Microglial responses partially mediate the effect of Aß on cognition in Alzheimer's disease.

INTRODUCTION: Microglial responses are an integral part of Alzheimer's disease (AD) pathology and are associated with amyloid beta (Aß) deposition. This study aimed to investigate the effects of Aß and microglial responses on global cognitive impairment. METHODS: In this longitudinal study, 28 patients with mild cognitive impairment and 11 healthy controls underwent 11C-PK11195 and 11C-Pittsburgh compound B positron emission tomography (PET), structural magnetic resonance imaging scans, and global cognitive ratings at baseline and 2-year follow-up. Correlations between PET uptake and global cognition were assessed. Additionally, the mediation effect of the microglial response on the association between Aß load and global cognition was assessed. RESULTS: Aß load and the microglial response were both independently detrimental to global cognitive performance at baseline; however, at 2-year follow-up the association between Aß load and global cognitive ratings was partially mediated by the microglial response. DISCUSSION: As AD progresses, the associated microglial response partially mediates the detrimental effect of aggregated Aß on cognition. HIGHLIGHTS: This was a longitudinal study of amyloid beta (Aß), microglial responses, and global cognitive performance. Aß and microglial responses both affect cognition in early Alzheimer's disease. Microglial response partially mediates the effect of Aß on cognition in later stages.

Amyloid-ß aggregates activate peripheral monocytes in mild cognitive impairment.

The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer's Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aß aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer's Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aß aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aß. Hydrodynamic calculations suggest Aß aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis.

Capillary dysfunction in healthy elderly APOE ε4 carriers with raised brain Aß deposition.

INTRODUCTION: Capillary dysfunction, characterized by disturbances in capillary blood flow distribution, might be an overlooked factor in the development of Alzheimer's disease (AD). This study investigated microvascular blood flow in preclinical and prodromal AD individuals. METHODS: Using dynamic susceptibility contrast magnetic resonance imaging and positron emission tomography, we examined alterations in microvascular circulation and levels of Aß deposition in two independent cohorts of APOE ε4 carriers. RESULTS: Capillary dysfunction was elevated in both prodromal and preclinical AD individuals compared to age-matched controls. Additionally, the prodromal group exhibited higher levels of capillary dysfunction compared to the preclinical group. DISCUSSION: These findings suggest that capillary dysfunction can be detected at the preclinical stage of AD and indicates a worsening of capillary dysfunction throughout the AD continuum. Understanding the interaction between capillary dysfunction and Aß could provide insights into the relationship between cardiovascular risk factors and the development of AD. HIGHLIGHTS: Alzheimer's disease (AD) is associated with disturbances in microvascular circulation. Capillary dysfunction can be detected in preclinical AD. As cognitive symptoms progress in prodromal AD, capillary dysfunction worsens. Capillary dysfunction may impede the clearance of beta-amyloid (Aß). Capillary dysfunction might contribute to the development of AD.

Performance on complex memory tests is associated with ß-amyloid in individuals at risk of developing Alzheimer's disease.

The pathophysiological development of Alzheimer's disease (AD) begins in the brain years before the onset of clinical symptoms. The accumulation of beta-amyloid (Aß) is thought to be the first cortical pathology to occur. Carrying one apolipoprotein E (APOE) ε4 allele increases the risk of developing AD at least 2-3 times and is associated with earlier Aß accumulation. Although it is difficult to identify Aß-related cognitive impairment in early AD with standard cognitive tests, more sensitive memory tests may be able to do this. We sought to examine associations between Aß and performance on three tests within three subdomains of memory, verbal, visual, and associative memory, to elucidate which of these tests were sensitive to Aß-related cognitive impairment in at-risk subjects. 55 APOE ε4 carriers underwent MRI, 11 C-Pittsburgh Compound B (PiB) PET, and cognitive testing. A composite cortical PiB SUVR cut-off score of 1.5 was used to categorise subjects as either APOE ε4 Aß+ or APOE ε4 Aß-. Correlations were carried out using cortical surface analysis. In the whole APOE ε4 group, we found significant correlations between Aß load and performance on verbal, visual, and associative memory tests in widespread cortical areas, the strongest association being with performance on associative memory tests. In the APOE ε4 Aß+ group, we found significant correlations between Aß load and performance of verbal and associative, but not visual, memory in localised cortical areas. Performance on verbal and associative memory tests provides sensitive markers of early Aß-related cognitive impairment in at-risk subjects.

