Clinicopathological study of dementia with grains presenting with parkinsonism compared with a typical case.

Argyrophilic grain disease (AGD) is one of the major pathological backgrounds of senile dementia. Dementia with grains refers to cases of dementia for which AGD is the sole background pathology responsible for dementia. Recent studies have suggested an association between dementia with grains and parkinsonism. In this study, we aimed to present two autopsy cases of dementia with grains. Case 1 was an 85-year-old man who exhibited amnestic dementia and parkinsonism, including postural instability, upward gaze palsy, and neck and trunk rigidity. The patient was clinically diagnosed with progressive supranuclear palsy and Alzheimer's disease. Case 2 was a 90-year-old man with pure amnestic dementia, clinically diagnosed as Alzheimer's disease. Recently, we used cryo-electron microscopy to confirm that the tau accumulated in both cases had the same three-dimensional structure. In this study, we compared the detailed clinical picture and neuropathological findings using classical staining and immunostaining methods. Both cases exhibited argyrophilic grains and tau-immunoreactive structures in the brainstem and basal ganglia, especially in the nigrostriatal and limbic systems. However, Case 1 had more tau immunoreactive structures. Considering the absence of other disease-specific structures such as tufted astrocytes, astrocytic plaques and globular glial inclusions, lack of conspicuous cerebrovascular disease, and no history of medications that could cause parkinsonism, our findings suggest an association between AGD in the nigrostriatal system and parkinsonism.

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

High sensitivity of asymmetric 18F-THK5351 PET abnormality in patients with corticobasal syndrome.

Corticobasal syndrome (CBS) is characterized by symptoms related to the asymmetric involvement of the cerebral cortex and basal ganglia. However, early detection of asymmetric imaging abnormalities can be challenging. Previous studies reported asymmetric 18F-THK5351 PET abnormalities in CBS patients, but the sensitivity for detecting such abnormalities in larger patient samples, including early-stage cases, remains unclear. Patients clinically diagnosed with CBS were recruited. All patients displayed asymmetric symptoms in the cerebral cortex and basal ganglia. Asymmetric THK5351 PET abnormalities were determined through visual assessment. Brain MRI, perfusion SPECT, and dopamine transporter (DAT) SPECT results were retrospectively reviewed. The 15 patients had a median age of 72 years (59-86 years) and a disease duration of 2 years (0.5-7 years). Four patients met the probable and 11 met the possible CBS criteria according to Armstrong criteria at the time of PET examination. All patients, including early-stage cases, exhibited asymmetric tracer uptake contralateral to their symptom-dominant side in the cerebral cortex/subcortical white matter and striatum (100%). The sensitivity for detecting asymmetric imaging abnormalities contralateral to the symptom-dominant side was 86.7% for brain MRI, 81.8% for perfusion SPECT, and 90% for DAT SPECT. White matter volume reduction was observed in the subcortical region of the precentral gyrus with increased THK5351 uptake, occurring significantly more frequently than gray matter volume reduction. THK5351 PET may be a sensitive imaging technique for detecting asymmetric CBS pathologies, including those in early stages.

CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease.

BACKGROUND AND OBJECTIVES: CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer disease (AD) and has recently been regarded to reflect ß-amyloid and/or p-tau deposition in the AD brain. Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by intranuclear inclusions in neurons, glial cells, and other somatic cells. Symptoms include dementia, neuropathy, and others. CSF biomarkers were not reported. The objective of this study was to investigate whether CSF biomarkers including p-tau181 are altered in patients with NIID. METHODS: This was a retrospective observational study. CSF concentrations of p-tau181, total tau, amyloid-beta 1-42 (Aß42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with Alzheimer clinical syndrome biologically confirmed based on CSF biomarker profiles, and patients clinically diagnosed with other neurocognitive disorders (dementia with Lewy bodies [DLB], 24; frontotemporal dementia [FTD], 13; progressive supranuclear palsy [PSP], 21; and corticobasal syndrome [CBS], 13). Amyloid PET using Pittsburgh compound B (PiB) was performed in 6 patients with NIID. RESULTS: The mean age of patients with NIID, AD, DLB, FTD, PSP, and CBS was 71.3, 74.6, 76.8, 70.2, 75.5, and 71.9 years, respectively. CSF p-tau181 was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared with DLB, PSP, and CBS and was comparable between NIID and AD. CSF p-tau181 was above the cutoff value (50.0 pg/mL) in 11 of 12 patients with NIID (91.7%). Within these patients, only 2 patients showed decreased CSF Aß42, and these patients showed negative or mild local accumulation in PiB PET, respectively. PiB PET scans were negative in the remaining 4 patients tested. The proportion of patients with increased CSF p-tau181 and normal Aß42 (A-T+) was significantly higher in NIID (75%) compared with DLB, PSP, and CBS (4.2%, 4.8%, and 7.7%, respectively). CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared with disease controls. DISCUSSION: CSF p-tau181 was increased in patients with NIID without amyloid accumulation. Although the deposition of p-tau has not been reported in NIID brains, the molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.

