Where Should I Draw the Line: PET-Driven, Data-Driven, or Manufacturer Cut-Off?

Background: The optimal cut-off for Alzheimer's disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aß1-42, pTau, tTau, and Aß1-42/Aß1-40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) were performed in all the patients. We established a cut-off for each single biomarker and Aß1-42/Aß1-40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aß1-42/Aß1-40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample's best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer's.

Plasma Phosphorylated Tau 231 Increases at One-Year Intervals in Cognitively Unimpaired Subjects.

Background: Plasma biomarkers of Alzheimer's disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid.

Polymyalgia rheumatica as presenting manifestation of vasculitis involving the lower extremities in a patient with ulcerative colitis.

Extraintestinal features may be observed in patients with ulcerative colitis (UC). We describe a 69-year-old woman who was initially diagnosed as having polymyalgia rheumatica (PMR). Prednisone was progressively tapered to complete discontinuation a year and a half after PMR diagnosis. However, at that time, she started to complain of asthenia, abdominal cramping and pain on the left side, weight loss and bloody diarrhoea. A colonoscopy confirmed a diagnosis of left-sided UC. She experienced several flares of the disease that required admission and treatment with high-dose corticosteroids and azathioprine. Colectomy was performed as the disease became refractory to these therapies. Four months after surgery, when the patient was not receiving any corticosteroid therapy, she started to feel dull and achy pain in the thighs along with claudication of the lower limbs. An 18F-fluorodeoxyglucosepositron emission tomography with CT (FDG PET/CT) disclosed an inflammatory process with mild-moderate diffuse increased metabolism in the thoracic aorta and markedly increased FDG uptake in the in the femoral and posterior tibial arteries on both sides. Treatment with the anti-TNF-alpha monoclonal antibody-adalimumab (40 mg every 2 weeks subcutaneously) along with prednisone (initial dose 15 mg/day) yielded rapid improvement of symptoms. Also, a new FDG PET/CT performed 4 months later disclosed marked decrease of FDG uptake in the involved arteries.This report emphasises the importance of suspecting the presence of large- and medium-vessel vasculitis in a patient with UC presenting with musculoskeletal features. It also highlights the beneficial effect of TNF-antagonists in vasculitis associated to UC.

Evaluation of choroidal thickness in prodromal Alzheimer's disease defined by amyloid PET.

OBJECTIVE: To assess and compare the involvement of choroidal thickness (CT) in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) defined by amyloid PET and healthy controls (HC). METHODS: Sixty-three eyes from 34 AD patients [12 eyes (19.0%) with dementia and 51 eyes (80.9%) with MCI], positive to 11C-labelled Pittsburgh Compound-B with positron emission tomography (11C-PiB PET/CT), and the same number of sex- and age-paired HC were recruited. All participants underwent enhanced depth imaging optical coherence tomography (EDI-OCT) assessing CT at 14 measurements from 2 B-scans. Paired Student t-test was used to compare CT measurements between MCI, dementia and sex- and age-paired HC. A univariate generalized estimating equations model (GEE) test was performed to compare MCI and dementia individually with all HC included. RESULTS: Compared with HC, eyes from patients with positive 11C-PiB PET/CT showed a significant CT thinning in 5 selected locations (in foveal thickness in vertical scan, in temporal scan at 1500µm, in superior scan at 500µm and in inferior scan at 1000µm and 1500µm, p = 0.020-0.045) whilst few significant CT reduction data was reported in MCI or dementia individually versus HC. However, the GEE test identified significant CT thinning in AD compared with all HC included (p = 0.015-0.046). CONCLUSIONS: To our knowledge, the present study is the first measuring CT in eyes from MCI and dementia eyes positive to 11C-PiB PET/CT reporting a significant trend towards CT thinning in MCI patients which became more pronounced in dementia stage. We support further investigation involving larger and prospective OCT studies in AD population characterized with available biomarkers to describe whether choroidal vascular damage occurs specifically in prodromal stages of AD.

