Is there utility for fluorine-18-fluorodeoxyglucose positron-emission tomography scan before surgery in breast cancer? A 15-year overall survival analysis.

BACKGROUND: The prognostic value of preoperative fluorine-18-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) scan for determining overall survival (OS) in breast cancer (BC) patients is controversial. AIM: To evaluate the OS predictive value of preoperative PET positivity after 15 years. METHODS: We performed a retrospective search of the Universitair Ziekenhuis Brussel patient database for nonmetastatic patients who underwent preoperative PET between 2002-2008. PET positivity was determined by anatomical region of interest (AROI) findings for breast and axillary, sternal, and distant sites. The prognostic role of PET was examined as a qualitative binary factor (positive vs negative status) and as a continuous variable [maximum standard uptake value (SUVmax)] in multivariate survival analyses using Cox proportional hazards models. Among the 104 identified patients who received PET, 36 were further analyzed for the SUVmax in the AROI. RESULTS: Poor OS within the 15-year study period was predicted by PET-positive status for axillary (P = 0.033), sternal (P = 0.033), and combined PET-axillary/sternal (P = 0.008) nodes. Poor disease-free survival was associated with PET-positive axillary status (P = 0.040) and combined axillary/sternal status (P = 0.023). Cox models confirmed the long-term prognostic value of combined PET-axillary/sternal status [hazard ratio (HR): 3.08, 95% confidence interval: 1.42-6.69]. SUVmax of ipsilateral breast and axilla as continuous covariates were significant predictors of long-term OS with HRs of 1.25 (P = 0.048) and 1.54 (P = 0.029), corresponding to relative increase in the risk of death of 25% and 54% per SUVmax unit, respectively. In addition, the ratio of the ipsilateral axillary SUVmax over the contralateral axillary SUVmax was the most significant OS predictor (P = 0.027), with 1.94 HR, indicating a two-fold relative increase of mortality risk. CONCLUSION: Preoperative PET is valuable for prediction of long-term survival. Ipsilateral axillary SUVmax ratio over the uninvolved side represents a new prognostic finding that warrants further investigation.

Pulmonary 99mTc-HMDP uptake correlates with restrictive ventilatory defects and abnormal lung reactance in transthyretin cardiac amyloidosis patients.

BACKGROUND: Pulmonary involvement in individuals with transthyretin cardiac amyloidosis is unclear. The aim of this study was to quantify 99mTc-hydroxy methylene diphosphonate (HMDP) lung retention in hereditary transthyretin (ATTRv) cardiac amyloidosis patients and to relate tracer uptake intensity to pulmonary function and aerobic capacity. METHODS: We prospectively enrolled 20 patients with biopsy-proven ATTRv cardiac amyloidosis and 20 control subjects. Cardiac involvement was confirmed by echocardiography and nuclear imaging using 99mTc-HMDP. Semi-quantitative analysis of the heart, rib and lung retention was assessed using a simple region of interest technique. Pulmonary function was evaluation by the means of whole-body plethysmography, diffusing capacity of the lung for carbon monoxide, forced oscillation technique and cardiopulmonary exercise testing. RESULTS: Pulmonary tracer uptake estimated by lung to rib retention ratio was higher in ATTRv amyloidosis patients compared with control subjects: median 0.62 (0.55-0.69) vs 0.51 (0.46-0.60); p = 0.014. Analysis of relation between lung 99mTc-HMDP retention and pulmonary function parameters shown statistically significant correlations with total lung volume (% predicted), lung reactance (Xrs 5 Hz) and peak VO2, suggesting total lung capacity restriction impaired elastic properties of the lung and poor aerobic capacity. CONCLUSION: Our study suggests that some grade of pulmonary retention of 99mTc-HMDP may occur in patients with cardiac ATTRv amyloidosis, which can elicit deleterious effects on patient's lung function and aerobic capacity.

Cognitive decline and brainstem hypometabolism in long COVID: A case series.