Brain PET Imaging of 11C-Methionine, 18F-FDG, and 18F-THK5351 in a Case of Lymphomatoid Granulomatosis.

ABSTRACT: A 52-year-old woman complained of upper respiratory symptoms and subsequently developed Wallenberg syndrome. Chest CT and brain MRI revealed multiple nodular lesions in the lungs and brain. She was pathologically diagnosed with low-grade lymphomatoid granulomatosis by lung biopsy. Brain PET examinations using 11C-methionine, 18F-FDG, and 18F-THK5351 were performed. Uptake of 11C-methionine and 18F-FDG was slightly increased in some lesions, likely reflecting the degree of inflammatory cell infiltration. 18F-THK5351 uptake was significantly increased in all lesions, likely reflecting the degree of reactive astrogliosis. This case illustrates the utility of PET studies for diagnosing lymphomatoid granulomatosis and provides insight into its pathophysiology.

Association between white matter alterations on diffusion tensor imaging and incidence of frailty in older adults with cardiometabolic diseases.

Diffusion tensor imaging (DTI) can be used for the early detection of abnormal changes in the integrity of cerebral white matter tracts, and we have previously reported that these changes are associated with indices of early atherosclerotic lesions. Although these changes have been demonstrated to be associated with the incidence of frailty in older adults, no studies have investigated this relationship in patients at high risk for vascular disease. In this longitudinal study, we followed outpatients with cardiometabolic diseases for a maximum of 6 years (median, 3 years) and evaluated the association of baseline DTI data of seven white matter tracts with the incidence of frailty. The modified version of the Cardiovascular Health Study criteria and the Kihon Checklist were used as indices of frailty; fractional anisotropy (FA) and mean diffusivity (MD) were used as indices of white matter changes. Patients who developed frailty based on both indices had low FA and high MD in many of the tracts tested, with the most significant difference found in the MD of the anterior thalamic radiation (ATR). Cox proportional hazard model analysis revealed a significantly high risk of frailty defined by both indices in the groups with high MD values in the left ATR. Similar results were found in patients with diabetes mellitus but not in those without diabetes mellitus. Therefore, abnormalities in the integrity of the left ATR could be associated with the progression of frailty in older adults with cardiometabolic disease, particularly those with diabetes mellitus.

[A geriatric case of hyperosmolar hyperglycemic state with osmotic demyelination syndrome that manifested with dysphagia].

The patient was an 84-year-old man who had been on insulin therapy for type 2 diabetes mellitus for 55 years. He had undergone bile duct stenting to avoid obstruction due to adenocarcinoma of the bile duct. The patient had suffered from fever and anorexia for two weeks, and had subsequently stopped insulin therapy. Since he showed signs of impaired consciousness, he was taken to the emergency room, and was diagnosed with a hyperosmotic hyperglycemic state (HHS) based on the following laboratory findings: blood glucose, 632 mg/dL; plasma osmolality, 391 mOsm/kg·H2O; and serum Na, 163 mEq/L, with urine ketone bodies±and sepsis (Klebsiella pneumoniae). He was therefore admitted to the hospital. His blood glucose and serum Na levels slowly improved following the administration of fluids, insulin, and antibiotics. The patient's consciousness disturbance also improved. However, on the third day after admission, dysphagia was newly observed when the patient resumed eating, and swallowing endoscopy revealed a delayed gag reflex and pharyngeal retention of saliva. Cranial magnetic resonance imaging showed a high-intensity area in the central pontine, which was considered to be caused by osmotic demyelination syndrome (ODS). The patient's oral intake ability recovered with swallowing rehabilitation. ODS is a rare complication of HHS. We report a case of HHS with ODS, in which the patient's chief complaint was dysphagia, which should be distinguished from other diseases.

