Elijah Mak

Baseline and longitudinal grey matter changes in newly diagnosed Parkinson's disease: ICICLE-PD study

Mild cognitive impairment in Parkinson’s disease (PDMCI) is associated with progression to dementia in a majority of patients. Mak et al. reveal accelerated cortical thinning in patients with PDMCI compared to non-cognitively impaired patients and healthy controls. Patterns of cortical thinning may constitute biomarkers for increased dementia risk.

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.

Cerebral white matter hyperintensity in Parkinson's disease: A major risk factor for mild cognitive impairment

BACKGROUND Mild cognitive impairment (MCI) and dementia contribute to a poor quality of life among patients with PD. The influence of cerebral ischemia as a risk factor for MCI in PD has not been adequately investigated. To address this issue, we examined the influence of the volume and distribution of white matter hyperintensity (WMH) as a risk factor for MCI in early PD. METHODS Prospective study of patients with early idiopathic PD. All patients had baseline MRI-FLAIR, clinical assessment and detailed neuropsychological evaluation. Data on demographics, vascular risk factors, cognitive performance and WMH volumes were analyzed. RESULTS 91 patients; mean age 64.9 years, mean education of 10.5 years. 24 patients fulfilled the Movement Disorder Society criteria for MCI and were classified as PD-MCI while the rest were classified as PD with no cognitive impairment (PD-NCI). Patients with PD-MCI and PD-NCI did not differ in Hoehn & Yahr staging. PD-MCI patients had a higher prevalence of diabetes mellitus, hypertension and hyperlipidemia. PD-MCI patients had significantly greater volume of periventricular (6.04 ml vs. 2.66 ml, p = 0.001) and deep subcortical WMH (2.16 vs.1.44, p = 0.002). Regional WMH was significantly greater among PD-MCI in the frontal, parietal and occipital regions. Logistic regression analyses demonstrated WMH to be associated with PD-MCI independent of age, education, and vascular risk factors. Increasing WMH volume was associated with lower performance on executive function, memory and language. CONCLUSIONS WMH is an important risk factor for PD-MCI independent of vascular risk factors. PD patients with WMH should be regularly screened for MCI.

Cognitive deficits in mild Parkinson's disease are associated with distinct areas of grey matter atrophy

Background and objectives The neuroanatomical substrates underlying cognitive impairment in Parkinsons disease (PD) remain poorly understood. To address this gap, we compared the grey matter atrophy patterns in PD patients with mild cognitive impairment (PD-MCI) with PD patients having no cognitive impairment (PD-NCI), and examined relationships between atrophic regions and cognitive performance in specific domains. Methods 90 non-demented PD patients (64.95±7.54 years, Hoehn and Yahr=1.88±0.39) were classified using formal diagnostic criteria as PD-MCI (n=23) or PD-NCI (n=67). Grey matter volume differences were examined using voxel-based morphometry on structural MRI, and multivariate linear regressions were employed to assess the relationships between cognitive performance in specific domains and atrophic regions. Results Patients with PD-MCI had lower global cognition scores compared with PD-NCI (Mini Mental State Examination: 26.9 vs28.4, p=0.011; Montreal Cognitive Assessment: 24.5 vs 27.0, p<0.001). The PD-MCI group demonstrated significantly poorer performance on executive function, attention, memory and language abilities. Patients with PD-MCI had reductions in grey matter volumes in the left insular, left superior frontal and left middle temporal areas compared to PD-NCI. Multiple regressions controlling for age, education and cardiovascular risk factors revealed significant positive correlations between left insular atrophy and executive–attention dysfunction. Conclusions Domain specific cognitive impairment in mild PD is associated with distinct areas of grey matter atrophy. These regions of atrophy are demonstrable early in the disease course and may serve as a biomarker for dementia in PD.

Neuroimaging correlates of cognitive impairment and dementia in Parkinson's disease.

There has been a gradual shift in the definition of Parkinsons disease, from a movement disorder to a neurodegenerative condition affecting multiple cognitive domains. Mild cognitive impairment (PD-MCI) is a frequent comorbidity in PD that is associated with progression to dementia (PDD) and debilitating consequences for patients and caregivers. At present, the pathophysiology underpinning cognitive impairment in PD is not established, although emerging evidence has suggested that multi-modal imaging biomarkers could be useful in the early diagnosis of PD-MCI and PDD, thereby identifying at-risk patients to enable treatment at the earliest stage possible. Structural MRI studies have revealed prominent grey matter atrophy and disruptions of white matter tracts in PDD, although findings in non-demented PD have been more variable. There is a need for further longitudinal studies to clarify the spatial and temporal progression of morphological changes in PD, as well as to assess their underlying involvement in the evolution of cognitive deficits. In this review, we discuss the aetiology and neuropsychological profiles of PD-MCI and PDD, summarize the putative imaging substrates in light of evidence from multi-modal neuroimaging studies, highlight limitations in the present literature, and suggest recommendations for future research.