Capillary dysfunction correlates with cortical amyloid load in early Alzheimer's disease.

Alterations in cerebral perfusion is increasingly considered to play a crucial role in Alzheimer's disease (AD) and together with accumulated amyloid-ß, deficiencies in the brain microvascular circulation may result in local hypoxia. Here, we studied alterations in cerebral circulation and the correlation between amyloid-ß load and cerebral perfusion in prodromal AD (pAD). Using dynamic susceptibility contrast MRI and PET, we evaluated cerebral perfusion and amyloid-ß levels in 19 individuals with mild cognitive impairment (MCI) and high amyloid-ß load (pAD-MCI), 13 MCI individuals without AD pathology and 21 healthy controls. The pAD-MCI group showed significantly lower microvascular blood flow and significantly higher heterogeneity of microvascular blood transit times (p < 0.01) compared with the other 2 groups. Additionally, in the pAD-MCI group raised amyloid-ß levels correlated with decreased microvascular blood flow and increased heterogeneity of microvascular blood flow in frontal and temporal areas (p < 0.01). These results indicate a close connection between levels of amyloid-ß deposition and brain microvascular perfusion in pAD. A vicious cycle may be established where amyloid-ß load and deficiencies in brain perfusion may reinforce each other.

Capillary function progressively deteriorates in prodromal Alzheimer's disease: A longitudinal MRI perfusion study.

Cardiovascular risk factors are associated with the development of Alzheimer's disease (AD), and increasing evidence suggests that cerebral microvascular dysfunction plays a vital role in the disease progression. Using magnetic resonance imaging, we investigated the two-year changes of the cerebral microvascular blood flow in 11 mild cognitively impaired (MCI) patients with prodromal AD compared to 12 MCI patients without evidence of AD and 10 cognitively intact age-matched controls. The pAD-MCI patients displayed widespread deterioration in microvascular cerebral perfusion associated with capillary dysfunction. No such changes were observed in the other two groups, suggesting that the dysfunction in capillary perfusion is linked to the AD pathophysiology. The observed capillary dysfunction may limit local oxygenation in AD leading to downstream ß-amyloid aggregation, tau hyperphosphorylation, neuroinflammation and neuronal dysfunction. The findings are in agreement with the capillary dysfunction hypothesis of AD, suggesting that increasing heterogeneity of capillary blood flow is a primary pathological event in AD.

Asymmetric amyloid deposition in preclinical Alzheimer's disease: A PET study.

Introduction: The typical spatial pattern of amyloid-ß (Aß) in diagnosed Alzheimer's disease (AD) is that of a symmetrical hemispheric distribution. However, Aß may be asymmetrically distributed in early stages of AD. Aß distribution on PET has previously been explored in MCI and AD, but it has yet to be directly investigated in preclinical AD (pAD). We examined how Aß was distributed in individuals with pAD and MCI using 11C-Pittsburgh Compound B (PiB) PET. Methods: In this PET study, 79 subjects were retrospectively enrolled, including 34 controls, 24 pAD, and 21 MCI. All subjects underwent APOE genotyping, 11C-PiB PET, MRI, and cognitive testing. We explored differences in Aß load, Aß lateralisation, and Aß distribution, as well as associations between Aß distribution and cognition. Results: The Aß asymmetry index (AI) differed between groups, with pAD having the highest Aß AI as compared to both controls and MCI. There was no clear Aß lateralisation in pAD, but there was a non-significant trend towards Aß being more left-lateralised in MCI. There were no correlations between the cognitive scores and Aß AI or Aß lateralisation in pAD or MCI. Conclusion: The distribution of Aß is most asymmetrical in pAD, as Aß first starts accumulating, and it then becomes less asymmetrical in MCI, when Aß has spread further, suggesting that more pronounced asymmetrical Aß distribution may be a distinguishing factor in pAD. Longitudinal studies examining the distribution of Aß across the AD continuum are needed.

Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson's disease.

BACKGROUND: Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls. METHODS: We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age-matched controls. We measured microglial activation as 11 C-(R)-PK11195 binding potentials, and dopamine terminal integrity with 18 F-dopa influx constants. RESULTS: The 11 C-(R)-PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = -4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11 C-(R)-PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11 C-(R)-PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18 F-dopa uptake was similar to healthy controls. CONCLUSIONS: In vivo 11 C-(R)-PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impaired perfusion and capillary dysfunction in prodromal Alzheimer's disease.

