Ajenthan Surendranathan

18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

The extent to which the tau tracer [18F]AV-1451 can differentiate between tauopathies is unknown. By comparing patients with Alzheimer’s disease and progressive supranuclear palsy (PSP), Passamonti et al. show that [18F]AV-1451 displays greater specificity for Alzheimer-related tau pathology than PSP-related pathology. A machine learning algorithm correctly diagnosed 94% of cases.

Neuroinflammation in Lewy body dementia

Neuroinflammation is increasingly recognized as a key factor in the pathogenesis of neurodegenerative conditions. However, it remains unclear whether it has a protective or damaging role. Studies of Alzheimers disease and Parkinsons disease have provided much of the evidence for inflammatory pathology in neurodegeneration. Here we review the evidence for inflammation in dementia with Lewy bodies and Parkinsons disease dementia. Neuroinflammation has been confirmed in vivo using PET imaging, with microglial activation seen in Parkinsons disease dementia and recently in dementia with Lewy bodies. In Parkinsons disease and Parkinsons disease dementia, microglial activation suggests a chronic inflammatory process, although there is also evidence of its association with cognitive ability and neuronal function. Alpha-synuclein in various conformations has also been linked to activation of microglia, with a broad range of components of the innate and adaptive immune systems associated with this interaction. Evidence of neuroinflammation in Lewy body dementia is further supported by pathological and biomarker studies. Genetic and epidemiological studies support a role for inflammation in Parkinsons disease, but have yet to provide the same for Lewy body dementia. This review highlights the need to identify whether the nature and extent of microglial activation in Lewy body dementia can be linked to structural change, progression of domain specific cognitive symptoms and peripheral inflammation as a marker of central microglial pathology. Answers to these questions will enable the evaluation of immunotherapies as potential therapeutic options for prevention or treatment of dementia with Lewy bodies and Parkinsons disease dementia.

Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study protocol: a deep phenotyping cohort study of the role of brain inflammation in dementia, depression and other neurological illnesses

Introduction Inflammation of the central nervous system is increasingly regarded as having a role in cognitive disorders such as dementia and depression, but it is not clear how such inflammation relates to other aspects of neuropathology, structural and functional changes in the brain and symptoms (as assessed via clinical and neuropsychological assessment and MRI). This study will explore these pathophysiological mechanisms using positron emission tomography (PET) which allows in vivo imaging of inflammation, amyloid and τ deposition, together with neuropsychological profiling, MRI and peripheral biomarker analysis. Methods and analysis Using PET imaging of the ligand [11C]PK11195, we will test for increased neuroinflammation in vivo in patients with Alzheimers disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, late-onset depression and mild cognitive impairment, when compared to healthy controls. We will assess whether areas of inflammatory change are associated with amyloid and τ deposition (assessed using 11C-labelled Pittsburgh Compound B ([11C]PiB) and 18F-labelled AV-1451, respectively), as well as structural and connectivity markers found on MRI. Inflammatory biomarker analysis and immune-phenotyping of peripheral blood monocytes will determine the correlation between central inflammation and peripheral inflammation. Finally, we will examine whether central inflammatory markers seen on PET imaging are associated with global and domain specific cognitive impairments or predict cognitive decline over 12 months. Ethics and dissemination The study protocol was approved by the local ethics committee, East of England—Cambridge Central Research Ethics Committee (reference: 13/EE/0104). The study is also Administration of Radioactive Substances Advisory Committee (ARSAC) approved as part of this process. Data will be disseminated by presentation at national and international conferences and by publication, predominantly in journals of clinical neuroscience, neurology and psychiatry.

Multi-modal MRI investigation of volumetric and microstructural changes in the hippocampus and its subfields in mild cognitive impairment, Alzheimer's disease, and dementia with Lewy bodies

Background: Volumetric atrophy and microstructural alterations in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in people with Alzheimers disease (AD) and mild cognitive impairment (MCI). However, no study to date has jointly investigated concomitant microstructural and volumetric changes of the hippocampus in dementia with Lewy bodies (DLB). Methods: A total of 84 subjects (23 MCI, 17 DLB, 14 AD, and 30 healthy controls) were recruited for a multi-modal imaging (3T MRI and DTI) study that included neuropsychological evaluation. Freesurfer was used to segment the total hippocampus and delineate its subfields. The hippocampal segmentations were co-registered to the mean diffusivity (MD) and fractional anisotropy (FA) maps obtained from the DTI images. Results: Both AD and MCI groups showed significantly smaller hippocampal volumes compared to DLB and controls, predominantly in the CA1 and subiculum subfields. Compared to controls, hippocampal MD was elevated in AD, but not in MCI. DLB was characterized by both volumetric and microstructural preservation of the hippocampus. In MCI, higher hippocampal MD was associated with greater atrophy of the hippocampus and CA1 region. Hippocampal volume was a stronger predictor of memory scores compared to MD within the MCI group. Conclusions: Through a multi-modal integration, we report novel evidence that the hippocampus in DLB is characterized by both macrostructural and microstructural preservation. Contrary to recent suggestions, our findings do not support the view that DTI measurements of the hippocampus are superior to volumetric changes in characterizing group differences, particularly between MCI and controls.