Distinctive Oculomotor Behaviors in Alzheimer's Disease and Frontotemporal Dementia.

Oculomotor behavior can provide insight into the integrity of widespread cortical networks, which may contribute to the differential diagnosis between Alzheimer's disease and frontotemporal dementia. Three groups of patients with Alzheimer's disease, behavioral variant of frontotemporal dementia (bvFTD) and semantic variant of primary progressive aphasia (svPPA) and a sample of cognitively unimpaired elders underwent an eye-tracking evaluation. All participants in the discovery sample, including controls, had a biomarker-supported diagnosis. Oculomotor correlates of neuropsychology and brain metabolism evaluated with 18F-FDG PET were explored. Machine-learning classification algorithms were trained for the differentiation between Alzheimer's disease, bvFTD and controls. A total of 93 subjects (33 Alzheimer's disease, 24 bvFTD, seven svPPA, and 29 controls) were included in the study. Alzheimer's disease was the most impaired group in all tests and displayed specific abnormalities in some visually-guided saccade parameters, as pursuit error and horizontal prosaccade latency, which are theoretically closely linked to posterior brain regions. BvFTD patients showed deficits especially in the most cognitively demanding tasks, the antisaccade and memory saccade tests, which require a fine control from frontal lobe regions. SvPPA patients performed similarly to controls in most parameters except for a lower number of correct memory saccades. Pursuit error was significantly correlated with cognitive measures of constructional praxis and executive function and metabolism in right posterior middle temporal gyrus. The classification algorithms yielded an area under the curve of 97.5% for the differentiation of Alzheimer's disease vs. controls, 96.7% for bvFTD vs. controls, and 92.5% for Alzheimer's disease vs. bvFTD. In conclusion, patients with Alzheimer's disease, bvFTD and svPPA exhibit differentiating oculomotor patterns which reflect the characteristic neuroanatomical distribution of pathology of each disease, and therefore its assessment can be useful in their diagnostic work-up. Machine learning approaches can facilitate the applicability of eye-tracking in clinical practice.

A snake that bites its own tail. Acquisition and loss of concepts in children and semantic dementia patients through the analysis of drawings.

OBJECTIVE: The structure of the semantic network is constructed and organized during childhood development. Previous publications have hypothesized that neurodegenerative diseases would lead to a disruption of this network reversing the steps acquired in childhood. Semantic Dementia (SD) is a subtype of frontotemporal lobe degeneration in which the main symptom is a specific loss of semantic memory. We aimed to describe the sequential acquisition of concepts in 3-8 years old children evaluated through the production of drawings and, in parallel, their progressive loss in SD patients. METHODS: 104 children between 40 and 96 months categorized into tertiles according to their age, 21 SD patients categorized into tertiles according to their score on a category fluency task and 34 healthy volunteers were asked to draw 12 items with, a priori, different age of acquisition and familiarity, belonging to four different semantic categories. We employed the drawings of the healthy volunteers to build a scoring scheme. We considered that a concept was acquired in children when 50% or more of its features were present in their drawings, and it was lost in patients when more than 50% were missing. RESULTS: Those concepts which the children were able to acquire earlier, according to our scoring scheme, tended to remain in patients with more advanced SD. While the items that children acquired later, were, in general, those that the SD patients lost at earlier disease stages. CONCLUSION: The patterns of concept acquisition in children were the mirror image of the loss in patients with SD. Our study supports the hypothesis that the sequence of concept acquisition in childhood is reversed in SD patients.

A Rare PSEN1 (Leu85Pro) Mutation Causing Alzheimer's Disease in a 29-Year-Old Woman Presenting as Corticobasal Syndrome.

Dementia is not just a disease of old age. Early-onset dementia affects people younger than 65 and its differential diagnosis is broader than in older people. Nevertheless, although young people are considerably more liable to develop a rare form of dementia, Alzheimer's disease (AD) remains the most common diagnosis. The aim of this article is to report on an early-onset AD patient associated with the rare pathogenic variant PSEN1 (Leu85Pro) presenting as a possible corticobasal syndrome with asymmetric limb apraxia, parkinsonian signs, and myoclonus.

