Neuroimaging in dementia

Over the last few years, advances in neuroimaging have generated biomarkers, which increase diagnostic certainty, provide valuable information about prognosis, and suggest a particular pathology underlying the clinical dementia syndrome. We aim to review the evidence for use of already established imaging modalities, along with selected techniques that have a great potential to guide clinical decisions in the future. We discuss structural, functional and molecular imaging, focusing on the most common dementias: Alzheimer's disease, fronto-temporal dementia, dementia with Lewy bodies and vascular dementia. Finally, we stress the importance of conducting research using representative cohorts and in a naturalistic set up, in order to build a strong evidence base for translating imaging methods for a National Health Service. If we assess a broad range of patients referred to memory clinic with a variety of imaging modalities, we will make a step towards accumulating robust evidence and ultimately closing the gap between the dramatic advances in neurosciences and meaningful clinical applications for the maximum benefit of our patients.     

Association of cerebral small vessel disease burden with brain structure and cognitive and vascular risk trajectories in mid-to-late life

We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96, SD = 5.18, 79% men). We used linear mixed-effects models to investigate associations of SVD burden with up to 25-year retrospective trajectories of vascular risk and cognitive performance. General linear modelling was used to investigate concurrent associations with grey matter (GM) density and white matter (WM) microstructure, and whether these associations were modified by cognitive status (Montreal Cognitive Asessment [MoCA] scores of < 26 vs. ≥ 26). Severe SVD burden in older age was associated with higher mean arterial pressure throughout midlife (β = 3.36, 95% CI [0.42-6.30]), and faster cognitive decline in letter fluency (β = −0.07, 95% CI [−0.13–−0.01]), and verbal reasoning (β = −0.05, 95% CI [−0.11–−0.001]). Moreover, SVD burden was related to lower GM volumes in 9.7% of total GM, and widespread WM microstructural decline (FWE-corrected p < 0.05). The latter association was most pronounced in individuals who demonstrated cognitive impairments on MoCA (MoCA < 26; F_3,608 = 2.14, p = 0.007). These findings highlight the importance of managing midlife vascular health to preserve brain structure and cognitive function in old age.     

Novel method of intraoperative liver tumour localisation with indocyanine green and near-infrared imaging

INTRODUCTIONFluorescence imaging (FI) with indocyanine green (ICG) is increasingly implemented as an intraoperative navigation tool in hepatobiliary surgery to identify hepatic tumours. This is useful in minimally invasive hepatectomy, where gross inspection and palpation are limited. This study aimed to evaluate the feasibility, safety and optimal timing of using ICG for tumour localisation in patients undergoing hepatic resection.METHODSFrom 2015 to 2018, a prospective multicentre study was conducted to evaluate feasibility and safety of ICG in tumour localisation following preoperative administration of ICG either on Day 0–3 or Day 4–7.RESULTSAmong 32 patients, a total of 46 lesions were resected: 23 were hepatocellular carcinomas (HCCs), 12 were colorectal liver metastases (CRLM) and 11 were benign lesions. ICG FI identified 38 (82.6%) lesions prior to resection. The majority of HCCs were homogeneous fluorescing lesions (56.6%), while CLRM were homogeneous (41.7%) or rim-enhancing (33.3%). The majority (75.0%) of the lesions not detected by ICG FI were in cirrhotic livers. Most (84.1%) of ICG-positive lesions detected were < 1 cm deep, and half of the lesions ≥ 1 cm in depth were not detected. In cirrhotic patients with malignant lesions, those given ICG on preoperative Day 0−3 and Day 4−7 had detection rates of 66.7% and 91.7%, respectively. There were no adverse events.CONCLUSIONICG FI is a safe and feasible method to assist tumour localisation in liver surgery. Different tumours appear to display characteristic fluorescent patterns. There may be no disadvantage of administering ICG closer to the operative date if it is more convenient, except in patients with liver cirrhosis.     

Cardiac abnormalities in end stage renal failure and anaemia

Thirteen anaemic children on dialysis were assessed to determine the incidence of cardiac changes in end stage renal failure. Nine children had an increased cardiothoracic ratio on radiography. The electrocardiogram was abnormal in every case but no child had left ventricular hypertrophy as assessed by voltage criteria. However, left ventricular hypertrophy, often gross, was found on echocardiography in 12 children and affected the interventricular septum disproportionately. Cardiac index was increased in 10 patients as a result of an increased left ventricular stroke volume rather than heart rate. Left ventricular hypertrophy was significantly greater in those on treatment for hypertension and in those with the highest cardiac index. Abnormal diastolic ventricular function was found in 6/11 children. Children with end stage renal failure have significant cardiac abnormalities that are likely to contribute to the high cardiovascular mortality in this group. Anaemia and hypertension, or its treatment, probably contribute to these changes. Voltage criteria on electrocardiogram are of no value in detecting left ventricular hypertrophy. Echocardiography must be performed, with the results corrected for age and surface area, in order to detect and follow these abnormalities.     

Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia.

OBJECTIVE: The authors sought to determine the diagnostic accuracy of 99mTc-HMPAO-SPECT in discriminating between Alzheimer disease (AD) and other dementias. METHODS: Articles published between 1985 and 2002 were retrieved systematically from MEDLINE and EMBASE, cross-referencing with personal collections and 13 narrative reviews. Of 301 studies identified, 48 survived exclusion criteria and contained extractable data. Two authors independently assessed and graded the methodology of all included studies. Diagnostic comparison groups included vascular dementia (VD; 13 studies), fronto-temporal dementia (FTD; 7 studies), normal healthy volunteers (27 studies), and non-dementia patients (13 studies). Where statistically justified, groups were pooled in a metaanalysis; summary receiver operating curves were constructed; and heterogeneity across studies examined by regression of the diagnostic odds ratio. RESULTS: The pooled weighted sensitivity of 99mTc-HMPAO-SPECT in discriminating clinically defined AD from VD was 71.3%; its specificity was 75.9%. The pooled weighted sensitivity and specificity for AD versus FTD were 71.5% and 78.2%, respectively. Variation in outcome across studies was not found to be attributable to any single factor. CONCLUSION: Pathological verification studies suggest that clinical criteria may be more sensitive in detecting AD than brain SPECT (81% versus 74%). However, SPECT studies provide a higher specificity against other types of dementia than clinical criteria (91% versus 70%). SPECT may, therefore, be helpful in the differential diagnosis of AD. Clinical follow-up studies are urgently required to establish its predictive validity with regard to natural history and treatment response.     

Possible structural abnormality of the brainstem in unipolar depressive illness: a transcranial ultrasound and diffusion tensor magnetic resonance imaging study

BACKGROUND: Most empirically derived antidepressants increase monoamine levels. The nuclei of cells synthesising these monoamines are located in the brainstem, and projection tracts such as the medial forebrain bundle reach virtually all other brain areas. Two studies of unipolar depressive illness using transcranial ultrasound have reported reduced echogenicity of the brainstem midline in unipolar depressed patients. This may be consistent with disruption of white matter tracts, including the medial forebrain bundle, and it has been suggested that the effect of such disruption could be reversed by antidepressants. OBJECTIVE: To replicate these findings in a group of unipolar depressed patients and controls. METHODS: Fifteen unipolar depressed patients and 15 controls were studied using transcranial ultrasound imaging and diffusion tensor magnetic resonance imaging (DT-MRI). RESULTS: No difference in echogenicity of the brainstem midline of unipolar depressed patients was found. A possible trend (Cohen's d = 0.39) in the direction of previous studies was found. Although the echogenicity of the brainstem midline of the control group was found to be similar to previous reports, there was no reduction in the patient group. Additionally, no structural abnormality of the brainstem was identified using DT-MRI. CONCLUSIONS: While these data do not replicate the findings of previous studies reporting a significant reduction in the echogenicity of the brainstem midline in unipolar depressed patients, the ultrasound investigation indicated that there may be a trend in this direction. Given the importance of identifying the causes of depressive illness, it is important that other groups attempt similar studies.     

The clinical manifestation of mental disorder in Huntington's disease: a retrospective case record study of disease progression

All cases (86) of Huntington's Disease presenting between 1970 and 1987 in the Grampian Health Board region were identified and a case note analysis of neurological and psychiatric syndromes carried out - the latter using the PSE syndrome check-list. The commonest syndromes were organic impairment, irritability, loss of interest and concentration and simple depression and these were often the presenting psychiatric syndromes. General anxiety, worrying and social unease occurred early, commonly before movement disorder and were associated with longer survival.     

