Prediction of Co-Occurrence of Lewy Body Disease with Alzheimer's Disease.

Identifying the coexistence of Lewy body (LB) pathology with Alzheimer's disease (AD) in clinical practice is important in the era of anti-amyloid-ß antibody therapy. However, few studies have predicted the presence of comorbid LB pathology with AD using indicative biomarkers of dementia with Lewy bodies or by collecting detailed clinical symptoms. We report the clinical progression of a 67-year-old patient diagnosed with AD who developed rapid eye movement sleep disorder-like symptoms and transient visual hallucinations 10 years after AD onset and was considered to have comorbid LB pathology based on imaging indicative biomarkers of dementia with Lewy bodies.

Micrographia after midbrain infarction alleviated by Japanese calligraphy-style writing: A case report.

•A 77-year-old right-handed man experienced an infarct in the right midbrain.•Ipsilesional progressive micrographia occurred after the midbrain infarct.•Micrographia improved when the patient wrote as if practicing Japanese calligraphy.•Further studies should confirm the utility of Japanese calligraphy in such cases.

Application of Suggestive Biomarkers in Dementia With Lewy Bodies With Masking of Typical Clinical Symptoms by Alzheimer Disease-type Pathology.

Dementia with Lewy bodies (DLB) is strongly associated with Alzheimer disease (AD)-type pathology and tends to mask the core clinical features of DLB. Therefore, there may be cases of undiagnosed DLB without suggestive biomarkers of DLB. We describe the case of a 63-year-old woman who was initially diagnosed as having AD and later diagnosed with DLB based on suggestive biomarkers of DLB. In this case, transient sleep talking with physical movements for several days led to the assessment of suggestive biomarkers for DLB in the absence of the core clinical features of DLB. For clinicians, diagnosing DLB in patients with AD-type pathology is challenging. However, the application of biomarkers suggestive of DLB to all patients with dementia is not realistic. To overcome the difficulties of clinical diagnosis of DLB, further research is needed regarding strategies for the application of suggestive biomarkers for DLB to appropriately diagnose DLB.

Simple and Objective Evaluation Items for the Prognosis and Mortality of Delirium in Real-World Clinical Practice: A Preliminary Retrospective Study.

Objective: Identifying factors associated with poor outcomes in patients with delirium is important for predicting prognosis. This retrospective study developed an easy and objective cognitive function measurement scale that can predict the prognosis and mortality related to delirium. Methods: Fifty-five patients aged ≥65 years and diagnosed with delirium were included. Objective data regarding attention and orientation related to time and place were extracted from their medical records during the first consultation, and in total, six points were evaluated. The patients were categorized into high and low cognitive function (LCF) groups. The severity at the first visit and 1-week post-treatment was evaluated using the Clinical Global Impressions-Severity scale. Outcomes (survival or death) at 6 months from the initial visit were evaluated by reviewing medical records. Results: Although the Clinical Global Impressions-Severity score at the first visit was not significantly different between the two groups, 1 week after treatment, it was significantly lower in the high cognitive function (HCF) group than in the LCF group. Regarding the outcome (survival or death) after 6 months, the LCF group had significantly higher mortality than the HCF group. A multivariate logistic regression analysis revealed the same result (OR = 17.049, 95% CI = 2.415-120.373, p = 0.004). Conclusion: A simple cognitive assessment of attention and orientation may help predict unfavorable outcomes, including mortality, in patients with delirium.

Effect of cerebrospinal fluid area mask correction on 123I-FP-CIT SPECT images in idiopathic normal pressure hydrocephalus.

BACKGROUND: Cerebrospinal fluid (CSF) area mask correction reduces the influence of low [123I]-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) accumulation in the volume of interest (VOI) by CSF area dilatation on the specific binding ratio (SBR) calculated using the Southampton method. We assessed the effect of CSF area mask correction on the SBR for idiopathic normal pressure hydrocephalus (iNPH) characterized by CSF area dilatation. METHODS: We enrolled 25 patients with iNPH who were assessed using 123I-FP-CIT single-photon emission computed tomography (SPECT) before shunt surgery or the tap test. The SBRs with and without CSF area mask correction were calculated, and changes in quantitative values were verified. Additionally, the number of voxels in the striatal and background (BG) VOI before and after CSF area mask correction were extracted. The number of voxels after correction was subtracted from that before correction, and the volume removed by the CSF area mask correction was calculated. The volumes removed from each VOI were compared to verify their effect on SBR. RESULTS: The images of 20 and 5 patients with SBRs that were decreased and increased, respectively, by CSF area mask correction showed that the volumes removed from the BG region VOI were higher and lower, respectively than those in the striatal region. CONCLUSIONS: The SBR before and after CSF area mask correction was associated with the ratio of the volume removed from the striatal and BG VOIs, and the SBR was high or low according to the ratio. The results suggest that CSF area mask correction is effective in patients with iNPH. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000044826. 11/07/2021.

