Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous lurcher mice (Lc/+) display ataxia due to a selective, cell‐autonomous, apoptotic death of 90% of cerebellar ...Purkinje cells during postnatal development. Homozygous lurcher mice (Lc/Lc) die shortly after birth due to massive loss of mid‐ and hindbrain neurons during late embryogenesis. We identified the mutations responsible for neurodegeneration in two independent Lc alleles as identical G‐to‐A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse d2 glutamate receptor gene (GluRE2). Lc/+ Purkinje cells displayed a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant Gluδd2Lc protein in Xenopus oocytes confirmed these results, demonstrating that lurcher is an inherited neurodegenerative disorder resulting from a gain‐of‐function mutation in a glutamate receptor gene. Further characterization of GluRδ2 signaling and the activation of apoptotic death in Lc Purkinje cells have begun to yield mechanistic insights into this neurodegenerative disease, and to highlight its relationship to neuronal loss following ischemia.
Objective
To report initial results of a planned multicenter year‐long prospective study examining the risk and impact of COVID‐19 among persons with neuroinflammatory disorders (NID), particularly ...multiple sclerosis (MS).
Methods
In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID‐19 in persons with NID (PwNID) and change in their neurological care.
Results
Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID‐19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID‐19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID‐19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID‐19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID‐19 (ORadj = 1.45, 1.17–1.84).
Interpretations
Our study of real‐time, patient‐reported experience during the COVID‐19 pandemic complements physician‐reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID‐19 similar to the reference population.
Objective
Genome‐wide association studies have linked variants in
TREM2
(triggering receptor expressed on myeloid cells 2) and
TREML2
with Alzheimer disease (AD) and AD endophenotypes. Here, we ...pursue a targeted analysis of the
TREM
locus in relation to cognitive decline and pathological features of AD.
Methods
Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes.
Results
We provide evidence that an intronic variant, rs6910730
G
, in
TREM1
, is associated with an increased burden of neuritic plaques (
p
= 3.7 × 10
−4
), diffuse plaques (
p
= 4.1 × 10
−3
), and Aβ density (
p
= 2.6 × 10
−3
) as well as an increased rate of cognitive decline (
p
= 5.3 × 10
−3
). A variant upstream of
TREM2
, rs7759295
C
, is independently associated with an increased tau tangle density (
p
= 4.9 × 10
−4
), an increased burden of neurofibrillary tangles (
p
= 9.1 × 10
−3
), and an increased rate of cognitive decline (
p
= 2.3 × 10
−3
). Finally, a cytometric analysis shows that the
TREM1
rs6910730
G
allele is associated with decreased TREM1 expression on the surface of myeloid cells (
p
= 1.7 × 10
−3
).
Interpretation
We provide evidence that 2 common variants within the
TREM
locus are associated with pathological features of AD and aging‐related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function. Ann Neurol 2015;77:469–477
BACKGROUND White matter hyperintensity volume (WMHV), cerebral infarcts, and total brain volume (TBV) are associated with cognitive function, but few studies have examined these associations in the ...general population or whether they differ by race. OBJECTIVE To examine the association of WMHV, cerebral infarcts, and TBV with global cognition and cognition in 5 separate domains in a biracial population sample. SETTING A biracial community population of Chicago, Illinois. DESIGN Cross-sectional population study. PARTICIPANTS The study population comprised 575 participants from the Chicago Health and Aging Project (CHAP). MAIN OUTCOME MEASURES Volumetric magnetic resonance imaging (MRI) measures of WMHV, TBV, and cerebral infarcts and detailed neuropsychological testing assessments of global cognition and 5 cognitive domains. RESULTS Overall and among those without dementia, cognition was inversely associated with WMHV and number of infarcts but was positively associated with TBV. When all 3 measures were simultaneously added to the model, the association of global cognition with WMHV and TBV remained significant and unchanged but was no longer significant with infarcts. Among subjects without dementia, all 3 MRI measures were associated with performance in multiple cognitive domains, specifically perceptual speed. However, among subjects with dementia, only TBV was associated with cognition and performance in multiple cognitive systems. Race did not significantly modify any of these associations. CONCLUSIONS In this biracial general population sample, the associations of MRI measures with cognition differed according to clinical status of subjects (stronger among subjects without dementia) and were not modified by race. These associations did not affect all cognitive domains equally but were more consistent with impairments in perceptual speed.Arch Neurol. 2010;67(4):475-482-->
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