INTRODUCTION: Cardiovascular disease increases the risk of developing Alzheimer's disease (AD), and growing evidence suggests an involvement of cerebrovascular pathology in AD. Capillary dysfunction, a condition in which capillary flow disturbances rather than arterial blood supply limit brain oxygen extraction, could represent an overlooked vascular contributor to neurodegeneration. We examined whether cortical capillary transit-time heterogeneity (CTH), an index of capillary dysfunction, is elevated in amyloid-positive patients with mild cognitive impairment (prodromal AD [pAD]). METHODS: We performed structural and perfusion weighted MRI in 22 pAD patients and 21 healthy controls. RESULTS: We found hypoperfusion, reduced blood volume, and elevated CTH in the parietal and frontal cortices of pAD-patients compared to controls, while only the precuneus showed focal cortical atrophy. DISCUSSION: We propose that microvascular flow disturbances antedate cortical atrophy and may limit local tissue oxygenation in pAD. We speculate that capillary dysfunction contributes to the development of neurodegeneration in AD.

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer's disease: a longitudinal PET study.

BACKGROUND: The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated ß-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. METHODS: Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine ß-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years. RESULTS: Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their ß-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising ß-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation. CONCLUSIONS: Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising ß-amyloid load show correlated levels of microglial activation which then later decline when the ß-amyloid load approaches AD levels. Later, as tau tangles form in ß-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Imaging dopamine function and microglia in asymptomatic LRRK2 mutation carriers.

Neuroinflammation (microglial activation) and subclinical nigrostriatal dysfunction have been reported in subjects at risk of Parkinsonism. Eight non-manifesting carriers (NMCs) of LRRK2 G2019S mutation had 11C-PK11195 and 18F-DOPA PET to assess microglial activation and striatal dopamine system integrity, respectively. Comparisons were made with healthy controls. Five LRRK2-NMCs had subclinical reductions of putaminal 18F-DOPA uptake. Three of them had significantly raised nigral 11C-PK11195 binding bilaterally. These findings indicate that nigrostriatal dysfunction and neuroinflammation occur in LRRK2-NMCs. Studies in larger cohorts with appropriate follow-up are needed to elucidate the significance of neuroinflammation in the premotor phase of LRRK2-PD.

Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer's disease.

BACKGROUND: Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer's disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised ß-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects. METHODS: Twenty-seven MCI or early AD cases with raised cortical ß-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics. RESULTS: Statistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping. CONCLUSION: We conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases-possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents.

Tau Tangles in Parkinson's Disease: A 2-Year Follow-Up Flortaucipir PET Study.

BACKGROUND: Flortaucipir PET, a marker of tau tangles, has shown lower than expected cortical uptake in Parkinson's disease (PD), than would be predicted from neuropathologic estimates of Alzheimer's disease co-pathology. Instead, the most characteristic finding of flortaucipir imaging in PD is decreased uptake in the substantia nigra, reflecting reduction in its "off-target" binding to neuromelanin. We have previously reported these observations in cross-sectional studies. OBJECTIVE: Here, we present two-year follow-up data of cortical and nigral flortaucipir uptake in PD patients. METHODS: Seventeen PD patients received repeat flortaucipir PET two years after baseline. We interrogated vertex-based group-wise cortical tracer binding (SUVRs) with a cerebellar reference using the general linear model while mean substantia nigra SUVRs were compared with volumes of interest group comparisons and voxel-wise group analyses using ANOVA. Finally, we performed linear regressions of tau load with changes in MoCA and UPDRS motor scores. RESULTS: We found no significant changes in substantia nigra or cortex flortaucipir uptake in Parkinson's disease patients over two years and no association with changes in cognitive symptoms. Signal reduction in the medial substantia nigra trended towards an association with worsening of motor symptoms. CONCLUSION: No significant increase in tau tangles occurred after a two-year follow-up of Parkinson's disease patients using flortaucipir PET.

Abnormal Amyloid Load in Mild Cognitive Impairment: The Effect of Reducing the PiB-PET Threshold.

BACKGROUND AND PURPOSE: In vivo detection of ß-amyloid (Aß) plaques in Alzheimer's disease (AD) is now possible with 11 C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as "amyloid-positive" and "amyloid-negative." It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11 C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally. METHODS: We serially determined the cortical amyloid load with 11 C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases. RESULTS: Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven "raised amyloid" MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period. CONCLUSION: Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects.