OBJECTIVE: To assess FDG cerebral PET in patients suffering from cognitive impairment linked to Long COVID. The COVID pandemic has affected dozens of millions of people around the world and has resulted in the deaths of more than 3 million people. Following the acute forms, it has been reported sometimes long forms of COVID, with involvements of several organs including the brain. Neurological complications can include cognitive disturbances (brain fog) that are very common and can seriously disturb the life of patients. METHODS: Fluorodeoxyglucose PETs were performed in 3 patients with cognitive decline following COVID infection. RESULTS: We report here 3 cases of brain fog with major hypometabolic areas of the pons revealed by the cerebral FDG PET. CONCLUSION: The dysfunction of the locus coeruleus in these patients could partly explain the cognitive disorders observed. Further studies involving larger cohorts of patients suffering from cognitive dysfunction will be needed to determine if the brainstem is frequently affected in these patients.

Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex.

Many patients who have suffered from acute COVID infections have long-lasting symptoms affecting several organs including the brain. This long COVID status can include "brain fog" and cognitive deficits that can disturb activities of daily living and can delay complete recovery. Here, we report two cases of neurological long COVID with abnormal FDG PET findings marked by hypometabolic regions of the cingulate cortex.

Breast cancer preoperative 18FDG-PET, overall survival prognostic separation compared with the lymph node ratio.

PURPOSE: To evaluate the overall survival prognostic value of preoperative 18F-fluorodeoxyglucose positron emission tomography (PET) in breast cancer, as compared with the lymph node ratio (LNR). METHODS: Data were abstracted at a median follow-up 14.7 years from a retrospective cohort of 104 patients who underwent PET imaging before curative surgery. PET-Axillary|Sternal was classified as PET-positive if hypermetabolism was visualized in ipsilateral nodal axillary and/or sternal region, else as PET-negative. The differences of 15 years restricted mean survival time ∆RMST according to PET and LNR were computed from Kaplan-Meier overall survival. The effect of PET and other patients' characteristics was analyzed through rankit normalization, which provides with Cox regression the Royston-Sauerbrei D measure of separation to compare the characteristics (0 indicating no prognostic value). Multivariate analysis of the normalized characteristics used stepwise selection with the Akaike information criterion. RESULTS: In Kaplan-Meier analysis, LNR > 0.20 versus ≤ 0.20 showed ∆RMST = 3.4 years, P = 0.003. PET-Axillary|Sternal positivity versus PET-negative showed a ∆RMST = 2.6 years, P = 0.008. In Cox univariate analyses, LNR appeared as topmost prognostic separator, D = 1.50, P < 0.001. PET ranked below but was also highly significant, D = 1.02, P = 0.009. In multivariate analyses, LNR and PET-Axillary|Sternal were colinear and mutually exclusive. PET-Axillary|Sternal improved as prognosticator in a model excluding lymph nodes, yielding a normalized hazard ratio of 2.44, P = 0.062. CONCLUSION: Pathological lymph node assessment remains the gold standard of prognosis. However, PET appears as a valuable surrogate in univariate analysis at 15-year follow-up. There was a trend towards significance in multivariate analysis that warrants further investigation.

Brain Glucose Metabolism in Cerebral Amyloid Angiopathy: An FDG-PET Study.

BACKGROUND AND PURPOSE: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is currently based on the Boston criteria, which largely rely on hemorrhagic features on brain magnetic resonance imaging. Adding to these criteria 18F-fluoro-deoxy-D-glucose (FDG) positron emission tomography, a widely available imaging modality, might improve their accuracy. Here we tested the hypothesis that FDG uptake is reduced in posterior cortical areas, particularly the primary occipital cortex, which pathologically bear the brunt of vascular Aß deposition. METHODS: From a large memory clinic database, we retrospectively included all patients in whom both brain magnetic resonance imaging and FDG positron emission tomography had been obtained as part of routine clinical care and who fulfilled the Boston criteria for probable CAA. None had a history of symptomatic intracerebral hemorrhage. FDG data processing involved (1) spatial normalization to the Montreal Neurology Institute/International Consortium for Brain Mapping 152 space and (2) generation of standardized FDG uptake (relative standardized uptake value; relative to the pons). The relative standardized uptake value data obtained in 13 regions of interest sampling key cortical areas and the cerebellum were compared between the CAA and age-matched control groups using 2 separate healthy subject databases and image-processing pipelines. The presence of significant hypometabolism (2-tailed P<0.05) was assessed for the bilaterally averaged regions-of-interest relative standardized uptake values. RESULTS: Fourteen patients fulfilling the Boston criteria for probable CAA (≥2 exclusively lobar microbleeds) were identified. Significant hypometabolism (P range, 0.047 to <0.0001) consistently affected the posterior cortical areas, including the superior and inferior parietal, primary visual, lateral occipital, lateral temporal, precuneus, and posterior cingulate regions of interest. The anterior cortical areas were marginally or not significantly hypometabolic, and the cerebellum was spared. CONCLUSIONS: Supporting our hypothesis, significant glucose hypometabolism predominantly affected posterior cortical regions, including the visual cortex. These findings from a small sample may have diagnostic implications but require replication in larger prospective studies. In addition, whether they generalize to CAA-related symptomatic intracerebral hemorrhage warrants specific studies.

