Cerebellum Ratio Research Articles

One-Year Longitudinal Changes in Tau Accumulation on [18F]PI-2620 PET in the Alzheimer Spectrum.

We investigated the longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients in the Alzheimer disease (AD) continuum using 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5c']dipyridine ([18F]PI-2620) PET. Methods: We prospectively enrolled 52 participants (age, 69.7 ± 8.4 y; 18 men and 34 women): 7 with normal cognition, 28 with mild cognitive impairment, and 17 with AD. They all completed the [18F]PI-2620 and [18F]florbetaben PET, MRI, and neuropsychologic tests at baseline and, excepting the [18F]florbetaben PET, at the 1-y follow-up. Amyloid-β (Aβ) PET images were visually scored as positive (+) or negative (-). Patients on the AD continuum, including Aβ+ mild cognitive impairment and AD, were classified into early-onset (EO+) (<65 y old) or late-onset (LO+) (≥65 y old) groups. [18F]PI-2620 PET SUV ratios (SUVRs) were determined by calculating the cerebral-to-inferior cerebellar ratio. Cortical volumes were calculated using 3-dimensional T1-weighted MRI. The correlation between tau accumulation progression and cognitive decline was also investigated. Results: The global [18F]PI-2620 PET SUVRs were 1.04 ± 0.07 in 15 Aβ- patients, 1.18 ± 0.21 in 20 LO+ patients (age, 76.7 ± 3.8 y), and 1.54 ± 0.38 in 17 EO+ patients (age, 63.4 ± 5.4 y; P < 0.001) at baseline. The global SUVR increased over 1 y by 0.05 ± 0.07 (3.90%) and 0.13 ± 0.22 (8.41%) in the LO+ and EO+ groups, respectively, whereas in the Aβ- groups, it remained unchanged. The EO+ group showed higher global and regional tau deposition than did the Aβ- and LO+ groups (P < 0.05 for each) and rapid accumulation in Braak stage V (0.15 ± 0.25; 9.10% ± 12.27%; P = 0.016 and 0.008), Braak stage VI (0.08 ± 0.12; 7.16% ± 10.06%; P < 0.006 and 0.005), and global SUVR (P = 0.013) compared with the Aβ- group. In the EO+ group, the changes in SUVR in Braak stages II-VI were strongly correlated with the baseline and changes in verbal memory (P < 0.03). The LO+ group showed higher tau accumulation in Braak stage I-IV areas than did the Aβ- group (P < 0.001 for each). In the LO+ group, the change in SUVR in Braak stages III and IV moderately correlated with the change in attention (P < 0.05), and the change in SUVR in Braak stages V and VI moderately correlated with the change in visuospatial function (P < 0.005). Conclusion: These findings suggest that [18F]PI-2620 PET can be a biomarker to provide regional and chronologic information about tau pathology in the AD continuum.

Differential Microglial activation and Astrocyte reactivity in Alzheimer’s trajectory

AbstractBackgroundMicroglial activation and astrocyte activation plays a significant role in the pathogenesis of AD. Here, we evaluate microglial activation, the interrelationship between microglial activation, amyloid and tau pathologies, and the impact of microglial activation in Alzheimer’s disease trajectory. We specifically focus on microglia as a major player in neuroinflammation and evaluate the spatial and temporal variation of microglial activation in the disease trajectory. Additionally, we evaluate astroglial activation using novel astrocyte marker and evaluate the relationship between amyloid, MRI volume changes and glucose metabolism in Alzheimer’s trajectory.MethodWe evaluated AD, MCI and cognitively normal subjects using amyloid PET, tau PET and neuroinflammation using TSPO PET scans. A separate group of AD, MCI and control subjects were evaluated using novel astrocyte marker [11C]BU99008 PET along with [18F]FDG PET and amyloid PET. [11C]PBR28 and [11C]BU99008 PET scans were analysed using two tissue compartmental model, while [18F]Flutemetamol was analysed using target to cerebellar ratio. [18F]FDG PET was analysed using pons as a reference region. We performed regional and voxel wise analysis for all the tracers.ResultMicroglial activation was elevated in different cortical regions in both AD and MCI subjects. Microglial activation was associated with lower grey matter density in later stages of the disease, while higher grey matter volume was associated with increased microglial activation in early mild cognitive impairment subjects. There were areas of increased astrocyte activation in both AD and MCI. Higher microglial activation was associated with increased tau formation and neuronal damage in later stages of the disease. Interestingly, there was increased astrocyte reactivity in the early stages of the disease.ConclusionWhile microglial activation in the late phase of the disease is associated with neuronal damage, however, in the early stages microglial activation was associated with higher grey matter volume. Microglial activation demonstrated a biphasic pattern of activation. In contrast to microglial activation, astrocyte activation was prominent in the early stage of the disease and may be associated with neuroprotection. This suggests that in targeting glial activation as a therapeutic strategy, we must target astrocyte and microglia separately and in different stages of the disease.

