Corticobasal syndrome mimicking Foix-Chavany-Marie syndrome with suggested 4-repeat tauopathy by tau PET.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative disease diagnosed based on clinical manifestations such as asymmetrical parkinsonism, limb apraxia, and speech and language impairment. The background pathology of CBS is commonly a variety of proteinopathies, but association with cerebrovascular disease has also been reported. Foix-Chavany-Marie syndrome (FCMS) is a rare neurological disorder characterized by facio-pharyngo-glossal diplegia with automatic-voluntary movement dissociation presenting with bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles. FCMS is commonly attributable to stroke. Transactive response DNA binding protein of 43 kD (TDP-43) proteinopathy is also known as the pathological background of FCMS, while the pathological background of the majority of CBS cases consists of diverse tauopathies instead of TDP-43 proteinopathy. In this report, we describe a case mimicking FCMS that was finally diagnosed as CBS with suggested 4-repeat tauopathy. CASE PRESENTATION: A 68-year-old female started experiencing difficulty speaking followed by difficulty writing, and especially texting, several years before her visit. Her impairment had been gradually worsening, and she came to our hospital. On neurological examination, she demonstrated the facial apraxia, frontal lobe dysfunction, and upper motor neuron signs. She presented some characteristics suggestive of FCMS. Her symptoms exhibited rapid progression and myoclonus, parkinsonism, and left-side dominant cortical sensory deficit occurred, resulting in the fulfillment of diagnostic criteria for CBS after 9 months. Tau PET imaging displayed notable ligand uptake in the brainstem, subthalamic nuclei, basal ganglia, and bilateral subcortical frontal lobe, suggesting that her pathological background was 4-repeat tauopathy. As a result of her progressive dysphagia, she became unable to eat and passed away after 12 months. CONCLUSION: We hereby present an atypical case of CBS showing clinical features mimicking FCMS at first presentation. TDP-43 proteinopathy was suspected based on the clinical symptoms in the early stages of the disease; however, the clinical course and imaging findings including tau PET suggested that her pathological background was 4-repeat tauopathy.

[Case of hereditary Y69H (p.Y89H) transthyretin variant leptomeningeal amyloidosis presenting with drop attacks and recurrent transient language disorder].

We report a 73-year-old woman who started developing recurrent transient aphasia at the age of 66 years. During the attacks, she was aware she could not understand what was being said and both her spoken and written speech were meaningless. The attacks usually lasted for a few days, following which she could explain what had happened. Anti-epileptics did not improve her symptoms. She also noticed tremor of her right hand and gait disturbance at the age of 71 years. The recurrent transient aphasia was followed by drop attacks. At the time of her admission to our hospital, she showed paraplegia, phonological paraphasia, and difficulty in understanding complex sentences. Her language disturbance resembled a logopenic variant of primary progressive aphasia. However, the symptoms fluctuated for a few days and subsequently improved. Electroencephalography showed no abnormalities. Gadolinium-enhanced brain and spinal MRI showed diffuse leptomeningeal enhancement over the surface of the spinal cord, brain stem, and cerebrum on T1-weighed imaging. Surgical biopsy of a varicose vein in the subarachnoid space at the level of the Th11 spinal cord was performed. Pathological evaluation of the biopsied specimens revealed TTR-immunolabeled amyloid deposits in the subarachnoid vessel walls and on the arachnoid membrane. Gene analysis revealed c.265T>C, p.Y89H (Y69H) TTR mutation, which is known as one of the causative mutations of familial leptomeningeal amyloidosis. Leptomeningeal forms of transthyretin amyloidosis might present transient focal neurological episodes.

The clinical application of optimized AT(N) classification in Alzheimer's clinical syndrome (ACS) and non-ACS conditions.

We aimed to assess the utility of AT(N) classification in clinical practice. We measured the cerebrospinal fluid levels of amyloid-ß (Aß) 42, Aß40, phosphorylated tau, total tau, and neurofilament light chain (NfL) in samples from 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non-ACS. The concordance of two A-markers (i.e., Aß42 alone and the Aß42/Aß40 ratio) was not significantly different between the ACS (87.4%) and non-ACS (74.1%) groups. However, the frequency of discordant cases with AAß42-alone+/AAß-ratio- was significantly higher in the non-ACS (23.8%) than in the ACS group (7.4%). The concordance of two N-markers (i.e., total tau and NfL) was 40.4% in the ACS group and 24.4% in the non-ACS group. In the ACS samples, the frequency of biological Alzheimer's disease (i.e., A+T+) in Ntau+ cases was 95% while that in NNfL+ cases was 65%. Reflecting Aß deposition and neurodegeneration more accurately, we recommend the use of AT(N) classification defined by cerebrospinal fluid AAß-ratioTNNfL in clinical practice.

Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy.

Objectives: Leigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP). Methods: Data from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses. Results: The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected. Discussion: These findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.

[Neuropsychological and regional cerebral blood flow of posterior parietal area features in patients with Parkinson's disease with mild cognitive impairment].

