Quantitative susceptibility mapping for susceptibility source separation with adaptive relaxometric constant estimation (QSM-ARCS) from solely gradient-echo data.

To separate the contributions of paramagnetic and diamagnetic sources within a voxel, a magnetic susceptibility source separation method based solely on gradient-echo data has been developed. To measure the opposing susceptibility sources more accurately, we propose a novel single-orientation quantitative susceptibility mapping method with adaptive relaxometric constant estimation (QSM-ARCS) for susceptibility source separation. Moreover, opposing susceptibilities and their anisotropic effects were determined in healthy volunteers in the white matter. Multiple spoiled gradient echo and diffusion tensor imaging of ten healthy volunteers was obtained using a 3 T magnetic resonance scanner. After the opposing susceptibility and fractional anisotropy (FA) maps had been reconstructed, the parametric maps were spatially normalized. To evaluate the agreements of QSM-ARCS against the susceptibility source separation method using R2 and R2* maps (χ-separation) by Bland-Altman plots, the opposing susceptibility values were measured using white and deep gray matter atlases. We then evaluated the relationships between the opposing susceptibilities and FAs in the white matter and used a field-to-fiber angle to assess the fiber orientation dependencies of the opposing susceptibilities. The susceptibility maps in QSM-ARCS were successfully reconstructed without large artifacts. In the Bland-Altman analyses, the opposing QSM-ARCS susceptibility values excellently agreed with the χ-separation maps. Significant inverse and proportional correlations were observed between FA and the negative and positive susceptibilities estimated by QSM-ARCS. The fiber orientation dependencies of the negative susceptibility represented a nonmonotonic feature. Conversely, the positive susceptibility increased linearly with the fiber angle with respect to the B0 field. The QSM-ARCS could accurately estimate the opposing susceptibilities, which were identical values of χ-separation, even using gradient echo alone. The opposing susceptibilities might offer direct biomarkers for assessment of the myelin and iron content in glial cells and, through the underlying magnetic sources, provide biologic insights toward clinical transition.

A case of autoimmune encephalitis in a patient with a solitary intracranial plasmacytoma.

A 65-year-old woman presented with fever and abnormal behavior. Magnetic resonance imaging showed swelling of the left medial temporal lobe and an intracranial extra-axial occipital tumor. While her neurological symptoms improved after the administration of corticosteroid therapy under the suspicion of autoimmune encephalitis, the occipital tumor unexpectedly shrank, and the diagnosis of a solitary plasmacytoma was confirmed by biopsy. Additional examinations revealed elevated anti-glutamate receptor antibodies in the cerebrospinal fluid. The patient was diagnosed with autoimmune encephalitis concurrent with an intracranial solitary plasmacytoma. Central nervous system involvement can be considered a neurological complication in patients with a solitary plasmacytoma.

Anisotropy of the R1/T2* value dependent on white matter fiber orientation with respect to the B0 field.

The R1 (1/T1) map divided by the T2* map (R1/T2* map) draws attention as a high-resolution myelin-related map. However, both R1 and R2* (1/T2*) values demonstrate anisotropy dependent on the white matter (WM) fiber orientation with respect to the static magnetic (B0) field. Therefore, this study primarily aimed to investigate the comprehensive impact of these angular-dependent anisotropies on the R1/T2* value. This study enrolled 10 healthy human volunteers (age = 25 ± 1.3) on the 3.0 T MRI system. For R1/T2* map calculation, whole brain R1 and T2* maps were repeatedly obtained in three head tilt positions by magnetization-prepared two rapid gradient echoes and multiple spoiled gradient echo sequences, respectively. Afterward, all maps were spatially normalized and registered to the Johns Hopkins University WM atlas. R1/T2*, R1, and R2* values were binned for fiber orientation related to the B0 field, which was estimated from diffusion-weighted echo-planar imaging data with 3° intervals, to investigate angular-dependent anisotropies in vivo. A larger change in the R1/T2* value in the global WM region as a function of fiber orientation with respect to the B0 field was observed compared to the R1 and R2* values alone. The minimum R1/T2* value at the near magic-angle range was 18.86% lower than the maximum value at the perpendicular angle range. Furthermore, R1/T2* values in the corpus callosum tract and the right and left cingulum cingulate gyrus tracts changed among the three head tilt positions due to fiber orientation changes. In conclusion, the R1/T2* value demonstrates distinctive and complicated angular-dependent anisotropy indicating the trends of both R1 and R2* values and may provide supplemental information for detecting slight changes in the microstructure of myelin and axons.

