Machine learning of brain structural biomarkers for Alzheimer's disease (AD) diagnosis, prediction of disease progression, and amyloid beta deposition in the Japanese population.

INTRODUCTION: We developed machine learning (ML) designed to analyze structural brain magnetic resonance imaging (MRI), and trained it on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In this study, we verified its utility in the Japanese population. METHODS: A total of 535 participants were enrolled from the Japanese ADNI database, including 148 AD, 152 normal, and 235 mild cognitive impairment (MCI). Probability of AD was expressed as AD likelihood scores (ADLS). RESULTS: The accuracy of AD diagnosis was 88.0% to 91.2%. The accuracy of predicting the disease progression in non-dementia participants over a 3-year observation was 76.0% to 79.3%. More than 90% of the participants with low ADLS did not progress to AD within 3 years. In the amyloid positron emission tomography (PET)-positive MCI, the hazard ratio of progression was 2.39 with low ADLS, and 5.77 with high ADLS. When high ADLS was defined as N+ and Pittsburgh compound B (PiB) PET positivity was defined as A+, the time to disease progression for 50% of MCI participants was 23.7 months in A+N+, whereas it was 52.3 months in A+N-. CONCLUSION: These results support the feasibility of our ML for the diagnosis of AD and prediction of the disease progression.

MRI features of Binswanger's disease predict prognosis and associated pathology.

OBJECTIVE: To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI with diffuse white matter lesions and scattered multiple lacunes (BD-MRI), and to describe neurological features and pathological outcomes of a community-based cohort study. METHODS: Of 697 participants (all 75 years old), 503 completed neurological examinations at baseline and were followed-up every 30 months thereafter with MRIs, the mini-mental state examination (MMSE) and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). Data from participants with BD-MRI were compared with those from participants with predominant white matter lesions (WML-MRI), scattered multiple lacunes (ML-MRI), or normal MRIs. RESULTS: Fourteen BD-MRI patients (2.8%) were detected at baseline. The mean MMSE scores in the BD-MRI, WML-MRI, ML-MRI, and normal MRIs groups were 26.4, 28.2, 28.4, and 28.5, respectively, and the mean UPDRSM scores were 9.1, 1.3, 3.1, and 1.7, respectively. At the 30-month follow-up, mortality rates in the normal MRIs, WML-MRI and ML-MRI were 4%, 9.1%, and 22.2%, respectively, and follow-up MRIs were available for 80%, 82%, and 61% of the participants, respectively. In the BD-MRI, however, five patients were deceased, and only five follow-up individual MRIs were available (33.3%). Autopsies were performed on six of eight BD-MRI brains, and these brains fulfilled the pathological criteria for BD independent of Alzheimer disease pathology. All these six individuals also showed systemic atherosclerosis and renal arterio-arteriolosclerosis. INTERPRETATION: The BD-MRI participants had poor prognoses and showed pure BD pathology with advanced systemic vascular disease. BD-MRI appears to be a predictor of vascular neurocognitive impairment.

Disproportionate subarachnoid space hydrocephalus-outcome and perivascular space.

OBJECTIVE: We sought to identify the prevalence of MRI features of disproportionately enlarged subarachnoid space hydrocephalus in possible idiopathic normal pressure hydrocephalus (DESH-iNPH) and to describe the clinico-radiological features and outcomes of a community-based investigation (The Vienna Trans-Danube Aging study). METHODS: Of the 697 inhabitants (all 75 years old), 503 completed extensive neurological examinations at baseline and were followed up every 30 months thereafter with MRIs, mini-mental state examination (MMSE), and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). The DESH-iNPH participant data were compared with the data from participants with Evans index ratios >0.3 (ex vacuo hydrocephalus), cerebral small-vessel diseases, and normal MRIs. The widening of perivascular space was also evaluated by MRI in these groups. RESULTS: Eight participants with DESH-iNPH (1.6%) and 76 with ex vacuo hydrocephalus (16.1%) at baseline were identified. The mean MMSE in DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs was 26.4, 27.9, and 28.3, respectively, and the mean UPDRSM was 9.75, 2.96, and 1.87, respectively. After a 90-month follow-up, the mortality rates for DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs were 25.0%, 21.3%, and 10.9%, respectively. The perivascular-space widening scores were significantly smaller in the DESH-iNPH cases, particularly at the centrum semiovale, compared to cerebral small-vessel disease and ex vacuo hydrocephalus cases. INTERPRETATION: The prevalence of DESH-iNPH was 1.6% for participants aged 75 years and revealed significantly lower MMSE and higher UPDRSM scores compared to the ex vacuo hydrocephalus and controls. Moreover, it is suggested that perivascular-space narrowing is a morphological and pathophysiological marker of DESH-iNPH.