[18 F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer's disease.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a frequent cause of both intracerebral hemorrhage (ICH) and cognitive impairment in the elderly. Diagnosis relies on the Boston criteria, which use magnetic resonance imaging markers including ≥2 exclusively lobar cerebral microbleeds (lCMBs). Although amyloid positron emission tomography (PET) may provide molecular diagnosis, its specificity relative to Alzheimer's disease (AD) is limited due to the prevalence of positive amyloid PET in cognitively normal elderly. Using early-phase 11 C-Pittsburgh compound B as surrogate for tissue perfusion, a significantly lower occipital/posterior cingulate (O/PC) tracer uptake ratio in probable CAA relative to AD was recently reported, consistent with histopathological lesion distribution. We tested whether this finding could be reproduced using [18 F]fluorodeoxyglucose (FDG)-PET, a widely available modality that correlates well with early-phase amyloid PET in both healthy subjects and AD. METHODS: From a large memory clinic database, we retrospectively included 14 patients with probable CAA (Boston criteria) and 21 patients with no lCMB fulfilling AD criteria including cerebrospinal fluid biomarkers. In all, [18 F]FDG-PET/computed tomography (CT) was available as part of routine care. No subject had a clinical history of ICH. Regional standardized [18 F]FDG uptake values normalized to the pons (standard uptake value ratio [SUVr]) were obtained, and the O/PC ratio was calculated. RESULTS: The SUVr O/PC ratio was significantly lower in CAA versus AD (1.02 ± 0.14 vs. 1.19 ± 0.18, respectively; p = 0.024). CONCLUSIONS: Despite the small sample, our findings are consistent with the previous early-phase amyloid PET study. Thus, [18 F]FDG-PET may help differentiate CAA from AD, particularly in cases of amyloid PET positivity. Larger prospective studies, including in CAA-related ICH, are however warranted.

Brain 18FDG-PET pattern in patients with alcohol-related cognitive impairment.

PURPOSE: Brain positron emission tomography using 18F-fluorodeoxyglucose (18FDG-PET) provides a metabolic assessment of brain function that is useful for differential diagnosis among several neurodegenerative diseases manifested by cognitive impairment (CI). The purpose of the study is to describe the pattern of 18FDG-PET abnormalities in patients with CI related to alcohol use disorder. METHODS: Patients admitted to the addiction medicine department of a university hospital in Paris between January 2017 and October 2018 with a confirmed diagnosis of alcohol-related cognitive impairment (ARCI) or Wernicke encephalopathy (WE) were included. Brain 18FDG-PET uptake was measured after at least 1 month of monitored abstinence from alcohol. Standardized uptake values were obtained for 13 regions of interest (ROI) and normalized to the pons. Individual patients' ROI Z-scores were calculated from healthy sex- and age-matched controls provided by Cortex ID software. RESULTS: Twenty-five patients were included in the analysis (20 males and 5 females; mean age 57.6 years (45-76 years old)). The group consisted of 19 ARCI and 6 WE cases. The mean hypometabolism was most severe in the prefrontal medial cortex (PFM) (- 2.80 (± 1.30)), the prefrontal lateral cortex (- 2.20 (± 1.35)), and the anterior cingulate cortex (- 2.24 (± 1.19)). Hypometabolism (Z-score < - 2) was most frequent in the PFM (72.0% of the sample, N = 18). Other regions were also affected (with 5.32/13 hypometabolic ROIs on average (SD = 4.16, range 0-13)). The Z-scores in the 13 ROIs did not differ significantly between the ARCI and WE patients (p ≥ 0.05). CONCLUSIONS: Predominant prefrontal and cingulate cortex hypometabolism was the most frequent brain 18FDG-PET pattern in our sample of patients with ARCI and WE.

PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions.

Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aß peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aß oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro-apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron-microglia co-cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine-month-old double-mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double-mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double-mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia-induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD.

The effect of combined corticotomy and low level laser therapy on the rate of orthodontic tooth movement: split mouth randomized clinical trial.

PURPOSE: The aim of this study was to evaluate the combined effect of corticotomy and Low-Level Laser Therapy(LLLT) on the rate of orthodontic tooth movement. METHODS: A randomized split-mouth design for 16 female patients compared the rate of maxillary canine retraction using corticotomy combined with LLLT versus corticotomy only. The device used in the present study was an In-Ga-As semiconductor diode laser emitting at 940 nm (IR) with these parameters: 0.5 W/ cm2 power density, 5 J/cm2 Fluence, CW, 240 sec time irradiation, weekly for the first month and twice monthly for the next three months. Assessment of the rate of canine retraction was carried out via a series of dental models. RESULTS: A non-significant statistical rate of canine retraction was achieved by LLLT combined to corticotomy compared with the corticotomy technique alone. CONCLUSION: Low-Level Laser Therapy combined to corticotomy could not achieve a higher rate of canine retraction compared to the golden standard corticotomy technique alone. No long-term adverse effects on the alveolar mucosa were detected following both techniques.

Pattern of care of prostate cancer patients across the Martinique: results of a population-based study in the Caribbean.

BACKGROUND: The French West-Indies rank first for both prostate cancer incidence and mortality rates. Analyzing diagnostic and therapeutic procedures among patients with prostate cancer, using data from a population-based cancer registry, is essential for cancer surveillance and research strategies. METHODS: This retrospective observational cohort study was based on data from the Martinique Cancer Registry. Records of 452 patients diagnosed with prostate cancer in 2013 were retrieved from the registry. Data extracted were: socio-demographic and clinical characteristics, circumstances of diagnosis, PSA level at diagnosis, Gleason score and risk of disease progression. Stage at diagnosis and patterns of care among prostate cancer patients were analyzed. RESULTS: Mean age at diagnosis was 67 ± 8 years; 103 (28.5%) were symptomatic at diagnosis. Digital rectal exam was performed in 406 (93.8%). Clinical stage was available in 385 (85.2%); tumours were localized in 322/385 (83.6%). Overall, 17.9% were at low risk, 36.4% at intermediate and 31.9% at high risk; 13.8% were regional/metastatic cancers. Median PSA level at diagnosis was 8.16 ng/mL (range 1.4-5000 ng/mL). A total of 373 patients (82.5%) received at least one treatment, while 79 (17.5%) had active surveillance or watchful waiting. Among patients treated with more than one therapeutic strategy, the most frequent combination was external radiotherapy with androgen deprivation (n = 102, 22.6%). CONCLUSIONS: This study provides detailed data regarding the quality of diagnosis and management of patients with prostate cancer in Martinique. Providing data on prostate cancer is essential for the development of high-priority public health measures for the Caribbean.

Cohort profile: the Martinique Cancer Registry and the quality of life prostate cancer cohort (QoL Prostate-MQ): challenges and prospects for reducing disparities in the Caribbean.

PURPOSE: Recording cancer data in cancer registries is essential for producing reliable population-based data for service planning, monitoring and evaluation. Prostate cancer (PCa) remains the most frequent type of cancer in terms of incidence and mortality in men in the Caribbean. The quality of life PCa cohort will assess quality of life and patient outcomes in Martinique using a digital platform for patient-reported outcome measures. PARTICIPANTS: The Martinique Cancer Registry database is the largest clinical database among the French population-based cancer registries in the Caribbean, including more than 38 000 cancer cases, with 1650 new cancer cases per year, including 550 new PCa cases per year (2010-2014 latest period). In 2018, follow-up will include vital status, assessment of quality of life with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core 30 and the Prostate cancer module QLQ-PR25. Urinary incontinence and erectile dysfunction recorded prior to treatment will be analysed 1 and 5 years after treatment. FINDINGS TO DATE: The registry includes data on circumstances of diagnosis, clinical stage at diagnosis. For PCa, the registry includes blood prostate-specific antigen level at the time of diagnosis, Gleason score and primary treatment. FUTURE PLANS: Further studies will provide detailed data regarding the quality of diagnosis and management of patients with PCa in Martinique; analysing quality of care will be the next challenge.Quality of life and patient outcomes will be evaluated using a digital platform for patient-reported outcome measurement and electronic records.

