Treatment of Alzheimer’s disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood– brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.
To validate the ability of candidate CSF biomarkers to distinguish between the 2 main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau).
Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2-center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined.
In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio <0.37 to distinguish FTLD-TDP from FTLD-Tau, AD, and healthy seniors with 82% sensitivity and 82% specificity.
A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies.
Classification of evidence:
This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.
C-reactive protein (CRP) participates in the systemic response to inflammation. Previous studies report inconsistent findings regarding the relationship between plasma CRP and Alzheimer’s disease (AD). We measured plasma CRP in 203 subjects with AD, 58 subjects with mild cognitive impairment (MCI) and 117 normal aging subjects and administered annual mini-mental state examinations (MMSE) during a three year follow-up period to investigate CRP’s relationship with diagnosis and progression of cognitive decline. Adjusted for age, sex, and education, subjects with AD had significantly lower levels of plasma CRP than subjects with MCI and normal aging. However, there was no significant association between plasma CRP at baseline and subsequent cognitive decline as assessed by longitudinal changes in MMSE score. Our results support previous reports of reduced levels of plasma CRP in AD and indicate its potential utility as a biomarker for the diagnosis of AD.
Alzheimer Disease; Mild Cognitive Impairment; C-Reactive Protein; Inflammation; Biological Markers
HIV causes rapid CD4+ T cell depletion in the gut mucosa, resulting in immune deficiency and defects in the intestinal epithelial barrier. Breakdown in gut barrier integrity is linked to chronic inflammation and disease progression. However, the early effects of HIV on the gut epithelium, prior to the CD4+ T cell depletion, are not known. Further, the impact of early viral infection on mucosal responses to pathogenic and commensal microbes has not been investigated. We utilized the SIV model of AIDS to assess the earliest host-virus interactions and mechanisms of inflammation and dysfunction in the gut, prior to CD4+ T cell depletion. An intestinal loop model was used to interrogate the effects of SIV infection on gut mucosal immune sensing and response to pathogens and commensal bacteria in vivo. At 2.5 days post-SIV infection, low viral loads were detected in peripheral blood and gut mucosa without CD4+ T cell loss. However, immunohistological analysis revealed the disruption of the gut epithelium manifested by decreased expression and mislocalization of tight junction proteins. Correlating with epithelial disruption was a significant induction of IL-1β expression by Paneth cells, which were in close proximity to SIV-infected cells in the intestinal crypts. The IL-1β response preceded the induction of the antiviral interferon response. Despite the disruption of the gut epithelium, no aberrant responses to pathogenic or commensal bacteria were observed. In fact, inoculation of commensal Lactobacillus plantarum in intestinal loops led to rapid anti-inflammatory response and epithelial tight junction repair in SIV infected macaques. Thus, intestinal Paneth cells are the earliest responders to viral infection and induce gut inflammation through IL-1β signaling. Reversal of the IL-1β induced gut epithelial damage by Lactobacillus plantarum suggests synergistic host-commensal interactions during early viral infection and identify these mechanisms as potential targets for therapeutic intervention.
The loss of intestinal CD4+ T cells in chronic HIV infection is associated with impaired immune responses to pathogens, aberrant immune activation, and defects in the gut epithelial barrier. While much is known about the pathogenesis of HIV in chronic disease, less is known about the defects that occur prior to gut CD4+ T cell depletion and whether these defects alter host interactions with pathogenic and commensal bacteria. Using a non-human primate model of HIV infection, we examined the immune and structural changes in the gastrointestinal tract 2.5 days following SIV infection. Paneth cells, in immediate proximity of SIV infected immune cells, generated a robust IL-1β response. This IL-1β response correlated with defects in epithelial tight junctions and preceded the IFN-α response, which is characteristic of innate antiviral immune responses. Despite this inflammatory environment, we did not observe defects in mucosal immune responses to pathogenic or commensal bacteria. In fact, commensal bacteria were able to dampen the IL-1β response and ameliorate tight junction defects. Our study highlights the importance of the gut epithelium in HIV infection, not just as a target of pathogenesis but also the initiator of immune responses to viral infection, which can be strongly influenced by commensal bacteria.
An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility is necessary.
We sought to develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS.
Academic medical center.
51 individuals with ALS and 23 individuals with a disorder associated with a four-repeat tauopathy (4R-tau).
MAIN OUTCOME MEASURE
CSF level of tau phosophorylated at threonine 181 (ptau), and ratio of ptau to total tau (ttau).
Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and ptau:ttau in ALS relative to 4R-tau and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS to 4R-tau showed sensitivity=92% and specificity=91.7%. Correct classification based on low CSF ptau:ttau was confirmed in 18 (85.7%) of 21 cases with autopsy-proven or genetically-determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity such as Mini Mental State Exam (n=51) and ALS Functional Rating Scale-Revised (n=42), and regression analyses related ptau:ttau to MRI (n=10) evidence of disease in the corticospinal tract and white matter projections involving prefrontal cortex.
