Clinical impact of amyloid PET using 18F-florbetapir in patients with cognitive impairment and suspected Alzheimer's disease: a multicenter study.

OBJECTIVE: Amyloid positron emission tomography (PET) can reliably detect senile plaques and fluorinated ligands are approved for clinical use. However, the clinical impact of amyloid PET imaging is still under investigation. The aim of this study was to evaluate the diagnostic impact and clinical utility in patient management of amyloid PET using 18F-florbetapir in patients with cognitive impairment and suspected Alzheimer's disease (AD). We also aimed to determine the cutoffs for amyloid positivity for quantitative measures by investigating the agreement between quantitative and visual assessments. METHODS: Ninety-nine patients suspected of having AD underwent 18F-florbetapir PET at five institutions. Site-specialized physicians provided a diagnosis of AD or non-AD with a percentage estimate of their confidence and their plan for patient management in terms of medication, prescription dosage, additional diagnostic tests, and care planning both before and after receiving the amyloid imaging results. A PET image for each patient was visually assessed and dichotomously rated as either amyloid-positive or amyloid-negative by four board-certified nuclear medicine physicians. The PET images were also quantitatively analyzed using the standardized uptake value ratio (SUVR) and Centiloid (CL) scale. RESULTS: Visual interpretation obtained 48 positive and 51 negative PET scans. The amyloid PET results changed the AD and non-AD diagnosis in 39 of 99 patients (39.3%). The change rates of 26 of the 54 patients (48.1%) with a pre-scan AD diagnosis were significantly higher than those of 13 of the 45 patients with a pre-scan non-AD diagnosis (χ2 = 5.334, p = 0.0209). Amyloid PET results also resulted in at least one change to the patient management plan in 42 patients (42%), mainly medication (20 patients, 20%) and care planning (25 patients, 25%). Receiver-operating characteristic analysis determined the best agreement of the quantitative assessments and visual interpretation of PET scans to have an area under the curve of 0.993 at an SUVR of 1.19 and CL of 25.9. CONCLUSION: Amyloid PET using 18F-florbetapir PET had a substantial clinical impact on AD and non-AD diagnosis and on patient management by enhancing diagnostic confidence. In addition, the quantitative measures may improve the visual interpretation of amyloid positivity.

Asparagine residue 368 is involved in Alzheimer's disease tau strain-specific aggregation.

In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed "tau strains") and acts as an aggregation "seed" templating the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the C-terminal region (243-406 amino acids (aa)) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited via templated aggregation are still unknown. Here, we sought to identify the key sequences of seed-dependent aggregation. To identify sequences for which deletion reduces tau aggregation, SH-SY5Y cells expressing a series of 10 partial deletion (Del 1-10, covering 244-400 aa) mutants of tau-CTF24 (243-441 aa) were treated with tau seeds prepared from a different tauopathy patient's brain (Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration) or recombinant tau, and then seed-dependent tau aggregation was assessed biochemically. We found that the Del 8 mutant lacking 353-368 aa showed significantly decreased aggregation in both cellular and in vitro models. Furthermore, to identify the minimum sequence responsible for tau aggregation, we systematically repeated cellular tau aggregation assays for the delineation of shorter deletion sites and revealed that Asn-368 mutation suppressed tau aggregation triggered by an AD tau seed, but not using other tauopathy seeds. Our study suggested that 353-368 aa is a novel aggregation-responsible sequence other than PHF6 and PHF6*, and within this sequence, the Asn-368 residue plays a role in strain-specific tau aggregation in different tauopathies.

Involvement of the Septo-Hippocampal Cholinergic Pathway in Association with Septal Acetylcholinesterase Upregulation in a Mouse Model of Tauopathy.

BACKGROUND: Cholinergic cell loss in the basal forebrain, the major source of hippocampal cholinergic projections, has been implicated in Alzheimer's disease. OBJECTIVE: To examine whether the septohippocampal pathway is involved in tauopathy model mice and to elucidate the tau-associated mechanism underlying cholinergic alteration. METHODS: Adult (6 to 8 months old) and old (16 to 18 months old) transgenic mice expressing wild-type human tau, Tg601, were examined using Ex vivo diffusion tensor magnetic resonance imaging (DTI) and 2-[18F]fluoro- 2-deoxy-D-glucose positron emission tomography (FDG-PET). Choline acetyltransferase (ChAT)-positive neurons in the medial septum (MS) were counted by stereological methods. Acetylcholinesterase (AChE) activity and AChE mRNA in 6 brain regions were measured. RESULTS: Ex vivo DTI revealed that the number of fractional anisotropy (FA) streamlines in the septohippocampal tract decreased with age in Tg601 mice. The FA value in the septum was lower in old Tg601 mice than in non-tg mice. A voxel-based statistical analysis of FDG-PET revealed the presence of low glucose uptake areas, involving the MS in adults, and spread over regions including the hippocampal dentate gyrus in old mice. In the MS, the number of choline acetyltransferase (ChAT)-positive neurons decreased in old Tg601 mice. AChE activity and AChE mRNA T transcripts were exclusively higher in the septum. CONCLUSION: The upregulation of AChE in the septum may result in the selective degeneration of the septohippocampal cholinergic pathway in the tauopathy mouse model.