A 5-year longitudinal evaluation in patients with mild cognitive impairment by 11C-PIB PET/CT: a visual analysis.

OBJECTIVE: The aim of this study was to evaluate the cerebral amyloid distribution in patients with mild cognitive impairment (MCI), assessed by carbon-11-Pittsburgh compound B (C-PIB) PET/CT, after 5 years of follow-up. PATIENTS AND METHODS: Ten amnestic MCI (A-MCI) and four nonamnestic (NA-MCI) patients were studied by C-PIB PET/CT and re-evaluated 5 years later by a new C-PIB PET/CT. PET/CT scans were acquired 60-90 min after the administration of 555 MBq C-PIB and analyzed visually, to obtain a score of the cerebral cortical C-PIB retention in the frontal, basal ganglia (BG), temporoparietal (TP), occipital, posterior cingulate, and cerebellum areas. Initial and 5-year follow-up C-PIB retentions were compared. RESULTS: Initially, 9/10 A-MCI patients were C-PIB positive and one was C-PIB negative. All four NA-MCI patients were C-PIB negative. Of the C-PIB-positive A-MCI patients, seven progressed to Alzheimer's disease dementia (AD-D), one to mixed dementia and one remained as A-MCI. The C-PIB-negative A-MCI patient remained as A-MCI. Of the four C-PIB-negative NA-MCI, one progressed to semantic dementia. All changes in C-PIB retention were of low intensity. The A-MCI patients who progressed to AD-D (n=7) showed an increase in C-PIB retention in the frontal (5/7), BG (3/7), TP (3/7), occipital (1/7), and posterior cingulate (1/7) regions. The A-MCI patient who progressed to mix dementia showed an increase in C-PIB retention in the frontal region. The C-PIB-positive A-MCI patient who remained as A-MCI showed an increase in C-PIB retention in the frontal, BG, and TP areas. The amyloid deposition in the anterior part of the brain (frontal, TP, and BG) increased more than that in the posterior part (occipital and precuneus) (7/9 vs. 2/9; P<0.05). CONCLUSION: PIB retention increased predominantly in the frontal, BG, and TP areas. C-PIB-positive A-MCI patients mostly progressed to AD-D, showing similar topographic changes in their cerebral C-PIB pattern than the patient who remained as A-MCI.

Ganglion cell layer thinning in prodromal Alzheimer's disease defined by amyloid PET.

INTRODUCTION: The objective of this study was to investigate and compare optic nerve and retinal layers in eyes of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) with paired control eyes using optical coherence tomography. METHODS: Sixty-three eyes of 34 subjects, 12 eyes with AD and 51 eyes with MCI, positive to 11C-labeled Pittsburgh Compound-B with positron emission tomography (11C-PiB PET/CT), and the same number of sex- and age-paired control eyes underwent optical coherence tomography scanning analyzing retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), Bruch's membrane opening-minimum rim width (BMO-MRW), inner plexiform layer (IPL), outer nuclear layer, and lamina cribrosa (LC). RESULTS: Compared with healthy controls, eyes of patients with positive 11C-PiB PET/CT showed a significant thinning of RNFL (P < .028) and GCL (P < .014). IPL and outer nuclear layer also showed significant thinning in two (P < .025) and one location (P < .010), respectively. No significant differences were found when optic nerve measurements BMO-MRW and LC were compared (P > .131 and P > .721, respectively). Temporal sector GCL, average RNFL, and temporal sector RNFL also exhibited significant thinning when MCI and control eyes were compared (P = .015, P = .005 and P = .050, respectively), and also the greatest area under the curve values (0.689, 0.647, and 0.659, respectively). GCL, IPL, and RNFL tend to be thinner in the AD group compared with healthy controls. DISCUSSION: Our study suggests that RNFL and GCL are useful for potential screening in the early diagnosis of AD. LC and BMO-MRW appear not to be affected by AD.

