Effects of Sitting and Supine Positions on Tongue Color as Measured by Tongue Image Analyzing System and Its Relation to Biometric Information.

Tongue diagnosis is one of the important diagnostic methods in Kampo (traditional Japanese) medicine, in which the color and shape of the tongue are used to determine the patient's constitution and systemic symptoms. Tongue diagnosis is performed with the patient in the sitting or supine positions; however, the differences in tongue color in these two different positions have not been analyzed. We developed tongue image analyzing system (TIAS), which can quantify tongue color by capturing tongue images in the sitting and supine positions. We analyzed the effects on tongue color in two different body positions. Tongue color was quantified as L∗a∗b∗ from tongue images of 18 patients in two different body positions by taking images with TIAS. The CIEDE 2000 color difference equation (ΔE00) was used to assess the difference in tongue color in two different body positions. Correlations were also determined between ΔE00, physical characteristics, and laboratory test values. The mean and median ΔE00 for 18 patients were 2.85 and 2.34, respectively. Of these patients, 77.8% had a ΔE00 < 4.1. A weak positive correlation was obtained between ΔE00 and systolic blood pressure and fasting plasma glucose. Approximately 80% of patients' tongue color did not change between the sitting and supine positions. This indicates that the diagnostic results of tongue color are trustworthy even if medical professionals perform tongue diagnosis in two different body positions.

Iatrogenic cerebral amyloid angiopathy in older adults.

BACKGROUND AND PURPOSE: An increasing number of cases of iatrogenic cerebral amyloid angiopathy (CAA) have now been reported worldwide. Proposed diagnostic criteria require a history of medical intervention with potential for amyloid-ß transmission, for example those using cadaveric dura mater or requiring instrumentation of the brain or spinal cord. Clinical presentation occurs after an appropriate latency (usually three or four decades); to date, most patients with iatrogenic CAA have had 'early-onset' disease (compared to sporadic, age-related, CAA), as a consequence of childhood procedures. RESULTS: We describe five cases of possible iatrogenic CAA in adults presenting in later life (aged 65 years and older); all had prior neurosurgical interventions and presented after a latency suggestive of iatrogenic disease (range 30-39 years). Use of cadaveric dura mater was confirmed in one case, and highly likely in the remainder. CONCLUSION: The presentation of iatrogenic CAA in older adults widens the known potential spectrum of this disease and highlights the difficulties of making the diagnosis in this age group, and particularly in differentiating iatrogenic from sporadic CAA. Increased vigilance for cases presenting at an older age is essential for furthering our understanding of the clinical phenotype and broader implications of iatrogenic CAA.

Frequency of Comorbid Pathologies and Their Clinical Impact in Multiple System Atrophy.

BACKGROUND: Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood. OBJECTIVE: We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates. METHODS: This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact. RESULTS: The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction. CONCLUSIONS: The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.

Validation Study of the MDS Criteria for the Diagnosis of Multiple System Atrophy in the Mayo Clinic Brain Bank.