Possibility of Enlargement in Left Medial Temporal Areas Against Cerebral Amyloid Deposition Observed During Preclinical Stage.

Neurodegenerative changes in the preclinical stage of Alzheimer's disease (AD) have recently been the focus of attention because they may present a range of treatment opportunities. A total of 134 elderly volunteers who lived in a local community were investigated and grouped into preclinical and mild cognitive impairment stages according to the Clinical Dementia Rating test; we also estimated amyloid deposition in the brain using positron emission tomography (PET). A significant interaction between clinical stage and amyloid PET positivity on cerebral atrophy was observed in the bilateral parietal lobe, parahippocampal gyri, hippocampus, fusiform gyrus, and right superior and middle temporal gyri, as previously reported. Early AD-specific voxel of interest (VOI) analysis was also applied and averaged Z-scores in the right, left, bilateral, and right minus left medial temporal early AD specific area were computed. We defined these averaged Z-scores in the right, left, bilateral, and right minus left early AD specific VOI in medial temporal area as R-MedT-Atrophy-score, L-MedT-Atrophy-score, Bil-MedT-Atrophy-score, and R_L-MedT-Atrophy-score, respectively. It revealed that the R_L-MedT-Atrophy-scores were significantly larger in the amyloid-positive than in the amyloid-negative cognitively normal (CN) elderly group, that is, the right medial temporal areas were smaller than left in amyloid positive CN group and these left-right differences were significantly larger in amyloid positive than amyloid negative CN elderly group. The L-MedT-Atrophy-score was slightly larger (p = 0.073), that is, the left medial temporal area was smaller in the amyloid-negative CN group than in the amyloid-positive CN group. Conclusively, the left medial temporal area could be larger in CN participants with amyloid deposition than in those without amyloid deposition. The area under the receiver operating characteristic curve for differentiating amyloid positivity among CN participants using the R_L-MedT-Atrophy-scores was 0.73; the sensitivity and specificity were 0.828 and 0.606, respectively. Although not significant, a negative correlation was observed between the composite cerebral standardized uptake value ratio in amyloid PET images and L-MedT-Atrophy-score in CN group. The left medial temporal volume might become enlarged because of compensatory effects against AD pathology occurring at the beginning of the amyloid deposition.

Subclinical Atherosclerosis, Vascular Risk Factors, and White Matter Alterations in Diffusion Tensor Imaging Findings of Older Adults With Cardiometabolic Diseases.

White matter abnormalities may reflect cerebral microvessel disease. Diffusion tensor imaging (DTI) can help detect early changes in white matter integrity in each tract. However, studies investigating the relationship between subclinical atherosclerosis markers and white matter alterations in DTI findings are limited. This study aimed to examine associations between cardiovascular risk factors and indices of subclinical atherosclerosis-ankle brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), and carotid artery intima-media thickness (IMT)-and altered white matter integrity in older patients. A total of 224 patients (aged ≥65 years) with cardiometabolic disease who underwent magnetic resonance imaging (MRI) and either plethysmography or cervical ultrasound at the start of the 3-year observational study period were included in this study. We measured fractional anisotropy (FA) and mean diffusivity (MD), which are indices of white matter integrity in seven white matter tracts. In a univariate analysis, lower ABI and higher baPWV values were associated with FA or MD abnormalities in several tracts, whereas IMT was scarcely associated with such change. In addition, high blood pressure and glycoalbumin/glycohemoglobin ratio (GA/HbA1c) and low body mass index (BMI) and triglyceride (TG) levels were associated with FA or MD abnormalities. In a multivariate analysis adjusted for age, sex, BMI, diastolic blood pressure, TG, and GA/HbA1c, the associations between ABI and FA or MD remained in all of either side of the following tracts: anterior thalamic radiation, forceps minor, inferior frontooccipital fasciculus (p < 0.001 for all) and superior longitudinal fasciculus (SLF; p < 0.05), whereas most of those between baPWV and FA or MD disappeared except for SLF (p < 0.05). These results indicate that low ABI could be an indicator of white matter abnormalities.

