...the clinical diagnosis of progressive supranuclear palsy is commonly associated with accumulation of misfolded tau pathology in the cerebrum and brainstem. ...because of the relatively early age ...of onset in affected individuals (typically age >65 years), progressive supranuclear palsy is usually a monoproteinopathy with little secondary co-pathology that could contribute to clinical disease. Demographic characteristics were representative of individuals with so-called typical progressive supranuclear palsy, and eligibility criteria included people with a diagnosis of possible progressive supranuclear palsy (who had either vertical supranuclear gaze palsy or postural instability with falls);6 however, diagnosis of progressive supranuclear palsy can be delayed, and the criteria for possible progressive supranuclear palsy could benefit from being updated, according to observations that allow earlier diagnosis with improved sensitivity.7 Among the features that could be helpful for earlier diagnosis are the presence of corticobasal syndrome, progressive gait freezing, a non-fluent speech or language disorder, or a frontal cognitive or behavioural disorder.
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene (GRN) causing impaired ...production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of >800 microRNAs (miRs), we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with <50% normal expression levels of three members of the microRNA-132 cluster (microRNA-132, microRNA-132*, and microRNA-212) in disease. Computational analyses, corroborated empirically, demonstrate that the top mRNA target of both microRNA-132 and microRNA-212 is TMEM106B; both microRNAs repress TMEM106B expression through shared microRNA-132/212 binding sites in the TMEM106B 3'UTR. Increasing TMEM106B expression to model disease results in enlargement and poor acidification of endo-lysosomes, as well as impairment of mannose-6-phosphate-receptor trafficking. Finally, endogenous neuronal TMEM106B colocalizes with progranulin in late endo-lysosomes, and TMEM106B overexpression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant overexpression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miR-based therapies in FTLD-TDP.
Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating ...brain-enriched microRNAs as potential biomarkers for Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).
In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer's Disease Center, the Parkinson's Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic. Each group was randomly divided into training and confirmation sets of equal size. To evaluate the potential of circulating microRNAs enriched in specific brain regions affected by NDs and present in synapses as biomarkers of NDs, the levels of 37 brain-enriched and inflammation-associated microRNAs in the plasma of all participants were measured using individual qRT-PCR. A "microRNA pair" approach was used for data normalization.
MicroRNA pairs and their combinations (classifiers) capable of differentiating NDs from control and from each other were defined using independently and jointly analyzed training and confirmation datasets. AD, PD, FTD, and ALS are differentiated from control with accuracy of 0.89, 0.90, 0.88, and 0.83 (AUCs, 0.96, 0.96, 0.94, and 0.93), respectively; NDs are differentiated from each other with accuracy ranging from 0.77 (AUC, 0.87) for AD vs. FTD to 0.93 (AUC, 0.98) for AD vs. ALS. The data further indicate sex dependence of some microRNA markers. The average increase in accuracy in distinguishing ND from control for all and male/female groups is 0.06; the largest increase is for ALS, from 0.83 for all participants to 0.92/0.98 for male/female participants.
The work presented here suggests the possibility of developing microRNA-based diagnostics for detection and differentiation of NDs. Larger multicenter clinical studies are needed to further evaluate circulating brain-enriched microRNAs as biomarkers for NDs and to investigate their association with other ND biomarkers in clinical trial settings.
Objective
To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP‐43 (FTLD‐TDP) or tau (FTLD‐Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using ...digital histopathology and to identify clinicopathological correlates of these distinct proteinopathies.
Methods
In an autopsy cohort of PPA (FTLD‐TDP = 13, FTLD‐Tau = 14), we analyzed laterality and regional distribution of postmortem pathology, quantified using a validated digital histopathological approach, in available brain tissue from up to 8 cortical regions bilaterally. We related digital pathology to antemortem structural neuroimaging and specific clinical language features.