Amyloid-PET burden and regional distribution in cerebral amyloid angiopathy: a systematic review and meta-analysis of biomarker performance.

INTRODUCTION: We performed a meta-analysis to synthesise current evidence on amyloid-positron emission tomography (PET) burden and presumed preferential occipital distribution in sporadic cerebral amyloid angiopathy (CAA). METHODS: In a PubMed systematic search, we identified case-control studies with extractable data on global and occipital-to-global amyloid-PET uptake in symptomatic patients with CAA (per Boston criteria) versus control groups (healthy participants or patients with non-CAA deep intracerebral haemorrhage) and patients with Alzheimer's disease. To circumvent PET studies' methodological variation, we generated and used 'fold change', that is, ratio of mean amyloid uptake (global and occipital-to-global) of CAA relative to comparison groups. Amyloid-PET uptake biomarker performance was then quantified by random-effects meta-analysis on the ratios of the means. A ratio >1 indicates that amyloid-PET uptake (global or occipital/global) is higher in CAA than comparison groups, and a ratio <1 indicates the reverse. RESULTS: Seven studies, including 106 patients with CAA (>90% with probable CAA) and 138 controls (96 healthy elderly, 42 deep intracerebral haemorrhage controls) and 72 patients with Alzheimer's disease, were included. Global amyloid-PET ratio between patients with CAA and controls was above 1, with an average effect size of 1.18 (95% CI 1.08 to 1.28; p<0.0001). Occipital-to-global amyloid-PET uptake ratio did not differ between patients with CAA versus patients with deep intracerebral haemorrhage or healthy controls. By contrast, occipital-to-global amyloid-PET uptake ratio was above 1 in patients with CAA versus those with Alzheimer's disease, with an average ratio of 1.10 (95% CI 1.03 to 1.19; p=0.009) and high statistical heterogeneity. CONCLUSIONS: Our analysis provides exploratory actionable data on the overall effect sizes and strength of amyloid-PET burden and distribution in patients with CAA, useful for future larger studies.

Amyloid-PET in sporadic cerebral amyloid angiopathy: A diagnostic accuracy meta-analysis.

OBJECTIVE: To perform a meta-analysis synthesizing evidence of the value and accuracy of amyloid-PET in diagnosing patients with sporadic cerebral amyloid angiopathy (CAA). METHODS: In a PubMed systematic literature search, we identified all case-control studies with extractable data relevant for the sensitivity and specificity of amyloid-PET positivity in symptomatic patients with CAA (cases) vs healthy participants or patients with spontaneous deep intracerebral hemorrhage (ICH) (control groups). Using a hierarchical (multilevel) logistic regression model, we calculated pooled diagnostic test accuracy. RESULTS: Seven studies, including 106 patients with CAA (>90% with probable CAA) and 151 controls, were eligible and included in the meta-analysis. The studies were of moderate to high quality and varied in several methodological aspects, including definition of PET-positive and PET-negative cases and relevant cutoffs. The sensitivity of amyloid-PET for CAA diagnosis ranged from 60% to 91% and the specificity from 56% to 90%. The overall pooled sensitivity was 79% (95% confidence interval [CI] 62-89) and specificity was 78% (95% CI 67-86) for CAA diagnosis. A predefined subgroup analysis of studies restricted to symptomatic patients presenting with lobar ICH CAA (n = 58 vs 86 controls) resulted in 79% sensitivity (95% CI 61-90%) and 84% specificity (95% CI 65-93%). In prespecified bivariate diagnostic accuracy meta-analysis of 2 studies using 18F-florbetapir-PET, the sensitivity for CAA-ICH diagnosis was 90% (95% CI 76-100%) and specificity was 88% (95% CI 74-100%). CONCLUSIONS: Amyloid-PET appears to have moderate to good diagnostic accuracy in differentiating patients with probable CAA from cognitively normal healthy controls or patients with deep ICH. Given that amyloid-PET labels both cerebrovascular and parenchymal amyloid, a negative scan might be useful to rule out CAA in the appropriate clinical setting.

