In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024.

Is there a spinal tap responder in progressive supranuclear palsy? The first prospective study.

OBJECTIVE: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease, and sometimes shows idiopathic normal pressure hydrocephalus (iNPH)-like presentations. We aimed to evaluate spinal tap responsiveness in patients with PSP, including the effect of sham spinal tap. METHODS: Eleven patients with PSP, ten with probable/definite iNPH, and eight control patients were prospectively enrolled. All participants underwent sham spinal tap and spinal tap procedures. Gait was evaluated using wearable inertial sensors. We defined "tap responders" as individuals with a 10% or more improvement from baseline in any of the gait parameters (timed up-and-go test total time, stride length, and velocity during straight walking under single-task and cognitive dual-task conditions). We compared the ratio of responders in patients with PSP to patients with iNPH and controls. RESULTS: The ratio of tap responders and the ratio of sham tap responders in patients with PSP were significantly higher than those in control patients, and not different from those in patients with iNPH. PSP patients with iNPH-like MRI features tended to respond to the spinal tap compared to those without such imaging features. Notably, one patient with PSP, who responded to the spinal tap beyond the effect of sham spinal tap, was treated by the shunt operation. CONCLUSION: This is the first prospective study to demonstrate tap and shunt responsiveness in patients with PSP while highlighting the placebo effects of the spinal tap in patients with PSP or iNPH. Our findings suggest that some PSP patients have impaired cerebrospinal fluid circulation, contributing to a distinct component of the clinical spectrum.

Association between mammillary body atrophy and memory impairment in retired athletes with a history of repetitive mild traumatic brain injury.

Cognitive dysfunction, especially memory impairment, is a typical clinical feature of long-term symptoms caused by repetitive mild traumatic brain injury (rmTBI). The current study aims to investigate the relationship between regional brain atrophy and cognitive impairments in retired athletes with a long history of rmTBI. Overall, 27 retired athletes with a history of rmTBI (18 boxers, 3 kickboxers, 2 wrestlers, and 4 others; rmTBI group) and 23 age/sex-matched healthy participants (control group) were enrolled. MPRAGE on 3 T MRI was acquired and segmented. The TBV and TBV-adjusted regional brain volumes were compared between groups, and the relationship between the neuropsychological test scores and the regional brain volumes were evaluated. Total brain volume (TBV) and regional brain volumes of the mammillary bodies (MBs), hippocampi, amygdalae, thalami, caudate nuclei, and corpus callosum (CC) were estimated using the SPM12 and ITK-SNAP tools. In the rmTBI group, the regional brain volume/TBV ratio (rmTBI vs. control group, Mann-Whitney U test, p < 0.05) underwent partial correlation analysis, adjusting for age and sex, to assess its connection with neuropsychological test results. Compared with the control group, the rmTBI group showed significantly lower the MBs volume/TBV ratio (0.13 ± 0.05 vs. 0.19 ± 0.03 × 10-3, p < 0.001). The MBs volume/TBV ratio correlated with visual memory, as assessed, respectively, by the Rey-Osterrieth Complex Figure test delayed recall (ρ = 0.62, p < 0.001). In conclusion, retired athletes with rmTBI have MB atrophy, potentially contributing to memory impairment linked to the Papez circuit disconnection.

Investigating neural dysfunction with abnormal protein deposition in Alzheimer's disease through magnetic resonance spectroscopic imaging, plasma biomarkers, and positron emission tomography.

In Alzheimer's disease (AD), aggregated abnormal proteins induce neuronal dysfunction. Despite the evidence supporting the association between tau proteins and brain atrophy, further studies are needed to explore their link to neuronal dysfunction in the human brain. To clarify the relationship between neuronal dysfunction and abnormal proteins in AD-affected brains, we conducted magnetic resonance spectroscopic imaging (MRSI) and assessed the neurofilament light chain plasma levels (NfL). We evaluated tau and amyloid-ß depositions using standardized uptake value ratios (SUVRs) of florzolotau (18F) for tau and 11C-PiB for amyloid-ß positron emission tomography in the same patients. Heatmaps were generated to visualize Z scores of glutamate to creatine (Glu/Cr) and N-acetylaspartate to creatine (NAA/Cr) ratios using data from healthy controls. In AD brains, Z score maps revealed reduced Glu/Cr and NAA/Cr ratios in the gray matter, particularly in the right dorsolateral prefrontal cortex (rDLPFC) and posterior cingulate cortex (PCC). Glu/Cr ratios were negatively correlated with florzolotau (18F) SUVRs in the PCC, and plasma NfL levels were elevated and negatively correlated with Glu/Cr (P = 0.040, r = -0.50) and NAA/Cr ratios (P = 0.003, r = -0.68) in the rDLPFC. This suggests that the abnormal tau proteins in AD-affected brains play a role in diminishing glutamate levels. Furthermore, neuronal dysfunction markers including Glu/tCr and NAA/tCr could potentially indicate favorable clinical outcomes. Using MRSI provided spatial information about neural dysfunction in AD, enabling the identification of vulnerabilities in the rDLPFC and PCC within the AD's pathological context.

Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease.

OBJECTIVE: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD. METHODS: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [11 C]PiB and [18 F]florzolotau, respectively. Myo-inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography. RESULTS: Myo-inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo-inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo-inositol and lactate levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p < 0.05). Significant correlations were noted between myo-inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05). INTERPRETATION: We found high myo-inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo-inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2023.

Long-term levodopa ameliorates sequence effect in simple, but not complex walking in early Parkinson's disease patients.

BACKGROUND: The sequence effect (SE) is characterized by the progressive decrement of movements and is often observed in Parkinson's disease (PD) patients. While acute effect of levodopa does not ameliorate the SE, the effect of long-term levodopa treatment for the SE remains unknown. OBJECTIVE: We aimed to elucidate the SEs during various gait conditions and their response to long-term levodopa treatment in drug-naïve PD patients. METHODS: Nineteen drug-naïve PD patients and 21 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors in the following conditions:1) straight walking, 2) circular walking: walking a circle of 1 m diameter in a clock-wise direction for 3 laps, 3) straight or circular walking under cognitive-motor dual-task (serial 7s subtractions). PD patients were evaluated at baseline, within 1 h after intravenous administration of levodopa, and after one, three, and six months treatment with levodopa. The SE was measured by a linear regression slope by plotting consecutive stride lengths over steps. Patients were also separately analyzed depending on laterality of symptoms. RESULTS: Long-term levodopa treatment ameliorated the SE only during single-task straight walking. The SE during circular walking was exacerbated after long-term levodopa treatment for right-side dominant patients. During dual-task straight walking, the SE at baseline was greater in right-side dominant PD patients. CONCLUSIONS: The SE only during single-task straight walking can be ameliorated by long-term levodopa treatment. However, the SE may be exaggerated by cognitive motor interference or by asymmetrical stride length with/without long-term levodopa treatment, depending on the laterality of symptoms.

Turning and multitask gait unmask gait disturbance in mild-to-moderate multiple sclerosis: Underlying specific cortical thinning and connecting fibers damage.

Multiple sclerosis (MS) causes gait and cognitive impairments that are partially normalized by compensatory mechanisms. We aimed to identify the gait tasks that unmask gait disturbance and the underlying neural correlates in MS. We included 25 patients with MS (Expanded Disability Status Scale score: median 2.0, interquartile range 1.0-2.5) and 19 healthy controls. Fast-paced gait examinations with inertial measurement units were conducted, including straight or circular walking with or without cognitive/motor tasks, and the timed up and go test (TUG). Receiver operating characteristic curve analysis was performed to distinguish both groups by the gait parameters. The correlation between gait parameters and cortical thickness or fractional anisotropy values was examined by using three-dimensional T1-weighted imaging and diffusion tensor imaging, respectively (corrected p < .05). Total TUG duration (>6.0 s, sensitivity 88.0%, specificity 84.2%) and stride velocity during cognitive dual-task circular walking (<1.12 m/s, 84.0%, 84.2%) had the highest discriminative power of the two groups. Deterioration of these gait parameters was correlated with thinner cortical thickness in regional areas, including the left precuneus and left temporoparietal junction, overlapped with parts of the default mode network, ventral attention network, and frontoparietal network. Total TUG duration was negatively correlated with fractional anisotropy values in the deep cerebral white matter areas. Turning and multitask gait may be optimal to unveil partially compensated gait disturbance in patients with mild-to-moderate MS through dynamic balance control and multitask processing, based on the structural damage in functional networks.

An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607).

Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90-110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

A Machine Learning-Based Approach to Discrimination of Tauopathies Using [18 F]PM-PBB3 PET Images.

BACKGROUND: We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. OBJECTIVE: We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. METHODS: Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. RESULTS: The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. CONCLUSIONS: These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography.