BACKGROUND AND OBJECTIVE: The second consensus criteria in 2008 have been used in diagnosing multiple system atrophy (MSA). The International Parkinson and Movement Disorder Society (MDS) proposed new diagnostic criteria for MSA in 2022. This study aimed to compare the diagnostic accuracy between these 2 criteria and validate the clinical utility of the newly proposed criteria for MSA. METHODS: We conducted a retrospective autopsy cohort study of consecutive patients with a clinical or pathologic diagnosis of MSA from the Mayo Clinic brain bank between 1998 and 2021. We studied 352 patients (250 pathologically diagnosed MSA and 102 non-MSA); MDS criteria and the second consensus criteria were applied. The sensitivity, specificity, and area under the curve (AUC) of receiver operating characteristic curves were compared between these criteria. Comparison was conducted between clinical subtypes and among clinically challenging cases (those with different clinical diagnoses or those with suspected but undiagnosed MSA before death). We also used machine learning algorithm, eXtreme Gradient Boosting, to identify clinical features contributing diagnostic performance. RESULTS: The sensitivity and specificity of clinically established and probable MSA by the MDS criteria were 16% and 99% and 64% and 74%, respectively. The sensitivity and specificity of probable MSA and possible MSA by the second consensus criteria were 72% and 52% and 93% and 21%, respectively. The AUC of MDS clinically probable MSA was the highest (0.69). The diagnostic performance did not differ between clinical subtypes. In clinically challenging cases, MDS clinically established MSA maintained high specificity and MDS clinically probable MSA demonstrated the highest AUC (0.62). MRI findings contributed to high specificity. In addition, combining core clinical features with 2 or more from any of the 13 supporting features and the absence of exclusion criteria also yielded high specificity. Among supporting features, rapid progression was most important for predicting MSA pathology. DISCUSSION: The MDS criteria showed high specificity with clinically established MSA and moderate sensitivity and specificity with clinically probable MSA. The observation that high specificity could be achieved with clinical features alone suggests that MSA diagnosis with high specificity is possible even in areas where MRI is not readily available.

Diffuse argyrophilic grain disease with TDP-43 proteinopathy and neuronal intermediate filament inclusion disease: FTLD with mixed tau, TDP-43 and FUS pathologies.

Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by degeneration of the frontal and temporal lobes, leading to progressive decline in language, behavior, and motor function. FTLD can be further subdivided into three main subtypes, FTLD-tau, FTLD-TDP and FTLD-FUS based which of the three major proteins - tau, TDP-43 or FUS - forms pathological inclusions in neurons and glia. In this report, we describe an 87-year-old woman with a 7-year history of cognitive decline, hand tremor and gait problems, who was thought to have Alzheimer's disease. At autopsy, histopathological analysis revealed severe neuronal loss, gliosis and spongiosis in the medial temporal lobe, orbitofrontal cortex, cingulate gyrus, amygdala, basal forebrain, nucleus accumbens, caudate nucleus and anteromedial thalamus. Tau immunohistochemistry showed numerous argyrophilic grains, pretangles, thorn-shaped astrocytes, and ballooned neurons in the amygdala, hippocampus, parahippocampal gyrus, anteromedial thalamus, insular cortex, superior temporal gyrus and cingulate gyrus, consistent with diffuse argyrophilic grain disease (AGD). TDP-43 pathology in the form of small, dense, rounded neuronal cytoplasmic inclusion with few short dystrophic neurites was observed in the limbic regions, superior temporal gyrus, striatum and midbrain. No neuronal intranuclear inclusion was observed. Additionally, FUS-positive inclusions were observed in the dentate gyrus. Compact, eosinophilic intranuclear inclusions, so-called "cherry spots," that were visible on histologic stains were immunopositive for α-internexin. Taken together, the patient had a mixed neurodegenerative disease with features of diffuse AGD, TDP-43 proteinopathy and neuronal intermediate filament inclusion disease. She met criteria for three subtypes of FTLD: FTLD-tau, FTLD-TDP and FTLD-FUS. Her amnestic symptoms that were suggestive of Alzheimer's type dementia are best explained by diffuse AGD and medial temporal TDP-43 proteinopathy, and her motor symptoms were likely explained by neuronal loss and gliosis due to tau pathology in the substantia nigra. This case underscores the importance of considering multiple proteinopathies in the diagnosis of neurodegenerative diseases.

APOE2 Exacerbates TDP-43 Related Toxicity in the Absence of Alzheimer Pathology.

OBJECTIVE: Recent evidence supports a link between increased TDP-43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP-43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP-43 pathology and related neurodegeneration in the absence of typical AD pathologies. METHODS: We overexpressed human TDP-43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe-knockout (Apoe-KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP-43 overexpression-related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP-43 pathology in 160 postmortem brains from autopsy-confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) in the Mayo Clinic Brain Bank. RESULTS: We found that TDP-43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe-KO mice. In the motor cortex of the ALS and FTLD-MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP-43-positive dystrophic neurites. INTERPRETATION: Our data suggest a genotype-specific effect of APOE on TDP-43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830-843.