Longitudinal Changes in Iron and Myelination Within Ischemic Lesions Associate With Neurological Outcomes: A Pilot Study.

BACKGROUND: Combined quantitative susceptibility mapping and R2* relaxometry can distinguish iron and myelin components in ischemic lesions. We aimed to investigate whether longitudinal changes in magnetic susceptibility and R2* values within ischemic lesions were associated with neurological outcomes. METHODS: In this single-center prospective study, we included patients, 20 to 90 years of age, who were consecutively admitted to the stroke care unit between August 2020 and March 2022 due to acute ischemic stroke. The participants underwent 2 instances of quantitative susceptibility mapping and R2* relaxometry scanning before and after stroke rehabilitation. We compared the changes in these quantitative measures across different subtypes of acute ischemic stroke. Multiple linear regression models were used to investigate the associations between the National Institutes of Health Stroke Scale scores and the mean magnetic susceptibility and R2* values in ischemic lesions. RESULTS: Among a total of 112 patients with acute ischemic stroke, 32 participants (aged 73.3±9.4 years; 20 men and 12 women) were evaluated. The median time from stroke onset to the first imaging was 5 days and that to the second imaging was 102 days. The changes in magnetic susceptibility values of branch atheromatous disease were higher than those of cardioembolism (mean difference, 0.018 [95% CI, 0.009-0.027] ppm; P<0.001) and lacunar (mean difference, 0.013 [95% CI, 0.005-0.020] ppm; P=0.004). Across all patients, the changes in National Institutes of Health Stroke Scale scores were associated with those of magnetic susceptibility values (coefficient, 0.311 [95% CI, 0.098-0.520]; P=0.017) but not with R2* values (coefficient, 0.114 [95% CI, -0.127 to 0.345]; P=0.291). CONCLUSIONS: The longitudinal changes in the magnetic susceptibility values within ischemic lesions were associated with neurological outcomes during the restorative stages poststroke in patients experiencing acute ischemic stroke. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000050719.

Voxel-based Morphometry of Alzheimer's Disease Using a Localizer Image: A Comparative Study with Magnetization Prepared Rapid Acquisition with Gradient Echo.

PURPOSE: Magnetization prepared rapid acquisition with gradient echo (MPRAGE) sequence is a gold-standard technique for voxel-based morphometry (VBM) because of high spatial resolution and excellent tissue contrast, especially between gray matter (GM) and white matter (WM). Despite its benefits, MPRAGE exhibits distinct challenge for VBM in some patients with neurological disease because of long scan time and motion artifacts. Speedily acquired localizer images may alleviate this problem. This study aimed to evaluate the feasibility of VBM using 3D Fast Low Angle Shot image captured for localizer (L3DFLASH). METHODS: Consecutive 13 patients with pathologically confirmed Alzheimer's disease (AD) (82 ± 9 years) and 21 healthy controls (HC) (79 ± 4 years) were included in this study. Whole-brain L3DFLASH and MPRAGE were captured and preprocessed using the Computational Anatomy Toolbox 12 (CAT12). Agreement with MPRAGE was evaluated for L3DFLASH using regional normalized volume for segmented brain areas. In addition to brain volume difference on VBM and Bland-Altman analysis, atrophic pattern of AD on VBM was evaluated using L3DFLASH and MPRAGE. RESULTS: Acquisition time was 18 s for L3DFLASH and 288 s for MPRAGE. There was a slight systematic difference in all regional normalized volumes from L3DFLASH and MPRAGE. For the whole cohort, GM volume measured from MPRAGE was greater than that from L3DFLASH in most of the region on VBM. When AD and HC were compared, AD-related atrophic pattern was demonstrated in both L3DFLASH and MPRAGE on VBM, although the difference was noted in significant clusters between them. CONCLUSION: Although systematic difference was noted in regional brain volume measured from L3DFLASH and MPRAGE, AD-related atrophic pattern was preserved in L3DFLASH on VBM. VBM, using speedily acquired localizer image, may provide limited but useful information for evaluating brain atrophy.

