Cerebellar and Cerebral Amyloid Visualized by [18F]flutemetamol PET in Long-Term Hereditary V30M (p.V50M) Transthyretin Amyloidosis Survivors.

Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS. Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8-25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls. Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD. Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

VALZ-Pilot: High-dose valacyclovir treatment in patients with early-stage Alzheimer's disease.

Introduction: Herpes simplex virus (HSV) may be involved in Alzheimer's disease (AD) pathophysiology. The antiviral valacyclovir inhibits HSV replication. Methods: This phase-II pilot trial involved valacyclovir administration (thrice daily, 500 mg week 1, 1000 mg weeks 2-4) to persons aged ≥ 65 years with early-stage AD, anti-HSV immunoglobulin G, and apolipoprotein E ε4. Intervention safety, tolerability, feasibility, and effects on Mini-Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarkers were evaluated. Results: Thirty-two of 33 subjects completed the trial on full dosage. Eighteen percent experienced likely intervention-related mild, temporary adverse events. CSF acyclovir concentrations were mean 5.29 ± 2.31 µmol/L. CSF total tau and neurofilament light concentrations were unchanged; MMSE score and CSF soluble triggering receptor expressed on myeloid cells 2 concentrations increased (P = .02 and .03). Discussion: Four weeks of high-dose valacyclovir treatment was safe, tolerable, and feasible in early-stage AD. Our findings may guide future trial design.

Combining ECG and echocardiography to identify transthyretin cardiac amyloidosis in heart failure.

AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure (HF). The aim of this study was to evaluate the efficacy of electrocardiogram (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients. METHODS: We investigated 58 patients with HF and an IVSd > 14 mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis HFpatients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy. We used echocardiography including 2D speckle-tracking strain and a 12-lead ECG to test the accuracy to differentiate the groups. RESULTS: We found high diagnostic accuracy (98%) for differentiating ATTR-CA from HF controls using a combination of R amplitude in -aVR from ECG and relative wall thickness acquired from echocardiography. With this combined model (RWT/R in -aVR), the sensitivity was 100% and specificity was 95% using a cut-off value of 0.90. Furthermore, the area under the curve was 99% and the negative predictive value was 100%. CONCLUSION: We found that a simple combination of ECG and echocardiographic parameters used in clinical settings was able to differentiate ATTR-CA from other aetiologies of HF with increased interventricular septum thickness. The high sensitivity and negative predictive value render the algorithm useful for selection of patients for further diagnostic procedures for ATTR-CA.

Cardiac transthyretin amyloidosis 99mTc-DPD SPECT correlates with strain echocardiography and biomarkers.

PURPOSE: Hereditary transthyretin-amyloid amyloidosis (ATTRv) is an underdiagnosed condition commonly manifesting as congestive heart failure. Recently, scintigraphy utilizing DPD as a tracer was shown to identify ATTRv and wild-type ATTR cardiomyopathy. The aim of this study was to determine the value of quantified scintigraphy utilizing 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) single-photon emission computed tomography (SPECT)/CT, and to correlate its uptake with well-established cardiac functional parameters. METHODS: Forty-eight patients with genetically verified ATTRv type-A fibril composition, positive 99mTc-DPD SPECT/CT, were retrospectively analyzed. Manual mapping of volumes of interest (VOIs) on DPD SPECT/CT examinations was used to quantify heart uptake. DPD mean and maximum uptake together with a calculated DPD-based amyloid burden (DPDload) was correlated with echocardiographic strain values and cardiac biomarkers. RESULTS: Statistically significant correlations were seen in VOIs between DPD uptakes and the corresponding echocardiographic strain values. Furthermore, DPDload had a strong correlation with echocardiographic strain parameters and also correlated with biomarkers troponin T and logarithmic NT-ProBNP. CONCLUSIONS: In patients with ATTRv cardiomyopathy, DPD SPECT/CT measures the amyloid distribution and provides information on cardiac amyloid load. DPD amyloid load correlates with functional cardiac parameters.

Prevalence of wild type transtyrethin cardiac amyloidosis in a heart failure clinic.