Case Report: Acupuncture is an effective treatment for olfactory dysfunction in the post COVID-19 condition.

Olfactory dysfunction in the post COVID-19 condition reported worldwide are refractory for some patients. For this reason, appropriate treatment is desired. In this article, we describe two cases of olfactory dysfunction in the post COVID-19 condition that was improved by traditional acupuncture treatment. By using the Yingxiang point (LI20), which is said to improve the sense of smell since ancient times, acupuncture treatment was performed 1-2 times a week in two patients about 6 and 7 months after the diagnosis of COVID-19. Acupuncture needles with a body length of 30 mm and a body diameter of 0.16 mm were inserted about 10 mm deep into the skin. We stimulated LI20 of the right and left sides until the patients felt the de qi sensation (acupuncture resonance), and left needles in the points for about 15 min. Immediately after the acupuncture treatment, the symptoms of olfactory dysfunction were alleviated, and the improvement in olfactory dysfunction lasted for 2-4 days. As the number of acupuncture treatments increased, the time until the flareup of olfactory dysfunction was prolonged, and the symptoms tended to decrease. In our experience, the acupuncture treatment was effective in a short period for treating residual olfactory dysfunction of the post COVID-19 condition, suggesting that acupuncture may serve as an adjunct to modern medical treatment, and it may also be a new option for patients who are resistant to Western medical treatment or unable to continue treatment because of side effects. In conclusion, acupuncture may be a new option for patients who are resistant to modern medical treatment or who are unable to continue treatment because of side effects.

Effect of donepezil for dementia prevention in Parkinson's disease with severe hyposmia (The DASH-PD study): A randomized long-term placebo-controlled trial.

Background: Dementia greatly contributes to poor prognosis in patients with Parkinson's disease (PD). We previously reported that severe olfactory dysfunction may be a good predictor of Parkinson's disease dementia (PDD). In this trial, we investigated whether early administration of donepezil to patients with severe hyposmia can reduce the development of PDD. Methods: This was a multi-centre, randomized, double-blind, parallel group, placebo-controlled trial in patients with non-demented PD with severe hyposmia (The Donepezil Application for Severe Hyposmic Parkinson's Disease [DASH-PD] study). A total of 201 patients were randomly allocated to receive donepezil or placebo in addition to standard therapy for PD. Patients were followed up every 6 months until the onset of PDD or for a maximum of 4 years. The primary endpoint was the onset of dementia. The secondary endpoint was cognitive impairment measured by Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Clinical Dementia Rating (CDR).(UMIN000009958: February 2013 to May 2019). Findings: A total of 201 hyposmic patients with PD were randomly assigned to a treatment: 103 to donepezil and 98 to placebo. Overall, 141 (70%) patients completed the 4-year intervention. During follow-up, 7 of 103 (6.8%) patients in the donepezil group and 12 of 98 (12.2%) patients in the placebo group developed PDD; however, the hazard ratio of PDD incidence was not statistically significant (hazard ratio (HR), 0.609; 95% confidence interval, 0.240 to 1.547; p = 0.2969). At week 208, the patients in the donepezil group had better scores on the ACE-R (p < 0.005) and the CDR (p < 0.005) than those taking placebo. Interpretation: Administration of donepezil to PD patients with severe olfactory dysfunction for 4 years did not change the incidence of dementia but had a beneficial effect on neuropsychological function, with good tolerability. Funding: The Ministry of Health Labour and Welfare and the Japan Agency for Medical Research and Development provided funding for this study.

[Analysis of Factors Affecting Proteinuria Onset Timing in Patients Treated with Bevacizumab].