Evaluation of Brain Perfusion with Radionuclide Imaging in Dementia Patients

Objective: This study aims to evaluate the perfusion in the affected brain lobes with radionuclide imaging in patients with dementia and to contribute to the literature by determining the relationship between the degree of dementia. Methods: In this retrospective study, 44 adult patients were included. The mean age of the patients was 73 (57-87). Twenty-three (52.3%) of these were female. All patients underwent mini-mental state test, neurological examinations and radionuclide brain perfusion imaging. The areas of interest of the frontal, parietal, temporal, and occipital lobes and the cerebellum were drawn, respectively, and the cerebellum ratios of the relevant lobes were compared. In this way, brain perfusion index values of lobes were obtained. Results: Brain perfusion in group 1 was higher than in other groups. Groups were also compared in pairs. There was no significant difference in perfusion values in the occipital lobe. There was a significant difference in perfusion between groups 1 and 2 in lobes other than the occipital lobe. This was also the case for Groups 1 and 3. When group 2 with early dementia symptoms, and group 3 with moderate dementia were compared, there was a significant difference between the perfusion values of only the right and left frontal lobes. Conclusion: Early diagnosis is very important in progressive dementia. Clinical tests are successfully applied to categorize patients. Evaluation of brain perfusion and metabolism with functional radionuclide imaging is significant in guiding the treatment and evaluating the success of the treatment.

One year longitudinal change of tau accumulation on [18F]PI‐2620 PET in Alzheimer spectrum

AbstractBackgroundWe investigated longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients with Alzheimer’s disease (AD) spectrum using [18F]PI‐2620 PET.MethodWe enrolled 54 (69.9±8.5 y, M:F = 16:38) participants (8 cognitively normal [NC], 28 mild cognitive impairment [MCI], 18 AD) who completed [18F]PI‐2620 PET scans at baseline and 1 y follow up. Subject also underwent [18F]florbetaben PET (baseline only), MRI and neuropsychological tests. Aβ PET images were visually scored as positive or negative. Aβ+ MCI &amp; AD were classified into early onset (&lt;65 y, EO+) and late onset (≥65, LO+) group. Standardized uptake value ratios (SUVr) of [18F]PI‐2620 PET were determined by cerebral to inferior cerebellar ratio and corrected for partial volume effect. Cortical volumes were calculated from 3D T1‐weighted MR images. We also investigated a correlation between the progression of tau accumulation and cognitive decline.ResultThirty eight out of 57 participants showed Aβ+ (1 NC, 20 MCI, 17 AD). Global SUVr values of [18F]PI‐2620 PET were 0.96±0.07 in 7 Aβ‐ NC, 1.23±0.41 in 17 LO+ (76.7±3.8y) and 1.86±0.87 in 20 EO+ (63.4±5.4y) (p&lt;0.001). It increased by 0.09±0.14 (7.0%) in LO+ and 0.14±0.27 (11.6%) in EO+ in contrast to no change in NC‐. EO+ showed abundant tau accumulation in Braak III‐V areas at baseline with rapid accumulation in Braak V area (0.33±0.41 [13.9%] vs. 0.08±0.14 [6.7%], p = 0.010) than LO+ group. It showed abundant and rapid accumulation on Braak 3 areas in LO+ group (1.61±0.53 at baseline, change: 0.15±0.25 [8.2%]). Deterioration of the visuospatial function and verbal memory was associated with the progression of tau accumulation in Braak III‐V areas in EO+ group. Progressive atrophy in Braak III‐V areas were associated with the progression of tau accumulation in LO+ group whereas hippocampal atrophy did in EO+ group.ConclusionTau accumulation measured by [18F]PI‐2620 in EO+ showed rapid accumulation in Braak III‐V areas and correlated with deterioration of the visuospatial function and verbal memory. It suggests that [18F]PI‐2620 PET is potential biomarker for selecting therapeutic target and monitoring treatment effect for tau targeting treatment.