The influence of limbic-predominant age-related TDP-43 encephalopathy on argyrophilic grain disease: A voxel-based morphometry analysis of pathologically confirmed cases.

BACKGROUND: The influence of limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathological change (LATE-NC) on structural alterations in argyrophilic grain disease (AGD) have not been documented. This study aimed to investigate the morphological impact of LATE-NC on AGD through voxel-based morphometry (VBM) technique. MATERIALS AND METHODS: Fifteen individuals with pathologically verified AGD, comprising 6 with LATE-NC (comorbid AGD [cAGD]) and 9 without LATE-NC (pure AGD [pAGD]), along with 10 healthy controls (HC) were enrolled. Whole-brain 3D-T1-weighted images were captured and preprocessed utilizing the Computational Anatomy Toolbox 12. VBM was employed to compare gray matter volume among (i) pAGD and HC, (ii) cAGD and HC, and (iii) pAGD and cAGD. RESULTS: In comparison to HC, the pAGD group exhibited slightly asymmetric gray matter volume loss, particularly in the ambient gyrus, amygdala, hippocampus, anterior cingulate gyrus, and insula. Alternatively, the cAGD group exhibited greater gray matter volume loss, with a predominant focus on the inferolateral regions encompassing the ambient gyrus, amygdala, hippocampus, and the inferior temporal area, including the anterior temporal pole. The atrophy of the bilateral anterior temporal pole and right inferior temporal gyrus persisted when contrasting the pAGD and cAGD groups. CONCLUSION: Comorbidity with LATE-NC is linked to different atrophic distribution, particularly affecting the inferolateral regions in AGD. Consequently, the consideration of comorbid LATE-NC is crucial in individuals with AGD exhibiting more widespread temporal atrophy.

A case of Elschnig's spots observed using optical coherence tomography-angiography after stenting for internal carotid artery dissection.

PURPOSE: We report the case of a 28-year-old man who developed Elschnig's spots after stenting for an internal carotid artery dissection using optical coherence tomography angiography (OCTA). METHODS: A case report. RESULTS: The patient developed a visual field defect in the left eye immediately after endovascular stenting for left internal carotid artery dissection. Fundus examination revealed white lesions and numerous mottled orange-red lesions in the posterior pole and mid-periphery of the left eye. Indocyanine green angiography revealed mottled hypofluorescein areas in the early and late stages, coinciding with the orange-red lesions. OCTA showed flow void areas in the choriocapillaris layer, consistent with the orange-red lesions, which were diagnosed as Elschnig's spots associated with choroidal circulatory failure. The spots disappeared approximately 2 months after surgery, and the flow void on OCTA also disappeared. CONCLUSION: We report a case of Elschnig's spots associated with transient choroidal circulatory failure after stenting for internal carotid artery dissection. OCTA detected improved circulation at the level of the choriocapillaris with the disappearance of Elschnig's spots.

Asymmetric Cerebral Peduncle Atrophy: A Simple Diagnostic Clue for Distinguishing Frontotemporal Lobar Degeneration from Alzheimer's Disease.