AIMS: Wild type transthyretin amyloidosis (ATTRwt) has gained interest during recent years due to better diagnostic tools and the emergence of treatment options. Little is known about the prevalence of the disease. We aimed to investigate the prevalence in a heart failure population with myocardial hypertrophy. METHODS AND RESULTS: All patients with an ICD code of heart failure living within the catchment area of Umeå University hospital and intraventricular septum >14 mm were offered screening with 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scan and a clinical work up. Out of 2238 patients with heart failure, 174 patients were found to have a septum >14 mm. Ten patients were already diagnosed with hereditary ATTR cardiomyopathy, 12 patients had ATTRwt cardiomyopathy, 12 patients had known HCM, one patient had AL amyloidosis, and four patients had already undergone a negative DPD scan (DPD uptake grade 0 and 1) within the last 3 years. This left 134 patients who we tried to contact for screening, but 48 patients had either died or declined to participate. Out of 86 screened patients, 13 had a DPD uptake of grade 2 or 3 without other amyloid disease making the total number of patients with ATTRwt in this population 25. CONCLUSIONS: Approximately 20% of investigated patients in a cohort with heart failure and increased myocardial wall thickness has ATTRwt. Calculated for the whole population of heart failure patients, the prevalence is just over 1.1%. Comparing this number to the total population would give an estimated prevalence of 1:6000.

Quantification of cardiac amyloid with [18F]Flutemetamol in patients with V30M hereditary transthyretin amyloidosis.

Background: Hereditary transthyretin amyloid (ATTRv) is a systemic amyloidosis with mainly neurological and cardiac symptoms. The aim of this study was to evaluate the outcome of [18F]Flutemetamol PET/CT-scan of the heart in long-term survivors with ATTRV30M amyloidosis.Methods: Twenty-one patients with ATTRV30M amyloidosis and predominantly neurological symptoms, mainly negative on cardiac 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD)-scintigraphy, were examined with a dynamic [18F]Flutemetamol PET/CT-scan. Five patients suffering from Alzheimer's disease and one healthy individual served as controls. Volumes of interests were drawn over the intraventricular septum, lateral wall of the left ventricle and free wall of the right ventricle. Clinical records were reviewed for data from previous completed DPD-scintigraphy of the heart and echocardiography.Results: Patients with ATTRv amyloidosis had a higher cardiac uptake than the control-group in all analysed regions of the heart and could be identified with high accuracy (sensitivity 88%, specificity 100%) in static image acquisition at 30 or 60 min. We found no correlation between cardiac [18F]Flutemetamol uptake and clinical variables.Conclusion: In this small study of selected patients, cardiac [18F]Flutemetamol PET/CT could differentiate between healthy individuals and patients with ATTRV30M. [18F]Flutemetamol PET/CT imaging of amyloidosis in patients with a negative DPD-scintigraphy has a potential as a diagnostic method.

Positron emission tomography (PET) utilizing Pittsburgh compound B (PIB) for detection of amyloid heart deposits in hereditary transthyretin amyloidosis (ATTR).

BACKGROUND: DPD scintigraphy has been advocated for imaging cardiac amyloid in ATTR amyloidosis. PET utilizing 11C-Pittsburgh compound B (PIB) is the gold standard for imaging brain amyloid in Alzheimer's disease. PIB was recently shown to identify cardiac amyloidosis in both AL and ATTR amyloidosis. In the ATTR population, two types of amyloid fibrils exist, one containing fragmented and full-length TTR (type A) and the other only full-length TTR (type B). The aim of this study was to further evaluate PIB-PET in patients with hereditary ATTR amyloidosis. METHODS: Ten patients with biopsy-proven V30M ATTR amyloidosis and discrete or no signs of cardiac involvement were included. Patients were grouped according to TTR-fragmentation. All underwent DPD scintigraphy, echocardiography, and PIB-PET. A left ventricular PIB-retention index (PIB-RI) was established and compared to five normal volunteers. RESULTS: PIB-RI was increased in all patients (P < 0.001), but was significantly higher in type B than in type A (0.129 ± 0.041 vs 0.040 ± 0.006 min-1, P = 0.009). Cardiac DPD uptake was elevated in group A and absent in group B. CONCLUSION: PIB-PET, in contrast to DPD scintigraphy, has the potential to specifically identify cardiac amyloid depositions irrespective of amyloid fibril composition. The heart appears to be a target organ for amyloid deposition in ATTR amyloidosis.

Radiation exposure in patients with inflammatory bowel disease and irritable bowel syndrome in the years 2001-2011.

