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Introduction: The level of the presynaptic protein growth‐associated protein 43 (GAP‐43) in cerebrospinal fluid (CSF) has previously been shown to be increased in Alzheimer's disease (AD) and thus may serve as an outcome measure in clinical trials and facilitate earlier disease detection. Methods: We developed an enzyme‐linked immunosorbent assay for CSF GAP‐43 and measured healthy controls (n = 43), patients with AD (n = 275), or patients with other neurodegenerative diseases (n = 344). In a subpopulation (n = 93), CSF GAP‐43 concentrations from neuropathologically confirmed cases were related to Aβ plaques, tau, α‐synuclein, and TDP‐43 pathologies. Results: GAP‐43 was significantly increased in AD compared to controls and most neurodegenerative diseases and correlated with the magnitude of neurofibrillary tangles and Aβ plaques in the hippocampus, amygdala, and cortex. GAP‐43 was not associated to α‐synuclein or TDP‐43 pathology. Discussion: The presynaptic marker GAP‐43 is associated with both diagnosis and neuropathology of AD and thus may be useful as a sensitive and specific biomarker for clinical research. [ABSTRACT FROM AUTHOR]

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology. [ABSTRACT FROM AUTHOR]

Introduction: The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1–42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α‐synuclein [α‐syn] for Lewy body pathology) may be needed to further improve the differential diagnosis. Methods: CSF total α‐syn, phosphorylated α‐syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays in 367 participants, followed by validation in 74 different neuropathologically confirmed cases. Results: CSF total α‐syn, when combined with amyloid β peptide 1–42 and either total tau or phosphorylated tau, improved the differential diagnosis of AD versus frontotemporal dementia, Lewy body disorders, or other neurological disorders. The diagnostic accuracy of the combined models attained clinical relevance (area under curve ∼0.9) and was largely validated in neuropathologically confirmed cases. Discussion: Combining CSF biomarkers representing AD and Lewy body pathologies may have clinical value in the differential diagnosis of AD. [ABSTRACT FROM AUTHOR]

Background: Normal aging and preclinical Alzheimer's Disease (AD) share common features, such as structural changes to medial temporal lobe regions and declining episodic memory. However, prior work suggests qualitative differences between AD‐related memory changes and those due to aging. Specifically, recollection‐based, or contextual, memory declines with both normal aging and AD. Alternatively, familiarity‐based, or item, memory is more specific to preclinical AD and atrophy in the perirhinal cortex. In the current analysis, we examined the relationship between these forms of memory with plasma biomarkers associated with AD and neurodegeneration. Method: At the Penn Alzheimer's Disease Research Center, 127 cognitively‐normal participants (age=73.12±6.62, 59% female, years of education=16.40±2.62, 80% Caucasian) completed an experimental memory paradigm assessing recollection and familiarity along with standard neuropsychological testing. In this paradigm, pictures of common objects were presented in 80 pairs at study and participants were told to pick the object they preferred. At test, 40 intact, 40 re‐arranged, and 40 novel object pairs were presented. Recollection was defined as the probability(intact)–probability(rearranged), while familiarity was defined as the probability(rearranged)/(1‐R). To account for differences in base rates of false alarms ("old" responses to novel pairs), familiarity was calculated using a measure of discrimination (d') derived from signal detection theory. Whole blood samples were collected in EDTA‐tubes, spun‐down, and stored at ‐80°C. Measures of glial fibrillary acidic protein (GFAP), neurofilament light chain (Nfl), and plasma tau (p‐Tau181) were generated with the Simoa HD‐X analyzer system. Result: Familiarity correlated with GFAP (r(125) =‐0.24, p<0.05) (Figure 1) and NfL (r(125) =‐0.23, p<0.05) (Figure 2). Further, a partial correlation controlling for age and days between the experimental and plasma measure remained significant for GFAP (r(125)=‐0.25, p<0.05). Additionally, recollection correlated with Nfl (r(125) =‐0.25, p<0.05) (Figure 3). Correlations with standard neuropsychological tests revealed no significant results. Conclusion: This study reveals that within the normal aging spectrum, familiarity‐based memory correlates with molecular measures that have been associated with amyloid (GFAP), while both measures correlated with a non‐specific measure of neurodegeneration (NfL). This supports the notion that familiarity may be sensitive to preclinical AD. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of dementia with Lewy bodies (DLB) remains challenging and biomarkers discriminating DLB from Alzheimer's disease (AD) are highly needed. We aimed to establish the specific cerebrospinal fluid (CSF) proteomic changes that underlie DLB and to identify translatable diagnostic biomarkers. Methods: Proximity extension‐based multiplex immunoassays were used to measure 665 proteins in 534 CSF samples from patients with Dementia with Lewy bodies (n=109), AD‐dementia (n=235) and cognitively‐unimpaired controls (CON, n=190) from the Amsterdam Dementia cohort (ADC) and Penn University. An additional multicenter cohort (n=307) from ADC and SPIN was used for validation of custom assays. A positive/negative AD CSF profile supported the diagnosis of AD and CON respectively. Results: Nested linear models identified 97 CSF proteins with altered abundance in DLB compared to controls (p<0.05). After comparison with the AD CSF proteome, we observed that 52 of these proteins (54%) were especially associated to DLB (e.g. DDC, GH, FCER2, MMP1), while 15 proteins (16%) showed opposite changes to those detected in AD patients (CRH, MMP3). The protein with the highest fold‐changed observed in DLB was L‐amino acid decarboxylase (DDC; >1.5 fold‐change vs.CN or AD; q<1E‐16), an enzyme involved in dopamine biosynthesis. DDC could optimally discriminate DLB from controls and AD patients (AUC: 0.91 and 0.81 respectively). Using penalized generalized linear modelling we identified a panel of 7‐CSF markers including DDC that could discriminate DLB from AD patients with high accuracy (AUC: 0.93, 95%CI: 0.86‐0.98), which have been successfully translated into customized multiplex assays (correlations > 0.84 with discovery measurements). Conclusions: We unveil CSF changes specifically related to DLB and identified a panel of 7‐CSF markers associated to several aspects of DLB pathophysiology that enables discrimination of these dementia types with high accuracy. Multiplex custom assays containing these markers are currently being clinically validated in independent cohorts for their potential use in diagnostic settings or clinical trials. [ABSTRACT FROM AUTHOR]