The profile of hippocampal metabolites differs between Alzheimer's disease and subcortical ischemic vascular dementia, as measured by proton magnetic resonance spectroscopy.

Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD) have overlapping pathologies and risk factors, but their underlying neurodegenerative mechanisms are basically different. We performed magnetic resonance spectroscopy (MRS) to study metabolite differences between the two diseases in vivo. The subjects were 31 patients with SIVD and 99 with AD. Additionally, 45 elderly subjects were recruited as controls. We measured N-acetylaspartate (NAA), glutamine and glutamate (Glx), and myoinositol (mIns) concentration quantitatively using a 1.5-T MR scanner. N-acetylaspartate and Glx concentrations decreased in the hippocampus and cingulate/precuneal cortices (PCC) in both AD and SIVD patients, and the NAA decrease in the hippocampus was more prominent in AD than in SIVD. Interestingly, the pattern of mIns concentration changes differed between the two disorders; mIns was increased in AD but not increased in SIVD. If one differentiates between AD and SIVD by the mIns concentration in the hippocampus, the area under the receiver operating characteristic curve was 0.95, suggesting a high potential for discrimination. Our results suggest that proton MRS can provide useful information to differentiate between AD and SIVD. The difference of mIns concentrations in the hippocampus and PCC seems to reflect the different neurodegenerative mechanisms of the two disorders.

Morphometric characterization of Binswanger's disease: comparison with Alzheimer's disease.

BACKGROUND AND PURPOSE: Dementia due to hypertensive vascular disease is a potential target to treat prophylactively before it progresses insidiously. Binswanger's disease (BD) is a type of subcortical vascular dementia, but its clinical features and pathophysiology are still obscure. We therefore tried to find a topographic distribution of brain atrophy in BD by morphometric analysis. METHODS: Twenty patients with BD, 50 patients with AD, and 80 elderly controls were recruited. We contrasted the gray matter atrophy of BD to that of AD to identify a pathognomic pattern using magnetic resonance imaging. We used DARTEL (diffeomorphic anatomical registration through exponential Lie algebra) for voxel-based morphometry, expecting that its sophisticated algorithm would work well to deal with the subjects with brain atrophy. RESULTS: Atrophy of cortices was predominant in the posterior cortices in AD but was in the anterior cortices in BD. Atrophy of amygdala and hippocampus was similar in each disease. In contrast, thalamus, caudate nucleus, insula, anterior cingulate cortex, and frontal cortices were significantly more atrophied in BD than in AD (z-score >3). CONCLUSIONS: We demonstrated topographic patterns of brain atrophy in BD. Since affected regions of BD match with the anatomical connections of frontal-subcortical circuits, it seems reasonable to suppose that BD pathology is the result of hypertensive vascular disease and subsequent regression from the white matter injuries.

Colocalization of 14-3-3 proteins with SOD1 in Lewy body-like hyaline inclusions in familial amyotrophic lateral sclerosis cases and the animal model.

BACKGROUND AND PURPOSE: Cu/Zn superoxide dismutase (SOD1) is a major component of Lewy body-like hyaline inclusion (LBHI) found in the postmortem tissue of SOD1-linked familial amyotrophic lateral sclerosis (FALS) patients. In our recent studies, 14-3-3 proteins have been found in the ubiquitinated inclusions inside the anterior horn cells of spinal cords with sporadic amyotrophic lateral sclerosis (ALS). To further investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical analysis of 14-3-3 proteins and compared their distributions with those of SOD1 in FALS patients and SOD1-overexpressing mice. METHODS: We examined the postmortem brains and the spinal cords of three FALS cases (A4V SOD1 mutant). Transgenic mice expressing the G93A mutant human SOD1 (mutant SOD1-Tg mice), transgenic mice expressing the wild-type human SOD1 (wild-type SOD1-Tg mice), and non-Tg wild-type mice were also subjected to the immunohistochemical analysis. RESULTS: In all the FALS patients, LBHIs were observed in the cytoplasm of the anterior horn cells, and these inclusions were immunopositive intensely for pan 14-3-3, 14-3-3ß, and 14-3-3γ. In the mutant SOD1-Tg mice, a high degree of immunoreactivity for misfolded SOD1 (C4F6) was observed in the cytoplasm, with an even greater degree of immunoreactivity present in the cytoplasmic aggregates of the anterior horn cells in the lumbar spinal cord. Furthermore, we have found increased 14-3-3ß and 14-3-3γ immunoreactivities in the mutant SOD1-Tg mice. Double immunofluorescent staining showed that C4F6 and 14-3-3 proteins were partially co-localized in the spinal cord with FALS and the mutant SOD1-Tg mice. In comparison, the wild-type SOD1-Tg and non-Tg wild-type mice showed no or faint immunoreactivity for C4F6 and 14-3-3 proteins (pan 14-3-3, 14-3-3ß, and 14-3-3γ) in any neuronal compartments. DISCUSSION: These results suggest that 14-3-3 proteins may be associated with the formation of SOD1-containing inclusions, in FALS patients and the mutant SOD1-Tg mice.