Longitudinal assessment of global and regional atrophy rates in Alzheimer's disease and dementia with Lewy bodies

Background & objective Percent whole brain volume change (PBVC) measured from serial MRI scans is widely accepted as a sensitive marker of disease progression in Alzheimers disease (AD). However, the utility of PBVC in the differential diagnosis of dementia remains to be established. We compared PBVC in AD and dementia with Lewy bodies (DLB), and investigated associations with clinical measures. Methods 72 participants (14 DLBs, 25 ADs, and 33 healthy controls (HCs)) underwent clinical assessment and 3 Tesla T1-weighted MRI at baseline and repeated at 12 months. We used FSL-SIENA to estimate PBVC for each subject. Voxelwise analyses and ANCOVA compared PBVC between DLB and AD, while correlational tests examined associations of PBVC with clinical measures. Results AD had significantly greater atrophy over 1 year (1.8%) compared to DLB (1.0%; p = 0.01) and HC (0.9%; p < 0.01) in widespread regions of the brain including periventricular areas. PBVC was not significantly different between DLB and HC (p = 0.95). There were no differences in cognitive decline between DLB and AD. In the combined dementia group (AD and DLB), younger age was associated with higher atrophy rates (r = 0.49, p < 0.01). Conclusions AD showed a faster rate of global brain atrophy compared to DLB, which had similar rates of atrophy to HC. Among dementia subjects, younger age was associated with accelerated atrophy, reflecting more aggressive disease in younger people. PBVC could aid in differentiating between DLB and AD, however its utility as an outcome marker in DLB is limited.

In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings.

In addition to the deposition of β-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimers disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging. In this article, we provide a comprehensive discussion of tau pathophysiology, its quantification with novel PET radiotracers, as well as a systematic review of tau PET imaging in normal aging and various dementia conditions: mild cognitive impairment, Alzheimers disease, frontotemporal dementia, progressive supranuclear palsy, and Lewy body dementia. We discuss the main findings in relation to group differences, clinical-cognitive correlations of tau PET, and multi-modal relationships among tau PET and other pathological markers. Collectively, the small but growing literature of tau PET has yielded consistent anatomical patterns of tau accumulation that recapitulate post-mortem distribution of neurofibrillary tangles which correlate with cognitive functions and other markers of pathology. In general, AD is characterised by increased tracer retention in the inferior temporal lobe, extending into the frontal and parietal regions in more severe cases. It is also noted that the spatial topography of tau accumulation is markedly distinct to that of amyloid burden in aging and AD. Tau PET imaging has also revealed characteristic spatial patterns among various non-AD tauopathies, supporting its potential role for differential diagnosis. Finally, we propose novel directions for future tau research, including (a) longitudinal imaging in preclinical dementia, (b) multi-modal mapping of tau pathology onto other pathological processes such as neuroinflammation, and (c) the need for more validation studies against post-mortem samples of the same subjects.

Progressive cortical thinning and subcortical atrophy in dementia with Lewy bodies and Alzheimer's disease

Patterns of progressive cortical thinning in dementia with Lewy bodies (DLB) remain poorly understood. We examined spatiotemporal patterns of cortical thinning and subcortical atrophy over 12 months in DLB (n = 13), compared with Alzheimers disease (AD) (n = 23) and healthy control subjects (HC) (n = 33). Rates of temporal thinning in DLB were relatively preserved compared with AD. Volumetric analyses subcortical changes revealed that the AD group demonstrated significantly increased hippocampal atrophy (-5.8%) relative to the HC (-1.7%; p < 0.001) and DLB groups (-2.5%, p = 0.006). Significant lateral ventricular expansion was also observed in AD (8.9%) compared with HC (4.3%; p < 0.001) and DLB (4.7%; p = 0.008) at trend level. There was no significant difference in subcortical atrophy and ventricular expansion between DLB and HC. In the DLB group, increased rates of cortical thinning in the frontal and parietal regions were significantly correlated with decline in global cognition (Mini-Mental State Examination) and motor deterioration (Unified Parkinsons Disease Rating Scale 3), respectively. Overall, AD and DLB are characterized by different spatiotemporal patterns of cortical thinning over time. Our findings warrant further consideration of longitudinal cortical thinning as a potential imaging marker to differentiate DLB from AD.

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.

Associations of hippocampal subfields in the progression of cognitive decline related to Parkinson's disease

Objective Hippocampal atrophy has been associated with mild cognitive impairment (MCI) in Parkinsons disease (PD). However, literature on how hippocampal atrophy affects the pathophysiology of cognitive impairment in PD has been limited. Previous studies assessed the hippocampus as an entire entity instead of their individual subregions. We studied the progression of cognitive status in PD subjects over 18 in relation to hippocampal subfields atrophy. Methods 65 PD subjects were included. Using the MDS task force criteria, PD subjects were classified as either having no cognitive impairment (PD-NCI) or PD-MCI. We extended the study by investigating the hippocampal subfields atrophy patterns in those who converted from PD-NCI to PD-MCI (PD-converters) compared to those who remained cognitively stable (PD-stable) over 18 months. Freesurfer 6.0 was used to perform the automated segmentation of the hippocampus into thirteen subregions. Results PD-MCI showed lower baseline volumes in the left fimbria, right CA1, and right HATA; and lower global cognition scores compared to PD-NCI. Baseline right CA1 was also correlated with baseline attention. Over 18 months, decline in volumes of CA2–3 and episodic memory were also seen in PD-converters compared to PD-stable. Baseline volumes of GC-DG, right CA4, left parasubiculum, and left HATA were predictive of the conversion from PD-NCI to PD-MCI. Conclusion The findings from this study add to the anatomical knowledge of hippocampal subregions in PD, allowing us to understand the unique functional contribution of each subfield. Structural changes in the hippocampus subfields could be early biomarkers to detect cognitive impairment in PD.