OBJECTIVES: To compare cumulative ionizing radiation in patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) for the years 2001-2011. To study how radiation exposure change over time in patients with newly diagnosed IBD and factors associated with radiation exposure. MATERIAL AND METHODS: All radiological investigations performed between 1 January 2001 and 31 December 2011 were retrospectively recorded in patients with Crohn's disease (CD) (n = 103), ulcerative colitis (UC) (n = 304) and IBS (n = 149). Analyses were done with Mann-Whitney and Chi-Square test. RESULTS: The median total cumulative radiation exposure in mSv for CD (20.0, inter quartile range (IQR) 34.8), UC (7.01, IQR 23.8), IBS (2.71, IQR 9.15) and the proportion of patients who had been exposed for more than 50 mSv during the study period (CD 19%, UC 11%, IBS 3%) were significantly higher in the patients with CD compared to patients with UC (p < .001) and IBS (p < .001), respectively. In turn, patients with UC had significantly higher doses than patients with IBS (p = .005). Risk factors for radiation exposure were female gender (CD), early onset (UC), ileocolonic location (CD), previous surgery (CD and UC), depression (IBS) and widespread pain (IBS). In newly diagnosed CD, there was a significant decline in median cumulative radiation dose in mSv (17.2 vs. 12.0; p = .048) during the study period. CONCLUSIONS: Patients with CD are at greatest risk for high cumulative radiation exposure, but there is a decline in exposure during the late 2000s. Non-colectomized patients with UC and patients with IBS have a relatively low risk of cumulative radiation exposure.

(99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis.

Aims In transthyretin amyloid (ATTR) amyloidosis various principal phenotypes have been described: cardiac, neuropathic, or a mixed cardiac and neuropathic. In addition, two different types of amyloid fibrils have been identified (type A and type B). Type B fibrils have thus far only been found in predominantly early-onset V30M and in patients carrying the Y114C mutation, whereas type A is noted in all other mutations currently examined as well as in wild-type ATTR amyloidosis. The fibril type is a determinant of the ATTR V30M disease phenotype. (99m)Tc-DPD scintigraphy is a highly sensitive method for diagnosing heart involvement in ATTR amyloidosis. The objective of this study was to determine the relationship between ATTR fibril composition and (99m)Tc-DPD scintigraphy outcome in patients with biopsy-proven ATTR amyloidosis. Methods Altogether 55 patients with biopsy-proven diagnosis of ATTR amyloidosis and amyloid fibril composition determined were examined by (99m)Tc-DPD scintigraphy. The patients were grouped and compared according to their type of amyloid fibrils. Cardiovascular evaluation included ECG, echocardiography, and cardiac biomarkers. The medical records were scrutinized to identify subjects with hypertension or other diseases that have an impact on cardiac dimensions. Results A total of 97% with type A and none of the patients with type B fibrils displayed (99m)Tc-DPD uptake at scintigraphy (p < 0.001). Findings from analyses of cardiac biomarkers, ECG, and echocardiography, though significantly different, could not differentiate between type A and B fibrils in individual patients. Conclusion In ATTR amyloidosis, the outcome of (99m)Tc-DPD scintigraphy is strongly related to the patients' transthyretin amyloid fibril composition.

Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis.

BACKGROUND: Hereditary transthyretin amyloid (ATTR) amyloidosis is a rare but fatal autosomal dominant condition that is present all over the world. A liver transplantation has been shown to halt the progress of the disease in selected patients and is currently considered to be the standard treatment. Gastrointestinal manifestations are common in hereditary ATTR amyloidosis and are important for the patients' morbidity and mortality. The aim of this study was to evaluate the long-term outcome of gastric emptying, gastrointestinal symptoms and nutritional status after liver transplantation for the disease. METHODS: Swedish patients with hereditary ATTR amyloidosis transplanted between 1990 and 2012 were included. A standardized method for measuring gastric emptying with a Tc(99m)-labelled meal followed by scintigraphy was utilized. Validated questionnaires were used to assess gastrointestinal symptoms and the modified body mass index (mBMI), in which BMI is multiplied by s-albumin, was used to evaluate nutritional status. Non-parametrical statistical tests were used. RESULTS: Gastric emptying rates and nutritional statuses were evaluated approximately eight months before and two and five years after liver transplantation, whereas gastrointestinal symptoms were assessed in median nine months before and two and nine years after transplantation. No significant change was found in gastric emptying (median half-time 137 vs. 132 vs. 125 min, p = 0.52) or nutritional status (median mBMI 975 vs. 991 vs. 973, p = 0.75) after transplantation. Gastrointestinal symptom scores, however, had increased significantly over time (median score 7 vs. 10 vs. 13, p < 0.01). CONCLUSIONS: Gastric emptying and nutritional status were maintained after liver transplantation for hereditary ATTR amyloidosis, although gastrointestinal symptom scores had increased over time.

