Neuroimaging in Dementia: More than Typical Alzheimer Disease

Alzheimer disease (AD) is the most common cause of dementia. The prevailing theory of the underlying pathology assumes amyloid accumulation followed by tau protein aggregation and neurodegeneration. However, the current antiamyloid and antitau treatments show only variable clinical efficacy. Three relevant points are important for the radiologic assessment of dementia. First, besides various dementing disorders (including AD, frontotemporal dementia, and dementia with Lewy bodies), clinical variants and imaging subtypes of AD include both typical and atypical AD. Second, atypical AD has overlapping radiologic and clinical findings with other disorders. Third, the diagnostic process should consider mixed pathologies in neurodegeneration, especially concurrent cerebrovascular disease, which is frequent in older age. Neuronal loss is often present at, or even before, the onset of cognitive decline. Thus, for effective emerging treatments, early diagnosis before the onset of clinical symptoms is essential to slow down or stop subsequent neuronal loss, requiring molecular imaging or plasma biomarkers. Neuroimaging, particularly MRI, provides multiple imaging parameters for neurodegenerative and cerebrovascular disease. With emerging treatments for AD, it is increasingly important to recognize AD variants and other disorders that mimic AD. Describing the individual composition of neurodegenerative and cerebrovascular disease markers while considering overlapping and mixed diseases is necessary to better understand AD and develop efficient individualized therapies

Neuroimaging in Dementia:More than Typical Alzheimer Disease

Alzheimer disease (AD) is the most common cause of dementia. The prevailing theory of the underlying pathology assumes amyloid accumulation followed by tau protein aggregation and neurodegeneration. However, the current antiamyloid and antitau treatments show only variable clinical efficacy. Three relevant points are important for the radiologic assessment of dementia. First, besides various dementing disorders (including AD, frontotemporal dementia, and dementia with Lewy bodies), clinical variants and imaging subtypes of AD include both typical and atypical AD. Second, atypical AD has overlapping radiologic and clinical findings with other disorders. Third, the diagnostic process should consider mixed pathologies in neurodegeneration, especially concurrent cerebrovascular disease, which is frequent in older age. Neuronal loss is often present at, or even before, the onset of cognitive decline. Thus, for effective emerging treatments, early diagnosis before the onset of clinical symptoms is essential to slow down or stop subsequent neuronal loss, requiring molecular imaging or plasma biomarkers. Neuroimaging, particularly MRI, provides multiple imaging parameters for neurodegenerative and cerebrovascular disease. With emerging treatments for AD, it is increasingly important to recognize AD variants and other disorders that mimic AD. Describing the individual composition of neurodegenerative and cerebrovascular disease markers while considering overlapping and mixed diseases is necessary to better understand AD and develop efficient individualized therapies.</p

Ethical framework for the detection, management and communication of incidental findings in imaging studies, building on an interview study of researchers' practices and perspectives

BACKGROUND: As thousands of healthy research participants are being included in small and large imaging studies, it is essential that dilemmas raised by the detection of incidental findings are adequately handled. Current ethical guidance indicates that pathways for dealing with incidental findings should be in place, but does not specify what such pathways should look like. Building on an interview study of researchers’ practices and perspectives, we identified key considerations for the set-up of pathways for the detection, management and communication of incidental findings in imaging research. METHODS: We conducted an interview study with a purposive sample of researchers (n = 20) at research facilities across the Netherlands. Based on a qualitative analysis of these interviews and on existing guidelines found in the literature, we developed a prototype ethical framework, which was critically assessed and fine-tuned during a two-day international expert meeting with bioethicists and representatives from large population-based imaging studies from the United Kingdom, Germany, Sweden and Belgium (n = 14). RESULTS: Practices and policies for the handling of incidental findings vary strongly across the Netherlands, ranging from no review of research scans and limited feedback to research participants, to routine review of scans and the arrangement of clinical follow-up. Respondents felt that researchers do not have a duty to actively look for incidental findings, but they do have a duty to act on findings, when detected. The principle of reciprocity featured prominently in our interviews and expert meeting. CONCLUSION: We present an ethical framework that may guide researchers and research ethics committees in the design and/or evaluation of appropriate pathways for the handling of incidental findings in imaging studies. The framework consists of seven steps: anticipation of findings, information provision and informed consent, scan acquisition, review of scans, consultation on detected abnormalities, communication of the finding, and further clinical management and follow-up of the research participant. Each of these steps represents a key decision to be made by researchers, which should be justified not only with reference to costs and/or logistical considerations, but also with reference to researchers’ moral obligations and the principle of reciprocity