海马区星形胶质细胞培养上清液体外诱导人脂肪基质细胞向神经元样细胞的分化

目的:观察海马区星形胶质细胞培养上清液能否在体外诱导人脂肪基质细胞向神经元样细胞分化。方法:实验于2004-10/2005-06在华北煤炭医学院中心实验室完成。在无菌条件下从Wistar乳鼠分离出海马组织,从分离的海马组织中获得星形胶质细胞,并收集其培养上清液。取外科手术获得的人腹部皮下脂肪组织进行人脂肪基质细胞的原代培养。30例患者均知情同意。取第3代人脂肪基质细胞接种到培养孔中,预先放置无菌盖玻片的24孔培养板,制备细胞爬片或者接种到培养瓶中,细胞生长达50%～60%融合时,去除培养液,换为海马区星形胶质细胞培养上清诱导液进行诱导,对照组培养液为无血清培养基。倒置相差显微镜下连续观察细胞生长情况和形态变化,应用免疫细胞化学、鉴定神经前体细胞的特异性标志神经巢蛋白、神经细胞的特异性标志神经元特异性烯醇化酶、微管联合蛋白2和神经胶质细胞的特异性标志胶质纤维酸性蛋白的表达。结果:①诱导培养第3天,部分人脂肪基质细胞开始变形,从原先的细长梭状细胞变成神经元样细胞,可见细胞伸出突起,多为双极或多极细胞。②刚分离接种的人脂肪基质细胞镜下呈圆形,悬浮状态,接种后24h内贴壁,并开始伸展,多呈梭形。1周后细胞融合成单层,排列出现方向性,但有少量圆形及卵圆形细胞混杂生长。③第4,5代人脂肪基质细胞在诱导48h后形态即开始发生变化,扁平的胞体较预诱导后逐渐回缩,向外伸出突起,72h后扁平的胞浆向胞核收缩,突起继续延长,以后随时间进展,具有典型神经细胞形态特点的细胞数量逐渐增多,形成双极或多极细胞。④免疫细胞化学检测人脂肪基质细胞诱导5d后发现有(10.5±3.7)%神经巢蛋白、(38.4±5.2)%胶质纤维酸性蛋白、(15.7±2.3)%神经元特异性烯醇化酶表达,未见微管联合蛋白2的表达。结论:海马区星形胶质细胞培养上清液可以在体外诱导人脂肪基质细胞向神经元样细胞方向分化。     

Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V Leiden

Patients with inflammatory bowel disease have an increased frequency of thromboembolism, and microvascular thrombosis has been proposed as a contributory pathogenic factor. The mechanism of enhanced procoagulant activity is not understood. We examined the clinical setting of thromboembolic events in 52 patients with Crohn's disease or ulcerative colitis, and assessed the procoagulant laboratory profile, including Factor V Leiden, in a subset of 20 patients to identify procoagulant risk factors. Patients who developed thrombosis tended to be young; 60% of thrombotic events occurred in patients under 50 years. Multiple thromboembolic episodes occurred in 13% and unusual sites of thrombosis (e.g. intracardiac, cerebral, inominate veins) in 11%. No risk factor was identifiable in 52% of cases and two-thirds of thromboses occurred in an out-patient setting. The mortality rate was 8%. Evidence for inflammatory disease activity was found in only 45% of patients with ulcerative colitis at the time of the thromboembolic event, in contrast to 89% of those with Crohn's disease. Assays for specific coagulation defects were negative in all cases tested (protein S, C were normal in 17/17; anti-thrombin III, anti-phospholipid antibodies and activated protein C resistance were negative in 20/20, and only 1/20 patients was found to be heterozygous for Factor V leiden. Thrombosis in inflammatory bowel disease is important because it occurs in a young population, often in unusual sites, and has a high mortality. The development of thrombosis is related to active inflammatory disease in most patients with Crohn's disease but apparently not in those with ulcerative colitis. Since approximately half of the patients had no other identifiable risk factor, there remains a substantial group of patients with IBD who develop thrombosis for unknown reasons.      

Thalidomide attenuates nitric oxide-driven angiogenesis by interacting with soluble guanylyl cyclase

Background and purpose:

Nitric oxide (NO) promotes angiogenesis by activating endothelial cells. Thalidomide arrests angiogenesis by interacting with the NO pathway, but its putative targets are not known. Here, we have attempted to identify these targets.

Experimental approach:

Cell-based angiogenesis assays (wound healing of monolayers and tube formation in ECV304, EAhy926 and bovine arterial endothelial cells), along with ex vivo and in vivo angiogenesis assays, were used to explore interactions between thalidomide and NO. We also carried out in silico homology modelling and docking studies to elucidate possible molecular interactions of thalidomide and soluble guanylyl cyclase (sGC).

Key results:

Thalidomide inhibited pro-angiogenic functions in endothelial cell cultures, whereas 8-bromo-cGMP, sildenafil (a phosphodiesterase inhibitor) or a NO donor [sodium nitroprusside (SNP)] increased these functions. The inhibitory effects of thalidomide were reversed by adding 8-bromo-cGMP or sildenafil, but not by SNP. Immunoassays showed a concentration-dependent decrease of cGMP in endothelial cells with thalidomide, without affecting the expression level of sGC protein. These results suggested that thalidomide inhibited the activity of sGC. Molecular modelling and docking experiments revealed that thalidomide could interact with the catalytic domain of sGC, which would explain the inhibitory effects of thalidomide on NO-dependent angiogenesis.

Conclusion and implications:

Our results showed that thalidomide interacted with sGC, suppressing cGMP levels in endothelial cells, thus exerting its anti-angiogenic effects. These results could lead to the formulation of thalidomide-based drugs to curb angiogenesis by targeting sGC.