18F-THK5351 PET Can Identify Core Lesions in Different Amyotrophic Lateral Sclerosis Phenotypes.

ABSTRACT: Two patients with different amyotrophic lateral sclerosis (ALS) phenotypes underwent 18F-THK5351 PET to visualize lesions undergoing astrogliosis by measuring monoamine oxidase B activity. Patient 1 was a 57-year-old man with flail leg syndrome. Elevated uptake was observed inside the motor cortex, corresponding to the leg area in a cortical homunculus. Patient 2 was a 64-year-old man with ALS-frontotemporal dementia semantic variant. Elevated uptake was observed around the left anterior temporal lobe. Both core lesions were consistent with their respective neurological features. Hence, 18F-THK5351 PET is a useful technique to assess ALS pathophysiology by visualizing the core lesions.

Diffusion-Weighted Imaging is Key to Diagnosing Specific Diseases.

This article reviews diseases for which persistent signal abnormalities on diffusion-weighted imaging are the key to their diagnosis. Specifically, updated knowledge regarding the neuroimaging patterns of the following diseases is summarized: sporadic Creutzfeldt-Jakob disease, neuronal intranuclear inclusion disease, and hereditary diffuse leukoencephalopathy with axonal spheroids-colony-stimulating factor receptors/adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. In addition, their differential diagnoses; clinical manifestations; and pathologic, genetic, and imaging correlates are discussed.

Differences in the association between white matter hyperintensities and gait performance among older adults with and without cognitive impairment.

AIM: Gait impairment implies subtle cognitive impairment (CI) and is associated with severity of white matter hyperintensities (WMHs). However, cognitive differences in such an association are not yet fully understood. This study examined the association between WMHs and gait performance among three cognitively different older groups. METHODS: Gait performance and WMHs were assessed in 150 community-dwelling older adults, comprising 53 with CI (Mini-Mental State Examination [MMSE] score <24), 63 with mild CI (MMSE score ≥24 and Montreal Cognitive Assessment [MoCA] score <25), and 34 who were cognitively normal or preserved (MMSE ≥24 and MoCA score ≥25). Gait velocity and variability were assessed on a 5-m electronic walkway. Furthermore, WMH volume was derived by automated segmentation using 1.5 T magnetic resonance imaging. RESULTS: Adjusted multiple regression analyses showed that greater WMHs were associated with slower gait velocity and greater temporal (stride time) and spatial (stride and step lengths) variabilities among older adults with CI. In contrast, WMH was only associated with spatial variability in older adults with mild CI and in cognitively normal or preserved older adults. CONCLUSIONS: Our findings suggest that gait variability measures are more sensitive to subtle underlying neurological pathologies including WMHs in older adults. The cognitive-dependent differences found in the association between WMHs and gait performance suggests that the level of cognitive function interferes with the association between WMH and gait performance. Geriatr Gerontol Int 2021; ••: ••-••.

Associations between sarcopenia and white matter alterations in older adults with diabetes mellitus: A diffusion tensor imaging study.

AIMS/INTRODUCTION: Older adults with diabetes mellitus are susceptible to sarcopenia. Diffusion tensor imaging studies have also shown that patients with diabetes have altered white matter integrity. However, the relationship between these structural changes in white matter and sarcopenia remains poorly understood. MATERIALS AND METHODS: The study included 284 older patients (aged ≥65 years) who visited the Tokyo Metropolitan Geriatric Hospital Frailty Clinic. We used diffusion tensor imaging to measure fractional anisotropy (FA) and mean diffusivity (MD) to evaluate changes in white matter integrity. We investigated the associations between sarcopenia, or its diagnostic components, and FA or MD in seven white matter tracts considered to be associated with sarcopenia according to the patients' diabetes status. RESULTS: We found significantly low FA or high MD values in the bilateral anterior thalamic radiations (ATR) and right inferior fronto-occipital fasciculus (IFOF) of patients with Asian Working Group for Sarcopenia 2019-defined sarcopenia, in all patients and those with diabetes. Using binominal regression analyses, we associated low FA values in the left ATR and right IFOF with sarcopenia in all patients and those with diabetes, after adjusting for age, gender, HbA1c, blood pressure, cognitive function, physical activity, depression, nutritional status, and inflammation. CONCLUSIONS: White matter alterations in left ATR and right IFOF are associated with the prevalence of sarcopenia in patients with diabetes. Specific changes to the left ATR and right IFOF tracts could play critical roles in the occurrence of sarcopenia in patients with diabetes.