This study aimed to clarify associations between neuropsychological scales and regional cerebral blood flow (rCBF) of on |123I-IMP-SPECT in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). Forty-two participants (mean age, 65.5 ± 8.9 years; mean disease duration, 11.1 ±5.7 years) were evaluated using the Wechsler Adult Intelligence Scale, third edition (WAIS-III), Wechsler Memory Scale, revised (WMS-R), Stroop test, Category word fluency, Auditory verbal learning test, Raven colored progressive matrices, Trail Making Test-B, and Clock drawing test. Participants were classified into PD-MCI and PD non-demented (PD-ND) using ten of these scales or its subtests. The rCBF of the posterior cingulate gyrus, precuneus, and parietal lobes was evaluated by |123I-IMP-SPECT using the easy Z-|score imaging system (eZIS analysis). Extent was the extent index of voxels showing z-score > 2, and Severity was mean z-score in those regions on eZIS analysis. Cingulate island sign score (CIScore) was the ratio of integrated z-scores of the posterior cingulate gyrus to those of the posterior cortex.Twenty-three participants were diagnosed with PD-MCI (55%). The rCBF indices were significantly increased in the PD-MCI group compared to the PD-ND group (Extent: P = 0.047; CIScore: P = 0.006). These indices were significantly correlated with WAIS-III Processing Speed (Extent: P = 0.041, R = -0.317; Severity: P = 0.047, R = -0.309), Stroop effect (Extent: P = 0.003, R = 0.443; Severity: P = 0.004, R = 0.437), WMS-R Visual memory (Extent: P = 0.019, R = -0.361; Severity: P = 0.014, R = -0.375), and Delayed memory score (Extent: P = 0.005, R = -0.423; Severity: P = 0.044, R = -0.312). The rCBF indices showed no correlations with the number of impaired cognitive domains. Collectively, decreased posterior parietal area rCBF and lower scores on selective neuropsychological scales might be helpful to detect a transition period from PD-MCI to PD-D.

Development of a Novel Nutrition-Related Multivariate Biomarker for Mild Cognitive Impairment Based on the Plasma Free Amino Acid Profile.

Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.

Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment.

Background: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants. Method: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted. Results: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group. Conclusion: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status. Clinical trial registration: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

[Effect of sodium pyruvate on exercise intolerance and muscle weakness due to mitochondrial myopathy: a case report].

We report the case of a 19-year-old woman who had been suffering from general fatigue and exercise intolerance since 15 years old. At 18 years old, she experienced muscle weakness and myalgia of the calves. Six months later, she was admitted to our hospital. She showed muscle weakness of the neck and proximal limbs, and myalgia of the calves was prominent. Serum levels of creatine kinase (CK) and lactic acid were elevated, as was the level of lactic acid in cerebrospinal fluid. T2-weighted and short-inversion-time inversion recovery (STIR) imaging of the lower limbs showed hyperintensity on bilateral gastrocnemius muscles, and the region revealed Gd enhancement. Based on histopathological findings from muscle and identification of a m.3271T>C point mutation, mitochondrial myopathy was diagnosed. Rest and administration of vitamins B1 and B2, coenzyme Q10, and L-carnitine improved serum CK levels; however, exercise intolerance, myalgia, and lactic acidemia remained. Sodium pyruvate was then administered, and lactic acid levels, exercise intolerance, and findings on magnetic resonance imaging improved. Sodium pyruvate could prove effective in addressing both elevated serum lactic acid levels and exercise intolerance in mitochondrial disease.

A fatal neuromuscular disease in an adult patient after poliomyelitis in early childhood: consideration of the pathology of post-polio syndrome.

Post-polio syndrome (PPS) characterized by new neuromuscular problems can appear many years after acute poliomyelitis in polio survivors. We report a 77-year-old man with antecedent poliomyelitis who newly developed neuromuscular disease with a clinical course of 27 years, the final 10 years of which were characterized by apparent progression, thus raising doubt as to the clinical diagnosis of amyotrophic lateral sclerosis (ALS) following PPS. Pathologically, plaque-like, old poliomyelitis lesions were found almost exclusively in the lumbosacral cord, showing complete neuronal loss and glial scars in the anterior horns. Although less severe, neuronal loss and gliosis were also evident outside the old lesions, including the intermediate zone. Moreover, symmetrical degeneration of the corticospinal tracts, as evidenced by CD68 immunostaining, was a feature of the white matter of the lower spinal cord. In the motor cortex, loss of Betz cells was also confirmed. Synaptophysin immunostaining of the lumbosacral cord also revealed decreased expression outside the old lesions, excluding the posterior horn. Interestingly, decreased expression of synaptophysin was also evident in the cervical anterior horns, where no old lesions were observed. No Bunina bodies, TDP-43 inclusions, or Golgi fragmentation were found. Neurogenic atrophy was evident in the iliopsoas and scalenus muscles, and inclusion body myositis-like changes were also observed in these muscles and the tongue. Was it possible to have diagnosed this patient as having ALS? We consider that the features in this case may have represented the pathology of long-standing and/or fatal PPS itself, and not ALS.