BACKGROUND: 18F-THK5351 was recently shown to bind to monoamine oxidase B (MAO-B) with high affinity. MAO-B is highly concentrated in astrocytes and increases during astrogliosis. Therefore, 18F-THK5351 accumulates in lesions undergoing astrogliosis. Cerebral infarction causes astrogliosis, which may be beneficial for repairing and regenerating injured cells and tissues in the lesions. Therefore, monitoring the degree of astrogliosis and stroke symptoms is essential for understanding the roles of astrogliosis in cerebral infarction. CASE PRESENTATION: A 72-year-old man, complaining of total loss of sensation in the left index finger, was diagnosed with acute cerebral infarction, and underwent 18F-THK5351 positron emission tomography (PET) on two occasions after the stroke. The first PET scan performed on day 27 revealed intense uptake in the infarct lesion located around the right precentral and postcentral gyri. However, the second PET scan on day 391 showed that the uptake had diminished significantly. The sensory deficit in the left index finger had improved by 30 and 70% at the times of the first and second PET scans, respectively. CONCLUSIONS: 18F-THK5351 uptake in the infarct lesion evidently changed between days 27 and 391, along with improved sensory deficit in the left index finger. Astrocytes reportedly play a role in restoring neuronal integrity. Therefore, the temporal course of astrogliosis may have been related to improving stroke symptoms in this patient, suggesting that the degree of astrogliosis in the infarct lesion may aid in assessing the prognosis in stroke patients.

Striatal Dopamine Denervation Impairs Gait Automaticity in Drug-Naïve Parkinson's Disease Patients.

BACKGROUND: Gait automaticity, which is impaired in patients with Parkinson's disease (PD), can be quantified by gait variability analysis. Among the 3 regions of the striatum (sensorimotor, executive, and limbic), the sensorimotor region may play a crucial role in motor automaticity in healthy individuals. However, neural correlates of impaired gait automaticity are poorly investigated in PD. OBJECTIVE: We aimed to examine the relationship between gait automaticity and striatal dopaminergic depletion in drug-naïve PD patients. METHODS: A total of 21 drug-naïve PD patients and 12 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors under fast-paced gait or cognitive dual-task conditions, and their respective coefficient of variation (CV) and dual-task cost were calculated. The extent of striatal dopaminergic depletion was evaluated by dopamine transporter (DAT) imaging with single-photon emission computed tomography using N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-[123 I]iodophenyl)nortropane. Correlation between DAT uptake and gait variables was analyzed using the region-of-interest analysis for the 3 right or left striatal regions and voxel-based analysis. RESULTS: PD had higher mean bilateral CV and dual-task cost of stride length than healthy controls. The mean bilateral CV of stride length was negatively correlated with DAT uptake in the bilateral executive regions of the striatum. Voxel-based analysis revealed a negative correlation between the mean bilateral CV of stride length and DAT uptake in the anteromedial striatum. CONCLUSIONS: Dopaminergic denervation in the anteromedial striatum, a part of the executive region, is associated with impaired gait automaticity in drug-naïve PD patients. This region may compensate for the posterior sensorimotor striatum, maintaining gait automaticity. © 2020 International Parkinson and Movement Disorder Society.

18F-THK5351 PET Can Identify Astrogliosis in Multiple Sclerosis Plaques.

A 26-year-old woman with relapsing-remitting multiple sclerosis (MS) underwent F-THK5351 PET during a remission period. PET imaging showed that small regions with elevated uptake of F-THK5351 were scattered in the brain and that the foci of F-THK5351 accumulations corresponded anatomically to MS plaques identified by MRI. Because F-THK5351 binds to monoamine oxidase B highly expressed in astrocytes, F-THK5351 accumulates in lesions undergoing astrogliosis. Hence, elevated uptake of F-THK5351 in the present case can represent ongoing astrogliosis in inactive MS lesions (plaques).

A novel mutation of PDE8B Gene in a Japanese family with autosomal-dominant striatal degeneration.

BACKGROUND: Autosomal-dominant striatal degeneration is a rare autosomal-dominant neurodegenerative movement disorder characterized by slowly progressive parkinsonism. Recently, a mutation of the cyclic nucleotide phosphodiesterase 8B gene was reported to be a causal gene mutation of this disease. METHODS: We report on the clinical characteristics of 2 patients of a Japanese family with autosomal-dominant striatal degeneration and the result of gene mutation analysis of this family. RESULTS: Clinical features of the patients are slowly progressive parkinsonism and brain MRI showing high signal intensity in T2-weighted images in the striatum. We found a heterozygous nonsense mutation in the first exon of cyclic nucleotide phosphodiesterase 8B gene, which is predicted to disrupt all important functional domains of the cyclic nucleotide phosphodiesterase 8B protein. CONCLUSIONS: This family is the second family with autosomal-dominant striatal degeneration after the first German family, confirming that cyclic nucleotide phosphodiesterase 8B gene is the causative gene for this disease.