Longitudinal trajectory of microglial activation and astrocyte activation

AbstractBackgroundNeuroinflammation plays a significant role in the pathogenesis of AD. Here, we evaluate neuroinflammation, the interrelationship between neuroinflammation, amyloid and tau pathologies, and the impact of neuroinflammation in disease trajectory. We specifically focus on microglia as a major player in neuroinflammation and spatial and temporal variation of microglial phenotypes and novel methods of evaluation of astroglial activation.HypothesisMicroglial activation is the driver of neuronal dysfunction and tau aggregation in neurodegenerative diseases, and that levels of microglial activation will correlate with tau aggregation.Astrocyte activation could be detected by novel astrocyte marker [11C]BU99008 PETMethodsWe evaluated AD, MCI and cognitively normal subjects using amyloid ([18F]Flutemetamol), tau ([18F]AV1451 and neuroinflammation using [11C]PBR28 PET scans. A separate group of AD, MCI and control subjects were evaluated using novel astrocyte marker [11C]BU99008 PET along with [18F]FDG PET and amyloid PET. [11C]PBR28 and [11C]BU99008 PET scans were analysed using two tissue compartmental model, while [18F]Flutemetamol was analysed using target to cerebellar ratio. [18F]FDG PET was analysed using pons as a reference region. We performed regional and voxel wise analysis for all the tracers.ResultsMicroglial activation was elevated in different cortical regions in both AD and MCI subjects. There were areas of increased astrocyte activation in both AD and MCI. Higher microglial activation was associated with increased tau formation and neuronal damage in later stages of the disease. Interestingly, there was increased astrocyte activation in the early stages of the disease.ConclusionWhile microglial activation in the late phase of the disease is associated with neuronal damage, activation of the astrocytes is prominent in the early stage of the disease and may be associated with neuroprotection. This suggests that in targeting glial activation as a therapeutic strategy, we must target astrocyte and microglia separately and in different stages of the disease.

Variation in Thyroid-Stimulating Hormone and Cognitive Disorders in Unmedicated Middle-Aged Patients with Major Depressive Disorder: A Proton Magnetic Resonance Spectroscopy Study.

Background Middle-aged (45-59 years old) patients with major depressive disorder (MDD) have a predilection for dementia and cognitive disorders (CDs); however, the characteristics and mechanisms of CDs in these patients remain unclear. There are also known connections between thyroid-stimulating hormone (TSH), brain biochemical metabolism, and cognitive function (CF); however, there is scanty of information about these connections in middle-aged MDD patients. Methods Cognitive assessment was performed on 30 first-episode, untreated middle-aged patients with MDD and 30 well-matched healthy controls (HCs) using the MATRICS Consensus Cognitive Battery (MCCB). N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in the prefrontal cortex (PFC) and cerebellum were also obtained via proton magnetic resonance spectroscopy (1H-MRS), and the TSH level was measured by chemiluminescence analysis. Results MDD patients presented significantly lower processing speed, working memory, verbal learning, reasoning problem-solving, visual learning, and composite cognition scores than controls, with a statistically lower NAA/Cr ratio in the right cerebellum. Age was positively related to reasoning problem-solving in the MDD group (r = 0.6249, p = 0.0220). Education also showed a positive association with visual learning, social cognition, and composite cognition. The 24-item Hamilton Depression Rating Scale (HDRS-24) score was negatively related to all domains of CF. TSH levels were markedly decreased in the MDD group, and a positive connection was determined between the NAA/Cr ratio in the right PFC and the TSH level. Conclusions Middle-aged MDD patients have multidimensional CDs. There are changes in PFC and cerebellar biochemical metabolism in middle-aged patients with MDD, which may be related to CDs or altered TSH levels.

Hepatic superscan on fluorine-18 fluorodeoxyglucose PET/computed tomography imaging: a specific manifestation for diagnosing lymphoma or leukemia involvement.