BACKGROUND: Due to confusing clinicoradiological features such as amnestic symptoms and hippocampal atrophy in frontotemporal lobar degeneration (FTLD), antemortem differentiation between FTLD and Alzheimer's disease (AD) can be challenging. Although asymmetric atrophy of the cerebral peduncle is regarded as a representative imaging finding in some disorders of the FTLD spectrum, the utility of this finding has not been sufficiently evaluated for differentiating between FTLD and AD. OBJECTIVE: This study aimed to explore the diagnostic performance of asymmetric cerebral peduncle atrophy on axial magnetic resonance imaging as a simple radiological discriminator between FTLD and AD. METHODS: Seventeen patients with pathologically confirmed FTLD, including six with progressive supranuclear palsy, three with corticobasal degeneration, eight with TAR DNA-binding protein 43 (FTLD-TDP), and 11 with pathologically confirmed AD, were investigated. Quantitative indices representing the difference between the volumes of the bilateral cerebral peduncles (i.e., cerebral peduncular asymmetry index [CPAI]), the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) Z-score representing the degree of hippocampal atrophy, and semiquantitative visual analysis to evaluate the asymmetry of the cerebral peduncle (visual assessment of cerebral peduncular asymmetry: VACPA) were compared between the two groups. RESULTS: Contrary to the VSRAD Z-score, the CPAI and VACPA scores demonstrated higher diagnostic performance in differentiating patients with FTLD from those with AD (areas under the receiver operating characteristic curve of 0.88, 082, and 0.60, respectively). CONCLUSIONS: Quantitative and visual analytical techniques can differentiate between FTLD and AD. These simple methods may be useful in daily clinical practice.

Assessing white matter microstructural changes in idiopathic normal pressure hydrocephalus using voxel-based R2* relaxometry analysis.

Background: R2* relaxometry and quantitative susceptibility mapping can be combined to distinguish between microstructural changes and iron deposition in white matter. Here, we aimed to explore microstructural changes in the white matter associated with clinical presentations such as cognitive impairment in patients with idiopathic normal-pressure hydrocephalus (iNPH) using R2* relaxometry analysis in combination with quantitative susceptibility mapping. Methods: We evaluated 16 patients clinically diagnosed with possible or probable iNPH and 18 matched healthy controls (HC) who were chosen based on similarity in age and sex. R2* and quantitative susceptibility mapping were compared using voxel-wise and atlas-based one-way analysis of covariance (ANCOVA). Finally, partial correlation analyses were performed to assess the relationship between R2* and clinical presentations. Results: R2* was lower in some white matter regions, including the bilateral superior longitudinal fascicle and sagittal stratum, in the iNPH group compared to the HC group. The voxel-based quantitative susceptibility mapping results did not differ between the groups. The atlas-based group comparisons yielded negative mean susceptibility values in almost all brain regions, indicating no clear paramagnetic iron deposition in the white matter of any subject. R2* and cognitive performance scores between the left superior longitudinal fasciculus (SLF) and right sagittal stratum (SS) were positively correlated. In addition to that, R2* and gait disturbance scores between left SS were negatively correlated. Conclusion: Our analysis highlights the microstructural changes without iron deposition in the SLF and SS, and their association with cognitive impairment and gait disturbance in patients with iNPH.

Microstructural Neurodegeneration of the Entorhinal-Hippocampus Pathway along the Alzheimer's Disease Continuum.

BACKGROUND: Conventional neuroimaging biomarkers for the neurodegeneration of Alzheimer's disease (AD) are not sensitive enough to detect neurodegenerative alterations during the preclinical stage of AD individuals. OBJECTIVE: We examined whether neurodegeneration of the entorhinal-hippocampal pathway could be detected along the AD continuum using ultra-high-field diffusion tensor imaging and tractography for ex vivo brain tissues. METHODS: Postmortem brain specimens from a cognitively unimpaired individual without AD pathological changes (non-AD), a cognitively unimpaired individual with AD pathological changes (preclinical AD), and a demented individual with AD pathological changes (AD dementia) were scanned with an 11.7T diffusion magnetic resonance imaging. Fractional anisotropy (FA) values of the entorhinal layer II and number of perforant path fibers counted by tractography were compared among the AD continuum. Following the imaging analyses, the status of myelinated fibers and neuronal cells were verified by subsequent serial histological examinations. RESULTS: At 250µm (zipped to 125µm) isotropic resolution, the entorhinal layer II islands and the perforant path fibers could be identified in non-AD and preclinical AD, but not in AD dementia, followed by histological verification. The FA value of the entorhinal layer II was the highest among the entorhinal laminae in non-AD and preclinical AD, whereas the FA values in the entorhinal laminae were homogeneously low in AD dementia. The FA values and number of perforant path fibers decreased along the AD continuum (non-AD>preclinical AD > AD dementia). CONCLUSION: We successfully detected neurodegenerative alterations of the entorhinal-hippocampal pathway at the preclinical stage of the AD continuum.

