighted imaging with DW imaging, T2-weighted imaging with DCE imaging, and T2-weighted imaging with DW and DCE imaging, with at least a 4-week interval between evaluations. Areas under the receiver operating characteristic curve (AUC) were calculated. Interreader agreement was assessed, and quantitative parameters (apparent diffusion coefficient [ADC], volume transfer constant [K(trans)], and rate constant [k(ep)]) were assessed at sextant- and patient-based levels with generalized estimating equations and the Wilcoxon rank sum test, respectively. At biopsy, recurrence was present in 35 (66%) of 53 patients. In detection of recurrent PCa, T2-weighted imaging with DW imaging yielded higher AUCs (reader 1, 0.79-0.86; reader 2, 0.75-0.81) than T2-weighted imaging alone (reader 1, 0.63-0.67; reader 2, 0.46-0.49 [P ≤ .014 for all]). DCE sequences did not contribute significant incremental value to T2-weighted imaging with DW imaging (reader 1, P > .99; reader 2, P = .35). Interreader agreement was higher for combinations of MP MR imaging than for T2-weighted imaging alone (κ = 0.34-0.63 vs κ = 0.17-0.20). Medians of quantitative parameters differed significantly (P < .0001 to P = .0233) between benign tissue and PCa (ADC, 1.64 × 10(-3) mm(2)/sec vs 1.13 × 10(-3) mm(2)/sec; K(trans), 0.16 min(-1) vs 0.33 min(-1); k(ep), 0.36 min(-1) vs 0.62 min(-1)). MP MR imaging has greater accuracy in the detection of recurrent PCa after RT than T2-weighted imaging alone, with no additional benefit if DCE is added to T2-weighted imaging and DW imaging.

BackgroundLower plasma ratio of amyloid beta (Ab42/Ab40) has been associated with brain amyloid, however, the mechanistic link is unclear. Systemic inflammation may contribute to plasma Ab levels and promote or reduce the accumulation of Alzheimer’s disease (AD) neuropathology. C reactive protein (CRP) is an inflammatory marker implicated in amyloidosis. Using a cross sectional analysis, we evaluated the relationship between blood levels of CRP and Ab ratio, global amyloid positron emission tomography (PET), and tau PET in the entorhinal cortex where tau accumulates early. We hypothesized that Ab positivity would modify the relationship between CRP and AD pathology.MethodIn 969 cognitively normal participants (age: 50‐87, 781 Ab‐/188 Ab+) (Table 1) from the Health and Aging Brain Study‐ Health Disparities (HABS‐HD), we acquired 18F‐PI‐2620 tau‐PET, florbetaben amyloid PET scans, and plasma measures of Ab 42/40 and CRP. Subjects were categorized by Ab + or Ab ‐ by a global amyloid PET standardized uptake value ratio (SUVR) cutoff of 1.08. Within Ab groups, we performed multiple regressions to evaluate associations between 1) global amyloid and entorhinal tau‐PET SUVRs and 2) plasma markers of Ab ratio and CRP. We covaried for age, gender, education, APOE4, and scanner and used false discovery rate (FDR) for multiple comparison corrections.ResultIn Ab+ participants, higher amyloid (b = ‐0.31, p = 0.0005) and tau PET (b = ‐0.36, p = 0.004) were significantly associated with low Ab ratio, but not in Ab‐ for amyloid or tau, with significant interactions by Ab positivity for amyloid (b = ‐0.45, p = 2.65×10−6) and tau (b = ‐0.77, p = 0.0002) (Figure 1). In Ab+ participants, higher CRP was associated with higher Ab ratio (b = 0.21, p = 0.04) and a trend toward lower amyloid (b = ‐0.15, p = 0.084) and tau PET (b = ‐0.22, p = 0.084), but not in Ab‐ participants, with a significant interaction by Ab positivity for Ab ratio (b = 0.46, p = 0.011) (Figure 2) and amyloid (b = ‐0.11, p = 0.0006) and tau PET (b = ‐0.17, p = 0.016).ConclusionIn cognitively intact Ab+ but not Ab‐ adults, higher plasma Ab ratio was associated with lower global amyloid and entorhinal tau PET. In Ab+ participants, higher CRP was associated with blood and brain amyloid and tau levels consistent with less AD pathology.

In this study, we examined whether topologic network analysis, using resting state functional magnetic resonance imaging (MRI), can detect abnormalities of functional brain connectivity in children with unilateral brain injury due to Sturge-Weber syndrome. Three children with Sturge-Weber syndrome (ages 1, 3, and 10 years) underwent structural and resting state functional MRI, glucose metabolism positron emission tomography (PET), and neurocognitive evaluation. Eight different resting state networks were compared between the affected and unaffected hemispheres by quantitatively accessing communication efficiency measures. Significantly reduced efficiency values were found in all 3 patients. Visual network deficiency was present in both children with a visual field defect; frontal network abnormalities were associated with fine motor impairment. Location of network abnormalities corresponded to and, in some cases, extended beyond structural MRI and glucose PET abnormalities. The presented approach can detect early functional abnormalities of specific brain networks in children with Sturge-Weber syndrome.

Alzheimer's disease (AD) is the most common cause of dementia. Neuropathological changes in AD patients occur up to 10–20 years before the emergence of clinical symptoms. Specific diagnosis and appropriate intervention strategies are crucial during the phase of mild cognitive impairment (MCI) and AD. The detection of biomarkers has emerged as a promising tool for tracking the efficacy of potential therapies, making an early disease diagnosis, and prejudging treatment prognosis. Specifically, multiple neuroimaging modalities, including magnetic resonance imaging (MRI), positron emission tomography, optical imaging, and single photon emission-computed tomography, have provided a few potential biomarkers for clinical application. The MRI modalities described in this review include structural MRI, functional MRI, diffusion tensor imaging, magnetic resonance spectroscopy, and arterial spin labelling. These techniques allow the detection of presymptomatic diagnostic biomarkers in the brains of cognitively normal elderly people and might also be used to monitor AD disease progression after the onset of clinical symptoms. This review highlights potential biomarkers, merits, and demerits of different neuroimaging modalities and their clinical value in MCI and AD patients. Further studies are necessary to explore more biomarkers and overcome the limitations of multiple neuroimaging modalities for inclusion in diagnostic criteria for AD.

Specific Substantial Dysconnectivity in Schizophrenia: A Transdiagnostic Multimodal Meta-analysis of Resting-State Functional and Structural Magnetic Resonance Imaging Studies

Distinguishing schizophrenia and bipolar disorder through a Multiclass Classification model based on multimodal neuroimaging data