To explore whether the markedly fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the liver (named hepatic superscan) is a specific manifestation of malignant involvement. From January 2014 to June 2019, 23 patients with such presentations were retrospectively reviewed. 18F-FDG uptake was semiquantified using maximal standardized uptake value (SUVmax), liver to cerebellum (L/C) ratio, liver to mediastinum (L/M) ratio, mean standardized uptake value (SUVmean), peak standardized uptake value (SUVpeak), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Some related laboratory examinations were also collected and analyzed. For comparison, 37 patients with mildly and moderately uptake in the liver were selected as the control group. The hepatic SUVmax, L/C ratio, L/M ratio, SUVmean, MTV and TLG of the superscan group were significantly higher than that of mild- or moderate-uptake group (P < 0.005). Malignant hematological tumors accounted for 91.3% of the superscan group, which was significantly higher than 51.4% of mild- or moderate-uptake group (P = 0.004). β2-microglobulin was observed to be significantly higher in the superscan group compared with mild- or moderate-uptake group (P < 0.001), but not lactate dehydrogenase (LDH) (P = 0.409). On the contrary, C-reactive protein (CRP) was significantly higher in mild- or moderate-uptake group than that in the superscan group (P < 0.001). Our study demonstrates that hepatic superscan is a strong indicator of malignant hematological tumors invading the liver.

Symptomatic hyperperfusion after combined revascularization surgery in patients with pediatric moyamoya disease: patient series

BACKGROUNDSymptomatic hyperperfusion after cerebral revascularization for pediatric moyamoya disease (MMD) is a rare phenomenon. The authors report a series of patients with this condition.OBSERVATIONSIn all three patients in this case series, the combined revascularization was on the left side, the patency of bypass grafts was confirmed after surgery, and focal hyperemia around the anastomotic site was observed on single photon emission computed tomography (SPECT). On the first to eighth days after surgery, all of the patients developed neurological manifestations, including motor aphasia, cheiro-oral syndrome, motor weakness of their right upper limbs, and severe headaches. These symptoms disappeared completely approximately 2 weeks after surgery, and all patients were discharged from the hospital. Quantitative SPECT was performed to determine the proportional change in cerebral blood flow (ΔRCBF) (to ipsilateral cerebellar ratio (denoted ΔRCBF) in the region of interest around the anastomoses, and the mean value was 1.34 (range, 1.29–1.41).LESSONSThis rare condition, which develops soon after surgery, requires an accurate diagnosis by SPECT. One indicator is that the ΔRCBF has risen to 1.3 or higher. Subsequently, strategic blood pressure treatment and fluid management could prevent the development of hemorrhagic stroke.

18F]Nifene PET/CT Imaging in Mice: Improved Methods and Preliminary Studies of α4β2* Nicotinic Acetylcholinergic Receptors in Transgenic A53T Mouse Model of α-Synucleinopathy and Post-Mortem Human Parkinson's Disease.

We report [18F]nifene binding to α4β2* nicotinic acetylcholinergic receptors (nAChRs) in Parkinson’s disease (PD). The study used transgenic Hualpha-Syn(A53T) PD mouse model of α-synucleinopathy for PET/CT studies in vivo and autoradiography in vitro. Additionally, postmortem human PD brain sections comprising of anterior cingulate were used in vitro to assess translation to human studies. Because the small size of mice brain poses challenges for PET imaging, improved methods for radiosynthesis of [18F]nifene and simplified PET/CT procedures in mice were developed by comparing intravenous (IV) and intraperitoneal (IP) administered [18F]nifene. An optimal PET/CT imaging time of 30–60 min post injection of [18F]nifene was established to provide thalamus to cerebellum ratio of 2.5 (with IV) and 2 (with IP). Transgenic Hualpha-Syn(A53T) mice brain slices exhibited 20–35% decrease while in vivo a 20–30% decrease of [18F]nifene was observed. Lewy bodies and α-synuclein aggregates were confirmed in human PD brain sections which lowered the [18F]nifene binding by more than 50% in anterior cingulate. Thus [18F]nifene offers a valuable tool for PET imaging studies of PD.

Influence of amyloid deposition on the interaction between tau and glucose metabolism