Cognitive and Behavioral Profiles of Left and Right Semantic Dementia: Differential Diagnosis with Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

BACKGROUND: Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by semantic memory loss and preserved abilities of other cognitive functions. The clinical manifestations of SD require a differential diagnosis with Alzheimer's disease (AD), especially those with early onset, and behavioral variant FTD (bvFTD). OBJECTIVE: The present study aimed to compare cognitive performances and neuropsychiatric symptoms in a population of AD, bvFTD, and left and right SD defined with the support of molecular imaging (amyloid and 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography) and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases. METHODS: Eighty-seven participants (32 AD, 20 bvFTD, and 35 SD (17 Left-SD and 18 Right-SD) completed a comprehensive neuropsychological battery that included memory, language, attention and executive functions, visuospatial function, visuoconstructional skills, and tasks designed specifically to evaluate prosopagnosia and facial emotions recognition. The Neuropsychiatric Inventory was administered to assess neuropsychiatric symptoms. RESULTS: An episodic memory test that included semantic cues, a visuospatial test (both impaired in AD), a naming test and a prosopagnosia task (both impaired in SD) were the four most valuable cognitive metrics for the differential diagnosis between groups. Several behavioral abnormalities were differentially present, of which aggression, self-care (both more frequent in bvFTD), and eating habits, specifically overeating and altered dietary preference (more frequent in SD), were the most valuable in group discrimination. CONCLUSION: Our study highlights the value of a comprehensive neuropsychological and neuropsychiatric evaluation for the differential diagnosis between FTD syndromes and AD.

Effect of positive carbon-11-choline PET/CT results in the therapeutic management of prostate cancer biochemical relapse.

OBJECTIVE: Carbon-11-(C)-choline PET/computed tomography (CT) has shown good results in re-staging of prostate cancer (PCa) with raised serum levels of prostate-specific antigen. Our aim was to evaluate the effect of positive C-choline PET/CT results in the therapeutic management of patients with PCa with biochemical relapse (BR) after curative intention treatment. PATIENTS AND METHODS: A total of 112 patients with PCa BR and positive C-choline PET/CT were retrospectively evaluated. PET/CT was acquired 20 min after intravenous administration of 555-740 MBq of C-choline. The therapeutic management after C-choline PET/CT was obtained from the clinical records. The minimum follow-up time was 18 months. RESULTS: In 80 (71.4%) of 112 patients, C-choline PET/CT showed local recurrence of PCa; in 17 (15.2%) patients, distant recurrence; and in 15 (13.4%) patients, local plus distant recurrence. A second malignancy was detected in five (4.5%) patients. The planned therapeutic management was changed as per positive C-choline PET/CT result in 74 (66.1%) patients and were treated as follows: 31 (27.7%) patients with HT, combined with other treatments in eight (7.1%), 17 (15.2%) with BT, 13 (11.6%) with external beam radiotherapy, one (0.9%) with RP, and four (3.6%) with chemotherapy. Treatment approach was not modified in 37 (33%) patients. No data was available from one (0.9%) patient. CONCLUSION: Positive C-choline PET/CT result had an important effect in the therapeutic management of patients with PCa and BR, leading to a change in the planned approach in two (66.1%) out of three patients. In addition, in 4.5% of the patients, the C-choline PET/CT allowed the detection of a second malignancy.

18F-FDG PET/CT in the follow-up of large-vessel vasculitis: A study of 37 consecutive patients.