Relationship between brain iron dynamics and blood-brain barrier function during childhood: a quantitative magnetic resonance imaging study.

BACKGROUND: Mounting evidence suggests that the blood-brain barrier (BBB) plays an important role in the regulation of brain iron homeostasis in normal brain development, but these imaging profiles remain to be elucidated. We aimed to establish a relationship between brain iron dynamics and BBB function during childhood using a combined quantitative magnetic resonance imaging (MRI) to depict both physiological systems along developmental trajectories. METHODS: In this single-center prospective study, consecutive outpatients, 2-180 months of age, who underwent brain MRI (3.0-T scanner; Ingenia; Philips) between January 2020 and January 2021, were included. Children with histories of preterm birth or birth defects, abnormalities on MRI, and diagnoses that included neurological diseases during follow-up examinations through December 2022 were excluded. In addition to clinical MRI, quantitative susceptibility mapping (QSM; iron deposition measure) and diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL; BBB function measure) were acquired. Atlas-based analyses for QSM and DP-pCASL were performed to investigate developmental trajectories of regional brain iron deposition and BBB function and their relationships. RESULTS: A total of 78 children (mean age, 73.8 months ± 61.5 [SD]; 43 boys) were evaluated. Rapid magnetic susceptibility progression in the brain (Δsusceptibility value) was observed during the first two years (globus pallidus, 1.26 ± 0.18 [× 10- 3 ppm/month]; substantia nigra, 0.68 ± 0.16; thalamus, 0.15 ± 0.04). The scattergram between the Δsusceptibility value and the water exchange rate across the BBB (kw) divided by the cerebral blood flow was well fitted to the sigmoidal curve model, whose inflection point differed among each deep gray-matter nucleus (globus pallidus, 2.96-3.03 [mL/100 g]-1; substantia nigra, 3.12-3.15; thalamus, 3.64-3.67) in accordance with the regional heterogeneity of brain iron accumulation. CONCLUSIONS: The combined quantitative MRI study of QSM and DP-pCASL for pediatric brains demonstrated the relationship between brain iron dynamics and BBB function during childhood. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier: UMIN000039047, registered January 6, 2020.

Direct Enhancement Effect of Hippocampal Cholinergic Neurostimulating Peptide on Cholinergic Activity in the Hippocampus.

The cholinergic efferent network from the medial septal nucleus to the hippocampus is crucial for learning and memory. This study aimed to clarify whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholinergic dysfunction of HCNP precursor protein (HCNP-pp) conditional knockout (cKO). Chemically synthesized HCNP or a vehicle were continuously administered into the cerebral ventricle of HCNP-pp cKO mice and littermate floxed (control) mice for two weeks via osmotic pumps. We immunohistochemically measured the cholinergic axon volume in the stratum oriens and functionally evaluated the local field potential in the CA1. Furthermore, choline acetyltransferase (ChAT) and nerve growth factor (NGF) receptor (TrkA and p75NTR) abundances were quantified in wild-type (WT) mice administered HCNP or the vehicle. As a result, HCNP administration morphologically increased the cholinergic axonal volume and electrophysiological theta power in HCNP-pp cKO and control mice. Following the administration of HCNP to WT mice, TrkA and p75NTR levels also decreased significantly. These data suggest that extrinsic HCNP may compensate for the reduced cholinergic axonal volume and theta power in HCNP-pp cKO mice. HCNP may function complementarily to NGF in the cholinergic network in vivo. HCNP may represent a therapeutic candidate for neurological diseases with cholinergic dysfunction, e.g., Alzheimer's disease and Lewy body dementia.

