Systematic Review of Clinical and Pathophysiological Features of Genetic Creutzfeldt-Jakob Disease Caused by a Val-to-Ile Mutation at Codon 180 in the Prion Protein Gene.

Genetic Creutzfeldt-Jakob disease (gCJD) is a subtype of genetic prion diseases (gPrDs) caused by the accumulation of mutated pathological prion proteins (PrPSc). gCJD has a phenotypic similarity with sporadic CJD (sCJD). In Japan, gCJD with a Val to Ile substitution at codon 180 (V180I-gCJD) is the most frequent gPrD, while the mutation is extremely rare in countries other than Japan and Korea. In this article, we aim to review previously elucidated clinical and biochemical features of V180I-gCJD, expecting to advance the understanding of this unique subtype in gCJD. Compared to classical sCJD, specific clinical features of V180I-gCJD include older age at onset, a relatively slow progression of dementia, and a lower positivity for developing myoclonus, cerebellar, pyramidal signs, and visual disturbance. Diffuse edematous ribboning hyperintensity of the cerebral cortex, without occipital lobes in diffusion-weighted magnetic resonance imaging, is also specific. Laboratory data reveal the low positivity of PrPSc in the cerebrospinal fluid and periodic sharp wave complexes on an electroencephalogram. Most patients with V180I-gCJD have been reported to have no family history, probably due to the older age at onset, and clinical and biochemical features indicate the specific phenotype associated with the prion protein gene mutation.

Circular walking is useful for assessing the risk of falls in early progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by early onset postural instability and frequent falls. Circular walking necessitates dynamic postural control, which is impaired in patients with PSP. We aimed to explore gait parameters associated with the risk of falls in patients with PSP, focusing on circular walking. METHODS: Sixteen drug-naïve patients with PSP, 22 drug-naïve patients with Parkinson's disease (PD), and 23 healthy controls were enrolled. Stride lengths/velocities and their coefficients of variation (CV) during straight and circular walking (walking around a circle of 1-m diameter) were measured under single-task and cognitive dual-task conditions. Correlation analysis was performed between gait parameters and postural instability and gait difficulty (PIGD) motor subscores, representing the risk of falls. RESULTS: Patients with PSP had significantly higher CVs of stride lengths/velocities during circular walking than those during straight walking, and the extent of exacerbation of CVs in patients with PSP was larger than that in patients with PD under single-task conditions. Stride lengths/velocities and their CVs were significantly correlated with PIGD motor subscores in patients with PSP only during single-task circular walking. In addition, patients with PSP showed progressive decrements of stride lengths/velocities over steps only during single-task circular walking. CONCLUSIONS: Worse gait parameters during circular walking are associated with an increased risk of falls in patients with PSP. Circular walking is a challenging task to demand the compromised motor functions of patients with PSP, unmasking impaired postural control and manifesting sequence effect. Assessing circular walking is useful for evaluating the risk of falls in patients with early PSP.

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine.

An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with a novel nucleoside derivative including a 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, in vitro and in vivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. In vitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. In vivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.

Erratum: Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4' -BNA/LNA with 9-(aminoethoxy)phenoxazine.

[This corrects the article DOI: 10.1016/j.omtn.2024.102161.].

Serial changes in regional cerebral blood flow in Gerstmann-Sträussler-Scheinker disease caused by a Pro-to-Leu mutation at codon 105 in the prion protein gene.

Gerstmann-Sträussler-Scheinker disease with a Pro-to-Leu substitution at codon 105 in the prion protein gene (GSS-P105L) is a rare variant of human genetic prion disease. Herein, we report the case of a patient with GSS-P105L, who showed serial changes in regional cerebral blood flow (rCBF) on single-photon emission computed tomography (SPECT). A 42-year-old woman, with an affected father presenting with similar symptoms, had a 1-year history of progressive gait disturbance, lower-limb spasticity, and psychiatric symptoms. Genetic analysis confirmed the diagnosis of GSS-P105L. Eleven months after disease onset, brain magnetic resonance imaging (MRI) showed bilateral frontal lobe-dominant cerebral atrophy without hyperintensity on diffusion-weighted imaging (DWI) sequences; meanwhile, SPECT revealed non-specific mild hypoperfusion. Follow-up MRI at 52 months after onset demonstrated progressive frontal lobe-dominant cerebral atrophy without hyperintensity on DWI, while SPECT revealed a marked decrease in rCBF in the bilateral right-dominant frontal lobe. Patients with GSS with a Pro-to-Leu substitution at codon 102 (GSS-P102L) have been reported to exhibit hyperintensity on DWI-MRI and a diffuse decrease in CBF with a mosaic-like pattern on SPECT, which is absent in patients with GSS-P105L, thereby possibly reflecting the differences in pathophysiology between GSS-P102L and GSS-P105L.

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.

Specific electroencephalogram features in the very early phases of sporadic Creutzfeldt-Jakob disease.

Studies on the very early electroencephalography (EEG) features prior to the emergence of generalized periodic discharges (GPDs, generally known as periodic sharp-wave complexes) in Creutzfeldt-Jakob disease (CJD) are rare. Fourteen patients with sporadic CJD (sCJD) (eight with MM1/classic and six with MM2c) were included in this study. The predominant findings of the first EEG were categorized as 1) lateralized periodic discharges (LPDs), 2) central sagittal sporadic epileptiform discharges (CSSEDs) showing midline predominant generalized spike-and-wave complexes and/or sharp waves in the central sagittal regions, or 3) focal epileptiform discharges. Clinical records, magnetic resonance imaging (MRI), and changes in EEG were compared between three groups (LPD in MM1/classic, CSSED in MM1/classic, and focal epileptiform discharge in MM2c). Three (37.5%) and five (62.5%) patients with MM1/classic sCJD were classified into the LPD and CSSED groups, respectively. Patients in the LPD group were accompanied by cortical hyperintensities at the corresponding areas on MRI, while those in the CSSED group showed hyperintensities on MRI at unassociated cortical areas. Follow-up EEG of three (100%) patients in the LPD group and four (80%) in the CSSED group showed transitions to GPDs. All patients with MM1/classic sCJD showed myoclonus on initial EEG, and the symptomatic side was opposite to the hemisphere showing LPDs or higher-amplitude central sagittal epileptiform activity. The periodicity after these EEGs likely contributes to the diagnostic confidence of physicians when patients are in the very early stages of MM1/classic sCJD.

Reversible Cerebral Vasoconstriction Syndrome without Headache That Was Initially Suspected of Being Primary Angiitis of the Central Nervous System.

A 48-year-old man had convulsions, and magnetic resonance angiography (MRA) showed diffuse constriction of the cerebral arteries. He was suspected of having primary angiitis of the central nervous system (PACNS) and treated with steroid for three days. The MRA abnormality disappeared after a week. After 69 days, he developed dizziness, and MRA revealed recurrence of cerebral artery stenosis. Nevertheless, the symptoms and abnormal MRA findings recovered promptly without treatment. He was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) without headache. This case suggests that RCVS should be a differential diagnosis in patients without headache whose MRA findings show multiple cerebral artery stenosis.

Focal sharp waves are a specific early-stage marker of the MM2-cortical form of sporadic Creutzfeldt-Jakob disease.

Periodic sharp wave complexes (PSWCs), identified using electroencephalography, are observed in less than half of patients with the methionine homozygosity type 2 cortical (MM2c) form of sporadic Creutzfeldt-Jakob disease (sCJD), and only at a later stage of the disease. In this study, we identified early and specific markers on the electroencephalograms (EEGs) of patients with MM2c-sCJD. We retrospectively investigated the clinical records, EEGs, and magnetic resonance imaging (MRI) scans of patients diagnosed with sCJD and compared the EEG findings of MM2c-sCJD and MM1/classic sCJD groups. The records of six patients with MM2c-sCJD and eight with MM1/classic sCJD were included. The median ages of onset in the MM2c- and MM1/classic sCJD groups were 75.0 (range, 60-83) and 72.5 (range, 51-74) years, respectively, and the average durations between disease onset and the first EEG were 9.17 (range, 4-15) and 1.88 (range, 1-4) months, respectively. Focal sharp waves and/or focal spike-and-wave complexes in the brain regions corresponding with cortical hyperintensities on MRI scans were identified on the EEGs of patients with MM2c-sCJD in the early stages of disease progression. In contrast, EEGs of patients in the early stages of MM1/classic sCJD showed lateralized or generalized diffuse sharp waves and spike-and-wave complexes, which were not limited to cortical hyperintensities identified with MRI scans. Our findings indicate that focal sharp waves and/or focal spike-and-wave complexes on the EEGs of patients in the early phase of MM2c-sCJD are characteristic of the disease, suggesting the possible usefulness of this characteristic for early diagnosis.