OBJECTIVE: 18F-FDG PET/CT has proved to be of potential value for early diagnosis of large-vessel vasculitis (LVV), which frequently involves the aorta. However, its role in the follow-up of these patients has not been well established. Our aim was to evaluate the contribution of 18F-FDG PET/CT in this clinical situation. METHODS: This study included 37 consecutive patients (28 women, 66.5 ± 9.9 years) with an initial 18F-FDG PET/CT positive for LVV and a mean ± standard deviation follow-up PET/CT of 7.5 ± 2.9 months after the initial scan. A semiquantitative analysis of aortic wall uptake was performed calculating the target-to-background ratio (TBR: aortic wall uptake divided by blood pool uptake). The initial and follow-up TBR as well as the clinical and laboratory outcome were compared. RESULTS: Overall, the mean TBR decreased from 1.7 ± 0.5 at the initial scan to 1.5 ± 0.3 at the time of follow-up (p = 0.0001). In the 21 patients who experienced clinical improvement following therapy the TBR also decreased from 1.8 ± 0.6 to 1.5 ± 0.3 (p = 0.0002). However, in the other 16 patients, in whom the treating physician considered that there was no clinical improvement following therapy, no statistically significant differences in TBR were found when data from the first and the follow-up PET/CT scans were compared (1.6 ± 0.3 versus 1.5 ± 0.3, p = 0.1416). Patients who experienced clinical improvement following therapy showed a nonstatistically significant higher TBR at the time of disease diagnosis (1.8 ± 0.6 versus 1.6 ± 0.3; p = 0.12). CONCLUSIONS: The results obtained in the present study highlight the impact of 18F-FDG PET/CT on the management of patients with LVV.

Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units.

The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

Complex partial status epilepticus is an unrecognised feature in SESA syndrome: new insights into its pathophysiology.

We report a patient diagnosed as having subacute encephalopathy with frequent seizures in alcoholics (SESA syndrome), in which recurrent, non-convulsive seizures of frontal origin contributed significantly to the alteration of the mental state. Our case suggests that the occurrence of episodes of complex partial status epilepticus (CPSE) may contribute greatly to the origin and pathophysiology of the confusional state in this rare, epileptic entity.

Diagnosis of common iliac artery thrombosis and renal artery thrombosis in a kidney transplant by radionuclide renography.

In a 58-year-old woman, the external iliac artery was accidentally dissected during the arterial anastomosis of a kidney transplant. An immediate CT angiogram showed an almost total occlusion of the common iliac artery. After the transplantation, radionuclide renography with Tc-99m MAG3 showed no flow across the right common iliac artery and no graft vascularization. Sequential images showed a photopenic area corresponding to the renal graft. These findings were interpreted as common iliac artery thrombosis and renal artery thrombosis associated with renal graft infarct. Excision of the transplant and iliofemoral bypass were performed. Pathologic examination of the graft showed massive acute renal infarct and renal artery thrombosis.

In-111 ibritumomab scintigraphy (planar and SPECT) and FDG PET/CT before Y-90 ibritumomab treatment in a patient with mantle cell lymphoma.

We report the case of a 75-year-old man, in whom Y-90 ibritumomab was requested because of relapse of blastoid variant mantle cell lymphoma diagnosed in 1995. Before Y-90 ibritumomab treatment, FDG PET and In-111 ibritumomab scintigraphy with planar views at 24 hours, 48 hours, and 5 days, including SPECT, were performed. Discordant information between both examinations was observed as, in addition to the lesions detected by In-111 ibritumomab imaging, FDG PET detected lesions that did not take up the ibritumomab. The discrepancy shown by both radiotracers has to be kept in mind before planning treatment with Y-90 ibritumomab, and for the correct evaluation of treatment response.

Erythema Nodosum-Like Panniculitis as a False-Positive 18F-FDG PET/CT in Advanced Melanoma Treated With Dabrafenib and Trametinib.

We present a 35-year-old woman with left axillary mass. Histopathological analysis revealed metastatic infiltration for BRAF-mutant melanoma. F-FDG PET/CT showed bilateral axillary lymphadenopathy as well as bone and subcutaneous metastases. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) combined therapy was started with a complete metabolic response established by 2 consecutive PET/CT scans. A follow-up PET/CT showed FDG uptake in several subcutaneous nodules in both distal legs, suggesting metastases. Painless cutaneous lesions were observed on physical examination, and biopsy revealed erythema nodosum-like panniculitis.