Atsushi Niwa

Clinical and neuropathological findings in a patient with familial Alzheimer disease showing a mutation in the PSEN1 gene.

Over 100 mutations have been described in the presenilin‐1 gene (PSEN1), resulting in familial Alzheimer disease (AD). However, of the limited number of autopsy cases, only one has been reported from an AD family with an L420R PSEN1 mutation. We describe here clinical and neuropathological features of a patient with dementia‐parkinsonism from a family with a PSEN1 mutation (L420R). A 43‐year‐old Japanese woman was autopsied 12 years after the onset of her progressive dementia and 4 years after the onset of parkinsonism. Throughout the neocortex and hippocampus, cotton wool plaques were identified, densely packed, in almost all the cortical layers along with neuronal loss, gliosis, NFT and neuropil threads. In addition, CAA affecting meningeal, subpial and cortical arterioles was found, as well as amyloid β‐protein (Aβ)‐deposition in the capillaries (capillary CAA) in the neocortex and subcortical nuclei. There was loss of pigmented neurons in the substantia nigra. The putamen was densely packed with diffuse plaques and rarely showed capillary CAA, whereas the globus pallidus showed extensive capillary CAA but no plaques. This differential distribution is similar to that reported for a previous patient with a mutation in PSEN1. It is concluded that neuropathological changes in the substantia nigra and lenticular nuclei were responsible for the patients parkinsonism. Capillary transport of Aβ unique to the respective tissue of the patient may result in the differential distribution of Aβ between the putamen and globus pallidus seen in individuals with a PSEN1 mutation.

Comparative Analysis of Cortical Microinfarcts and Microbleeds using 3.0-Tesla Postmortem Magnetic Resonance Images and Histopathology

Microvascular lesions including cortical microinfarctions (CMIs) and cerebral lobar microbleeds (CMBs) are usually caused by cerebral amyloid angiopathy (CAA) in the elderly and are correlated with cognitive decline. However, their radiological-histopathological coincidence has not been revealed systematically with widely used 3-Tesla (3T) magnetic resonance imaging (MRI). The purpose of the present study is to delineate the histopathological background corresponding to MR images of these lesions. We examined formalin-fixed 10-mm thick coronal brain blocks from 10 CAA patients (five were also diagnosed with Alzheimer’s disease, three with dementia with Lewy bodies, and two with CAA only) with dementia and six non CAA patients with neurodegenerative disease. Using 3T MRI, both 3D-fluid attenuated inversion recovery (FLAIR) and 3D-double inversion recovery (DIR) were examined to identify CMIs, and T2* and susceptibility-weighted images (SWI) were examined to identify CMBs. These blocks were subsequently examined histologically and immunohistochemically. In CAA patients, 48 CMIs and 6 lobar CMBs were invariably observed in close proximity to degenerated Aβ-positive blood vessels. Moreover, 16 CMIs (33%) of 48 were detected with postmortem MRI, but none were seen when the lesion size was smaller than 1 mm. In contrast, only 1 undeniable CMI was founded with MRI and histopathology in 6 non CAA patients. Small, cortical high-intensity lesions seen on 3D-FLAIR and 3D-DIR images likely represent CMIs, and low-intensity lesions in T2* and SWI correspond to CMBs with in vivo MRI. Furthermore, a close association between amyloid-laden vessels and these microvascular lesions indicated the contribution of CAA to their pathogenesis.

Double-seropositive myasthenia gravis with acetylcholine receptor and low-density lipoprotein receptor-related protein 4 antibodies associated with invasive thymoma

We describe two cases of myasthenia gravis (MG) with double seropositivity for acetylcholine receptor (AChR) and low-density lipoprotein receptor-related protein 4 (LRP4) antibodies (AChR/LRP4-MG) with invasive thymoma. Both cases showed myasthenic weakness, which was restricted to the ocular muscles for >5 months from onset, and then unprovoked severe clinical deterioration supervened with predominant bulbar symptoms. The patients responded adequately to therapeutic intervention. Serum AChR antibody levels at post-intervention were markedly decreased, whereas LRP4 antibodies were almost unchanged in case 1 and slightly decreased in case 2. Although our results suggest that patients with AChR/LRP4-MG are likely to present with more severe symptoms than those with LRP4-MG, none of the previously reported cases had thymomas. Coexistence of autoantibodies may reflect breakdown of self-tolerance caused by invasive thymomas. The main cause affecting symptoms of MG in our cases was probably AChR antibodies, and anti-LRP4 antibodies might have been an exacerbating factor.

Comparison of Premortem Magnetic Resonance Imaging and Postmortem Autopsy Findings of a Cortical Microinfarct

An 85-year-old woman diagnosed with amyotrophic lateral sclerosis died of pneumonia and was autopsied. Magnetic resonance imaging (MRI) performed 16 days before death revealed an intracortical high-intensity lesion in her right temporal cortex on three-dimensional (3D)-double inversion recovery (DIR) and 3D-fluid-attenuated inversion recovery (FLAIR) images. Histopathological examination indicated a cortical microinfarct (CMI) juxtaposed to cerebral amyloid angiopathy. Recently, in vivo detection of CMIs using 3D-DIR and 3D-FLAIR on 3-tesla MRI has been reported, and postmortem MRI study confirmed the presence of CMIs. This is the first case study to compare CMI findings detected upon premortem MRI to the CMI itself discovered upon postmortem neuropathological examination.

Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex

Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype-phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients.

Proposition of zinc supplementation during levodopa-carbidopa intestinal gel treatment: XXXX

Levodopa–carbidopa intestinal gel (LCIG) infusion is a useful therapy for the wearing‐off phenomenon of advanced Parkinsons disease (PD) patients. Recently, we found three PD patients that may have had a zinc deficiency after the LCIG infusion, possibly due to the zinc‐chelating action of levodopa. This study aims to evaluate changes in serum zinc levels in three patients that received LCIG treatment and to determine possible remedies for zinc deficiency during treatment.

Complement Activation in Capillary Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is classified as type 1 with capillary amyloid β (Aβ) or type 2 without capillary Aβ. While it is known that CAA activates complement, an inflammatory mediator, there is no information on the relationship between capillary Aβ and complement activation. Methods: We evaluated 34 autopsy brains, including 22 with CAA and 12 with other neurodegenerative diseases. We assessed the vascular density of CAA by analyzing the expression of complement (C1q, C3d, C6, C5b-9), macrophage scavenger receptor (MSR), and apolipoprotein E (ApoE). Results: Capillary immunostaining for C1q, C3d, MSR, and ApoE was identified almost exclusively in CAA-type1 brains. There was intense expression of C1q, C3d, MSR, and ApoE, as well as weaker expression of C5b-9 and C6 in the arteries/ arterioles of both CAA subtypes, but not in control brains. C5b-9 and C6 were preferentially expressed in arteries/arterioles with subcortical hemorrhage or cortical superficial siderosis. Triple immunofluorescence revealed that C1q, C3d, and ApoE were colocalized with Aβ in CAA brain capillaries. Conclusion: Complement, MSR, and ApoE were only coexpressed in the presence of Aβ accumulation in capillaries, suggesting a role for complement activation in the propagation of Aβ. Additionally, C5b-9 expression may be associated with hemorrhagic brain injury in CAA.