CONCLUSIONS AND RELEVANCE
CSF ptau:ttau may be a candidate biomarker to provide objective support for the diagnosis of ALS.
amyotrophic lateral sclerosis; cerebrospinal fluid; phosphorylated tau; biomarker
Frontotemporal Degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language and motor phenotypes for which there are currently no effective therapies. This manuscript is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Dementia Treatment Study Group (FTSG), a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This manuscript discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease (AD). Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw upon this experience to create a roadmap for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.
The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans.
Chronic immune activation despite long-term therapy poses an obstacle to immune recovery in HIV infection. The role of antigen presenting cells (APCs) in chronic immune activation during HIV infection remains to be fully determined. APCs, the frontline of immune defense against pathogens, are capable of distinguishing between pathogens and non-pathogenic, commensal bacteria. We hypothesized that HIV infection induces dysfunction in APC immune recognition and response to some commensal bacteria and that this may promote chronic immune activation. Therefore we examined APC inflammatory cytokine responses to commensal lactobacilli. We found that APCs from HIV-infected patients produced an enhanced inflammatory response to Lactobacillus plantarum WCFS1 as compared to APCs from healthy, HIV-negative controls. Increased APC expression of TLR2 and CD36, signaling through p38-MAPK, and decreased expression of MAP kinase phosphatase-1 (MKP-1) in HIV infection was associated with this heightened immune response. Our findings suggest that chronic HIV infection enhances the responsiveness of APCs to commensal lactobacilli, a mechanism that may partly contribute to chronic immune activation.
While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI).
Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide.
Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.
It is difficult to longitudinally characterize cognitive impairment in amyotrophic lateral sclerosis (ALS) due to motor deficits, and existing instruments aren’t comparable with assessments in other dementias.
The ALS Brief Cognitive Assessment (ALS-BCA) was validated in 70 subjects (37 with ALS) who also underwent detailed neuropsychological analysis. Cognitive predictors for poor survival were then analyzed in a longitudinal cohort of 171 ALS patients.
The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D). ALS-D patients had shorter overall survival, primarily due to the poor survival among ALS-D patients with disinhibited or apathetic behaviors after adjusting for demographic variables, ALS site of onset, medications, and supportive measures. ALS-D without behavioral changes was not a predictor of poor survival.
ALS-D can present with or without prominent behavioral changes. Cognitive screening in ALS patients should focus on behavioral changes for prognosis, while non-behavioral cognitive impairments may impact quality of life without impacting survival.
The effects of applying clinical versus neuropathological diagnosis and the inclusion of cases with coincident neuropathological diagnoses have not been assessed specifically when studying cerebrospinal fluid (CSF) biomarker classification cutoffs for patients with neurodegenerative diseases that cause dementia. Thus, 142 neuropathologically diagnosed neurodegenerative dementia patients [71 Alzheimer’s disease (AD), 29 frontotemporal lobar degeneration (FTLD), 3 amyotrophic lateral sclerosis, 7 dementia with Lewy bodies, 32 of which cases also had coincident diagnoses] were studied. 96 % had enzyme-linked immunosorbant assay (ELISA) CSF data and 77 % had Luminex CSF data, with 43 and 46 controls for comparison, respectively. Aβ42, total, and phosphorylated tau181 were measured. Clinical and neuropathological diagnoses showed an 81.4 % overall agreement. Both assays showed high sensitivity and specificity to classify AD subjects against FTLD subjects and controls, and moderate sensitivity and specificity for classifying FTLD subjects against controls. However, among the cases with neuropathological diagnoses of AD plus another pathology (26.8 % of the sample), 69.4 % (ELISA) and 96.4 % (Luminex) were classified as AD according to their biomarker profiles. Use of clinical diagnosis instead of neuropathological diagnosis led to a 14–17 % underestimation of the biomarker accuracy. These results show that while CSF Aβ and tau assays are useful for diagnosis of AD and neurodegenerative diseases even at MCI stages, CSF diagnostic analyte panels that establish a positive diagnosis of Lewy body disease and FTLD are also needed, and must be established based on neuropathological rather than clinical diagnoses.
Biomarker; Cerebrospinal fluid; Alzheimer’s disease; Frontotemporal lobar degeneration; Amyloid beta; Tau
Neuronal and glial changes associated with tau, TAR DNA binding protein of ~43 kD (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice.
Biomarker; diagnosis; frontotemporal dementia; tau; tauopathy; TDP-43
TAR DNA binding protein-43 (TDP-43) immunoreactive neuronal inclusions are detected in 20–30% of Alzheimer disease (AD) brains, but the distribution of this pathology has not been rigorously studied. In this report we describe region-specific distribution and density of TDP-43 positive neuronal cytoplasmic inclusions (NCIs) in clinically demented individuals with high probability AD pathology, all with Braak neurofibrillary tangle stages of V or VI. Sections of hippocampus, amygdala, as well as temporal, frontal and parietal neocortex were analyzed with TDP-43 immunohistochemistry, and the density of NCIs was assessed using a semiquantitative scoring method. Of the 29 cases, 6 had TDP-43 positive NCIs in the amygdala only, and 7 had TDP-43 inclusions restricted to amygdala and hippocampus. In 16 cases TDP-43 immunoreactivity was more widespread, affecting temporal, frontal or parietal neocortex. These findings indicate that medial temporal lobe limbic structures are vulnerable to TDP-43 pathology in advanced AD, and that the amygdala appears to be the most vulnerable region. The distribution of the lesions in this cross-sectional analysis may suggest a progression of TDP-43 pathology in AD, with limbic structures in the medial temporal lobe affected first followed by higher order association cortices.
Amygdala; FTLD-U; FTLD-MND; frontotemporal dementia; motor neuron disease
Most people with Parkinson's disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD.
A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, i.e. proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients.
Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p<0.001); many of the other 10 analytes co-varied with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an eightfold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients.
Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.
Epidermal growth factor; EGF; Parkinson's Disease; Parkinson's Disease with Dementia; Biomarker; Plasma
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
Three Indian rhesus macaques, Ad-SIV primed/protein boosted and exposed twice to high-dose mucosal SIVmac251 challenges, exhibited elite control of viremia over 6½ years. They were negative for host factors associated with control of SIV infection. After a third intrarectal challenge with SIVsmE660, all controlled viremia, with one (macaque #5) maintaining undetectable viremia in blood. Acquisition was not blocked, but virus was contained in the jejunum and draining lymph nodes. Polyfunctional memory T cell responses and high-titered neutralizing and non-neutralizing serum and mucosal antibodies were present before and maintained post-challenge. The level of protection seen for animal #5 was predicted from analyses of gene transcription in jejunum 2 weeks post-challenge. Macaques #7 and #9, exhibiting lower pre-challenge cellular and humoral immunity, partially controlled the SIVsmE660 challenge. Initial vaccine-induced control by macaque #5 extended to the SIVsmE660 challenge due to multiple immune mechanisms that were boosted and augmented by cryptic SIV exposure.
SIV; elite-control; virus sequestration; multifaceted immunity; vaccine; memory
We compare patterns of grey matter loss on MRI in subjects presenting as corticobasal syndrome (CBS) with Alzheimer disease pathology (CBS-AD) to those presenting as CBS with corticobasal degeneration pathology (CBS-CBD). Voxel-based morphometry was used to compare patterns of grey matter loss in pathologically confirmed CBS-AD subjects (n=5) and CBS-CBD subjects (n=6) to a group of normal controls (n=20), and to each other. Atlas based parcellation using the automated anatomic labeling atlas was also utilized in a region-of-interest analysis to account for laterality. The CBS-AD subjects were younger at the time of scan compared to CBS-CBD subjects (median: 60 years vs 69; P=0.04). After adjusting for age at time of MRI scan, the CBS-AD subjects showed loss in posterior frontal, temporal, and superior and inferior parietal lobes, while CBS-CBD showed more focal loss predominantly in the posterior frontal lobes, compared to controls. In both CBS-AD and CBS-CBD groups there was basal ganglia volume loss, yet relative sparing of hippocampi. On direct comparisons between the two subject groups, CBS-AD showed greater loss in both temporal and inferior parietal cortices than CBS-CBD. No regions showed greater loss in the CBS-CBD group compared to the CBS-AD group. These findings persisted when laterality was taken into account. In subjects presenting with CBS, prominent temporoparietal, especially posterior temporal and inferior parietal, atrophy may be a clue to the presence of underlying AD pathology.
Voxel based morphometry; Alzheimer’s disease; Corticobasal syndrome; Corticobasal degeneration; Region-of-Interest
TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLDTDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.
TMEM106B; Frontotemporal lobar; degeneration; Amyotrophic lateral sclerosis; Cognitive impairment; Frontotemporal dementia; FTLD-TDP; ALS; TDP-43
Ante-mortem diagnosis of neurodegenerative disorders based on clinical features alone is associated with variable sensitivity and specificity, and biomarkers can potentially improve the accuracy of clinical diagnosis. In patients suspected of having Alzheimer’s disease (AD), alterations in cerebrospinal fluid (CSF) biomarkers that reflect the neuropathologic changes of AD strongly support the diagnosis, although there is a trade-off between sensitivity and specificity due to similar changes in cognitively healthy subjects. Here we review the current approaches in using CSF AD biomarkers (total tau, p-tau181, and Aβ42) to predict the presence of AD pathology, and our recent work using multi-analyte profiling to derive novel biomarkers for biofluid-based AD diagnosis. We also review our use of the multi-analyte profiling strategy to identify novel biomarkers that can distinguish between subtypes of frontotemporal lobar degeneration, and those at risk of developing cognitive impairment in Parkinson’s disease. Multi-analyte profiling is a powerful tool for biomarker discovery in complex neurodegenerative disorders, and analytes associated with one or more diseases may shed light on relevant biological pathways and potential targets for intervention.
Biomarker; diagnosis; Alzheimer’s disease; frontotemporal dementia; Lewy bodie; tau; tauopathy; TDP-43
Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43– and ubiquitin-immunoreactive pathologic lesions.
To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis.
Design, Setting, and Patients
Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries.
Main Outcome Measures
Clinical phenotypes and survival patterns of patients.
A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P<.001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P=.005).
Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.
Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer’s disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Aβ42, tau and p-tau181). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Aβ42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1α), but not in cognitively normal subjects. A multiprong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1α, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1α and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.
Amyloid beta; Abeta42; Diagnosis; IL-1α; MCI; NrCAM; PDGF; Resistin; TECK; TDP-43; Tau
Human intestinal macrophages contribute to tissue homeostasis in noninflamed mucosa through profound down-regulation of pro-inflammatory cytokine release. Here, we show that this down-regulation extends to Toll-like receptor (TLR)-induced cytokine release, as intestinal macrophages expressed TLR3–TLR9 but did not release cytokines in response to TLR-specific ligands. Likely contributing to this unique functional profile, intestinal macrophages expressed markedly down-regulated adapter proteins MyD88 and Toll interleukin receptor 1 domain-containing adapter-inducing interferon β, which together mediate all TLR MyD88-dependent and -independent NF-κB signaling, did not phosphorylate NF-κB p65 or Smad-induced IκBα, and did not translocate NF-κB into the nucleus. Importantly, transforming growth factor-β released from intestinal extracellular matrix (stroma) induced identical down-regulation in the NF-κB signaling and function of blood monocytes, the exclusive source of intestinal macrophages. Our findings implicate stromal transforming growth factor-β-induced dysregulation of NF-κB proteins and Smad signaling in the differentiation of pro-inflammatory blood monocytes into noninflammatory intestinal macrophages.
Cytokines/TGFbeta; Development Differentiation/Tissue; Immunology/Innate Immunity; Immunology/LPS; Immunology/Toll Receptors; Signal Transduction; Intestine; Mucosal
TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately 1/4 of subjects with pathologically confirmed Alzheimer's disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine if subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging or pathological features compared to subjects with AD without abTDP-43 immunoreactivity.
Eighty-four subjects were identified that had a pathological diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data was collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared to age and gender matched controls.
Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death, and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared to controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathological predictor of abTDP-43 immunoreactivity.
The presence of abTDP-43 immunoreactivity is associated with a modified AD clinicopathological and radiological phenotype.
The pathology causing progressive aphasia is typically a variant of frontotemporal lobar degeneration, especially with ubiquitin-positive-inclusions (FTLD-U). Less commonly the underlying pathology is Alzheimer disease (AD).
To compare clinicopathological and MRI features of subjects with progressive aphasia and AD pathology, to subjects with aphasia and FTLD-U pathology, and subjects with typical AD.
We identified 5 subjects with aphasia and AD pathology and 5 with aphasia and FTLD-U pathology with an MRI from a total of 216 aphasia subjects. Ten subjects with typical AD clinical features and AD pathology were also identified. All subjects with AD pathology underwent pathological re-analysis with TDP-43 immunohistochemistry. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aphasia cases with AD pathology, aphasia cases with FTLD-U, and typical AD cases with AD pathology, compared to a normal control group.
All aphasic subjects had fluent speech output. However, those with AD pathology had better processing speed than those with FTLD-U pathology. Immunohistochemistry with TDP-43 antibodies was negative. VBM revealed grey matter atrophy predominantly in the temporoparietal cortices with notable sparing of the hippocampus in the aphasia with AD subjects. In comparison, the aphasic subjects with FTLD-U showed sparing of the parietal lobe. Typical AD subjects showed temporoparietal and hippocampal atrophy.
A temporoparietal pattern of atrophy on MRI in patients with progressive fluent aphasia and relatively preserved processing speed is suggestive of underlying AD pathology rather than FTLD-U.
Primary progressive aphasia; Progressive non-fluent aphasia; Logopenic progressive aphasia; frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes; Voxel based morphometry