Background: Biomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) with tau (FTLD‐tau) from TDP‐43 (FTLD‐TDP). In FTLD patients with autopsy‐ or mutation‐confirmed pathology, we tested the glial fibrillary acidic protein (GFAP) to neurofilament light chain (NfL) ratio (GFAP/NfL) in plasma. We validated application of GFAP/NfL ratio in an independent sample of frontotemporal dementia (FTD). Methods: Training sample was composed of 105 FTLD‐TDP and 44 FTLD‐tau participants, with pathology confirmed by either autopsy or pathogenic mutations (MAPT, C9orf72, GRN, TARDBP). Average accumulations of postmortem tau, TDP‐43, and amyloid across neocortical, limbic and brainstem regions were scored on a 0‐3 scale. Regression tested differences in analytes (log transformed) across FTLD‐tau and FTLD‐TDP, covarying for age, interval to death, and sex. Regression tested association of analytes (log transformed) with postmortem tau and TDP‐43 accumulation, covarying for postmortem amyloid‐β and plasma‐to‐death interval. Receiver operating characteristic (ROC) analyses and area under the curve (AUC) analyses were performed in patients with negligible secondary pathology. We defined an optimal cut‐point to discriminate FTLD‐tau from FTLD‐TDP using plasma GFAP/NfL. We tested the defined cut‐point in an independent validation sample of FTD patients with a clinical diagnosis of progressive supranuclear palsy (PSP) with likely tau (FTD‐tau; n=33) or diagnosis of amytrophic lateral sclerosis (ALS) with likely TDP‐43 (FTD‐TDP; n=35). Results: Plasma GFAP was lower in FTLD‐TDP than FTLD‐tau (β=‐0.24, p=0.021) with small effect size (partial η2=0.082). Plasma NfL was higher in FTLD‐TDP than FTLD‐tau (β=0.57, p=1.0e‐05) with medium effect size (partial η2=0.24). GFAP/NfL was significantly lower in FTLD‐TDP than FTLD‐tau (β=‐0.82, SE=0.13, p=2.2e‐09) with large effect size (partial η2=0.39). Higher plasma GFAP was associated with higher postmortem tau accumulation (β=0.15, p=0.032). Higher levels of plasma NfL were associated with increased TDP‐43 burden (β=0.2, p=0.024). ROC revealed excellent discrimination by plasma GFAP/NfL in the autopsy/test sample (AUC=0.89). In the validation sample, plasma GFAP/NfL had good overall discrimination accuracy (AUC=0.85); there was 0.79 sensitivity and 0.77 specificity when applying the training‐derived GFAP/NfL threshold. Conclusion: Plasma GFAP and NfL relate to pathological accumulation of tau and TDP‐43, respectively. The plasma ratio of GFAP/NfL is a promising candidate to discriminate FTLD‐tau from FTLD‐TDP. [ABSTRACT FROM AUTHOR]

Objective Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. Methods We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein ( SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Results Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts ( P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum ( P = 0.005). Interpretation Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine. [ABSTRACT FROM AUTHOR]

The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ, or highest t-tau/Aβ and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance. [ABSTRACT FROM AUTHOR]

Objective Cognitive decline occurs in multiple neurodegenerative diseases, including Alzheimer's disease ( AD) and Parkinson's disease ( PD). Shared underlying mechanisms may exist and manifest as shared biomarker signatures. Previously, we nominated plasma epidermal growth factor ( EGF) as a biomarker predicting cognitive decline in patients with established PD. Here, we investigate EGF as a predictive biomarker in prodromal PD, as well as AD. Methods A cohort of PD patients ( n = 236) was recruited to replicate our finding that low baseline EGF levels predict future cognitive decline. Additionally, plasma EGF and cognitive outcome measures were obtained from individuals with normal cognition ( NC, n = 58), amnestic mild cognitive impairment ( AD- MCI, n = 396), and Alzheimer's disease ( AD, n = 112) in the Alzheimer's Disease Neuroimaging Initiative ( ADNI) cohort to investigate whether low EGF levels correlate with cognitive status and outcome in AD- MCI and AD. Third, plasma EGF and cognitive measures were evaluated in the high-risk asymptomatic Parkinson's Associated Risk Study ( PARS) cohort ( n = 165) to investigate the association of EGF and cognitive performance in a PD prodromal context. Results In both PD and AD- MCI, low baseline plasma EGF predicted poorer long-term cognitive outcomes. In asymptomatic individuals at highest risk for developing PD from the PARS cohort, low baseline plasma EGF associated with poorer performance in the visuospatial domain but not in other cognitive domains. Interpretation Low plasma EGF at baseline predicts cognitive decline in both AD and PD. Evidence for this signal may exist in prodromal stages of both diseases. [ABSTRACT FROM AUTHOR]