Bevacizumab (BV) is a recombinant and humanized monoclonal antibody that inhibits vascular endothelial growth factor. BV is used to treat various types of cancer. Proteinuria is a characteristic adverse event that occurs as a result of treatment with BV. However, the onset timing of proteinuria after BV administration remains unclear. In the present study, we examined the risk factors affecting the timing of proteinuria onset upon BV administration. Medical records of 135 patients (62 males and 73 females; mean age: 67.8±10.7 years) treated with BV were reviewed at the Kindai University Nara Hospital from April 2011 to December 2019. Proteinuria was identified in 44.4% (60/135) of the studied patients. The time to the first onset of proteinuria was significantly shorter in the administration of doses of BV (≥10) and history of diabetes mellitus. The median cumulative dose associated with the onset of proteinuria was 30.0 (16.1-58.8) mg/kg. When this cumulative dose was compared with 10 mg/kg, no significant difference was observed (p=0.319). The present study demonstrated that the administration of doses of BV (≥10) and history of diabetes mellitus are one of the main risk factors for early-onset proteinuria. These findings may be useful for the future treatment of early-onset proteinuria in patients treated with BV.

Early presentation of lower urinary tract and bowel dysfunction in sporadic amyotrophic lateral sclerosis: A case report.

An autopsy case of sporadic amyotrophic lateral sclerosis (ALS) with lower urinary tract (LUT) and bowel dysfunction is reported. The dysfunction occurred simultaneously with motor neuron symptoms in the early stages of the illness. A 75-year-old man developed exertional dyspnea and constipation following weight loss. Subsequently, he developed swallowing disturbance, fecal incontinence, and urinary retention. Neurological examination showed dysphagia, muscle weakness of the upper limbs, and prominent fasciculation affecting all four limbs and the tongue. All deep tendon reflexes were diminished, but the left plantar response was extensor. Orthostatic hypotension (OH) and the anal reflex were absent. Neuropathological findings did not show neuronal loss and gliosis in the thoracic and sacral intermediolateral nucleus (IML) and in Onuf's nucleus, whereas gliosis was observed in the periaqueductal gray (PAG) and striatum. Therefore, urinary retention may have resulted from involvement of the PAG. Phosphorylated TAR DNA binding protein 43 kDa (p-TDP-43)-positive inclusions were present in the peripheral nerves within the thoracic sympathetic ganglia, as well as the IML of the thoracic spinal cord. However, considering the lack of OH, the IML and peripheral sympathetic nerves unlikely played major roles. Furthermore, neuronal loss or p-TDP-43-immunoreactive deposits were absent in the Auerbach and Meissner plexuses of the rectum, suggesting that the responsible anatomical sites for fecal incontinence could not be found. Although it is difficult to elucidate the precise neuropathological lesions corresponding to LUT and bowel dysfunction, physicians need to recognize that neurogenic bladder and bowel dysfunction can occur in patients with ALS.

Old age amyotrophic lateral sclerosis and limbic TDP-43 pathology.

This study aimed to assess and compare the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate-to-severe Alzheimer's disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death: 75 years or older (old-ALS, n = 8), 64-74 years (middle-ALS, n = 23), and 63 years or younger (young-ALS, n = 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS-CBS), were summarized. Sections of paraffin-embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho-TDP-43 immunohistochemistry. The burden of TDP-43 pathology was analyzed using digital image analysis. The TDP-43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old-ALS than in young-ALS and middle-ALS. TDP-43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS-CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP-43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic-predominant, age-related TDP-43 encephalopathy neuropathologic change.

Neuropathology of Parkinson's disease after focused ultrasound thalamotomy.

Focused ultrasound (FUS) thalamotomy is an emerging treatment for tremor-dominant Parkinson's disease (PD). We report the first postmortem neuropathologic study of FUS thalamotomy in a 68-year-old man with tremor-dominant PD, which was performed seven months before he died. Although the peak voxel temperature at the target was <54 °C, his tremor improved on intraoperative and postoperative assessments. Additionally, postoperative MRI demonstrated a thalamic lesion. Lewy body-related pathology consistent with PD was detected. There was also a 5-mm lesion in the ventral lateral thalamus characterized by demyelination and neuropil loss, with many lipid-laden macrophages, but no lymphocytic infiltrates and relatively preserved neurons and axons. Additional pathological assessments after FUS thalamotomy are needed to determine if the observed brain changes are typical of this procedure.

