Neuroinflammation following anti-parkinsonian drugs in early Parkinson's disease: a longitudinal PET study.

The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson's disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection remain unclear. To elucidate this, we examined changes in microglial activation, nigrostriatal degeneration, and clinical symptoms longitudinally after dopamine replacement therapy in early, optimally-controlled PD patients with and without zonisamide treatment using positron emission tomography (PET). We enrolled sixteen PD patients (Hoehn and Yahr stage 1-2), and age-matched normal subjects. PD patients were randomly divided into two groups: one (zonisamide+) that did and one (zonisamide-) that did not undergo zonisamide therapy. Annual changes in neuroinflammation ([11C]DPA713 PET), dopamine transporter availability ([11C]CFT PET) and clinical severity were examined. Voxelwise differentiations in the binding of [11C]DPA713 (BPND) and [11C]CFT (SUVR) were compared with normal data and between the zonisamide+ and zonisamide- PD groups. The cerebral [11C]DPA713 BPND increased with time predominantly over the parieto-occipital region in PD patients. Comparison of the zonisamide+ group with the zonisamide- group showed lower levels in the cerebral [11C]DPA713 BPND in the zonisamide+ group. While the striatal [11C]CFT SUVR decreased longitudinally, the [11C]CFT SUVR in the nucleus accumbens showed a higher binding in the zonisamide+ group. A significant annual increase in attention score were found in the zonisamide+ group. The current results indicate neuroinflammation proceeds to the whole brain even after anti-parkinsonian therapy, but zonisamide coadministration might have the potential to ameliorate proinflammatory responses, exerting a neuroprotective effect in more damaged nigrostriatal regions with enhanced attention in PD.

Localized focal cortical dysplasia type II: seizure freedom with lesionectomy guided by MRI and FDG-PET.

OBJECTIVE: The authors perform thorough, noninvasive presurgical evaluations for intractable epilepsy at their center and avoid unnecessary intracranial EEG when possible. The purpose of this study was to clarify the appropriateness of their lesion-oriented surgical strategy for localized focal cortical dysplasia (FCD) type II. METHODS: Fifty-one patients with pathologically proven localized FCD type II who were followed for at least 1 year after surgery were included. Patients with FCD type II with lobar or multilobar distribution were excluded. The results of presurgical evaluations, including thin-slice 3-T MRI, FDG-PET, and ictal SPECT, as well as surgical procedures and postoperative seizure and functional outcomes, were examined retrospectively. RESULTS: MRI was positive in 46 (90%) of 51 patients, and FDG-PET revealed localized hypo- or hypermetabolism in 47 (92%) of 51 patients. Ictal SPECT revealed concordant hyperperfusion in 37 of 42 patients examined. Intracranial EEG was used in only 13 patients (25%), including 5 with negative MRI results and 4 with subtle MRI findings. Of the 15 patients with FCD in the vicinity of eloquent (sensorimotor and language) areas, intracranial EEG was used in 4. Lesionectomy was performed in all 51 patients. Intraoperative electrocorticography (ECoG) was performed in 8 patients, but the findings were not used to tailor the extent of resection. Postoperative seizure outcomes were Engel class I in 47 patients (92%) and Ia in 45 (88%). In the 15 patients with FCD in the vicinity of eloquent areas, 13 (87%) achieved a class I outcome. Predictive factors for favorable seizure outcome were complete resection of the MRI lesion (p = 0.006) and frontal lobe surgery (p = 0.012). Postoperative neurological deficits were noted in only 4 (27%) of 15 patients with FCD in the vicinity of eloquent areas. All 5 MRI-negative patients achieved an Engel class I outcome. CONCLUSIONS: In most of the patients with localized FCD type II, MRI and/or FDG-PET detected the localized abnormality. Lesionectomy without intracranial EEG led to seizure freedom in most cases. Even when lesions were in the vicinity of eloquent areas, seizure and functional outcomes were favorable. Intraoperative ECoG may thus be unnecessary. Complete resection of the lesion is essential for favorable seizure outcome in MRI-positive patients. In MRI-negative patients, surgery with intracranial EEG guided by FDG-PET provided seizure-free outcomes.