In vivo [18F]THK-5351 imaging detected reactive astrogliosis in argyrophilic grain disease with comorbid pathology: A clinicopathological study.

Quantification of in vivo reactive astrogliosis, which represents neural inflammation and remodeling in the brain, is an emerging methodology for the evaluation of patients with neurodegenerative diseases. [18F]THK-5351 is a positron emission tomography (PET) tracer for monoamine oxidase B (MAO-B), a molecular marker of reactive astrogliosis. We performed in vivo [18F]THK-5351 PET in a patient who at autopsy was found to have argyrophilic grain disease (AGD) with comorbid pathology to visualize reactive astrogliosis for the first time. We aimed to validate an imaging-pathology correlation using [18F]THK-5351 PET and the autopsy brain. The patient, a 78-year-old man, was pathologically diagnosed with AGD combined with limbic-predominant age-related transactive response DNA-binding protein of 43 kDa encephalopathy and Lewy body disease without Alzheimer disease-related neuropathological changes. Reactive astrogliosis in the postmortem brain was abundant in the inferior temporal gyrus, insular gyrus, entorhinal cortex, and ambient gyrus where premortem [18F]THK-5351 signals were high. We found a proportional correlation between the amount of reactive astrogliosis in the postmortem brain and the in vivo [18F]THK-5351 standardized uptake value ratio (r = 0.8535, p = 0.0004). These results indicated that reactive astrogliosis in AGD with comorbid pathology could be identified and quantified by in vivo MAO-B imaging.

Clinicopathological diversity of semantic dementia: Comparisons of patients with early-onset versus late-onset, left-sided versus right-sided temporal atrophy, and TDP-type A versus type C pathology.

Semantic dementia (SD) is a unique clinicopathological entity associated with TDP-type C pathology. We present four cases of SD that illustrate the clinicopathological diversity of TDP-43 pathology, including early-onset cases of TDP-type C with corticospinal tract (CST) and motor neuron pathology and late-onset cases of TDP-type A with combined pathology. Case 1 was a 62-year-old man with semantic variant of primary progressive aphasia (svPPA) with left-predominant temporal atrophy and TDP-type C pathology with low Alzheimer's disease neuropathologic changes (ADNC). Case 2 was a 63-year-old woman with right-predominant temporal atrophy and TDP-type C pathology who had prosopagnosia and personality changes. Phosphorylated(p)-TDP-43-positive long dystrophic neurites (DNs) were observed throughout the cerebral cortex; they were more abundant in the relatively spared cortices and less so in the severely degenerated cortices. We observed CST degeneration with TDP-43 pathology in the upper and lower motor neurons, without apparent motor symptoms, in SD with TDP-type C pathology. Case 3 was a 76-year-old man who had svPPA and personality changes, with left-predominant temporal atrophy and TDP-type A pathology with high ADNC and argyrophilic grain (AG) stage 3. Case 4 was an 82-year-old man who had prosopagnosia and later developed symptoms of dementia with Lewy bodies (DLB) with right-predominant temporal atrophy and TDP-type A pathology with high ADNC, DLB of diffuse neocortical type, and AG stage 3. The distribution of p-TDP-43-positive NCIs and short DNs was localized in the anterior and inferior temporal cortices. An inverse relationship between the extent of TDP pathology and neuronal loss was also observed in SD with TDP-type A pathology. In contrast, the extent of AD, DLB, and AG pathology was greater in severely degenerated regions. CST degeneration was either absent or very mild in SD with TDP-type A. Understanding the clinicopathological diversity of SD will help improve its diagnosis and treatment.

Valosin-containing protein Asp395Gly mutation in a patient with frontotemporal dementia: a case report.

