Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer’s Disease: A PET (THK5351, PiB) and Resting fMRI Study

Background: Imaging studies in Alzheimer’s disease (AD) have yet to answer the underlying questions concerning the relationship among tau retention, neuroinflammation, network disruption and cognitive decline. We compared the spatial retention patterns of 18F-THK5351 and resting state network (RSN) disruption in patients with early AD and healthy controls.Methods: We enrolled 23 11C-Pittsburgh compound B (PiB)-positive patients with early AD and 24 11C-PiB-negative participants as healthy controls. All participants underwent resting state functional MRI and 18F-THK5351 PET scans. We used scaled subprofile modeling/principal component analysis (SSM/PCA) to reduce the complexity of multivariate data and to identify patterns that exhibited the largest statistical effects (variances) in THK5351 concentration in AD and healthy controls.Findings: SSM/PCA identified a significant spatial THK5351 pattern composed by mainly three clusters including precuneus/posterior cingulate cortex (PCC), right and left dorsolateral prefrontal cortex (DLPFC) which accounted for 23.6% of the total subject voxel variance of the data and had 82.6% sensitivity and 79.1% specificity in discriminating AD from healthy controls. There was a significant relationship between the intensity of the 18F-THK5351 covariation pattern and cognitive scores in AD. The spatial patterns of 18F-THK5351 uptake showed significant similarity with intrinsic functional connectivity, especially in the PCC network. Seed-based connectivity analysis from the PCC showed significant decrease in connectivity over widespread brain regions in AD patients. An evaluation of an autopsied AD patient with Braak V showed that 18F-THK5351 retention corresponded to tau deposition, monoamine oxidase-B (MAO-B) and astrogliosis in the precuneus/PCC.Interpretation: We identified an AD-specific spatial pattern of 18F-THK5351 retention in the precuneus/PCC, an important connectivity hub region in the brain. Disruption of the functional connections of this important network hub may play an important role in developing dementia in AD

Enzymatic properties and clinical associations of serum alpha‐galactosidase A in Parkinson's disease

Abstract Objective Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha‐galactosidase A (GLA) and compared them with the clinical parameters of PD. Methods The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km) and maximal velocity (Vmax) by Lineweaver–Burk plot analysis. Serum GLA protein concentration was measured by enzyme‐linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. Results Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. Interpretation This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity

Pattern of THK 5351 retention in normal aging involves core regions of resting state networks associated with higher cognitive function

We aimed to elucidate the distribution pattern of the positron emission tomography probe [18F]THK 5351, a marker for astrogliosis and tau accumulation, in healthy aging. We also assessed the relationship between THK5351 retention and resting state networks. We enrolled 62 healthy participants in this study. All participants underwent magnetic resonance imaging/positron emission tomography scanning consisting of T1-weighted images, resting state functional magnetic resonance imaging, Pittsburgh Compound-B and THK positron emission tomography. The preprocessed THK images were entered into a scaled subprofile modeling/principal component analysis to extract THK distribution patterns. Using the most significant THK pattern, we generated regions of interest, and performed seed-based functional connectivity analyses. We also evaluated the functional connectivity overlap ratio to identify regions with high between-network connectivity. The most significant THK distributions were observed in the medial prefrontal cortex and bilateral putamen. The seed regions of interest in the medial prefrontal cortex had a functional connectivity map that significantly overlapped with regions of the dorsal default mode network. The seed regions of interest in the putamen showed strong overlap with the basal ganglia and anterior salience networks. The functional connectivity overlap ratio also showed that three peak regions had the characteristics of connector hubs. We have identified an age-related spatial distribution of THK in the medial prefrontal cortex and basal ganglia in normal aging. Interestingly, the distribution’s peaks are located in regions of connector hubs that are strongly connected to large-scale resting state networks associated with higher cognitive function

Severe hyposmia and aberrant functional connectivity in cognitively normal Parkinson’s disease

<div><p>Objective</p><p>Severe hyposmia is a risk factor of dementia in Parkinson’s disease (PD), while the underlying functional connectivity (FC) and brain volume alterations in PD patients with severe hyposmia (PD-SH) are unclear.</p><p>Methods</p><p>We examined voxel-based morphometric and resting state functional magnetic resonance imaging findings in 15 cognitively normal PD-SH, 15 cognitively normal patients with PD with no/mild hyposmia (PD-N/MH), and 15 healthy controls (HCs).</p><p>Results</p><p>Decreased gray matter volume (GMV) was observed in the bilateral cuneus, right associative visual area, precuneus, and some areas in anterior temporal lobes in PD-SH group compared to HCs. Both the PD-SH and PD-N/MH groups showed increased GMV in the bilateral posterior insula and its surrounding regions. A widespread significant decrease in amygdala FC beyond the decreased GMV areas and olfactory cortices were found in the PD-SH group compared with the HCs. Above all, decreased amygdala FC with the inferior parietal lobule, lingual gyrus, and fusiform gyrus was significantly correlated with both reduction of Addenbrooke’s Cognitive Examination-Revised scores and severity of hyposmia in all participants. Canonical resting state networks exhibited decreased FC in the precuneus and left executive control networks but increased FC in the primary and high visual networks of patients with PD compared with HCs. Canonical network FC to other brain regions was enhanced in the executive control, salience, primary visual, and visuospatial networks of the PD-SH.</p><p>Conclusion</p><p>PD-SH showed extensive decreased amygdala FC. Particularly, decreased FC between the amygdala and inferior parietal lobule, lingual gyrus, and fusiform gyrus were associated with the severity of hyposmia and cognitive performance. In contrast, relatively preserved canonical networks in combination with increased FC to brain regions outside of canonical networks may be related to compensatory mechanisms, and preservation of brain function.</p></div

Seed-based connectivity analysis from the basolateral nucleus of amygdala and other brain voxels in the PD-N/MH and PD-SH groups.

<p>In the PD-SH group, seed-based connectivity analysis of the basolateral nucleus of the amygdala showed widespread decreases in functional connectivity (FC) to other brain regions. Areas of decreased FC were more extensive than those of decreased GMV.</p

Independent component analysis (ICA) in the PD-SH group compared with HCs.

<p>(a) Analysis of FC changes, relative to controls, within canonical resting state networks (RSNs; green) showed significantly decreased connectivity within the precuneus network (blue) but increases within the primary and high visual networks (red). (b) Analyses of FC changes, relative to HCs, between canonical RSNs and brain regions outside of these networks showed decreased connectivities between several networks, including the left executive control network (ECN), dorsal default mode network (DMN), high visual, and visuospatial brain regions, and regions outside of these networks. More prominent increased connectivity changes were observed than decreased changes between canonical networks, including the primary visual network, left and right ECNs, visuospatial network, salience network, and dorsal/ventral DMNs, and brain regions outside of each network. A threshold-free cluster enhancement technique was used to control for multiple comparisons (FWE p < 0.05).</p

Regression analysis of amygdala connectivity with the OSIT-J and Addenbrooke’s Cognitive Examination-Revised (ACE-R) scores in all participants.

<p>The regression analysis in revealed that amygdala FC was significantly correlated with the inferior parietal lobule, lingual gyrus, fusiform gyrus, and superior and middle temporal gyrus when the OSIT-J score was masked by the contrast of the group comparison result and also when the ACE-R score was masked by the contrast of the group comparison and OSIT-J results in all participants. All maps were corrected for multiple comparisons using FWEc p < 0.05 and CDT p = 0.001.</p