Mesial temporal lobe epilepsy with amygdalar hamartoma-like lesion: Is it a distinct syndrome?

INTRODUCTION: We examined the clinical, semiological, scalp electroencephalographic (EEG), and neuropsychological features of patients with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS). METHODS: This retrospective study included 9 patients with mesial temporal lobe epilepsy (MTLE) who had an amygdalar lesion on preoperative MRI; underwent mesial temporal resection; were diagnosed with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS); were followed up for at least 2 years after surgery; and had a favourable postoperative seizure outcome (Engel Class I). There were 5 women and 4 men, and age at surgery ranged from 19 to 54 (mean, 36.6) years. Clinical characteristics, auras, video-recorded seizure semiology, interictal and ictal EEG, and preoperative neuropsychological data were reviewed. Twenty patients with MTLE with HS who had favourable postoperative seizure outcomes (Engel Class I) were selected as controls. RESULTS: Age at seizure onset was significantly higher in patients with AHL without HS than in those with HS. Fear was more frequently seen in patients with AHL (44 %) than in those with HS (5 %) (P = 0.022). There were no significant differences in interictal epileptiform discharges or ictal EEG pattern. Preoperative full-scale IQ score was significantly higher in the AHL group than in the HS group (mean, 92.9 v. 74.8, P = 0.004), as was preoperative memory quotient score (mean 100.7 v. 85.1, P = 0.028). CONCLUSION: We clarified the clinical, semiological, and neuropsychological features of patients with MTLE-AHL. These findings may be useful for preoperative evaluation, especially of patients with suspected MTLE but without apparent HS on preoperative MRI.

Periictal water drinking revisited: Occurrence and lateralizing value in surgically confirmed patients with focal epilepsy.

OBJECTIVE: Periictal water drinking (PIWD), which is a rare seizure-related autonomic behavior, has been reported in temporal lobe epilepsy (TLE) but only rarely in extra-TLE. Additionally, the lateralizing value of PIWD is controversial. We aimed to clarify the occurrence and lateralizing value of PIWD in patients with focal epilepsy. METHODS: This retrospective study included 240 focal epilepsy patients aged >10 years with a favorable postoperative seizure outcome (Engel class I). PIWD was defined as water drinking behavior during a seizure or within 2 min in the postictal phase. The occurrence of PIWD documented on video-electroencephalogram monitoring was assessed. The lateralizing value of PIWD was analyzed among patients whose language dominant hemisphere was identified. RESULTS: Twenty-three (9.5%) patients exhibited PIWD. PIWD occurred more frequently in frontal lobe epilepsy (FLE; eight of 41 patients, 19.5%) than in TLE (15 of 188 patients, 8%). The occurrence of PIWD was significantly different between FLE and extra-FLE (P = 0.035), with a low positive predictive value (34.8%). In FLE with PIWD, all but one patient underwent resective surgery involving the medial frontal lobe. In 194 patients whose language dominant hemisphere was determined, the lateralizing value of PIWD in FLE and TLE showed no statistical significance (P = 0.69 and P = 0.27, respectively). SIGNIFICANCE: Periictal water drinking occurred more often in FLE than TLE. Thus, PIWD might not be a specific periictal symptom in TLE. There was no evidence for the lateralizing value of PIWD in FLE and TLE. These findings can provide useful clinical clues for preoperative evaluations to estimate the epileptogenic zone based on seizure semiology and allow for a better understanding of pathophysiological insights into PIWD.

A Single-center Analysis of Three Japanese Patients with Mahjong-related Seizures.