Results
Postmortem cortical pathology was left‐lateralized in both FTLD‐TDP (beta = −0.15, standard error SE = 0.05, p = 0.007) and FTLD‐Tau (beta = −0.09, SE = 0.04, p = 0.015), but the degree of lateralization decreased with greater overall dementia severity before death (beta = −8.18, SE = 3.22, p = 0.015). Among 5 core pathology regions sampled, we found greatest pathology in left orbitofrontal cortex (OFC) in FTLD‐TDP, which was greater than in FTLD‐Tau (F = 47.07, df = 1,17, p < 0.001), and in left midfrontal cortex (MFC) in FTLD‐Tau, which was greater than in FTLD‐TDP (F = 19.34, df = 1,16, p < 0.001). Postmortem pathology was inversely associated with antemortem magnetic resonance imaging cortical thickness (beta = −0.04, SE = 0.01, p = 0.007) in regions matching autopsy sampling. Irrespective of PPA syndromic variant, single‐word comprehension impairment was associated with greater left OFC pathology (t = −3.72, df = 10.72, p = 0.004) and nonfluent speech with greater left MFC pathology (t = −3.62, df = 12.00, p = 0.004) among the 5 core pathology regions.
Interpretation
In PPA, FTLD‐TDP and FTLD‐Tau have divergent anatomic distributions of left‐lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits. Although other brain regions may be implicated in neural networks supporting these complex language measures, our observations may eventually help to improve antemortem diagnosis of neuropathology in PPA. Ann Neurol 2019;85:630–643
C9orf72
promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether
C9orf72
hypermethylation is associated with prolonged ...disease in
C9orf72
mutation carriers.
C9orf72
methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118
C9orf72
repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether
C9orf72
hypermethylation was associated with age at onset, disease duration, age at death, or hexanucleotide repeat expansion size. Permutation analysis was performed to determine whether
C9orf72
methylation is heritable. We observed a high correlation between
C9orf72
methylation across tissues including cerebellum, frontal cortex, spinal cord and peripheral blood. While
C9orf72
methylation was not significantly different between ALS and FTD and did not predict age at onset, brain and blood
C9orf72
hypermethylation was associated with later age at death in FTD (brain:
β
= 0.18,
p
= 0.006; blood:
β
= 0.15,
p
< 0.001), and blood
C9orf72
hypermethylation was associated with longer disease duration in FTD (
β
= 0.03,
p
= 0.007). Furthermore,
C9orf72
hypermethylation was associated with smaller hexanucleotide repeat length (
β
= −16.69,
p
= 0.033). Finally, analysis of pedigrees with multiple mutation carriers demonstrated a significant association between
C9orf72
methylation and family relatedness (
p
< 0.0001).
C9orf72
hypermethylation is associated with prolonged disease in
C9orf72
repeat expansion carriers with FTD. The attenuated clinical phenotype associated with
C9orf72
hypermethylation suggests that slower clinical progression in FTD is associated with reduced expression of mutant
C9orf72
. These results support the hypothesis that expression of the hexanucleotide repeat expansion is associated with a toxic gain of function.
Primary Progressive Aphasia and Stroke Aphasia Grossman, Murray; Irwin, David J
Continuum (Minneapolis, Minn.),
06/2018, Letnik:
24, Številka:
3, BEHAVIORAL NEUROLOGY AND PSYCHIATRY
Journal Article
Odprti dostop
This article summarizes the clinical and anatomic features of the three named variants of primary progressive aphasia (PPA): semantic variant PPA, nonfluent/agrammatic variant PPA, and logopenic ...variant PPA. Three stroke aphasia syndromes that resemble the PPA variants (Broca aphasia, Wernicke aphasia, and conduction aphasia) are also presented.
Semantic variant PPA and Wernicke aphasia are characterized by fluent speech with naming and comprehension difficulty; these syndromes are associated with disease in different portions of the left temporal lobe. Patients with nonfluent/agrammatic variant PPA or Broca aphasia have nonfluent speech with grammatical difficulty; these syndromes are associated with disease centered in the left inferior frontal lobe. Patients with logopenic variant PPA or conduction aphasia have difficulty with repetition and word finding in conversational speech; these syndromes are associated with disease in the left inferior parietal lobe. While PPA and stroke aphasias resemble one another, this article also presents their distinguishing features.