Diffuse Lewy body disease presenting as Parkinson's disease with progressive aphasia.

Primary progressive aphasia (PPA) is a progressive language disorder often due to an underlying neurodegenerative disease. The most common pathologies associated with PPA include frontotemporal lobar degeneration (FTLD)-tau, FTLD-associated with transactivation response DNA-binding protein of 43 kDa (TDP-43) (FTLD-TDP), and Alzheimer's disease (AD). Accumulating evidence has suggested that Lewy body disease (LBD) can also be associated with PPA. We herein report a 78-year-old Caucasian woman who initially presented with levodopa-responsive parkinsonism at age 67 and later developed cognitive impairment, visual hallucinations, rapid eye movement sleep behavior disorder, and progressive aphasia, characterized by reduced spontaneous speech, word-finding difficulty, and difficulties in writing and reading. 18 Fluorodeoxyglucoase (FDG)-positron emission tomography (PET) performed at the age of 73 years identified hypometabolism in the frontal (right > left), temporal (left > right), and parietal (left > right) lobes. Neuropathological assessment revealed diffuse LBD (DLBD), AD, and TDP-43 stage 6 with prehippocampal sclerosis. Senile plaques were numerous, but only a few neurofibrillary tangles were present in the neocortex. The Braak neurofibrillary tangle stage was IV, and the Thal amyloid phase was 3. Lewy-related pathology was severe in the neocortex, as well as limbic cortices, basal forebrain, amygdala, and brainstem. Compared to 166 DLBD cases with a clinical diagnosis of dementia with Lewy bodies (DLB), the Lewy body count of the patient in this report was highest in the inferior parietal cortex, followed by midfrontal and superior temporal cortices. The findings suggest that severe cortical LBD pathology has contributed to her progressive aphasia. Autopsy cases of LBD presenting as PPA have been reported, but patients with PD and autopsy-proven DLBD who later developed progressive aphasia have not been reported. Our findings indicate that PD can be associated with progressive aphasia later in the disease course. Although uncommon, LBD should be considered as a differential diagnosis of progressive aphasia.

Concurrent tau pathologies in frontotemporal lobar degeneration with TDP-43 pathology.

AIMS: Accumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP-43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP-43 pathology (FTLD-TDP). METHODS: The study included 146 autopsy-confirmed cases of FTLD-TDP and 55 cases of FTLD-TDP with motor neuron disease (FTLD-MND). Sections from the basal forebrain were screened for tau pathology with phosphorylated-tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9orf72, GRN and MAPT was performed on select cases. RESULTS: We found 72 cases (36%) with primary age-related tauopathy (PART), 85 (42%) with ageing-related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD) and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD-TDP and CBD had C9orf72 mutation and relatively mild tau pathology, consistent with incidental CBD. CONCLUSION: The coexistence of TDP-43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, patients with FTLD can have multiple neurodegenerative proteinopathies. The absence of TDP-43-positive astrocytic plaques may suggest that CBD and FTLD-TDP were independent disease processes in the two patients with both tau and TDP-43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.

[Cerebral amyloid angiopathy-related transient focal neurological episodes with diffusion-weighted imaging hyperintense lesions in subcortical white matter and cortical superficial siderosis].

A 72-year-old man presented with two episodes of migratory left-sided paresthesia lasting 10 min. At the first episode, diffusion-weighted imaging hyperintense lesions (DWIHLs) were seen in the right parietal lobe, suggesting an initial diagnosis of acute ischemic stroke, for which we administered antiplatelet therapy for secondary prevention. Four months later, he again developed transient migratory left-sided paresthesia. Gradient-echo T2*-weighted imaging at this time showed disseminated cortical superficial siderosis (cSS) and strictly cerebral microbleeds around the DWIHLs in the right parietal lobe. These findings led to a diagnosis of cerebral amyloid angiopathy and its related findings, including transient focal neurological episodes (TFNE) and DWIHLs, and antiplatelet medication was stopped. In clinical settings, although it is challenging to distinguish TFNE of hemorrhagic origin from cerebral ischemic symptoms, including transient ischemic attacks, this case suggests that even when elderly patients with transient neurological symptoms present with cortical DWIHLs, paramagnetic-sensitive MRI should be performed to check for cSS around the DWIHLs.