Mahjong is one of the most popular Chinese tile games played in Japan. Mahjong-related seizures (MRS) are rare praxis-induced seizures. We identified three patients with MRS from February 2000 to February 2021. All cases were men, with a middle-age onset, generalized convulsive seizures, and lack of non-provoked, myoclonic, and absence seizures. All patients had no or non-specific neuroimaging or electroencephalogram abnormalities. They did not have features linked to idiopathic generalized epilepsy. All patients were seizure-free after behavioral adjustments, although one patient required anti-seizure medication and avoided long duration games. These changes may help other patients with MRS continue playing Mahjong.

In vivo Illustration of Altered Dopaminergic and GABAergic Systems in Early Parkinson's Disease.

Background: Changes in γ-aminobutyric acid (GABA) function are noted in patients with Parkinson's disease (PD) who have some non-motor impairments. However, dopamine-related GABA function and GABA-related cognitive changes are still unclear. Methods: Thirteen drug-naive early-stage PD patients underwent a series of PET scans with [11C]flumazenil(FMZ) and [11C]CFT. The [11C]FMZ binding potential (BPND) derived from a Logan plot analysis was compared between PD patients and age-matched controls. The [11C]CFT radioactivity relative to the cerebellar counterpart was estimated as a semiquantitative value [11C]CFT SUVR. Correlations between [11C]FMZ BPND and [11C]CFT SUVR in the same region of interest were also examined. Results: In patients in the PD group, [11C]CFT SUVR was significantly lower in the putamen. The levels of [11C]FMZ BPND in the cerebral cortex (frontal lobe dominancy) and the affected-side putamen were also reduced. In addition, [11C]CFT SUVR was negatively correlated with the [11C]FMZ BPND level in the affected-side putamen. In patients in the PD group, the total frontal assessment battery (FAB) score was positively correlated with the [11C]FMZ BPND in the frontal region. Conclusion: GABAergic dysfunction coexists with dopaminergic loss not only in the putamen but also over the extrastriatal region in patients with early PD and is related to frontal dysfunction. The negative correlation of [11C]CFT SUVR with [11C]FMZ BPND in the affected putamen suggests that a greater dopaminergic demise would decelerate GABA release (or an increase in tracer binding), resulting in persistent failure of the GABAergic system in PD patients.

PRRT2 mutation in a Japanese woman: Adult-onset focal epilepsy coexisting with movement disorders and cerebellar atrophy.

Proline-rich transmembrane protein 2 (PRRT2) was confirmed as the causative gene of paroxysmal kinesigenic dyskinesia (PKD) as shown by genome-wide linkage analyses. PRRT2 mutations are also associated with benign familial infantile seizures, infantile convulsions and choreoathetosis, and childhood absence epilepsy, but few reports have investigated adult-onset epilepsy. We describe here a rare presentation of adult-onset focal epilepsy with a PRRT2 mutation in a 31-year-old woman who showed cerebellar atrophy, familial paroxysmal kinesigenic dyskinesia, and paroxysmal non-kinesigenic dystonia. Video-electroencephalography (EEG) demonstrated focal impaired awareness seizures, in which ictal EEG changes showed left temporal onset with rhythmic theta activity over the left temporal region. Magnetic resonance imaging showed mild cerebellar atrophy. The administration of lamotrigine 50 mg/day resulted in freedom from her seizures and lamotrigine 150 mg/day reduced paroxysmal non-kinesigenic dystonia. Furthermore, she had a rare frameshift mutation, c.604_607del, p.Ser202fs of which the pathogenicity has been reported in ClinVar, but it has not been reported in Japan. Mutation of the PRRT2 gene can cause adult-onset epilepsy, paroxysmal non-kinesigenic movement disorder, and cerebellar atrophy, suggesting an expanding clinical phenotypic spectrum associated with PRRT2 mutations.

Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer's disease.

BACKGROUND AND PURPOSE: Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET). METHODS: Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [18 F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [11 C]Pittsburgh Compound-B (PiB) and [18 F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models. RESULTS: [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. CONCLUSIONS: In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.

Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer's disease.

BACKGROUND: Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer's disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. METHODS: Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. RESULTS: The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. CONCLUSIONS: Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

Alice in wonderland syndrome in an elderly patient with focal onset epilepsy.

Alice in wonderland syndrome (AIWS) is a rare perceptual disorder characterized by subjective distortions of visual and somatosensory perception. Symptoms of AIWS are attributable to functional and structural changes of the visual and somatosensory perceptual system; however, few reports have investigated the pathophysiology of AIWS with regard to epilepsy, especially ictal electroencephalogram (EEG) changes. Herein, we describe the case of an 82-year-old woman with focal onset epilepsy presenting with AIWS, whose seizures were documented by video-EEG monitoring. Video-EEG revealed multiple focal impaired awareness seizures, and ictal EEG changes arose from the right occipital region with small periodic positive discharges with evolution towards the right centro-parietal regions. Our case highlights not only a relationship between epileptic seizures and AIWS but also provides pathological insight into AIWS.

Coexistence of cerebral hypometabolism and neuroinflammation in the thalamo-limbic-brainstem region in young women with functional somatic syndrome.

BACKGROUND: Functional somatic syndrome (FSS) is a disorder characterized by clusters of medically unexplained symptoms. Some women suffer from persistent FSS after human papillomavirus (HPV) vaccination. However, a causal relationship has not been established, and the pathophysiology of FSS remains elusive. Here, we aimed to identify the brain regions showing altered cerebral metabolism and neuroinflammation in patients with FSS and to correlate the measures of positron emission tomography (PET) with clinical data. Twelve women diagnosed with FSS following HPV vaccination (FSS group) underwent both [18F]FDG-PET to measure glucose metabolism and [11C]DPA713-PET to measure neuroinflammation. [18F]FDG standardized uptake value ratio (SUVR) and [11C]DPA713 binding potential (BPND) values were compared voxel-wise between the FSS and control groups (n = 12 for [18F]FDG, n = 16 for [11C]DPA713). A region-of-interest (ROI)-based analysis was performed to correlate PET parameters with clinical scores. Statistical significance was set at p < 0.05 corrected for multiple comparisons. RESULTS: Statistical parametric mapping revealed a concomitant significant decrease of [18F]FDG SUVR and increase of [11C]DPA713 BPND in the regions covering the thalamus, mesial temporal area, and brainstem in the FSS group. Correlation analysis revealed that intelligence and memory scores were significantly positively correlated with [18F]FDG SUVR and negatively so with [11C]DPA713 BPND in these regions. A direct comparison between [18F]FDG SUVR and [11C]DPA713 BPND revealed a significant positive correlation in the right hippocampus and amygdala. CONCLUSIONS: Cerebral hypometabolism with neuroinflammation occurring in the thalamo-limbic-brainstem region may reflect the pathophysiology of FSS.

In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease.

OBJECTIVE: In vivo glycolysis-related glucose metabolism and electron transport chain-related mitochondrial activity may be different regionally in the brains of patients with Alzheimer disease (AD). To test this hypothesis regarding AD pathophysiology, we measured the availability of mitochondrial complex-I (MC-I) with the novel PET probe [18F]2-tert- butyl-4-chloro-5-2H- pyridazin-3-one ([18F]BCPP-EF), which binds to MC-I, and compared [18F]BCPP-EF uptake with 18F-fluorodeoxyglucose ([18F]FDG) uptake in the living AD brain. METHODS: First, the total distribution volume (VT) of [18F]BCPP-EF from 10 normal controls (NCs) was quantified using arterial blood samples and then tested to observe whether VT could substitute for the standard uptake value relative to the global count (SUVRg). Eighteen NCs and 14 different NCs underwent PET with [18F]BCPP-EF or [18F]FDG, respectively. Second, 32 patients with AD were scanned semiquantitatively with double PET tracers. Interparticipant and intraparticipant comparisons of the levels of MC-I activity ([18F]BCPP-EF) and glucose metabolism ([18F]FDG) were performed. RESULTS: The [18F]BCPP-EF VT was positively correlated with the [18F]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [18F]BCPP-EF SUVRg, but not the [18F]FDG SUVRg, was significantly lower in the parahippocampus in patients with AD, highlighting the prominence of oxidative metabolic failure in the medial temporal cortex. Robust positive correlations between the [18F]BCPP-EF SUVRg and [18F]FDG SUVRg were observed in several brain regions, except the parahippocampus, in early-stage AD. CONCLUSIONS: Mitochondrial dysfunction in the parahippocampus was shown in early-stage AD. Mitochondria-related energy failure may precede glycolysis-related hypometabolism in regions with pathologically confirmed early neurodegeneration in AD.

Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination.

In 32 patients with prolonged central nervous system symptoms after human papillomavirus (HPV) vaccination, we measured conventional and immunological markers in cerebrospinal fluid (CSF) and compared with the levels in disease controls. Our studies revealed significantly decreased chloride and neuron-specific enolase (NSE) levels in CSF of patients with CNS symptoms after HPV vaccination compared to disease controls. IL-4, IL-13, and CD4(+) T cells increased significantly in patients, and IL-17 increased significantly from 12 to 24months after symptom onset. Chemokines (IL-8 and MCP-1) were also elevated, but CD8(+) T cells, PDGF-bb and IL-12 were reduced. Antibodies to GluN2B-NT2, GluN2B-CT and GluN1-NT increased significantly. These results suggest biological, mainly immunological, changes in the CSF of patients after HPV vaccination.

Progressive supranuclear palsy and Parkinson's disease overlap: A clinicopathological case report.

We describe a woman with a 13-year history of postural instability, vertical gaze palsy and dopa-responsive parkinsonism - a clinical profile that corresponds to progressive supranuclear palsy (PSP) and Parkinson's disease (PD). The patient died at the age of 82 years. Neuropathological features included neuronal loss and gliosis in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, thoracic intermediolateral nucleus and nucleus basalis of Meynert, in addition to the typical pathology of PSP. Immunohistochemical studies demonstrated that PSP-tau pathology was localized in the central nervous system, but Lewy body-related α-synucleinopathy was extensive in the central and peripheral nervous systems. Although PSP and PD may represent independent processes, this case could provide insight into a common defect in either protein phosphorylation or the proteinase surveillance system that contributes to human aging.

Extensive cortical spongiform changes with cerebellar small amyloid plaques: the clinicopathological case of MV2K+C subtype in Creutzfeldt-Jakob disease.

We report a clinical case report of the MV2K+C subtype of sporadic Creutzfeldt-Jakob disease (sCJD). The patient was a 72-year-old woman who exhibited progressive dementia over the course of 22 months. Diffusion-weighted MRI during this period showed abnormal hyperintensity in the cerebral cortex in the early stage. The clinical course was similar to that of previously reported patients with the MV2K or MV2K+C subtype of sCJD. However, histopathological examination revealed unique features: severe extensive spongiform changes with perivacuolar deposits in the cerebrum and basal ganglia, plaque-like PrP deposits in the cerebrum, and only mild changes in the cerebellum with small amyloid plaques (∼20 µm in diameter), smaller than those in the MV2K subtype or variant CJD (40-50 µm in diameter). Molecular analysis showed a methionine/valine heterozygosity at codon 129 and no pathogenic mutation in the PrP gene (PRNP). Western blot analysis of the protease-resistant PrP (PrP(Sc) ) in the right temporal pole revealed the type 2 pattern, which is characterized by a single unglycosylated band, in contrast to the doublet described for the typical MV2 subtype of sCJD. The other intermediate band might exist in the cerebellum with kuru plaques. Therefore, small amyloid plaques in the cerebellum can be crucial for MV2K+C subtype.