The Effect of 40-Hz Light Therapy on Amyloid Load in Patients with Prodromal and Clinical Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. AD pathology is characterized by abnormal aggregation of the proteins amyloid-ß (Aß) and hyperphosphorylated tau. No effective disease modifying therapies are currently available. A short-duration intervention with 40 Hz light flicker has been shown to reduce brain Aß load in transgenic mice. We aimed to test the effect of a similar short-duration 40 Hz light flicker regime in human AD patients. We utilized a Light Emitting Diode (LED) light bulb with a 40 Hz flicker. Six Aß positive patients received 10 days of light therapy, had 2 hours of daily exposure, and underwent a postintervention PiB PET on day 11. After 10 days of light therapy, no significant decrease of PiB SUVR values was detected in any volumes of interest tested (primary visual cortex, visual association cortex, lateral parietal cortex, precuneus, and posterior cingulate) or in the total motor cortex, and longer treatments may be necessary to induce amyloid removal in humans.

Does inflammation precede tau aggregation in early Alzheimer's disease? A PET study.

OBJECTIVE: Our aim was to assess with positron emission tomography (PET) the temporal and spatial inter-relationships between levels of cortical microglial activation and the aggregated amyloid-ß and tau load in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). METHODS: Six clinically probable AD and 20 MCI subjects had inflammation (11C-(R)-PK11195), amyloid (11C-PiB) and tau (18F-flortaucipir) PET, magnetic resonance imaging (MRI) and a neuropsychological assessment. Parametric images of tracer binding were interrogated at a voxel level and by region of interest analyses. RESULTS: 55% of MCI and 83% of AD subjects had a high amyloid-ß load. We have previously reported that clusters of correlated amyloid and inflammation levels are present in cortex. Here we found no correlation between levels of inflammation (11C-(R)-PK11195 BPND) and tau (18F-flortaucipir SUVR) or MMSE scores in high amyloid-ß cases. INTERPRETATION: While correlated levels of amyloid-ß and inflammation can be seen in MCI, we did not detect an association between levels of cortical tau tangles and inflammation in our series of high amyloid-ß cases. High levels of inflammation could be seen in amyloid-ß positive MCI cases where 18F-flortaucipir signals were low suggesting microglial activation precedes tau tangle formation. Inflammation levels were higher in high amyloid-ß MCI than in early AD cases, compatible with it initially playing a protective role.

Decreased noradrenaline transporter density in the motor cortex of Parkinson's disease patients.

Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical 11 C-MeNER binding in PD patients. Thirty PD patients and 12 healthy control subjects comparable in age, sex, and cognitive performance underwent PET imaging with 11 C-MeNER, a specific ligand of the noradrenaline transporter. Cortical noradrenaline transporter binding was compared at a voxel level using Statistical Parametric Mapping, whereas cortical thickness was assessed using FreeSurfer software with MRI. PD patients showed reduced 11 C-MeNER binding in the primary motor cortex unrelated to cortical thickness; other cortical regions did not differ between groups. In a subgroup analysis, patients with higher Hoehn & Yahr stage exhibited more pronounced 11 C-MeNER binding reductions. Loss of cortical noradrenergic projections to the primary motor cortex occurs in PD associated with disease stage. © 2018 International Parkinson and Movement Disorder Society.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder.

BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease.

See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-ß have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.

In Vivo cortical tau in Parkinson's disease using 18F-AV-1451 positron emission tomography.

BACKGROUND: Alzheimer's disease copathology is common in PD at autopsy. In non-PD subjects with mild cognitive impairment, tau depositions can be detected using 18F-AV-1451 PET. We hypothesized that 18F-AV-1451 PET would show tau aggregation in PD with mild cognitive impairment and correlate with cognitive dysfunction. OBJECTIVES: To describe tau aggregation in PD patients. METHODS: Twenty-six PD patients and 23 controls had 18F-AV-1451 PET and neuropsychological assessment to detect mild cognitive impairment. RESULTS: Nine PD patients (35%) were identified with mild cognitive impairment. Regional analyses showed no significant differences between groups. Voxel-wise analyses showed no correlation with cognitive domain z-scores within patients. One patient with mild cognitive impairment was estimated Braak tau stage 5; all other patients were stage 0. CONCLUSION: Our results indicate that tau pathology, as detected by 18F-AV-1451, is uncommon in PD with mild cognitive impairment and shows no significant correlation with cognitive dysfunction at this stage. © 2017 International Parkinson and Movement Disorder Society.