Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease

Abstract

Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.

Keywords: Alzheimer’s disease; biomarker; cerebrospinal fluid; mild cognitive impairment; neurogranin.

Synaptic dysfunction precedes neurodegeneration and cognitive impairment in Alzheimer’s disease. Portelius et al. show that CSF levels of the postsynaptic protein neurogranin are increased in early-stage Alzheimer’s disease, and that the increase predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.

Figure 1

CSF neurogranin levels in different diagnostic groups. (A) Scatter plots showing CSF neurogranin levels in healthy control, stable MCI (sMCI), progressive MCI (pMCI) and Alzheimer’s disease (AD). Among the healthy control subjects, 32 individuals progressed to MCI or Alzheimer’s disease dementia during follow-up (progressive healthy controls) (B). The data are presented as medians and interquartile ranges. Differences between groups were assessed by linear regression, adjusted for age and sex. *P < 0.05; **P < 0.01; ***P < 0.0001.

Figure 2

Scatter plot showing the subjects included in the study classified as amyloid positive (+) or negative (−) based on a previously established cut-off (CSF amyloid-β₄₂ < 192 pg/ml). The data are presented as medians and interquartile ranges. Differences between groups were assessed by linear regression, adjusted for age and sex. *P < 0.05; **P < 0.01; ***P < 0.001. Ng = neurogranin.

Figure 3

CSF neurogranin levels in relation to tau biomarkers. Correlations between CSF neurogranin levels and total tau and phosphorylated tau in healthy control (A), stable MCI (B), progressive MCI (C) and Alzheimer’s disease (D). Open circles and the solid line represent the correlation between total tau and neurogranin while closed circles and the dashed line represents the correlation between phosphorylated tau and neurogranin. The association between neurogranin and total and phosphorylated tau was investigated with Spearman’s correlation. The regression lines in the figures are only for visualization.

Figure 4

CSF neurogranin in relation to cognition and future cognitive change. MMSE and ADAS-Cog at baseline (A and B) and over time (C and D) as a function of baseline CSF neurogranin (Ng) in different diagnostic groups. Shaded areas indicate 95% confidence interval (CI) of the mean. CN = cognitively normal (green); sMCI = stable MCI (red); pMCI = progressive MCI (blue); AD = Alzheimer’s disease (grey).

Figure 5

CSF neurogranin in relation to brain structure and cognition. Hippocampal volume and FDG-PET at baseline (A and B) and over time (C and D) as a function of baseline CSF neurogranin in different diagnostic groups. Shaded areas indicate 95% CI of the mean. CN = cognitively normal (green); sMCI = stable MCI (red); pMCI = progressive MCI (blue); AD = Alzheimer’s disease (grey).

Figure 6

CSF neurogranin as a predictor of disease progression. The patients were divided into quartiles according to CSF neurogranin levels at baseline. All trend lines were calculated using local regression. (A) Patients with higher levels of CSF neurogranin at baseline have faster disease progression over time as measured by change in MMSE scores. Quartile 1: n = 43, quartile 2: n = 43, quartile 3: n = 42 and quartile 4: n = 45. (B) Patients with higher levels of CSF neurogranin at baseline have faster disease progression over time as measured by change in ADAS-Cog scores. However, Q2 and Q1 overlap. Quartile 1: n = 43, quartile 2: n = 43, quartile 3: n = 42 and quartile 4: n = 45. (C) Generally, patients with higher levels of CSF neurogranin at baseline have faster disease progression over time as measured by hippocampal volume change. However, the patients with the highest levels of CSF neurogranin (Q4) progress slower than Q3. Quartile 1: n = 43, quartile 2: n = 42, quartile 3: n = 42 and quartile 4: n = 43. (D) Patients with higher levels of CSF neurogranin at baseline have faster disease progression over time as measured by change in FDG-PET signals. However, Q3 and Q4 overlap. Quartile 1: n = 19, quartile 2: n = 26, quartile 3: n = 21 and quartile 4: n = 22. SUVR=standardized uptake value ratio.