Voxel-based morphometry focusing on medial temporal lobe structures has a limited capability to detect amyloid ß, an Alzheimer's disease pathology.

Voxel-based morphometry (VBM) analysis of nuclear Magnetic Resonance Imaging (MRI) data allows the identification of medial temporal lobe (MTL) atrophy and is widely used to assist the diagnosis of Alzheimer's disease (AD). However, its reliability in the clinical environment has not yet been confirmed. To determine the credibility of VBM, amyloid positron emission tomography (PET) and VBM studies were compared retrospectively. Patients who underwent Pittsburgh Compound B (PiB) PET were retrospectively recruited. Ninety-seven patients were found to be amyloid negative and 116 were amyloid positive. MTL atrophy in the PiB positive group, as quantified by thin sliced 3D MRI and VBM software, was significantly more severe (p =0.0039) than in the PiB negative group. However, data histogram showed a vast overlap between the two groups. The area under the ROC curve (AUC) was 0.646. MMSE scores of patients in the amyloid negative and positive groups were also significantly different (p = 0.0028), and the AUC was 0.672. Thus, MTL atrophy could not reliably differentiate between amyloid positive and negative patients in a clinical setting, possibly due to the wide array of dementia-type diseases that exist other than AD.

Multifaceted structural magnetic resonance imaging findings in demented patients with pathologically confirmed TDP-43 proteinopathy.

This short report clarifies the heterogeneity of structural magnetic resonance imaging (MRI) findings in seven demented patients due to pathologically accumulated TAR DNA-binding protein-43 (TDP-43) protein using visual analyses including visual rating scales (i.e., global cortical atrophy and medial temporal atrophy scales). In addition to the well-known frontotemporal lobar atrophy, structural MRI has revealed multifaceted imaging findings including asymmetric atrophy of the frontoparietal lobe and cerebral peduncle, midbrain atrophy, and localized or diffuse white matter T2 hyperintensity. Understanding of these multifaceted neuroimaging findings is important for the precise antemortem diagnosis of TDP-43 proteinopathy.

Identifying patients with neuronal intranuclear inclusion disease in Singapore using characteristic diffusion-weighted MR images.

PURPOSE: Adult-onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder described mainly in the Japanese population, with characteristic DWI abnormalities at the junction between gray and white matter. We identify possible cases of NIID in the picture archive and communication system (PACS) of a tertiary neurological referral hospital in Singapore and describe their radiological features. METHODS: The neuroradiology imaging database was reviewed using keyword search of radiological reports to identify patients who had "subcortical U fibre" abnormalities on DWI. MRI were retrospectively reviewed, and those fulfilling inclusion criteria were invited for skin biopsy to detect nuclear inclusions by light and electron microscopy. RESULTS: Twelve Chinese patients (nine female; median age 70.5 years) were enrolled. Seven patients were being assessed for dementia and five for other neurological indications. In all patients, DWI showed distinctive subcortical high signal with increased average apparent diffusion coefficient (ADC), involving frontal, parietal, and temporal more than occipital lobes; the corpus callosum and external capsule were affected in some patients. On T2-weighted images, cerebral and cerebellar atrophy and white matter hyperintensity of Fazekas grade 2 and above were seen in all patients. Three patients underwent skin biopsy; all were positive for intranuclear hyaline inclusion bodies on either p62 staining or electron microscopy, which are pathognomonic for NIID. CONCLUSION: Previously undiagnosed patients with NIID can be identified by searching for abnormalities at the junction between gray and white matter on DWI in PACS and subsequently confirmed by skin biopsy. Radiologists should recognize the distinctive neuroimaging pattern of this dementing disease.