Transfer learning improves supervised image segmentation across imaging protocols

The variation between images obtained with different scanners or different imaging protocols presents a major challenge in automatic segmentation of biomedical images. This variation especially hampers the application of otherwise successful supervised-learning techniques which, in order to perform well, often require a large amount of labeled training data that is exactly representative of the target data. We therefore propose to use transfer learning for image segmentation. Transfer-learning techniques can cope with differences in distributions between training and target data, and therefore may improve performance over supervised learning for segmentation across scanners and scan protocols. We present four transfer classifiers that can train a classification scheme with only a small amount of representative training data, in addition to a larger amount of other training data with slightly different characteristics. The performance of the four transfer classifiers was compared to that of standard supervised classification on two magnetic resonance imaging brain-segmentation tasks with multi-site data: white matter, gray matter, and cerebrospinal fluid segmentation; and white-matter-/MS-lesion segmentation. The experiments showed that when there is only a small amount of representative training data available, transfer learning can greatly outperform common supervised-learning approaches, minimizing classification errors by up to 60%

The bidirectional relationship between brain structure and physical activity:A longitudinal analysis in the UK Biobank

Physical activity is a protective factor against brain atrophy, while loss of brain volume could also be a determinant of physical activity. Therefore, we aimed to explore the bidirectional association of physical activity with brain structures in middle-aged and older adults from the UK Biobank. Overall, 3027 participants (62.45 ± 7.27 years old, 51.3% females) had data at two time points. Hippocampal volume was associated with total (β=0.048, pFDR=0.016) and household (β=0.075, pFDR&lt;0.001) physical activity. Global fractional anisotropy (β=0.042, pFDR=0.028) was also associated with household physical activity. In the opposite direction, walking was negatively associated with white matter volume (β=-0.026, pFDR=0.008). All these associations were confirmed by the linear mixed models. Interestingly, sports at baseline were linked to hippocampal and frontal cortex volumes at follow-up but these associations disappeared after adjusting for multiple comparisons (pall&gt;0.104). In conclusion, we found more consistent evidence that a healthier brain structure predicted higher physical activity levels than for the inverse, more established relationship.</p

Seasonality of cognitive function in the general population:the Rotterdam Study

Seasonal variation in cognitive function and underlying cerebral hemodynamics in humans has been suggested, but not consistently shown in previous studies. We assessed cognitive function in 10,276 participants from the population-based Rotterdam Study, aged 45 years and older without dementia, at baseline and at subsequent visits between 1999 and 2016. Seasonality of five cognitive test scores and of a summary measure of global cognition were determined, as well as of brain perfusion. Using linkage with medical records, we also examined whether a seasonal variation was present in clinical diagnoses of dementia. We found a seasonal variation of global cognition (0.05 standard deviations [95% confidence interval: 0.02–0.08]), the Stroop reading task, the Purdue Pegboard test, and of the delayed world learning test, with the best performance in summer months. In line with these findings, there were fewer dementia diagnoses of dementia in spring and summer than in winter and fall. We found no seasonal variation in brain perfusion. These findings support seasonality of cognition, albeit not explained by brain perfusion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00485-0

Clinical Relevance of Cortical Cerebral Microinfarcts on 1.5T Magnetic Resonance Imaging in the Late-Adult Population