AbstractBackgroundPathological hallmarks of Alzheimer’s disease include the formation of extracellular Aβ plaques and intracellular neurofibrillary tau tangles, which with recent PET imaging advances can be assessed in vivo. Accumulation of tau has been closely linked to metabolic abnormalities in PET imaging studies, with inverse associations between tau deposition and glucose metabolism. This study aimed to assess whether the association between [18F]FDG and [18F]AV1451 in cognitively impaired patients is dependent on the presence of significant amyloid pathology.Method240 patients with mild cognitive impairment or Alzheimer’s disease (Mean age = 74.5 years, SD = 8.03) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). All participants completed a T1‐weighted MPRAGE MRI, amyloid ([18F]AV45 or [18F]florbetaben), [18F]AV1451 and [18F]FDG scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a whole brain cerebellar ratio with a cut‐off value of 1.11 ([18F]AV45) and 1.08 ([18F)florbetaben). Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.ResultThere were significant negative associations between AV1451 and FDG tracer uptake in the medial temporal lobe (r = ‐0.389, p &lt;0 .001), occipital lobe (r = ‐0.276, p = 0.001), parietal lobe (r = ‐0.209, p = 0.014), and posterior cingulate (r = ‐0.245, p = 0.004) in Aβ‐positive patients. Similarly, a strong negative relationship was observed between the imaging modalities in Aβ‐negative patients in the medial temporal lobe (r = ‐0.345, p &lt; 0.001), however a significant positive association was also observed in the anterior cingulate cortex (r = 0.350, p &lt; 0.001).ConclusionThis study demonstrated that [18]FDG and [18F]AV1451 tracers have strong regional signal associations in patients with cognitive impairment. The results indicate that tau has a detrimental effect on glucose metabolism in the medial temporal lobe, independent of significant amyloid plaque formation. In patients determined as amyloid‐negative, we may be observing some compensatory regional increase in glucose metabolism in the early stages of tau accumulation.

Evaluating the relationship between soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and pathological substrates of Alzheimer’s disease (AD)

AbstractBackgroundDeveloping novel biomarkers of Alzheimer’s disease (AD) is critical for early disease detection and intervention. sTREM2 has proposed to be an early marker of glial activation. However, there has been significant controversy about the function of sTREM2. This study investigated the relationship between cerebral spinal fluid (CSF) sTREM2, and pathological changes in AD.MethodWe included patients with mild cognitive impairment, AD and healthy controls (n= 493, mean age= 73.7, SD= 6.1) were recruited for the Alzheimer’s Disease Neuroimaging Initiative. All participants completed a T1‐weighted MPRAGE MRI, amyloid ([18F]AV45 or [18F]Florbetaben), [18F]AV1451 and [18F]FDG scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within cortical regions. Amyloid status (Aβ positive/Aβ negative) was determined from processed data using a whole brain cerebellar ratio with a cut‐off value of 1.11. Correlations between CSF measurements, ROI, and voxel‐wise analyses were conducted using data from ADNI.ResultROI analyses demonstrated that increased CSF sTREM2 was associated with increased amyloid load in the whole brain, temporal, parietal, and occipital lobes of MCI patients. Additionally, increased CSF sTREM2 was associated with decreased glucose metabolism in the Posterior cingulate and parietal lobe in MCI patients. On the other hand, CSF sTREM2 was not significantly correlated with pathological changes in AD patients. However, voxel‐wise analysis comparing Aβ+ MCI patients to Aβ‐ CN subjects showed that increased CSF sTREM2 levels were associated with greater Aβ deposition in temporal and motor regions, increased grey matter volume in frontal and parietal regions, and decreased grey matter volume in the MT gyrus.ConclusionsTREM2 levels are associated with amyloid deposition in MCI patients but not in the late stage of AD patients, this suggest that glial activation is associated early on the disease.

Clinical value of PET/CT imaging of cerebral blood flow and metabolism in patients with chronic disorders of consciousness

Objective To investigate the value of PET/CT imaging of cerebral glucose metabolism (CGM) and cerebral blood flow (CBF) in evaluating chronic disorders of consciousness (CDC). Methods A total of 10 CDC patients (5 males, 5 females, age (50.9±17.2) years) and 10 healthy controls (5 males, 5 females, age (52.0±10.3) years) from January 2016 to March 2017 were recruited to perform brain PET/CT of CGM and CBF. The brain PET imaging using 13N-Ammonia was performed and followed by 18F-fluorodeoxyglucose (FDG) PET. The mean standardized uptake values (SUVmean) of frontal, parietal, temporal and occipital lobes as well as basal ganglia, thalamus were obtained. The SUVmean of cerebral regions/SUVmean of cerebellum ratios (SUVr) were acquired. The SUVr were compared between the patients and controls. The imaging characteristics of CGM and CBF were investigated, and their relationships with clinical scores were further analyzed. Two-sample t test and Pearson correlation analysis were used to analyze the data. Results The radioactive distribution in the brain of healthy controls was symmetrical. SUVr of cerebral regions in the affected side of patients were significantly lower than those of the controls both in CGM imaging and CBF imaging (t values: 2.90-5.19, all P<0.05). In 10 CDC patients, there were 9 with hypometabolism in basal ganglia and thalamus, 8 with hypometabolism in frontal and parietal lobes, and 7 with hypometabolism in temporal and occipital lobes. At the same time, there were 7 with parietal hypoperfusion and 6 with hypoperfusion in other cerebral regions in the CDC patients. In the frontal, parietal lobes and basal ganglia, the CGM and CBF were both correlated with the clinical scores (r values: 0.473-0.606, all P<0.05). Abnormal metabolism-perfusion patterns were divided into 3 types. Type Ⅰ included 2 patients and their hypometabolism and hypoperfusion were mismatched completely. Type Ⅱ included 3 patients and their hypometabolism and hypoperfusion were matched in frontal, parietal, occipital and temporal lobes, while mismatched in basal ganglia and thalamus. Type Ⅲ included 5 patients and their hypometabolism and hypoperfusion were matched completely. The clinical scores of typeⅠ, Ⅱand Ⅲ were 10.5, 8.3 and 5.6, respectively. Conclusion The PET/CT imaging of cerebral blood flow and metabolism is useful in evaluating the disorders of consciousness. Key words: Consciousness disorders; Positron-emission tomography; Tomography, X-ray computed; Deoxyglucose; Ammonia