[A case of Guillain-Barré syndrome accompanied by syndrome of inappropriate secretion of antidiuretic hormone].

A 73-year-old Japanese male was admitted because of difficulty in standing up after acute upper respiratory inflammation with mild fever followed by watery diarrhea. Neurological examination revealed moderate proximal muscle weakness and loss of tendon reflexes in all extremities. The blood sodium level was 106 mEq/l on admission. The blood level of antidiuretic hormone (ADH), renin and aldsterone was 11.3 pg/ml (normal value 0.3-4.2), 0.2 ng/ml/h (0.2-2.7) and less than 10.0 pg/ml (38.9-307.0), respectively. The plasma osmolarity was 221 mOsm/kg (270-295), and the urine osmolarity was 416 mOsm/kg (50-1400). EMG and nerve conduction studies suggested acute demyelination in the motor and sensory nerves. CSF revealed 10 cells/mm3 and elevated protein to 98 mg/dl. The clinical course, laboratory data and electrophysiological findings suggested coexistence of the syndrome of inappropriate secretion of ADH (SIADH) and Guillain-Barré syndrome (GBS) from the very early clinical stage of the diseases. The clinical and laboratory findings improved after intravenous administration of saline over three weeks. When GBS is associated with SIADH, hyponatremia is commonly seen at the peak of motor paralysis, often accompanied by autonomic or respiratory failure requiring mechanical ventilation. This was not the case in the present patient. It is postulated that SIADH, like GBS, might be caused by an autoimmune mechanism.

Shunt-responsive parkinsonism and reversible white matter lesions in patients with idiopathic NPH.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially treatable dementia and gait disorder with abnormal CSF dynamics. OBJECTIVE: To investigate and characterize the changes in motor symptoms and CT and MRI features of iNPH before and after a shunt operation using specific evaluation criteria. METHODS: We studied 17 definitive iNPH patients, diagnosed according to the clinical guidelines of both the Japanese Society of NPH and the International NPH Consultant Group, with ventricular enlargement (Evan's index > 0.3) and narrowed CSF spaces at the high convexity on CT scan and /or MRI. The pre- and post-operative evaluation criteria for the gait and motor disturbances included the Japanese NPH Grading Scale-Revised (JNPHGSR), the Timed "Up and Go" test and the motor sections of the Unified Parkinson Disease Rating Scale. For cognitive impairments, the JNPHGSR, Mini Mental State Examination, Frontal Assessment Battery and Trail Making Test were used. White matter lesions were rated from the CT and/or MRI using a validated visual rating scale. RESULTS: All patients showed specific CT and MRI findings, consisting of diffusely-dilated Sylvian fissure, as well as narrowed CSF space at the high convexity. Fifteen patients (88%) showed white matter lesions on their CT or MRI images. These signs were ameliorated in all patients after the shunt operation. Evan's index and the mean total scores on the visual scale for white matter lesions also improved significantly. Clinically, the patients had frequent parkinsonism (71%), but relatively few had a history of either small-vessel diseases (29%), hypertension (41%) or diabetes (35%). All patients showed gait disturbances, and these symptoms, including postural instability and body bradykinesia, improved significantly after the operation. Over half also showed signs of cognitive impairment and urinary incontinence, and all such symptoms and signs improved significantly. CONCLUSION: iNPH often appears as a shunt-responsive type of parkinsonism and reversible white matter lesions among the geriatric population.

Accumulation of Hsc70 and Hsp70 in glial cytoplasmic inclusions in patients with multiple system atrophy.