Background and Purpose: Cortical cerebral microinfarcts (CMIs) have been linked with dementia and impaired cognition in cross-sectional studies. However, the clinical relevance of CMIs in a large population-based setting is lacking. We examine the association of cortical CMIs detected on 1.5T magnetic resonance imaging with cardiovascular risk factors, cerebrovascular disease, and brain tissue volumes. We further explore the association between cortical CMIs with cognitive decline and risk of stroke, dementia, and mortality in the general population. Methods: Two thousand one hundred fifty-six participants (age: 75.7±5.9 years, women: 55.6%) with clinical history and baseline magnetic resonance imaging (January 2009-December 2013) were included from the Rotterdam Study. Cortical CMIs were graded based on a previously validated method. Markers of cerebrovascular disease and brain tissue volumes were assessed on magnetic resonance imaging. Cognition was assessed using a detailed neuropsychological test at baseline and at 5 years of follow-up. Data on incident stroke, dementia, and mortality were included until January 2016. Results: Two hundred twenty-seven individuals (10.5%) had ≥1 cortical CMIs. The major risk factors of cortical CMIs were male sex, current smoking, history of heart disease, and stroke. Furthermore, presence of cortical CMIs was associated with infarcts and smaller brain volume. Persons with cortical CMIs showed cognitive decline in Stroop tests (color-naming and interference subtasks; β for color-naming, 0.18 [95% CI, 0.04-0.33], P interaction ≤0.001 and β for interference subtask, 1.74, [95% CI, 0.66-2.82], P interaction ≤0.001). During a mean follow-up of 5.2 years, 73 (4.3%) individuals developed incident stroke, 95 (5.1%) incident dementia, and 399 (19.2%) died. People with cortical CMIs were at an increased risk of stroke (hazard ratio, 1.18 [95% CI, 1.09-1.28]) and mortality (hazard ratio, 1.09 [95% CI, 1.00-1.19]). Conclusions: Cortical CMIs are highly prevalent in a population-based setting and are associated with cardiovascular disease, cognitive decline, and increased risk of stroke and mortality. Future investigations will have to show whether cortical CMIs are a useful biomarker to intervene upon to reduce the burden of stroke.</p

Progression of arterial calcifications:what, where, and in whom?

Objectives: There is a lack of information on the development of arteriosclerosis over time. This study aims to assess long-term sex-specific changes in arterial calcifications in five arteries, and the influence of cardiovascular risk factors hereon. Methods: From a population-based cohort, 807 participants (mean baseline age, 65.8; SD, 4.2) underwent a non-contrast computed tomography (CT) examination between 2003 and 2006, and after a median follow-up of 14 years. We assessed incidences and changes in volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC) and intracranial carotid artery calcification (ICAC), and vertebrobasilar artery calcification (VBAC). We investigated the simultaneous presence of severe progression (upper quartile of percentual change volumes). Associations of cardiovascular risk factors with changes in calcification volumes were assessed using multivariate linear regression models. Results: The difference in AAC was most substantial; the median volume (mm3) increased from of 129 to 916 in men and from 93 to 839 in women. For VBAC, no change in volumes was observed though more than a quarter of participants without baseline VBAC developed VBAC during follow-up. Severe progression was most often observed in only one artery at the same time. Hypertension was most consistently associated with increase in calcifications. Associations of diabetes, hypercholesterolemia, and smoking with changes in calcifications varied across arteries and sex. Conclusions: We found a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors were associated with increase of calcifications with sex-specific differential effects across arteries. Clinical relevance statement: There is a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors are associated with increase of calcifications with sex-specific differential effects across arteries; thus, assessing changes in only one artery may thus not provide a good reflection of the systemic development of arteriosclerosis. Key Points: • Assessing change in arterial calcification in only one artery does not reflect the systemic development of arterial calcification. • Cardiovascular risk factors are associated with progression of arterial calcifications. • Progression of arterial calcification is sex and artery-specific. Graphical Abstract: [Figure not available: see fulltext.].</p

New horizons in cognitive and functional impairment as a consequence of cerebral small vessel disease

Cerebral small vessel disease (cSVD) is a frequent finding in imaging of the brain in older adults, especially in the concomitance of cardiovascular disease risk factors. Despite the well-established link between cSVD and (vascular) cognitive impairment (VCI), it remains uncertain how and when these vascular alterations lead to cognitive decline. The extent of acknowledged markers of cSVD is at best modestly associated with the severity of clinical symptoms, but technological advances increasingly allow to identify and quantify the extent and perhaps also the functional impact of cSVD more accurately. This will facilitate a more accurate diagnosis of VCI, against the backdrop of concomitant other neurodegenerative pathology, and help to identify persons with the greatest risk of cognitive and functional deterioration. In this study, we discuss how better assessment of cSVD using refined neuropsychological and comprehensive geriatric assessment as well as modern image analysis techniques may improve diagnosis and possibly the prognosis of VCI. Finally, we discuss new avenues in the treatment of cSVD and outline how these contemporary insights into cSVD can contribute to optimise screening and treatment strategies in older adults with cognitive impairment and multimorbidity.</p