Primary progressive and stroke aphasia syndromes interrupt the left perisylvian language network, resulting in identifiable aphasic syndromes.
We have recently shown acetylation of tau at lysine residue 280 (AC-K280) to be a disease-specific modification in Alzheimer disease (AD), corticobasal degeneration, and progressive supranuclear ...palsy, likely representing a major regulatory tau modification. Herein, we extend our observations using IHC with a polyclonal antibody specific for AC-K280. Thirty brain regions were examined in argyrophilic grain disease (AGD; n = 5), tangle-predominant senile dementia (TPSD; n = 5), Pick disease ( n = 4), familial AD (FAD; n = 2; PSEN1 p.G206A and p.S170P), and frontotemporal dementia with parkinsonism linked to chromosome-17 (FTDP-17; n = 2; MAPT p.P301L and IVS10 + 16). All AGD, TPSD, FAD, and FTDP-17 cases had significant AC-K280 reactivity that was similar in severity and distribution to phosphorylated tau. AC-K280 robustly labeled grain pathological characteristics in AGD and was predominantly associated with thioflavin-S–positive neurofibrillary tangles and less reactive in neuropil threads and extracellular tangles in TPSD and FAD. Thioflavin-S–negative neuronal and glial inclusions of patients with FTDP-17 were robustly AC-K280 reactive. A low degree of AC-K280 was found in a subset of 4-repeat tau-containing lesions in Pick disease. AC-K280 is a prominent feature of both neuronal and glial tau aggregations in tauopathies of various etiologies. The close association of AC-K280 with amyloid and pre-amyloid conformations of tau suggests a potential role in tangle maturation and, thus, could serve as a useful biomarker or therapeutic target in a variety of tauopathies.
The primary aims of this work were to: 1) establish a calibrator surrogate matrix for quantification of amyloid-β (Aβ)42 in human cerebrospinal fluid (CSF) and preparation of quality control samples ...for LC-MS-MS methodology, 2) validate analytical performance of the assay, and 3) evaluate its diagnostic utility and compare it with the AlzBio3 immunoassay. The analytical methodology was based on a 2D-UPLC-MS-MS platform. Sample pretreatment used 5 M guanidine hydrochloride and extraction on μElution SPE columns as previously described. A column cleaning procedure involved gradual removal of aqueous solvents by acetonitrile assured consistent long-term chromatography performance. Receiver-operator characteristic (ROC) curve and correlation analyses evaluated the diagnostic utility of UPLC-MS-MS compared to AlzBio3 immunoassay for detection of Alzheimer's disease (AD). The surrogate matrix, artificial CSF containing 4 mg/mL of BSA, provides linear and reproducible calibration comparable to human pooled CSF as calibration matrix. Appropriate cleaning of the trapping and analytical columns provided every-day, trouble-free runs. Analyses of CSF Aβ42 showed that UPLC-MS-MS distinguished neuropathologically-diagnosed AD subjects from healthy controls with at least equivalent diagnostic utility to AlzBio3. Comparison of ROC curves for these two assays showed no statistically significant difference (p = 0.2229). Linear regression analysis of Aβ42 concentrations measured by this mass spectrometry-based method compared to the AlzBio3 immunoassay showed significantly higher but highly correlated results. In conclusion, the newly established surrogate matrix for 2D-UPLC-MS-MS measurement of Aβ42 provides selective, reproducible, and accurate results. The documented analytical performance and diagnostic performance for AD versus controls supports consideration as a candidate reference method.
Summary Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric ...symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. Methods We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov , number NCT00545974. Findings Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI −3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, −0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). Interpretation Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. Funding Forest Research Institute.
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. Aβ
42
, total, and phosphorylated tau
181
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.
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