BACKGROUND: Variants in the valosin-containing protein (VCP) gene were identified as one of the causes for inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (FTD). Previously identified pathogenic variants in VCP are associated with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) pathologically, but p.Asp395Gly VCP was recently reported to cause familial FTD with tauopathy characterized by neurofibrillary tau tangles (NFT) and not FTLD-TDP. We describe the clinical and genetic findings of a patient with p.Asp395Gly valosin-containing protein (VCP), who was diagnosed with FTD without a family history and in the absence of muscle or bone disease comorbidity. CASE PRESENTATION: The patient was a 62-year-old man, who developed atypical depression at the age of 37 years. Subsequently, he presented with self-centered behavior at the age of 45 years. The self-centered behavior intensified from around the age of 50 years, which was accompanied by the development of executive dysfunction; therefore, he visited our hospital at 52 years of age. Magnetic resonance imaging revealed bilateral frontal lobe atrophy. Brain perfusion single-photon emission computed tomography revealed bilateral frontal lobe hypoperfusion. The patient fulfilled the diagnostic criteria for behavioral variant of FTD. Ten years after the diagnosis, computed tomography of the trunk and limbs, muscle biopsy, and bone scintigraphy revealed the absence of concomitant muscle and bone disease. The concentrations of cerebrospinal fluid (CSF) total tau and phosphorylated tau proteins were 389 pg/mL and 53.2 pg/mL (cut-off: 50 pg/mL), respectively. Genetic analyses were performed using the whole-exome and Sanger sequencing methods. We identified p.Asp395Gly VCP in this patient with pure FTD. CONCLUSIONS: p.Asp395Gly VCP was identified in a patient with likely sporadic FTD without concomitant muscle and bone disease. The CSF analysis suggested that our patient may have FTD due to NFT accumulation similar to the familial FTD patients with p.Asp395Gly VCP recently reported. Our findings suggest that a genetic search for the pathogenic variants of VCP should be considered not only for familial FTD, but also for patients with sporadic FTD, even in the absence of comorbid muscle or bone disease.

Comparing Medial Temporal Atrophy Between Early-Onset Semantic Dementia and Early-Onset Alzheimer's Disease Using Voxel-Based Morphometry: A Multicenter MRI Study.

BACKGROUND: Early-onset Semantic dementia (EOSD) and early-onset Alzheimer's disease (EOAD) are often difficult to clinically differentiate in the early stages of the diseases because of the overlaps of clinical symptoms such as language symptoms. We compared the degree of atrophy in medial temporal structures between the two types of dementia using the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD). METHODS: The participants included 29 (age: 61.7±4.5 years) and 39 (age: 60.2±4.9 years) patients with EOSD and EOAD, respectively. The degree of atrophy in medial temporal structures was quantified using the VSRAD for magnetic resonance imaging data. Receiver operating characteristic (ROC) analysis was performed to distinguish patients with EOSD and EOAD using the mean Z score (Z-score) in bilateral medial temporal structures and the absolute value (laterality score) of the laterality of Z-score (| right-left |) for indicating the degree of asymmetrical atrophy in medial temporal structures. RESULTS: The EOSD group had significantly higher Z and laterality scores than the EOAD group (Zscores: mean ± standard deviation: 3.74±1.05 vs. 1.56±0.81, respectively; P<0.001; laterality score: mean ± standard deviation: 2.35±1.23 vs. 0.68±0.51, respectively; P<0.001). In ROC analysis, the sensitivity and specificity to differentiate EOSD from EOAD by a Z-score of 2.29 were 97% and 85%, respectively and by the laterality score of 1.05 were 93% and 85%, respectively. CONCLUSION: EOSD leads to more severe and asymmetrical atrophy in medial temporal structures than EOAD. The VSRAD may be useful to distinguish between these dementias that have several clinically similar symptoms.

Dopamine Transporter Imaging for Frontotemporal Lobar Degeneration With Motor Neuron Disease.

Introduction: Frontotemporal lobar degeneration (FTLD) is a clinical syndrome with pathological heterogeneity, including Pick's disease and trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). A previous study reported abnormal findings on dopamine transporter (DAT) imaging in 30% of patients with frontotemporal dementia (FTD) in FTLD. However, the previous study did not consider the pathological heterogeneity of FTD regarding the pathomechanism leading to abnormal DAT findings. Recently, abnormal DAT findings were reported in two patients with FTLD with motor neuron disease (MND), of which FTLD-TDP type B was the most common pathological presentation. This study investigated the DAT findings of patients with a final diagnosis of FTLD-MND to determine the frequency of occurrence of DAT abnormalities in FTLD-MND. Methods: Twenty patients with FTLD who underwent DAT single photon emission computed tomography (DAT-SPECT) were screened, and six patients with a final diagnosis of FTLD-MND were ultimately included. The patients' DAT-SPECT findings were analyzed visually and quantitatively. Neuronal loss and astrogliosis in brain regions (substantia nigra, caudate, and putamen) that could possibly affect DAT findings were evaluated in the three pathologically confirmed cases. Result: All six patients with FTLD-MND showed abnormal visual DAT-SPECT findings. In addition, in a quantitative assessment, the specific binding ratio in the striatum calculated by the Southampton method was below the lower limit of the 95% prediction interval of the healthy controls by age in all the present cases. Interestingly, three of the six patients showed abnormal findings on DAT-SPECT more than half a year before the onset of MND. Neuronal loss and astrogliosis in brain regions that may affect DAT findings were observed in three pathologically confirmed cases. Conclusion: Dopamine transporter single photon emission computed tomography revealed abnormal findings in patients with FTLD-MND, which may manifest even before the onset of MND symptoms. We believe that the possibility of future development of MND should be considered if DAT-SPECT shows abnormal findings in FTLD.