Crossed Cerebellar Atrophy in Perinatal Stroke.

Background and Purpose- Perinatal stroke causes most hemiparetic cerebral palsy and lifelong disability. Crossed cerebellar atrophy (CCA) is chronic cerebellar volume loss following contralateral motor pathway injury. We hypothesized that CCA is quantifiable in perinatal stroke and associated with poor motor outcome. Methods- Term-born children with perinatal stroke, magnetic resonance imaging beyond 6 months of age, and no additional neurological disorders were recruited. Blinded scorers measured cerebellar volumes expressed as ratios (contralesional/ipsilesional), with values <1 suggesting CCA. Motor outcomes including perinatal stroke outcome measure (PSOM) motor and cognitive scores (good/poor), Assisting Hand Assessment, and Melbourne Assessment were compared with cerebellar volume measures. Results- Seventy-three children met criteria (53% male). Mean cerebellar ratios were <1.0 (0.975±0.04; range, 0.885-1.079; P<0.001) suggesting occurrence of CCA. Cerebellar ratios did not differ between stroke types or across PSOM motor outcomes. Larger ipsilesional cerebellar volume was associated with poor PSOM cognitive outcome (P=0.042), possibly with poor PSOM motor outcome (P=0.063), and overall PSOM score (P=0.034). Conclusions- CCA occurs in perinatal stroke but is not strongly associated with motor outcome. However, ipsilesional cerebellar volume is associated with poor cognitive and overall outcomes.

Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease

Alzheimer's disease is characterized by the histopathological presence of amyloid-β plaques and tau-containing neurofibrillary tangles. Microglial activation is also a recognized pathological component. The relationship between microglial activation and protein aggregation is still debated. We investigated the relationship between amyloid plaques, tau tangles and activated microglia using PET imaging. Fifty-one subjects (19 healthy controls, 16 mild cognitive impairment and 16 Alzheimer's disease subjects) participated in the study. All subjects had neuropsychometric testing, MRI, amyloid (18F-flutemetamol), and microglial (11C-PBR28) PET. All subjects with mild cognitive impairment and Alzheimer's disease and eight of the controls had tau (18F-AV1451) PET. 11C-PBR28 PET was analysed using Logan graphical analysis with an arterial plasma input function, while 18F-flutemetamol and 18F-AV1451 PET were analysed as target:cerebellar ratios to create parametric standardized uptake value ratio maps. Biological parametric mapping in the Statistical Parametric Mapping platform was used to examine correlations between uptake of tracers at a voxel-level. There were significant widespread clusters of positive correlation between levels of microglial activation and tau aggregation in both the mild cognitive impairment (amyloid-positive and amyloid-negative) and Alzheimer's disease subjects. The correlations were stronger in Alzheimer's disease than in mild cognitive impairment, suggesting that these pathologies increase together as disease progresses. Levels of microglial activation and amyloid deposition were also correlated, although in a different spatial distribution; correlations were stronger in mild cognitive impairment than Alzheimer's subjects, in line with a plateauing of amyloid load with disease progression. Clusters of positive correlations between microglial activation and protein aggregation often targeted similar areas of association cortex, indicating that all three processes are present in specific vulnerable brain areas. For the first time using PET imaging, we show that microglial activation can correlate with both tau aggregation and amyloid deposition. This confirms the complex relationship between these processes. These results suggest that preventative treatment for Alzheimer's disease should target all three processes.