Voxel-Based and Surface-Based Morphometry Analysis in Patients with Pathologically Confirmed Argyrophilic Grain Disease and Alzheimer's Disease.

BACKGROUND: Due to clinicoradiological similarities, including amnestic cognitive impairment and limbic atrophy, differentiation of argyrophilic grain disease (AGD) from Alzheimer's disease (AD) is often challenging. Minimally invasive biomarkers, especially magnetic resonance imaging (MRI), are valuable in routine clinical practice. Although it is necessary to explore radiological clues, morphometry analyses using new automated analytical methods, including whole-brain voxel-based morphometry (VBM) and surface-based morphometry (SBM), have not been sufficiently investigated in patients with pathologically confirmed AGD and AD. OBJECTIVE: This study aimed to determine the volumetric differences in VBM and SBM analyses between patients with pathologically confirmed AGD and AD. METHODS: Eight patients with pathologically confirmed AGD with a lower Braak neurofibrillary tangle stage (

Contributions of blood-brain barrier imaging to neurovascular unit pathophysiology of Alzheimer's disease and related dementias.

The blood-brain barrier (BBB) plays important roles in the maintenance of brain homeostasis. Its main role includes three kinds of functions: (1) to protect the central nervous system from blood-borne toxins and pathogens; (2) to regulate the exchange of substances between the brain parenchyma and capillaries; and (3) to clear metabolic waste and other neurotoxic compounds from the central nervous system into meningeal lymphatics and systemic circulation. Physiologically, the BBB belongs to the glymphatic system and the intramural periarterial drainage pathway, both of which are involved in clearing interstitial solutes such as ß-amyloid proteins. Thus, the BBB is believed to contribute to preventing the onset and progression for Alzheimer's disease. Measurements of BBB function are essential toward a better understanding of Alzheimer's pathophysiology to establish novel imaging biomarkers and open new avenues of interventions for Alzheimer's disease and related dementias. The visualization techniques for capillary, cerebrospinal, and interstitial fluid dynamics around the neurovascular unit in living human brains have been enthusiastically developed. The purpose of this review is to summarize recent BBB imaging developments using advanced magnetic resonance imaging technologies in relation to Alzheimer's disease and related dementias. First, we give an overview of the relationship between Alzheimer's pathophysiology and BBB dysfunction. Second, we provide a brief description about the principles of non-contrast agent-based and contrast agent-based BBB imaging methodologies. Third, we summarize previous studies that have reported the findings of each BBB imaging method in individuals with the Alzheimer's disease continuum. Fourth, we introduce a wide range of Alzheimer's pathophysiology in relation to BBB imaging technologies to advance our understanding of the fluid dynamics around the BBB in both clinical and preclinical settings. Finally, we discuss the challenges of BBB imaging techniques and suggest future directions toward clinically useful imaging biomarkers for Alzheimer's disease and related dementias.

Diverse limbic comorbidities cause limbic and temporal atrophy in lewy body disease.

BACKGROUND: In contrast to Alzheimer's disease (AD)-related pathology, the influence of comorbid limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) or argyrophilic grains (AG) on structural imaging in Lewy body disease (LBD) has seldom been evaluated. OBJECTIVE: This study aimed to investigate whether non-AD limbic comorbidities, including LATE-NC and AG, cause cortical atrophy in LBD. METHODS: Seventeen patients with pathologically confirmed LBD with lower Braak neurofibrillary tangle stage (

Reduction of glutamatergic activity through cholinergic dysfunction in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice.