(11)C-acetate PET/CT in pre-therapeutic lymph node staging in high-risk prostate cancer patients and its influence on disease management - a retrospective study.

BACKGROUND: Radiation treatment with simultaneous integrated boost against suspected lymph node metastases may be a curative therapeutic option in patients with high-risk prostate cancer (>15% estimated risk of pelvic lymph node metastases according to the Cagiannos nomogram). (11)C-acetate positron emission tomography/computed tomography (PET/CT) can be used for primary staging as well as for detection of suspected relapse of prostate cancer. The aims of this study were to evaluate the association between positive (11)C-acetate PET/CT findings and the estimated risk of pelvic lymph node metastases and to assess the impact of (11)C-acetate PET/CT on patient management in high-risk prostate cancer patients. METHODS: Fifty consecutive prostate cancer patients referred for primary staging with (11)C-acetate PET/CT prior to radiotherapy with curative intention were enrolled in this retrospective study. RESULTS: All patients showed increased (11)C-acetate uptake in the prostate. Pelvic lymph node uptake was seen in 42% (21/50) of the patients, with positive external iliac lymph nodes in 71% (15/21) of these. The overall observed proportion of PET/CT-positive pelvic lymph nodes at patient level was higher than the average estimated risk, especially in low-risk groups (<15%). There was a significant association between observed proportion and estimated risk of pelvic lymph node metastases in groups with ≤45 and >45% estimated risk. Treatment strategy was altered due to (11)C-acetate PET/CT findings in 43% (20/47) of the patients. CONCLUSIONS: The observed proportion of (11)C-acetate PET/CT findings suggestive of locoregional metastases was higher than the estimated risk, suggesting that the Cagiannos nomogram underestimates the risk for metastases. The imaging results with (11)C-acetate PET/CT have a considerable impact on patient management.

Subcentimeter tumor lesion delineation for high-resolution 18F-FDG PET images: optimizing correction for partial-volume effects.

UNLABELLED: In PET, partial-volume effects cause errors in estimation of size and activity for small objects with radiopharmaceutical uptake. Recent methods for image reconstruction, compared with traditional reconstruction techniques, include algorithms for resolution recovery that result in images with higher resolution and enable quantification of size and activity of smaller objects. The purpose of this study was to evaluate a combination of 2 algorithms for volume delineation and partial-volume correction on uptake volumes smaller than 0.7 mL using image reconstruction algorithms with and without resolution recovery. METHODS: Volumes of interests (VOIs) were delineated using a threshold intensity calculated as a weighted sum of tumor and background intensities. These VOIs were used for calculating correction factors by convolving a tumor mask with the system point-spread function. The methods algorithms were evaluated using a phantom constructed from 5 small different-sized balloons filled with (18)F-FDG in background activity. Six different backgrounds were used. Data were acquired using a PET/CT scanner, and the images were reconstructed using 2 iterative algorithms, one of which used a resolution recovery algorithm. RESULTS: For the images reconstructed using the resolution recovery algorithm, the method for volume delineation resulted in VOI sizes that were correct within 1 SD for all balloons of a volume of 0.35 mL (equivalent diameter, 8.8 mm) and larger, in all backgrounds. For the images reconstructed without resolution recovery, the VOI sizes were background-dependent and generally less accurate. Correct volume delineations generally led to accurate activity estimates. CONCLUSION: The algorithms tested on the phantom developed for this study could, for this PET camera and these reconstruction algorithms, be used for accurate volume delineation and activity quantification of lesions 0.35 mL and larger.

Gaussian prefiltering of 123I DAT SPECT images when using depth-independent resolution recovery.

Previously we have investigated a depth-independent compensation for collimator detector response (CDR) included in the OSEM reconstruction, intended for SPECT images that have been corrected for scatter and septal penetration using convolution-based methods. In this work, the aim was to study how different filtering strategies affect contrast as a function of noise when using Gaussian smoothing filters in combination with the above-described CDR compensation. The evaluation was performed for (123)I dopamine transporter (DAT) SPECT images. Prefiltering with 2D Gaussian filter kernels, where the deterioration in resolution is included in the depth-independent CDR compensation, was compared to conventional postfiltering with 3D Gaussian filter kernels. Images reconstructed without filtering are also included in the comparison. It was found that there is little benefit in noise reduction when using CDR compensation. However, this variant of prefiltering gives consistently higher contrasts as a function of noise compared with the postfiltering alternative, and that could be of interest when using other types of filters with contrast improving properties.

Altered cerebral blood flow in chronic neck pain patients but not in whiplash patients: a 99mTc-HMPAO rCBF study.