Preoperative [18]fluorodeoxyglucose-positron emission tomography/computed tomography in early stage breast cancer: Rates of distant metastases.

AIM: To investigate rates of distant metastases (DM) detected with [18]fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) in early stage invasive breast cancer. METHODS: We searched the English language literature databases of PubMed, EMBASE, ISI Web of Knowledge, Web of Science and Google Scholar, for publications on DM detected in patients who had 18FDG-PET/CT scans as part of the staging for early stages of breast cancer (stage I and II), prior to or immediately following surgery. Reports published between 2011 and 2017 were considered. The systematic review was conducted according to the PRISMA guidelines. RESULTS: Among the 18 total studies included in the analysis, the risk of DM ranged from 0% to 8.3% and 0% to 12.9% for stage I and II invasive breast cancer, respectively. Among the patients with clinical stage II, the rate of occult metastases diagnosed by 18FDG-PET/CT was 7.2% (range, 0%-19.6%) for stage IIA and 15.8% (range, 0%-40.8%) for stage IIB. In young patients (< 40-year-old), 18FDG-PET/CT demonstrated a higher prevalence of DM at the time of diagnosis for those with aggressive histology (i.e., triple-negative receptors and poorly differentiated grade). CONCLUSION: Young patients with poorly differentiated tumors and stage IIB triple-negative breast cancer may benefit from 18FDG-PET/CT at initial staging to detect occult DM prior to surgery.

Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update.

Sporadic cerebral amyloid angiopathy (CAA) is a very common small vessel disease of the brain, showing preferential and progressive amyloid-ßdeposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. CAA now encompasses not only a specific cerebrovascular pathological trait, but also different clinical syndromes - including spontaneous lobar intracerebral haemorrhage (ICH), dementia and 'amyloid spells' - an expanding spectrum of brain parenchymal MRI lesions and a set of diagnostic criteria - the Boston criteria, which have resulted in increasingly detecting CAA during life. Although currently available validated diagnostic criteria perform well in multiple lobar ICH, a formal diagnosis is currently lacking unless a brain biopsy is performed. This is partly because in practice CAA MRI biomarkers provide only indirect evidence for the disease. An accurate diagnosis of CAA in different clinical settings would have substantial impact for ICH risk stratification and antithrombotic drug use in elderly people, but also for sample homogeneity in drug trials. It has recently been demonstrated that vascular (in addition to parenchymal) amyloid-ßdeposition can be detected and quantified in vivo by positron emission tomography (PET) amyloid tracers. This non-invasive approach has the potential to provide a molecular signature of CAA, and could in turn have major clinical impact. However, several issues around amyloid-PET in CAA remain unsettled and hence its diagnostic utility is limited. In this article we systematically review and critically appraise the published literature on amyloid-PET (PiB and other tracers) in sporadic CAA. We focus on two key areas: (a) the diagnostic utility of amyloid-PET in CAA and (b) the use of amyloid-PET as a window to understand pathophysiological mechanism of the disease. Key issues around amyloid-PET imaging in CAA, including relevant technical aspects are also covered in depth. A total of six small-scale studies have addressed (or reported data useful to address) the diagnostic utility of late-phase amyloid PET imaging in CAA, and one additional study dealt with early PiB images as a proxy of brain perfusion. Across these studies, amyloid PET imaging has definite diagnostic utility (currently tested only in probable CAA): it helps rule out CAA if negative, whether compared to healthy controls or to hypertensive deep ICH controls. If positive, however, differentiation from underlying incipient Alzheimer's disease (AD) can be challenging and so far, no approach (regional values, ratios, visual assessment) seems sufficient and specific enough, although early PiB data seem to hold promise. Based on the available evidence reviewed, we suggest a tentative diagnostic flow algorithm for amyloid-PET use in the clinical setting of suspected CAA, combining early- and late-phase PiB-PET images. We also identified ten mechanistic amyloid-PET studies providing early but promising proof-of-concept data on CAA pathophysiology and its various manifestations including key MRI lesions, cognitive impairment and large scale brain alterations. Key open questions that should be addressed in future studies of amyloid-PET imaging in CAA are identified and highlighted.

Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-ß, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-ß plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-ß plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-ß plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-ß plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-ß plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-ß plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.

Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value?

Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1-6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aß-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD.