Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.
Cell 165(4):921 (2016)
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progre...
Distinct Lysosomal Network Protein Profiles in Parkinsonian Syndrome Cerebrospinal Fluid.
Journal of Parkinson's Disease 6(2):307 (2016)
Clinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem.
Since impaired ...
Plasma neurofilament light chain predicts progression in progressive supranuclear palsy.
Annals of clinical and translational neurology 3(3):216 (2016)
Blood-based biomarkers for neurodegenerative conditions could improve diagnosis and treatment development. Neurofilament light chain (NfL), a marker of axonal injury, is elevated in cerebrospinal fluid (CSF) of patients with progressive supranuclear palsy (PSP). The goal of this study was to det...
Amyloid in dementia associated with familial FTLD: not an innocent bystander.
Neurocase 22(1):76 (2016)
Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case-control study compared clinical features, fluorodeoxyglucose-positron emission to...
Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain.
Molecular Neurodegeneration 11(1):31 (2016)
Biological pathways that significantly contribute to sporadic Alzheimer's disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted...
Prosaposin is a regulator of progranulin levels and oligomerization.
Nature Communications 7:11992 (2016)
Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a ...
Divergent CSF τ alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy.
Journal of Neurology, Neurosurgery & Psychiatry 86(3):244 (2015)
Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in ...
Rarity of the Alzheimer disease-protective APP A673T variant in the United States.
JAMA Neurology 72(2):209 (2015)
Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this varia...
Apolipoprotein ε4 is associated with lower brain volume in cognitively normal Chinese but not white older adults.
PLoS ONE 10(3):e0118338 (2015)
Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and fun...
A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques.
Acta neuropathologica communications 3(1):19 (2015)
Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.
We describe a pedigre...
Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer's disease.
BMC Neurology 15(1):47 (2015)
Heritability of Alzheimer's disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in c...
The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia.
NeuroImage: Clinical 9:283 (2015)
The serotonin transporter length polymorphism (5-HTTLPR) short allele (5-HTTLPR-s) has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by red...
Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.
JAMA Neurology 71(11):1394 (2014)
Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.
To investigate the effects of known Alzheimer disease risk lo...
AMYLOID IN DEMENTIA ASSOCIATED WITH FAMILIAL FTLD: NOT AN INNOCENT BYSTANDER
Alzheimer's & Dementia 10(4):P249 (2014)
Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients.
Journal of Neurology, Neurosurgery & Psychiatry 85(3):266 (2014)
Apolipoprotein E ε4 (ApoE4) has been associated with an increased risk of Alzheimer's disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and ...
An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.
PLoS Genetics 10(3):e1004211 (2014)
Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia--progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD)--revealed significant d...
Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia.
Neurology 82(6):512 (2014)
To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study.
Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healt...
Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration.
Annals of Neurology 75(1):116 (2014)
Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders, including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD.
CSF NfL, amyloid-β1-42 (Aβ42), tau, and phosphorylated tau concen...
C9ORF72 repeat expansions in cases with previously identified pathogenic mutations.
Neurology 81(15):1332 (2013)
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutation...
TDP-43 frontotemporal lobar degeneration and autoimmune disease.
Journal of Neurology, Neurosurgery & Psychiatry 84(9):956 (2013)
The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need...