Heat shock proteins (HSPs) are molecular chaperones which can be induced by several kinds of stresses, and Hsc70 and Hsp70 are two major members of the family of 70 kDa HSPs. A major component of Lewy bodies (LBs) is alpha-synuclein, and Hsp70 has been observed in the LBs of brains with Parkinson's disease. Hsp70 has also been demonstrated to have the ability to suppress alpha-synuclein toxicity in vitro and in vivo. To investigate the precise role of Hsc70 and Hsp70 in patients with multiple system atrophy (MSA), which is another alpha-synuclein-related disease, we performed immunohistochemical studies on Hsc70 and Hsp70 using autopsied brains from 7 normal subjects and 15 patients with MSA. In the normal human brains, both neurons and glial cells, including oligodendrocytes, showed only weak Hsc70 and Hsp70 immunoreactivities. In contrast, in the brains with MSA, numerous glial cytoplasmic inclusions (GCIs) were intensely immunostained with Hsc70, and strong Hsc70 immunoreactivity was also found in glial intranuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs) and neuronal intranuclear inclusions (NNIs) as well as dystrophic neurites. The immunolabeling pattern for Hsp70 in the MSA brains was slightly different from that of Hsc70, and Hsp70 immunoreactivity was observed in many reactive astrocytes as well as some glial and neuronal inclusions. Our results suggest that the widespread accumulation of Hsc70 and Hsp70 may occur in brains with MSA, and that Hsc70 and Hsp70 may be associated with the pathogenesis of MSA.

alpha-Synuclein is colocalized with 14-3-3 and synphilin-1 in A53T transgenic mice.

alpha-Synuclein is a major constituent of Lewy bodies, the neuropathological hallmark of Parkinson's disease (PD). Three types of alpha-synuclein mutations, A53T, A30P, and E46K, have been reported in familial PD. Wild-type alpha-synuclein accumulates at high concentrations in Lewy bodies, and this process is accelerated with mutated A53T alpha-synuclein. The accumulation of alpha-synuclein is thought to be toxic, and causes neuronal death when alpha-synuclein aggregates into protofibrils and fibrils. Lewy bodies contain not only alpha-synuclein, but also other proteins including 14-3-3 proteins and synphilin-1. 14-3-3 Proteins exist mainly as dimers and are related to intracellular signal transduction pathways. Synphilin-1 is known to interact with alpha-synuclein, promoting the formation of cytoplasmic inclusions like Lewy bodies in vitro. To investigate the colocalization of alpha-synuclein, synphilin-1, and 14-3-3 proteins, we performed immunohistochemical studies on alpha-synuclein, 14-3-3 proteins, and synphilin-1 in the brain and spinal cord of A53T transgenic mice. In homozygous mouse brains, alpha-synuclein immunoreactivity was observed in the neuronal somata and processes in the medial part of the brainstem, deep cerebellar nuclei, and spinal cord. The distribution of 14-3-3 proteins and synphilin-1 immunoreactivity was similar to that of alpha-synuclein in the homozygous mice. Double immunofluorescent staining showed that alpha-synuclein and synphilin-1 or 14-3-3 proteins were colocalized in the pons and spinal cord. These results indicate that the accumulation of mutant alpha-synuclein occurs in association with 14-3-3 proteins and synphilin-1, and may cause the sequestration of important proteins including 14-3-3 proteins and synphilin-1. The sequestration and subsequent decrease in 14-3-3 proteins and synphilin-1 levels may account for neuronal cell death.

Upregulated expression of 14-3-3 proteins in astrocytes from human cerebrovascular ischemic lesions.

BACKGROUND AND PURPOSE: Several types of chaperone proteins, such as heat shock proteins, have been reported to be associated with brain ischemia. The purpose of this study was to investigate whether an abnormal expression of 14-3-3 proteins, a novel type of molecular chaperones, occurs in human gray and white matter ischemic lesions. METHODS: We prepared formalin-fixed, paraffin-embedded sections from 33 autopsied brains, consisting of 7 normal controls, 4 cases with cerebral thrombosis, 5 cases with cerebral embolism, 8 cases with multiple lacunar infarctions, and 9 cases with Binswanger disease. Deparaffinized sections from all cases were immunostained with anti-14-3-3 antibodies using the avidin-biotin-peroxidase complex method, and some sections were also double-immunostained for 14-3-3 and glial markers. RESULTS: In the normal control brains, 14-3-3 immunoreactivity was mainly localized to the neuronal somata and processes. Strongly 14-3-3-immunopositive astrocytes were distributed in the infarct lesions and were particularly abundant in infarcts at the chronic stage. Intensely 14-3-3-immunolabeled astrocytes were also observed in the ischemic white matter lesions, and in the severely affected white matter lesions from patients with Binswanger disease, dense 14-3-3 immunoreactivity was found in clasmatodendritic astroglia as well as in reactive astrocytes. CONCLUSIONS: Our results suggest that 14-3-3 proteins may be induced mainly in astrocytes from human cerebrovascular ischemic lesions, and that the upregulated expression of 14-3-3 proteins in astrocytes may be involved in the formation of astrogliosis.