Zonisamide attenuates the severity of levodopa-induced dyskinesia via modulation of the striatal serotonergic system in a rat model of Parkinson's disease.

Glutamate, GABA, acetylcholine, dopamine, and serotonin interact with each other to regulate the flow of neural information in the striatum. Serotonin type 1A receptor (5HT1A) is primarily expressed on glutamatergic nerve terminals, and 5HT1B is expressed on GABAergic medium spiny neurons (MSNs). Zonisamide (ZNS) reportedly improves the off period without worsening levodopa-induced dyskinesia (LID) in patients with advanced Parkinson's disease. In this study, LID model rats were prepared by administrating levodopa to unilaterally 6-OHDA-lesioned rats. We analyzed changes in serotonergic neurotransmission of LID model rats to elucidate the relationship between LID and the serotonergic system and pathomechanism of the anti-dyskinetic effects of ZNS. Abnormal involuntary movements (AIMs) were most severe in intermittently levodopa-treated rats but milder in rats intermittently medicated with levodopa and ZNS. Continuously levodopa-infused rats or intermittently ZNS-injected rats did not develop AIMs, and no differences in the expression of brain-derived neurotrophic factor, 5-HT transporter, 5HT1A, and 5HT1B mRNA between the lesioned striatum and normal side were observed. Expression of 5HT1B mRNA was elevated in the lesioned striatum of intermittently levodopa-treated rats, but this elevation was normalized by concomitant use of ZNS. The severity of AIMs was correlated with the ratio of 5HT1B to 5HT1A mRNA expression in the lesioned striatum, indicating that the anti-LID effect of ZNS is based on inhibition via 5HT1B receptors to direct pathway MSNs sensitized by intermittent levodopa treatment. Selectively acting serotonergic drugs, especially those that lower the 5HT1B to 5HT1A ratio, are promising new therapeutic agents to attenuate LID development.

An autopsy case report of neuronal intermediate filament inclusion disease presenting with predominantly upper motor neuron features.

We describe an autopsy case of neuronal intermediate filament inclusion disease (NIFID), a subtype of frontotemporal lobar degeneration (FTLD) with the appearance of fused-in-sarcoma (FUS) inclusions (FTLD-FUS). A 57-year-old man developed dysarthria and dysphagia. One year and five months later, he was admitted to a hospital, and pseudobulbar palsy and right upper motor neuron signs were observed on examination. Needle electromyography revealed no active or chronic denervation. His neurological symptoms gradually deteriorated, and behavioral alterations occurred. He died of hemoperitoneum secondary to rupture of a ureteric tumor. The total duration of the disease was six years and 10 months. Neuropathologically, the frontal cortex, including the motor cortex, and the pyramidal tract were severely affected, whereas the lower motor neurons in the spinal cord and brainstem were mildly damaged. The striatum and substantia nigra were also severely damaged. Hyaline conglomerate inclusions, neuronal cytoplasmic inclusions with a distinct eosinophilic core (so-called cherry spot), Pick body-like inclusions, and eosinophilic round inclusions were observed in the remaining neurons. Immunohistochemical examination revealed that these inclusions were immunoreactive for FUS. HC inclusions were also immunoreactive for α-internexin and phosphorylated neurofilament protein. FUS-immunoreactive NCIs were abundant in the basal ganglia but not in the hippocampus, in contrast to previously reported NIFID cases. Furthermore, Bunina bodies identified by immunohistochemistry for cystatin C were also observed in the lower motor neurons. Bunina bodies may be present in NIFID. This case confirms the pathological heterogeneity of NIFID and supports the notion of the difference between amyotrophic lateral sclerosis and NIFID.