A cross-sectional study to investigate regional cerebral blood flow (rCBF) in patients with chronic whiplash syndrome and chronic neck pain patients without previous history of trauma along with a healthy control group. Chronic neck pain is a common disorder and a history of cervical spine injury including whiplash trauma constitute a risk factor for persistent neck pain. The aetiology of the late whiplash syndrome is unknown with no specific diagnostic criteria based on imaging, physiological, or psychological examination. Earlier studies indicate a parieto-occipital hypoperfusion but it is unclear if the hypoperfusion represents a response to chronic pain. The rCBF was monitored in 45 patients with chronic neck pain: 27 cases with chronic whiplash syndrome and 18 age and gender matched cases with non-traumatic chronic neck pain. The rCBF was estimated with single-photon emission computed tomography (SPECT) using technetium-99m hexamethylpropylene amine oxime (HMPAO). The non-traumatic patients displayed rCBF changes in comparison with the whiplash group and the healthy control group. These changes included rCBF decreases in a right temporal region close to hippocampus, and increased rCBF in left insula. The whiplash group displayed no significant differences in rCBF in comparison with the healthy controls. The present study suggests different pain mechanisms in patients with chronic neck pain of non-traumatic origin compared to those with chronic neck pain due to a whiplash trauma.

Memory-provoked rCBF-SPECT as a diagnostic tool in Alzheimer's disease?

PURPOSE: Alzheimer's disease (AD) is a primary degenerative disease that progressively affects all brain functions, with devastating consequences for the patient, the patient's family and society. Rest regional cerebral blood flow (rCBF) could have a strategic role in differentiating between AD patients and normal controls, but its use for this purpose has a low discriminatory capacity. The purpose of this study was to evaluate whether the diagnostic sensitivity of rCBF single-photon emission computed tomography (SPECT) could be increased by using an episodic memory task provocation, i.e. memory-provoked rCBF-SPECT (MP-SPECT). METHODS: Eighteen persons (73.2+/-4.8 years) with mild AD and 18 healthy elderly (69.4+/-3.9 years) were included in the study. The subjects were injected with (99m)Tc-hexamethylpropylene amine oxime (HMPAO) during memory provocation with faces and names, followed by an rCBF-SPECT study. The rCBF (99m)Tc-HMPAO SPECT images were analysed using statistical parametric mapping (SPM2). Peaks with a false discovery rate corrected value of 0.05 were considered significant. RESULTS: On MP-SPECT, the AD group showed a significant rCBF reduction in the left parietal cortex in comparison with healthy elderly. At rest, no significant group differences were seen. CONCLUSION: Memory provocation increased the sensitivity of rCBF-SPECT for the detection of AD-related blood flow changes in the brain at the group level. Further studies are needed to evaluate MP-SPECT as a diagnostic tool at the individual level. If a higher sensitivity for AD at the individual level is verified in future studies, a single MP-SPECT study might be sufficient in the clinical setting.

Memory functions and rCBF (99m)Tc-HMPAO SPET: developing diagnostics in Alzheimer's disease.

Alzheimer's disease (AD) is a primary degenerative disease of the brain. The prevalence increases with age, with devastating consequences for the individual and society. The aim of this study was to evaluate whether patients with early AD show an altered regional cerebral blood flow (rCBF) compared with control persons. Furthermore, we aimed to investigate the correlation between rCBF in sublobar volumes of the brain and performance on memory tests. Memory tests were chosen to evaluate episodic and semantic memory. Fourteen patients (aged 75.2+/-8.8 years) with early AD and 15 control persons (aged 71.4+/-3.2 years) were included. rCBF measurements with single-photon emission tomography (SPET) using technetium-99m hexamethylpropylene amine oxime (HMPAO) were performed. The rCBF (99m)Tc-HMPAO SPET images were spatially transformed to fit a brain atlas and normalised for differences in rCBF (Computerised Brain Atlas software). Cortical and subcortical volumes of interest (VOIs) were analysed and compared. Compared with the controls, AD patients showed a significantly lower rCBF ratio in temporoparietal regions, including the left hippocampus. The diagnostic sensitivity and specificity for AD were high in temporoparietal regions. AD patients had significantly reduced performance on semantic and, in particular, episodic memory tests compared with age-matched normative data, and their performance on several episodic tests correlated with rCBF ratios in parietal and temporal regions, including the left hippocampus. The correlation between rCBF ratio and level of episodic memory performance suggests that abnormalities in rCBF pattern underlie impaired episodic memory functioning in AD.