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Background and purpose: Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET). Methods: Amyloid‐ and tau‐positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [18F]2‐tert‐butyl‐4‐chloro‐5–2H‐pyridazin‐3‐one (BCPP‐EF), [11C]Pittsburgh Compound‐B (PiB) and [18F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel‐based regressions models. Results: [18F]BCPP‐EF standardized uptake value ratio (SUVR) was positively correlated with [18F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18F]BCPP‐EF SUVR were associated with domain‐specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. Conclusions: In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [18F]BCPP‐EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD. [ABSTRACT FROM AUTHOR]

Objectives To determine the potential utility of the frontal assessment battery ( FAB) in assessing cognitive impairments in amyotrophic lateral sclerosis ( ALS), we investigated the association between the FAB score and regional gray matter volume, and ascertained whether the regional brain alterations related to cognitive impairments occur in relatively mild stage of ALS. Materials and Methods Twenty-four ALS patients with a Mini-Mental State Examination score of >23, a normal score on the Self-Rating Depression Scale, little or no disturbance in speech and handling utensils on the ALS Functional Rating Scale ( ALSFRS), and normal measures on respiratory tests (respiratory function test and arterial blood gas analysis), and two age-matched normal control groups (one for FAB assessment and the other for brain morphometry) underwent FAB testing and structural magnetic resonance imaging. We applied voxel-based morphometry to investigate the relationship between the FAB score and regional brain alteration, and assessed the relationship between the altered regional brain volume and ALSFRS or respiratory tests. Results Frontal assessment battery scores were significantly lower in ALS patients than in normal controls. Volume reduction in the right orbitofrontal gyrus in ALS was correlated with a lower FAB score. There was no correlation between the right orbitofrontal gyrus volume and ALSFRS or respiratory tests. Conclusions The results suggest that the FAB is an adequate tool for detecting cognitive impairments related to frontal lobe pathology in the relatively mild stage of ALS, independent of physical dysfunctions. [ABSTRACT FROM AUTHOR]

Background Recent studies have linked cognitive impairment in amyotrophic lateral sclerosis to frontotemporal pathology. Aim We examined possible associations between behavior changes and regional gray matter volume in early amyotrophic lateral sclerosis, and assessed whether the volume changes were independent of physical impairments. Methods A total of 17 amyotrophic lateral sclerosis patients with Mini-Mental State Examination score ≥ 24, no need for assistance in daily life and normal respiratory tests (respiratory function test and arterial blood gas analytes), and 11 age-matched controls underwent structural magnetic resonance imaging. Behavioral changes were assessed with family-rating Frontal Systems Behavior Scale. We applied voxel-based morphometry to investigate the correlation between the Frontal Systems Behavior Scale and gray matter volume, and assessed the correlation of volume with amyotrophic lateral sclerosis Functional Rating Scale and respiratory tests. Results Current Frontal Systems Behavior Scale scores were significantly higher than retrospective scores assessing the status before onset, most notably in apathy. The volumes of right middle and left medial frontal gyri in amyotrophic lateral sclerosis were negatively correlated with the Frontal Systems Behavior Scale, whereas they were not correlated with amyotrophic lateral sclerosis Functional Rating Scale and respiratory tests. The volume of the right frontal cluster, but not the left medial frontal cluster, was significantly smaller than that of controls. Conclusions Regional atrophy within the frontal lobe was associated with behavioral dysfunction in early amyotrophic lateral sclerosis, this association was independent of physical factors. [ABSTRACT FROM AUTHOR]

Aceruloplasminemia is an autosomal recessive disease characterized by an abnormal iron metabolism. The absence of ferroxidase activity caused by mutation of ceruloplasmin leads to iron overload in the brain, liver and other organs. We report a 35-year-old man who was diagnosed with aceruloplasminemia without neurological manifestation despite the accumulation of iron in the brain and liver. To prevent the development of neurodegenerative disorder related to iron toxicity, iron depletion therapy was performed. Iron chelator deferasirox was effective in reducing serum ferritin level and to prevent the progression of the disease. [ABSTRACT FROM AUTHOR]