Characterization of 3 Novel Tau Radiopharmaceuticals, 11C-RO-963, 11C-RO-643, and 18F-RO-948, in Healthy Controls and in Alzheimer Subjects

11C-RO-963, 11C-RO-643, and 18F-RO-948 (previously referred to as 11C-RO6924963, 11C-RO6931643, and 18F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Methods: Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of 11C-RO-963, 11C-RO-643, or 18F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with 18F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated 18F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan with 18F-RO-948. Results: In younger controls, SUVpeak was observed in the temporal lobe with values of approximately 3.0 for 11C-RO-963, 1.5 for 11C-RO-643, and 3.5 for 18F-RO-948. Over all brain regions and subjects, the trend was for 18F-RO-948 to have the highest SUVpeak, followed by 11C-RO-963 and then 11C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11C-RO-643 and 18F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11C-RO-643 had lower brain entry than either 11C-RO-963 or 18F-RO-948 and that 18F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18F-RO-948. Both voxelwise and region-based analysis of 18F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F (1,21) = 45, P < 10-5). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). Conclusion: 18F-RO-948 demonstrates characteristics superior to 11C-RO-643 and 11C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18F-RO-948 compare favorably with other existing tau PET tracers.

Deuterated 18F-9-O-hexadeutero-3-fluoropropoxyl-(+)-dihydrotetrabenazine (D6-FP-(+)-DTBZ): A vesicular monoamine transporter 2 (VMAT2) imaging agent

IntroductionVesicular monoamine transporters 2 (VMAT2) in the brain serve as transporter for packaging monoamine in vesicles for normal CNS neurotransmission. Several VMAT2 imaging agents, [11C]-(+)-DTBZ, dihydrotetrabenazine and [18F]FP-(+)-DTBZ (9-O-fluoropropyl-(+)-dihydro tetrabenazine, a.k.a. [18F]AV-133), are useful for studying the changes in brain function related to monoamine transmission by in vivo imaging. Deuterated analogs have been reported targeting VMAT2 binding sites. MethodsA novel deuterated [18F]9-O-hexaduterofluoropropyl-(+)-dihydrotetrabenazine, [18F]D6-FP-(+)-DTBZ, [18F]1, was prepared as a VMAT2 imaging agent. This 18F agent which targeted VMAT2 was evaluated by in vitro binding, in vivo biodistribution and microPET imaging studies in rodents. ResultsThe one step radiolabeling reaction led to the desired [18F]D6-FP-(+)-DTBZ, [18F]1, which showed excellent binding affinity to VMAT2 (Ki=0.32±0.07nM) comparable to that of FP-(+)-DTBZ (Ki=0.33±0.02nM) using [18F]FP-(+)-DTBZ and rat striatum membrane homogenates. In vivo biodistribution in normal rats showed that 1, exhibited excellent brain uptake and comparable high ratio of striatum to cerebellum (target/background) ratio at 1h after injection (ratio of 6.05±0.43 vs 5.66±0.72 for [18F]FP-(+)-DTBZ vs [18F]1, respectively). MicroPET imaging studies in rats further confirm that the striatum with high VMAT2 concentration was clearly delineated in normal rat brain after iv injection of [18F]1. We observed minor changes of metabolism in rat plasma between these two agents; however, the changes showed little effect on regional brain uptake and retention. ConclusionsThe results reported here lend support for using [18F]D6-FP-(+)-DTBZ, [18F]1, as in vivo PET imaging agent for VMAT2 binding in the brain.

Depressive and anxiety symptoms and cortical amyloid deposition among cognitively normal elderly persons: the Mayo Clinic Study of Aging.

Little is known about the association of cortical Aβ with depression and anxiety among cognitively normal (CN) elderly persons. We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB-) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex. Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00-1.06) and BAI (OR = 1.04; 1.01-1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83-2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.77; 0.97-3.22). As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.

Proton Magnetic Resonance Spectroscopy Study on the Metabolism Changes of Cerebellum in Patients with Post-Stroke Depression

Objective: To study the metabolic changes of cerebellum by proton magnetic resonance Spectroscopy (¹H-MRS) and discuss the relationships between the cerebellar changes and depression severity in patients with post-stroke depression. Methods and Results: Data of demographic characteristics, individual history and life style of all subjects were collected. 40 patients with stroke and 20 controls were enrolled. All groups received T1WI, T2WI, DWI and ¹H-MRS examination. The cerebral infarction volume and the distribution and severity of leukoaraiosis were evaluated. The ratios of NAA/Cr, Cho/Cr and Cho/NAA in the cerebellum were calculated. There were no statistical significant difference in the NAA/Cr, Cho/Cr and Cho/NAA ratios in bilateral cerebellum between CONT group and NORM group. The Cho/Cr and Cho/NAA ratios in the cerebellum contralateral to the stroke region were higher in PSD group than those in NORM and CONT groups, and the Cho/Cr and Cho/NAA ratios in the cerebellum ipsilateral to the stroke region were similar with those in NORM and CONT groups. However, there were no statistical significant difference in the NAA/Cr ratios in bilateral cerebellum among three groups. Conclusion: The result shows preliminarily that the cerebellum involves in the development of post-stroke depression.

