Abeta42 is essential for parenchymal and vascular amyloid deposition in mice.

Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.

Single-dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a devastating, degenerative neurological disorder. It is inherited as an autosomal recessive trait caused by loss-of-function mutations in the galactocerebrosidase (GALC) gene. Previously, we have shown that peripheral injection of recombinant GALC, administered every other day, results in a substantial improvement in early clinical phenotype in the twitcher mouse model of GLD. While we did detect active enzyme in the brain following peripheral administration, most of the administered enzyme was localized to the periphery. Given the substantial central nervous system (CNS) involvement in this disease, we were interested in determining whether or not a single-dose administration of the recombinant enzyme directly to the CNS, which could potentially be achieved clinically, would result in any substantial improvement. Following intracerebroventricular (i.c.v.) administration of GALC we noted a significant, 16.5%, reduction in the GALC substrate psychosine, the abnormal accumulation of which is believed to play a pivotal role in the CNS pathology observed in this disease. Moreover, recombinant GALC was found not only in periventricular regions but also at sites distant to the injection such as the cerebral cortex and cerebellum. Most importantly, animals receiving a single i.c.v. dose of the enzyme at postnatal day 20 survived up to 51 days, which compares favorably to the control twitcher animals, which normally only live to postnatal day 40/42. These results indicate that even a single i.c.v. administration of the recombinant enzyme can have significant clinical impact and suggests that other lysosomal storage disorders with significant CNS involvement may similarly benefit.

Improving Hospital-to-Home Transitions for Children Entering Foster Care.

BACKGROUND AND OBJECTIVES: Hospital-to-home transitions present safety risks for patients. Children discharged with new foster caregivers may be especially vulnerable to poor discharge outcomes. With this study, our objective is to identify differences in discharge quality and outcomes for children discharged from the hospital with new foster caregivers compared with children discharged to their preadmission caregivers. METHODS: Pediatric patients discharged from the Barbara Bush Children's Hospital at Maine Medical Center between January 2014 and May 2017 were eligible for inclusion in this retrospective cohort study. Chart review identified patients discharged with new foster caregivers. These patients were compared with a matched cohort of patients discharged with preadmission caregivers for 5 discharge quality process measures and 2 discharge outcomes. RESULTS: Fifty-six index cases and 165 matched patients were identified. Index cases had worse performance on 4 of 5 discharge process measures, with significantly lower use of discharge readiness checklists (75% vs 92%; P = .004) and teach-back education of discharge instructions for caregivers (63% vs 79%; P = .02). Index cases had twice the odds of misunderstandings needing clarification at the postdischarge call; this difference was not statistically significant (26% vs 13%; P = .07). CONCLUSIONS: Hospital-to-home transition quality measures were less often implemented for children discharged with new foster caregivers than for the cohort of patients discharged with preadmission caregivers. This may lead to increased morbidity, as suggested by more frequent caregiver misunderstandings. Better prospective identification of these patients and enhanced transition improvement efforts targeted at their new caregivers may be warranted.

Foster Caregiver Experience of Pediatric Hospital-to-Home Transitions: A Qualitative Analysis.

OBJECTIVE: Children entering foster care after discharge from the hospital are at risk for adverse events associated with the hospital-to-home transition. Education of foster caregivers regarding transitional care needs is key. However, little is known about the unique needs of foster caregivers as they transition from hospital to home with a new foster child or how hospital-based health care teams can better support foster caregivers. We aimed to examine the experiences and preferences of foster caregivers' regarding hospital-to-home transitions of children newly discharged into their care and to identify opportunities for inpatient providers to improve outcomes for these children. METHODS: We conducted semistructured telephone interviews of foster caregivers who newly assumed care of a child at the time of hospital discharge between May 2016 and June 2017. Interviews were continued until thematic saturation was reached. Interviews were audio recorded, transcribed, and analyzed to identify themes using a general inductive approach. RESULTS: Fifteen interviews were completed. All subjects were female, 87% were Caucasian, and 73% were first-time foster caregivers. Thirteen themes were identified and grouped into the following domains: 1) knowing the child, 2) medicolegal issues, 3) complexities of multistakeholder communication, and 4) postdischarge preparation and support. CONCLUSIONS: Caregivers of children newly entering foster care following hospital discharge face unique challenges and may benefit from enhanced care processes to facilitate successful transitions. Hospitalization provides an opportunity for information gathering and sharing, clarification of custodial status, and facilitation of communication among multistakeholders, including child protective services and biological parents.

Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy.

Lewy bodies (LBs) are alpha-synuclein-immunoreactive neuronal inclusions with a predilection for specific cortical and subcortical regions, including the amygdala. In this study, the presence of LBs was assessed in 347 cases of Alzheimer disease (AD). In 87 cases, LB pathology was diagnostic of brainstem (n=3), transitional (n=32), or diffuse (n=52) Lewy body disease (LBD). The remaining 260 cases of AD were screened for amygdala LBs (AD/ALB) and 62 (24%) cases were found. If AD/LBD cases are included, LBs were detected in 149 (43%) cases of AD. The presence alpha-synuclein pathology was assessed in multiple brain regions of the 62 cases of AD/ALB and 57 randomly selected cases of AD, and only sparse alpha-synuclein pathology was detected in both. The burden of alpha-synuclein pathology in brainstem nuclei, amygdala, and neocortex was significant lower in AD/ALB than in AD/LBD. In comparison to AD/LBD, AD/ALB did not differ in age at death, disease duration, male-to-female ratio, brain weight, Braak neurofibrillary tangle stage, average senile plaque density, or apolipoprotein E epsilon4 allele frequency. The results suggest that AD/ALB is pathologically different from AD/LBD, suggesting that it is a neuropathologically distinct and isolated alpha-synucleinopathy.

Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment.

A previous autopsy study of patients with amnestic-type mild cognitive impairment (MCI) suggested an overrepresentation of argyrophilic grain disease (AGD). We studied 34 patients who had diagnoses of amnestic MCI during progression to dementia and who came to autopsy. Neuropathologic evaluation included routine histochemical and immunohistochemical methods, including a 4-repeat tau-specific marker (ET3). AGD was found in association with a variety of neuropathologic diseases in 18 (53%) cases but was the primary pathologic finding in only one (3%) case. ET3 allowed the detection of AGD in 5 additional cases missed using standard techniques. Cases with AGD were significantly older than those without (mean, 94 vs 84 years; p < 0.004, rank sum test). No significant differences were found between groups for other demographic variables, association of AGD with neuropathologic findings of Alzheimer disease, Lewy body, or cerebrovascular disease, or global measures of cognitive function, although there was a nonsignificant trend towards worsening cognitive status in cases with AGD. AGD is a common pathologic finding in subjects who have been diagnosed with amnestic MCI.

Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe disease is a devastating, degenerative neurological disorder caused by mutations in the galactosylceramidase (GALC) gene that severely affect enzyme activity. Currently, treatment options for this disorder are very limited. Enzyme replacement therapy (ERT) has been shown to be effective in lysosomal storage disorders with predominantly peripheral manifestations such as type I Gaucher's and Fabry's disease. Little however is known about the possible benefit of ERT in GLD, which has a substantial central nervous system component. In this study, we examined the effect of peripheral GALC injections in the twitcher mouse model of the disease. Although we were unable to block the precipitous decline that normally occurs just before death, we did observe significant early improvements in motor performance, a substantial attenuation in the initial failure to thrive, and an increase in life span. Immunohistochemical and activity analyses demonstrated GALC uptake in multiple tissues, including the brain. This was associated with a decrease in the abnormal accumulation of the GALC substrate psychosine, which is thought to play a pivotal role in disease pathology. These results indicate that peripheral ERT is likely to be beneficial in GLD.

The Economic Burden of Schizophrenia in the United States in 2013.