Genotype-phenotype correlations of cysteine replacement in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by cerebral infarction related to mutations in the notch homolog protein 3 (NOTCH3). We enrolled 10 patients whose brain magnetic resonance imaging (MRI) fluid-attenuated inversion recovery images showed hyperintensities (HIs) in the deep white matter and the external capsule. We then investigated the mutations in NOTCH3 using direct sequencing within the region of intron-exon boundaries in exons 2-24 of NOTCH3. Eight patients harboring NOTCH3 mutations (8 of 10) were identified, including a novel mutation, p.C162Y, and 3 cases with a sporadic form. Seven patients with cysteine replacement showed HI in the anterior part of the temporal lobes (ATLs), whereas these changes were not detected in 1 patient without cysteine replacement, p.R75P. Reviewing previous reports, we conclude that the patients can clearly be divided in 2 groups: those with cysteine replacement who showed HI in the ATL and those without cysteine replacement who showed no HI in the ATL. Our findings expand the understanding of genotype-phenotype correlations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice.

Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 to 18 months old) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1ß, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD.

Fibromyalgia syndrome and cognitive dysfunction in elderly: a case series.

AIM: Fibromyalgia syndrome (FMS) is an extremely rare complication of neurocognitive disorders (NCDs). We experienced seven such cases, and we discuss their clinical manifestation and pathomechanisms. METHODS: Seven patients with FMS as a complication of NCD were enrolled. We used the patients' medical records to identify clinical manifestations and obtain experimental data, such as pain questionnaire scores, cognitive tests, genetics and radiological imaging of the brain. RESULTS: The seven patients were clinically diagnosed with frontotemporal NCD (n = 3) or Alzheimer's disease (n = 4). No patient presented with any organic disorder that would explain their chronic pain. Through their courses, they experienced refractory widespread pain continuously despite analgesics. Brain magnetic resonance imaging revealed moderate or severe atrophic changes in the temporal lobes and hippocampus. Three-dimensional stereotactic surface projection (3D-SSP) analysis of brain single photon emission computed tomography (SPECT), indicated severe hypoperfusion on the right side of the medial temporal lobe, both sides of the anterior corpus callosum, anterior cingulate gyrus, and primary sensory area. Genetic analysis uncovered no pathogenic mutations. CONCLUSIONS: Neurodegenerative disorders are rarely complicated by FMS, which is associated with relatively severe pain. Central sensitization may be a possible risk factor of widespread pain in elderly patients with NCD.

[Adult-onset case of idiopathic neurodegeneration with brain iron accumulation without mutations in the PANK2 and PLA2G6 genes].

A 47-year-old man with a 15-year history of bipolar disorder treated with anti-depressants, lithium carbonate or neuroleptics was admitted because of marked difficulty in gait and speech. At the age 45, he was unable to walk without bilateral assists and became a wheel-chair state. There was no family history and his mother, father and younger sister were neurologically free. General physical examinations revealed no abnormalities. Neurologically, he was moderately demented (mini mental state examination: 18/30) and showed bilateral horizontal gaze nystagmus, parkinsonism, cerebellar ataxia, dysarthria and moderate spastic paraparesis. No involuntary movements were noted. Wet blood smear showed acanthocytes, while blood chemistries revealed no abnormalities including levels of serum creatine kinase, hepatic enzymes and blood beta-lipoprotein. Kell antigen expressions of the red blood cells were within normal limit. Western blot analysis with anti-chorein antibody detected normal chorein expression levels of the red blood cells. Cranial MRI showed severe symmetric atrophy of the frontotemporal lobes, caudate nuclei, putamen, and brainstem. Also, MRI-gradient echo showed symmetric iron accumulation in the medial portion of the globus pallidus without surrounding high intensity areas, so called "eye-of-the-tiger sign". Genetic analyses revealed no mutations in the PANK2 and PLA2G6 genes. Therefore, he was diagnosed as idiopathic neurodegeneration with brain iron accumulation (NBIA). These findings suggest that NBIA is heterogeneous and other additional genes remain to be found.

Extensive hemispheric lesions with radiological evidence of blood-brain barrier integrity in a patient with neuromyelitis optica.

Anti-aquaporin-4 antibody (NMO-IgG) is used as a diagnostic marker for neuromyelitis optica (NMO). Although the mechanism of spinal cord lesions in NMO has been investigated, that of extensive hemispheric lesions with brain edema remains unclear. Here we report a 36-year-old woman with NMO positive for NMO-IgG, who developed an acute disseminating encephalomyelitis (ADEM)-like episode after Mycoplasma pneumoniae infection. Brain MRI T2-weighted images demonstrated asymmetric tumefactive hyperintense lesions in the subcortical white matter. Importantly, no lesions on T1-weighted images were enhanced after intravenous gadolinium administration on serial brain MRIs, suggesting preserved integrity of the blood-brain barrier (BBB). Likewise, the corresponding apparent diffusion coefficient maps demonstrated persistent hyperintensity changes, which represented vasogenic edema associated with glial damage and consequent neuronal loss. The findings suggest possible involvement of deficient water elimination associated with seropositivity to NMO-IgG in the induction of vasogenic edema even in the presence of intact and functional BBB.