18F-FDG super bone marrow uptake: A highly potent indicator for the malignant infiltration.

The present study was performed to investigate whether the markedly 2-deoxy-2-(fluorine-18) fluoro-D-glucose (18F-FDG) uptake in the bone marrow (BM) is a presentation of malignant infiltration (MI).Super bone marrow uptake (super BMU) was used to name the markedly 18F-FDG uptake on BM, which was similar to or higher than that of the brain. From April 2008 to December 2015, 31 patients with such presentation were retrospectively reviewed. The 18F-FDG uptake was semiquantified using SUVmax and BM to cerebellum (BM/C) ratio. The origin of super BMU was diagnosed by pathology. Some blood parameters, as well as fever, were also collected and analyzed. For comparison, 106 patients with mildly and moderately uptake in BM and 20 healthy subjects were selected as the control group.Bone marrow MI was diagnosed in 93.5% (29/31) patients with super BMU, which mostly originated from acute leukemia and highly aggressive lymphoma. The super BMU group had markedly higher 18F-FDG uptake in the BM than those of mildly and moderately uptake, and the control subjects (all P = 0.000) and the BM/C ratio reached a high of 1.24 ± 0.36. The incidence of bone marrow MI in the super BMU group was markedly higher than that of mildly and moderately uptake (93.5% vs 36.8%, P = 0.000). Based on the receiver operating characteristic analysis, when cut-off values of BM/C and SUVmax were set at 0.835 and 6.560, the diagnostic specificity for bone marrow MI reached the high levels of 91.4% and 95.7%, respectively. In 15 patients with bone marrow MI, the extra-BM malignant lesions were simultaneously detected by 18F-FDG PET/CT. The liver and the nasal cavity involvements were only found in the patients with lymphoma, but not in those with leukemia. A decrease of leukocyte, hemoglobin, and platelet counts was noted in 48.4%, 86.2%, and 51.5% of patients with bone marrow MI, respectively.The present study revealed that super BMU was a highly potent indicator for the bone marrow MI.

Volumetric Analysis of Cerebral Peduncles and Cerebellar Hemispheres for Predicting Hemiparesis After Hemispherectomy.

In some cases of refractory epilepsy, hemispherectomy is the final invasive treatment option. However, predictors of postoperative hemiparesis in these patients have not been widely studied. To investigate how the volumetric analysis of cerebral peduncles and cerebellar hemispheres in patients who have undergone hemispherectomy may determine prognostic implications for postoperative hemiparesis. Twenty-two patients who underwent hemispherectomy at our institution were retrospectively included. Using iPlan/BrainLAB (BrainLAB, Feldkirchen, Germany) imaging software and a semiautomatic voxel-based segmentation method, we calculated the preoperative cerebral peduncle and cerebellar hemisphere volumes. Cerebral peduncle and cerebellar hemisphere ratios were compared between patients with worsened or unchanged/better hemiparesis postoperatively. The ratios of ipsilateral/contralateral cerebral peduncles (0.570 vs 0.828; P = .02) and contralateral/ipsilateral cerebellar hemispheres (0.885 vs 1.031; P = .009) were significantly lower in patients who had unchanged/improved hemiparesis postoperatively compared with patients who had worsened hemiparesis. Relative risk of worsening hemiparesis was significantly higher in patients with a cerebral peduncle ratio < 0.7 (relative risk, 4.3; P = .03) or a cerebellar ratio < 1.0 (relative risk, 6.4; P = .006). Although patients who undergo hemispherectomy are heterogeneous, we report a method of predicting postoperative hemiparesis using only standard volumetric magnetic resonance imaging. This information could be used in preoperative discussions with patients and families to help better understand that chance of retaining baseline motor function. CST, corticospinal tractfMRI, functional magnetic resonance imagingTMS, transcranial magnetic stimulation.