OBJECTIVE: The objective of this study was to estimate the US societal economic burden of schizophrenia and update the 2002 reported costs of $62.7 billion given the disease management and health care structural changes of the last decade. METHODS: A prevalence-based approach was used to assess direct health care costs, direct non-health care costs, and indirect costs associated with schizophrenia (ICD-9 codes 295.xx) for 2013, with cost adjustments where necessary. Direct health care costs were estimated using a retrospective matched cohort design using the Truven Health Analytics MarketScan Commercial Claims and Encounters, Medicare Supplemental, and Medicaid Multistate databases. Direct non-health care costs were estimated for law enforcement, homeless shelters, and research and training. Indirect costs were estimated for productivity loss from unemployment, reduced work productivity among the employed, premature mortality (ie, suicide), and caregiving. RESULTS: The economic burden of schizophrenia was estimated at $155.7 billion ($134.4 billion-$174.3 billion based on sensitivity analyses) for 2013 and included excess direct health care costs of $37.7 billion (24%), direct non-health care costs of $9.3 billion (6%), and indirect costs of $117.3 billion (76%) compared to individuals without schizophrenia. The largest components were excess costs associated with unemployment (38%), productivity loss due to caregiving (34%), and direct health care costs (24%). CONCLUSIONS: Schizophrenia is associated with a significant economic burden where, in addition to direct health care costs, indirect and non-health care costs are strong contributors, suggesting that therapies should aim at improving not only symptom control but also cognition and functional performance, which are associated with substantial non-health care and indirect costs.

Alpha-synuclein immunoreactivity in neuronal nuclear inclusions and neurites in multiple system atrophy.

We examined neuronal and oligodendroglial nuclear inclusions and neurites in the pontine base of multiple system atrophy brains using an antibody to alpha-synuclein. Immunohistochemistry showed alpha-synuclein positive inclusions in the nuclei of some neurons and oligodendroglia. Immunoelectron microscopy showed that the labeled inclusions were composed of bundles of tightly packed straight filaments with a diameter of 10-20 nm. The filaments were similar, if not identical, in morphology and immunoreactivity, to those found in the soma of neurons and oligodendrocytes with glial cytoplasmic inclusions. In addition, similar immuno-positive filaments were found in dendrites or unmyelinated axons, but not in myelinated axons. The functional significance of these inclusions in terms of transcriptional and axonal dysfunction is unknown.

Suppression of galactosylceramidase (GALC) expression in the twitcher mouse model of globoid cell leukodystrophy (GLD) is caused by nonsense-mediated mRNA decay (NMD).

The twitcher mouse is a pathologically and enzymatically authentic model of globoid cell leukodystrophy (GLD, Krabbe disease) that has been widely used for the evaluation of potential therapeutic approaches. This naturally occurring mouse model contains a premature stop codon (W339X) in the galactosylceramidase (GALC) gene that abolishes enzymatic activity. Using either immunocytochemical approaches or Western blot methodology, we have been unable to detect the truncated form of GALC expected to be produced in these animals. Nonsense-mediated mRNA decay (NMD) is a cellular protection mechanism that degrades newly synthesized transcripts containing a premature termination codon (PTC). Since the naturally occurring mutation in the twitcher mouse introduces a PTC, we hypothesized that NMD might affect the degradation of GALC mRNA in these animals. Consistent with this hypothesis, we determined that the amount of GALC transcript was inversely proportional to the number of twitcher containing alleles. Similar reductions in GALC mRNA were detected in a twitcher-derived Schwann cell line (TwS1) when compared to wild-type Schwann cells (IMS32). Anisomycin, emetine and puromycin, inhibitors of NMD, effectively increased the level of GALC transcript in the TwS1 cells providing further support for nonsense-mediated mRNA decay being the mechanism by which no GALC protein is detected in these animals. Understanding the mechanistic differences between the lack of enzymatic activity in the twitcher model and that observed with the missense mutations that cause human disease yields not only novel therapeutic insights but also highlights the need for additional animal models.

Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.