Background: Understanding sex dimorphism in neurodevelopment and neurodegeneration is imperative for therapeutic strategy, clinical trial enrichment, and personalized medicine. However, the cellular underpinning of sex dimorphism in Alzheimer's disease (AD) pathophysiology is still poorly understood. Here, we aimed to investigate the effect of sex on microglial activation and its effect on cognition using the major targets of AD clinical trials – amyloid ([18F]AZD4694), tau ([18F]MK6240), and neuroinflammation ([11C]PBR28) – through a multimodal PET study in humans and rats. Method: A total of 108 participants (70 CN, 25 MCI, and 13 AD; 36 M, 72 F) with a high‐affinity binder for TSPO from the TRIAD cohort underwent 3 PET scans and MMSE for cognitive assessment. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. Furthermore, 29 rats (8 WT, 21 Tg; 13 M, 16 F) underwent a 60‐min dynamic [18F]AZD4694 and [11C]PBR28 PET scans. All PET images were normalized to the average template. [18F]AZD4694 and [11C]PBR28 BPND were quantified based on SRTM method using Pons and midbrain as a reference region, respectively. The sex effect on neuroinflammation is evaluated based on a linear regression model in humans and rats. Consequently, sex dimorphism induced neuroinflammation effect on cognition was assessed using MMSE. All the models were corrected for age, APOE, education, amyloid and tau status. Result: In this study, females showed greater [11C]PBR28 binding in basal temporal regions in humans and parietotemporal cortex, hippocampus, and basal forebrain in rats. Consequently, greater neuroinflammation in females showed negative effects on MMSE but not in males, p = 0.033. Conclusion: This study demonstrated the greater microglia activation in females compared to males. Considering the difference in the microglia reaction to amyloidosis in rodents compared to humans, the increased microglial activation effect on cognition was only assessed in humans. Here, microglial sex dimorphism showed deleterious effects on cognition only in females. This study highlights the difference in microglial reactivity leading to greater vulnerability to cognitive decline in females. As such, it is imperative to explore a sex‐specific therapeutic strategy for AD clinical trial. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disorder (PTLD) with CNS involvement is an uncommon and fatal side effect of immunosuppressants. A 55-year-old man presented with non-fluent aphasia, fever, neck stiffness and disturbance of consciousness. Twenty-one years previously, the patient had undergone kidney transplantation for chronic renal failure. Brain MRI revealed multiple lesions in the bilateral cerebrum, right cerebellum and medulla oblongata. The brain biopsy showed EBV-positive lymphocytes infiltrating into the subarachnoid and Virchow-Robins space. The diagnosis of PTLD was made and the patient received a reduction in immunosuppressants. However, the patient died of massive bleeding from a rectal ulcer 3 months after the onset. An autopsy conducted 1 month after the biopsy revealed a diffuse large B-cell lymphoma at the biopsy site and extracranial PTLD lesions. Moreover, a human cytomegalovirus infection involving the rectum, pancreas, trachea and bladder was confirmed. Comparisons with past cases clarified the characteristics of this case, in particular, the clinicopathological involvement of leptomeninges. In addition, there have so far been only a limited number of such reports demonstrating detailed pathological findings, including both biopsy and autopsy findings. We herein describe the relationship between clinical and pathological findings and demonstrate the way CNS PTLD lesion progresses. [ABSTRACT FROM AUTHOR]

Mutations in the glucocerebrosidase gene ( GBA) increase the risk for Parkinson's disease and are also associated with an earlier onset of the disease and an akinetic parkinsonian phenotype. To investigate the underlying pathogenesis of this condition, we assessed cerebral metabolism using positron emission tomography (PET) in GBA mutation carriers with and without parkinsonism. [18F]-fluorodeoxyglucose (FDG)-PET using a three-dimensional stereotactic surface projection analysis was used to measure the cerebral metabolic rates of glucose (CMRGlc) in a patient with parkinsonism and Gaucher disease (GD) and five subjects with a heterozygous GBA mutation, including three patients with parkinsonism and three asymptomatic carriers in comparison to 10 healthy controls in the same age range. Dopaminergic neuronal activity was investigated using [11C] CFT- and [11C] raclopride-PET. All GBA mutation carriers displayed a significant CMRGlc decrease in the supplemental motor area (SMA). The carriers with parkinsonism showed additional hypometabolism in the parietooccipital cortices. The CFT and raclopride PET images in the asymptomatic carriers demonstrated the CFT binding to be within normal values in the putamen and a significant increase was observed in the caudate nucleus while raclopride binding in the striatum was in the normal range. An advanced parkinsonian carrier showed decreased CFT binding and increased raclopride binding in the striatum. The decreased CMRGlc in the SMA was characteristic of the GBA mutation carriers. The hypometabolism in the SMA may, therefore, be involved in the clinical characteristics of parkinsonism associated with GBA mutations when the carriers manifest parkinsonism. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]