Clinical prevalence of Lewy body dementia

BackgroundThe prevalence of dementia with Lewy bodies (DLB) and dementia in Parkinson’s disease (PDD) in routine clinical practice is unclear. Prevalence rates observed in clinical and population-based cohorts and neuropathological studies vary greatly. Small sample sizes and methodological factors in these studies limit generalisability to clinical practice.MethodsWe investigated prevalence in a case series across nine secondary care services over an 18-month period, to determine how commonly DLB and PDD cases are diagnosed and reviewed within two regions of the UK.ResultsPatients with DLB comprised 4.6% (95% CI 4.0–5.2%) of all dementia cases. DLB was represented in a significantly higher proportion of dementia cases in services in the North East (5.6%) than those in East Anglia (3.3%; χ2 = 13.6, p < 0.01). DLB prevalence in individual services ranged from 2.4 to 5.9%. PDD comprised 9.7% (95% CI 8.3–11.1%) of Parkinson’s disease cases. No significant variation in PDD prevalence was observed between regions or between services.ConclusionsWe found that the frequency of clinical diagnosis of DLB varied between geographical regions in the UK, and that the prevalence of both DLB and PDD was much lower than would be expected in this case series, suggesting considerable under-diagnosis of both disorders. The significant variation in DLB diagnostic rates between these two regions may reflect true differences in disease prevalence, but more likely differences in diagnostic practice. The systematic introduction of more standardised diagnostic practice could improve the rates of diagnosis of both conditions.

Imaging tau, neuroinflammation and Aβ in dementia with Lewy bodies: a deep-phenotyping case-report: Tau, neuroinflammation and Aβ in DLB

Dementia with Lewy bodies (DLB) is the second-leading cause of degenerative dementia in older people after Alzheimer’s disease (AD). The cardinal features of DLB include cognitive fluctuations, parkinsonism, REM sleep behavior disorder (RBD), and visual hallucinations. In addition to the presence of Lewy bodies, amyloid plaques (Aβ) and tau neurofibrillary tangles often co-occur, and evidence of increased inflammation is accumulating. Clarifying the interactions across these processes in DLB is critical for the optimization of therapeutic approaches, but until recently could only be evaluated at postmortem.

Clinical imaging in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a common neurodegenerative dementia in older people; however, the clinical features, particularly cognitive fluctuations and rapid eye movement sleep disorder, are often hard to elicit, leading to difficulty in making the diagnosis clinically. Here we examine the literature for the evidence behind imaging modalities that could assist in making the diagnosis. Dopamine transporter (DAT) imaging remains the best modality for differentiation from dementia of Alzheimer’s type with high sensitivity and specificity reported based on pathological diagnoses. 123Iodine-metaiodobenzylguanidine myocardial scintigraphy (MIBG) however is rapidly becoming an alternative imaging modality for the diagnosis of DLB, though studies assessing its accuracy with postmortem verification are still awaited. However, there are suggestions that MIBG may be better in the differentiation of vascular parkinsonism from DLB than DAT scans but may have lower sensitivity for detecting DLB compared with the 80% sensitivity seen in DAT imaging. Structural MRI scans have long been used for the diagnosis of dementia; however, their utility in DLB is limited to revealing the presence of coexisting Alzheimer’s disease. Fluorodeoxyglucose (FDG) PET is an alternative biomarker that can also differentiate Alzheimer’s disease and DLB but lacks the evidence base of both DAT and MIBG scans.

DELAYS IN DIAGNOSING LEWY BODY DEMENTIA

NY, USA; Emory University, Atlanta, GA, USA; Jefferson University, Philadelphia, PA, USA; University of California San Diego, San Diego, CA, USA; Columbia University, New York, NY, USA; Georgetown University, Washington, D.C. USA; Johns Hopkins University, Baltimore, MD, USA; Georgetown University, Washington, D.C., USA; Johns Hopkins University School of Medicine, Baltimore, MD, USA; Stanford University, Palo Alto, CA, USA; Oregon Health and Science University, Portland, OR, USA; University of Rochester, Rochester, NY, USA; Barrow Neurological Institute, Phoenix, AZ, USA; Ohio State University, Columbus, OH, USA; George Washington School of Medicine and Health Sciences, Washington, D.C., USA; Lewy Body Dementia Association, Lilburn, GA, USA. Contact e-mail: bboeve@mayo.edu

In vivo coupling of tau pathology and cortical thinning in Alzheimer's disease

The deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimers disease (AD) remain unclear.

INVESTIGATE THE RELATIONSHIP BETWEEN TAU AND NEUROINFLAMMATION IN ALZHEIMER’S DISEASE USING PET AND REACTION RATE MODELLING

in CBD was distinctly different from patterns in controls or patients with AD or PSP. Cortical atrophy measured with MRI was much more widespread than the cortical retention of F-AV1451 in CBD, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results were in sharp contrast to AD, where F-AV-1451 retention was more widespread than cortical atrophy and correlated well with cortical thickness and hypometabolism. Conclusions: Patients with CBD exhibited AV-1451 uptake in the motor cortex, corticospinal tract and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD or PSP. However, decreased F-Fluorodeoxyglucose (FDG) uptake and cortical atrophy, assessed with MRI, were more widespread than F-AV-1451 uptake and probably represent earlier, yet less specific, markers of pathology.