The cerebrospinal fluid neurogranin (Ng)/β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) ratio may reflect synaptic affection resulting from reduced beta-amyloid (Aβ) clearance. We hypothesize that increased Ng/BACE1 ratio predicts the earliest cognitive decline in Alzheimer's disease.

Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.

Recent findings of morphological and functional changes in Parkinson's disease brains have shown altered synapse formation, but their role in cognitive decline is still an area under exploration. Here we measured the concentration of three key synaptic proteins, Rab3A, SNAP25 and neurogranin by enzyme-linked immunosorbent assay, in cerebrospinal fluid from a total of 139 participants (87 controls and 52 Parkinson's disease patients out of which 30 were drug-naïve) and explored their associations with motor and cognitive symptoms. Associations with motor disease stage (assessed by Hoehn and Yahr scale) and cognitive performance (assessed by the Montreal Cognitive Assessment scores) were explored. An overall increase in the concentration of SNAP25 was found in Parkinson's disease patients (p = 0.032). Increased neurogranin levels were found in the drug naïve patients subgroup (p = 0.023). Significant associations were observed between increased concentration of neurogranin and cognitive impairment in total Parkinson's disease group (p = 0.017), as well as in the drug naïve (p = 0.021) and with motor disease stage (p = 0.041). There were no significant disease-driven changes observed in the concentration of Rab3a. Concentrations SNAP25 and neurogranin were increased in cerebrospinal fluid of Parkinson's disease patients in a disease specific manner and related to cognitive and motor symptom severity. Future longitudinal studies should explore whether cerebrospinal fluid synaptic proteins can predict cognitive decline in Parkinson's disease.

Cognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid-β species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid-β release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid-β, and presynaptic deposits of α-synuclein. We expect a correlation between hypometabolism, CSF amyloid-β, and the synapse related-markers CSF neurogranin and α-synuclein.

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as "predementia AD with depression".

Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA-containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α-synuclein-containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post-mortem samples from the parietal cortex of 25 DLB patients and 17 age-matched controls were processed for phospholipidomics analyses using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA-phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA-phospholipid species were subsequently validated with further LC-MS/MS measurements. Of the DHA-containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta-amyloid (Aβ42) levels, whilst three also correlated with phosphorylated α-synuclein (all p < 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p < 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets.