Amyloid-ß PET-Correlation with cerebrospinal fluid biomarkers and prediction of Alzheimer´s disease diagnosis in a memory clinic.

BACKGROUND: Alzheimer's disease (AD) remains a clinical diagnosis but biomarkers from cerebrospinal fluid (CSF) and more lately amyloid imaging with positron emission tomography (PET), are important to support a diagnosis of AD. OBJECTIVE: To compare amyloid-ß (Aß) PET imaging with biomarkers in CSF and evaluate the prediction of Aß PET on diagnosis in a memory clinic setting. METHODS: We included 64 patients who had lumbar puncture and Aß PET with 18F-Flutemetamol performed within 190 days. PET was binary classified (Flut+ or Flut-) and logistic regression analyses for correlation to each CSF biomarker; Aß 42 (Aß42), total tau (T-tau) and phosphorylated tau (P-tau), were performed. Cut-off values were assessed by receiver operating characteristic (ROC) curves. Logistic regression was performed for prediction of clinical AD diagnosis. We assessed the interrater agreement of PET classification as well as for diagnoses, which were made both with and without knowledge of PET results. RESULTS: Thirty-two of the 34 patients (94%) in the Flut+ group and nine of the 30 patients (30%) in the Flut- group had a clinical AD diagnosis. There were significant differences in all CSF biomarkers in the Flut+ and Flut- groups. Aß42 showed the highest correlation with 18F-Flutemetamol PET with a cut-off value of 706.5 pg/mL, corresponding to sensitivity of 88% and specificity of 87%. 18F-Flutemetamol PET was the best predictor of a clinical AD diagnosis. We found a very high interrater agreement for both PET classification and diagnosis. CONCLUSIONS: The present study showed an excellent correlation of Aß42 in CSF and 18F-Flutemetamol PET and the presented cut-off value for Aß42 yields high sensitivity and specificity for 18F-Flutemetamol PET. 18F-Flutemetamol PET was the best predictor of clinical AD diagnosis.

Mutated Thyroid Hormone Transporter OATP1C1 Associates with Severe Brain Hypometabolism and Juvenile Neurodegeneration.

BACKGROUND: Thyroid hormones (TH) are essential for brain development and function. The TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporter1 C1 (OATP1C1) facilitate the transport of TH across the blood-brain barrier and into glia and neuronal cells in the brain. Loss of MCT8 function causes Allan-Herndon-Dudley syndrome (AHDS, OMIM 300523) characterized by severe intellectual and motor disability due to cerebral hypothyroidism. Here, the first patient with loss of OATP1C1 function is described. The patient is a 15.5-year-old girl with normal development in the first year of life, who gradually developed dementia with spasticity and intolerance to cold. Brain imaging demonstrated gray and white matter degeneration and severe glucose hypometabolism. METHODS: Exome sequencing of the patient and parents was performed to identify the disease-causing mutation, and the effect of the mutation was studied through a panel of in vitro experiments, including thyroxine uptake studies, immunoblotting, and immunocytochemistry. Furthermore, the clinical effects of treatment with the triiodothyronine analogue triiodothyroacetic acid (Triac) are described. RESULTS: Exome sequencing identified a homozygous missense mutation in OATP1C1, changing the highly conserved aspartic acid 252 to asparagine (D252N). In vitro, the mutated OATP1C1 displays impaired plasma membrane localization and decreased cellular thyroxine uptake. After treatment with Triac, the clinical condition improved in several domains. CONCLUSIONS: This is the first report of human OATP1C1 deficiency compatible with brain-specific hypothyroidism and neurodegeneration.

[Sentinel lymph node biopsy in breast cancer]. / Vaktpostlymfeknuteoperasjon ved brystkreft.

BACKGROUND: Sentinel lymph node (SN) biopsy is a technique for identifying axillary metastases from primary breast cancer. The present paper reports our results with the method. MATERIAL AND METHODS: SN biopsies have been routinely performed at Ullevål University Hospital since 2000 and the results have been prospectively recorded. 1409 patients with breast cancer or ductal carcinoma in situ grade 3, were injected with peritumoral radiocolloid the day before the biopsy and with blue dye per-operatively to detect the SN. RESULTS: The SN was detected in 90 % of the operations. Metastases to SN were detected in 25 % of the patients and 52 % of these had no further positive nodes in the axilla. Thus, axillary lymph node clearance was omitted in 948 patients. Three patients had local recurrence in the axilla within one year after the successful SN procedure. Ductal carcinoma in situ grade 3 was diagnosed preoperatively in 162 patients (cytology); 88 had the diagnosis after histology and the rest had invasive cancer or combinations with in situ lesions of other grades. Axillary metastases were found in 4.8 % of these patients. Isolated tumour cells (< 0.2 mm diameter) were found in 9 patients for whom axillary clearance has not been performed. INTERPRETATION: SN biopsy has replaced routine axillary clearance as a routine operation in breast cancer. The method is safe when performed correctly, as metastases in the axilla after a negative SN rarely occur.