Cholinergic activation can enhance glutamatergic activity in the hippocampus under pathologic conditions, such as Alzheimer's disease. The aim of the present study was to elucidate the relationship between glutamatergic neural functional decline and cholinergic neural dysfunction in the hippocampus. We report the importance of hippocampal cholinergic neurostimulating peptide (HCNP) in inducing acetylcholine synthesis in the medial septal nucleus. Here, we demonstrate that HCNP-precursor protein (pp) knockout (KO) mice electrophysiologically presented with glutamatergic dysfunction in the hippocampus with age. The impairment of cholinergic function via a decrease in vesicular acetylcholine transporter in the pre-synapse with reactive upregulation of the muscarinic M1 receptor may be partly involved in glutamatergic dysfunction in the hippocampus of HCNP-pp KO mice. The results, in combination with our previous reports that show the reduction of hippocampal theta power through a decrease of a region-specific choline acetyltransferase in the stratum oriens of CA1 and the decrease of acetylcholine concentration in the hippocampus, may indicate the defined cholinergic dysfunction in HCNP-pp KO mice. This may also support that HCNP-pp KO mice are appropriate genetic models for cholinergic functional impairment in septo-hippocampal interactions. Therefore, according to the cholinergic hypothesis, the model mice might are potential partial pathological animal models for Alzheimer's disease.

Quantitative susceptibility mapping as an imaging biomarker for Alzheimer's disease: The expectations and limitations.

Alzheimer's disease (AD) is the most common type of dementia and a distressing diagnosis for individuals and caregivers. Researchers and clinical trials have mainly focused on ß-amyloid plaques, which are hypothesized to be one of the most important factors for neurodegeneration in AD. Meanwhile, recent clinicopathological and radiological studies have shown closer associations of tau pathology rather than ß-amyloid pathology with the onset and progression of Alzheimer's symptoms. Toward a biological definition of biomarker-based research framework for AD, the 2018 National Institute on Aging-Alzheimer's Association working group has updated the ATN classification system for stratifying disease status in accordance with relevant pathological biomarker profiles, such as cerebral ß-amyloid deposition, hyperphosphorylated tau, and neurodegeneration. In addition, altered iron metabolism has been considered to interact with abnormal proteins related to AD pathology thorough generating oxidative stress, as some prior histochemical and histopathological studies supported this iron-mediated pathomechanism. Quantitative susceptibility mapping (QSM) has recently become more popular as a non-invasive magnetic resonance technique to quantify local tissue susceptibility with high spatial resolution, which is sensitive to the presence of iron. The association of cerebral susceptibility values with other pathological biomarkers for AD has been investigated using various QSM techniques; however, direct evidence of these associations remains elusive. In this review, we first briefly describe the principles of QSM. Second, we focus on a large variety of QSM applications, ranging from common applications, such as cerebral iron deposition, to more recent applications, such as the assessment of impaired myelination, quantification of venous oxygen saturation, and measurement of blood- brain barrier function in clinical settings for AD. Third, we mention the relationships among QSM, established biomarkers, and cognitive performance in AD. Finally, we discuss the role of QSM as an imaging biomarker as well as the expectations and limitations of clinically useful diagnostic and therapeutic implications for AD.

Absence of diffusion-weighted imaging abnormalities in a patient with neuronal intranuclear inclusion disease.

INTRODUCTION: Herein, we report a genetically confirmed case of neuronal intranuclear inclusion disease without characteristic subcortical hyperintensities on diffusion-weighted imaging. CASE PRESENTATION: A 75-year-old man was admitted to our hospital with subacute onset of conscious disturbance. Except for gastric cancer, he had no apparent past medical or family history. He presented with transient fever, vomiting, and urinary retention. On admission, no apparent abnormal intensity was detected on diffusion-weighted imaging. The symptoms improved within 10 days, without any medical treatment. Additional inspections were performed under suspicion of neuronal intranuclear inclusion disease. Intranuclear inclusions were found not only from skin biopsy but also from his stomach specimens, which had been resected 6 years previously. Subsequent genetic testing revealed repeat expansion of GGC amplification in NOTCH2NLC. CONCLUSION: Characteristic neuroimaging and skin biopsy findings are important clues for diagnosing neuronal intranuclear inclusion diseases. Nonetheless, confirming a diagnosis is difficult due to the diversity of clinical manifestations and radiological features. Clinicians should suspect neuronal intranuclear inclusion disease in patients with transient encephalitic episodes, even if no abnormalities are detected on diffusion-weighted imaging.