Intraoperative, radio-guided sentinel lymph node mapping in 110 nonsmall cell lung cancer patients.

BACKGROUND: Sentinel lymph node identification has been tested in lung cancer patients with conflicting results. The present study was designed to assess the sensitivity, negative predictive value, and accuracy of intraoperative sentinel lymph node mapping by means of a radio-guided method in patients with nonsmall cell lung cancer to find the most appropriate definition of sentinel lymph node and to evaluate the usefulness of different particle sizes of radiocolloid. METHODS: One hundred ten patients with clinically N0 nonsmall cell lung cancer were enrolled in the pilot study of intraoperative sentinel node identification. Four quadrants of the peritumoral tissue were injected with 2 mL of 0.5 mCi technetium-99m suspension. Four radiocolloids of different particle size were used. After complete lymphadenectomy, all resected lymph nodes were examined with hematoxylin-eosin staining. All sentinel nodes negative for metastases by routine staining were searched further for metastatic deposits with both serial sections and immunohistochemistry for cytokeratins. RESULTS: The radio-guided method had a high identification rate, a high sensitivity, and a high negative predictive value (100%, 87%, and 93%, respectively) when immunohistochemistry was considered. When standard hematoxylin and eosin staining was applied, sensitivity and negative predictive value of sentinel lymph node labeling was lower (74% and 89%, respectively). No significant differences were found in either the sensitivity or negative predictive value among the colloid solutions of different particle size used in radio labeling, although smaller particles have shown a tendency to produce better results. CONCLUSIONS: The radio-guided technique provides efficient sentinel lymph node identification in lung cancer. Further studies are warranted to confirm the clinical utility of this strategy.

Low-renin status in therapy-resistant hypertension: a clue to efficient treatment.

OBJECTIVE: Therapy resistance is an enduring problem in clinical hypertension. Our aims were to estimate: (1) the contribution of a low-renin status in therapy resistance; (2) whether such status could give a clue to more successful treatment; and (3) the contribution by adrenal cortical adenomas and by primary aldosteronism. SETTING: Patients were referred from general and internal medicine practices following written invitations and included consecutively. Participants were examined and followed-up on an outpatient basis. DESIGN AND INTERVENTIONS: Patients were divided according to renin status. Low-renin patients were treated with an aldosterone inhibitor in a prospective, randomized, placebo-controlled, double-blind, cross-over study. MAIN OUTCOME MEASURES: Prevalence of low-renin status in therapy resistance. Blood pressure and hormonal responses to specific treatment. Numbers of adrenocortical adenomas and primary aldosteronism. RESULTS: In 90 treatment-resistant hypertensive, 67% had plasma renin activity (PRA) below 0.5 nmol/l per hour. Of the 60 low-renin patients, 38 were studied on a fixed combination of amiloride and hydrochlorothiazide. Three weeks' treatment reduced blood pressure by 31/15 mmHg compared to placebo (P < or = 0.0001). Serum aldosterone and plasma renin activity increased substantially during active treatment. Through the subsequent 6-12 months of open treatment, seven patients (18%) showing an escape phenomenon had their high blood pressure effectively treated by extra amiloride. Of the 60 low-renin patients, eight had adrenal adenoma. CONCLUSION: A low-renin status characterized two-thirds of patients with treatment-resistant hypertension, who could be treated efficiently by aldosterone inhibition. Patients with an escape phenomenon (18%) could effectively be treated by increasing the aldosterone inhibitor. Low-renin hypertensives had high prevalence of adrenocortical adenomas and primary aldosteronism.

[Diagnostic imaging techniques in the investigation of dementia]. / Bildediagnostiske metoder ved demensutredning.

BACKGROUND: Neuroimaging can provide valuable information in the diagnostic work-up of patients presenting with suspected dementia. MATERIAL AND METHODS: Based on our experience from a memory clinic at Ullevål University Hospital in Oslo, Norway and on relevant literature identified on Medline, we give an overview of the use of neuroimaging methods in patients with suspected dementia. RESULTS AND INTERPRETATION: CT of the brain should be offered to all patients with suspected dementia as CT can provide essential diagnostic information regarding focal cerebral pathology (tumour, haemorrhage, normal pressure hydrocephalus). A CT scan is of no value in the diagnostic evaluation of patients with mild to moderate Alzheimer's disease as age-related atrophy may be a confounding factor. CT is necessary to reveal infarcts when vascular dementia is suspected, but lacks sensitivity in the detection of diffuse cerebrovascular disease. MRI is recommended in younger patients and may be used to diagnose subcortical lesions, e.g. leukoariosis. The accuracy of SPECT in the assessment of patients with cognitive impairment is not yet established though it seems to be a promising method for the detection of frontotemporal dementia. Functional MR may play a role in the work-up of dementia in the future.