Clinical Correlates of Cerebrospinal Fluid 14-3-3 Protein in Non-Prion Rapid Progressive Dementia

Abstract

Background:

The 14-3-3 protein in cerebrospinal fluid (CSF) is a suitable biomarker for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, it has also been detected in various non-prion-related rapidly progressive dementia (RPD), which affected its diagnostic performance and clinical utilization.

Objective:

To investigate the general disease distribution with positive 14-3-3 result and to evaluate the association between CSF 14-3-3 protein and the clinical features in patients with non-prion RPD.

Methods:

A total of 150 patients with non-prion RPD were enrolled. The clinical data were collected and CSF 14-3-3 test was performed for all patients. The distribution of various diseases with a positive 14-3-3 result was analyzed and the association of CSF 14-3-3 with clinical features was tested.

Results:

The CSF 14-3-3 protein was detected in 23.3% of non-prion RPD patients, and the most frequent diagnoses were autoimmune encephalitis (22.9%) and neurodegenerative disease (22.9%). CSF 14-3-3 protein was more common in older patients (p = 0.028) and those presenting myoclonus (p = 0.008). In subgroup analysis, the positive 14-3-3 test was more common in neurodegenerative disease with a long time from the symptom onset to CSF 14-3-3 test (p = 0.014).

Conclusion:

CSF 14-3-3 protein could be detected in a broad spectrum of non-prion RPD. In particular, patients with autoimmune encephalitis and rapidly progressive neurodegenerative diseases and those with myoclonus have a greater likelihood of a positive 14-3-3 result. These results could help clinicians interpret the results of CSF 14-3-3 protein more reasonably.

Keywords

14-3-3 protein biomarker cerebrospinal fluid rapidly progressive dementia

INTRODUCTION

Rapidly progressive dementia (RPD) is a cognitive disorder that progresses from an asymptomatic stage to dementia within several weeks to months [1, 2], and it can be triggered by neurodegenerative, autoimmune, infectious, and metabolic diseases. Creutzfeldt-Jakob disease (CJD), a fatal neurodegenerative disorder, is the prototypic diagnosis [3, 4]. It is necessary to differentiate between CJD and non-prion RPD to prevent potential iatrogenic spread and improve patient prognosis. Cerebrospinal fluid (CSF) markers, particularly the 14-3-3 protein, is a widely used biomarker for differential diagnosis.

The 14-3-3 protein is abundantly expressed in the brain and is important for signaling pathways, and cellular growth and apoptosis [5, 6]. It is released into the CSF in response to acute neuronal injury [7, 8] and is considered a reliable surrogate marker of CJD and was included in WHO diagnostic criteria [9 –12]. However, the CSF 14-3-3 protein has been detected in non-prion diseases such as infectious or autoimmune encephalitis, and the specificity was relatively lower (40% –92%) [5 , 13–17]. Furthermore, the sensitivity is relatively lower in Asian cohorts compared to those of the other regions [18 –20]. All these reasons challenge the diagnostic value of CSF 14-3-3 protein. Previous studies have identified some factors that might influence the 14-3-3 results in CJD, such as codon 129 genotype, PrP^Sc type and disease duration [21]. But, hitherto, no study investigated the influencing factors of 14-3-3 protein in non-prion cases. Therefore, it is still unclear whether there is a relationship between CSF 14-3-3 protein and clinical features in the non-prion RPD group.

To this end, our objective was to explore the general distribution of underlying diseases in non-prion RPD positive for the CSF 14-3-3 test and investigate the association between clinical features and positive CSF 14-3-3 in non-prion RPD patients.

METHODS

Ethics statement

This study was approved by the ethics committee of Xuanwu Hospital, Capital Medical University. Written informed consent was provided by all participants and/or their legal next of kin.

Participants

Participants were referred to the Department of Neurology, Xuanwu Hospital, Capital Medical University from 2010 to April 2019. We adopt the generally accepted definition that the interval from the first symptom to dementia onset is measured in weeks or months, with the patients with RPD progressing from independence to complete (or nearly complete) dependence within 1 to 2 years [22]. The patients who were diagnosed with definite and probable prion diseases according to World Health Organization (WHO) criteria at both baseline and follow-up, and who did not undergo CSF 14-3-3 test were excluded [23]. All included patients were followed up for 2 years or until death and the patients who were lost to follow-up were also excluded. Accordingly, 150 patients were enrolled, and the flow chart is shown in Fig. 1.

Fig. 1

Flow diagram of patient enrollment.

The patients included were divided into neurodegenerative diseases, autoimmune encephalitis, infectious diseases, central nervous system (CNS) neoplasms or paraneoplastic diseases, cerebrovascular disease, inherited metabolic diseases, hypoxic-ischemic encephalopathy, and unknown etiologies. Alzheimer’s disease (AD) was diagnosed according to the criteria of the National Institute on Aging and Alzheimer’s Association (NIA-AA), and only A+T+(N)+ cases were enrolled [24]. Frontotemporal degeneration, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal degeneration were diagnosed mainly based on clinical features, neuroimaging examinations, and reasonable exclusion of alternative causes according to the relevant criteria [25 –28]. Autoimmune encephalitis was diagnosed as per the criteria established by Graus et al. [29]. Definite autoimmune encephalitis must find related neuronal antibodies. The National Institute of Neurological and Communicative Disorders and the Stroke Association criteria were used to define vascular dementia [30]. Infectious or neoplastic-related diseases must detect relevant microbiological biomarkers or tumor cells. Inherited metabolic disease should detect relative gene mutations. Hypoxic-ischemic and toxic encephalopathy should have a specific history of hypoxia or toxic exposure apart from relative clinical features and auxiliary examinations.

All diseases were diagnosed by treating clinicians and validated by the study authors. Due to the extremely low rate of brain biopsy or postmortem examinations in China, all patients were followed up for at least 2 years by telephone or face-to-face interviews to improve diagnostic accuracy. We adopted different follow-up protocols according to different diseases, the condition of patients, and the cooperation of patients and their families.

Data collection

Clinical data, including epidemiological information, clinical symptoms and signs, and CSF test results were collected for all enrolled patients. The clinical symptoms and signs included psychiatric anomalies (anxiety, depression, apathy, autism, excitement, disinhibition, abnormal emotion or behavior, change in personality), visual disturbances (deteriorated or blurred vision, restricted visual field, and disturbed perception of structures and colors), visual hallucinations, myoclonus, epilepsy, pyramidal signs (spastic increase of muscle tone and the pyramidal reflexed of Babinski, Oppenheimer and Chaddock), extrapyramidal signs (rigidity, tremor, hypokinesia, dystonia and involuntary movement), disturbed cerebellar movements (ataxia, dysmetria, disdiadochokinesia, and nystagmus), sleep disorders, weakness or sensory disturbance, speech disorders (aphasia and dysarthria), akinetic mutism, and decorticate rigidity. The CSF analyses included white blood cells (pleocytosis, >5 white blood cells/mm³), total protein levels (normal range 15–45 mg/dl), glucose levels (normal range 45–80 mg/dl) and oligoclonal bands. The onset to lumbar puncture (LP) was defined as the time from beginning of the first symptom to LP for the 14-3-3 test.

Detection of 14-3-3 protein in CSF

CSF samples were obtained in our hospital and transferred to the Chinese Center for Disease Control and Prevention (CDC) for the 14-3-3 test. The samples were divided into 50μl aliquots and stored at –80°C. CSF 14-3-3 protein was detected by western blotting. Briefly, 20μl CSF samples were diluted in 5X loading buffer and separated by 12% SDS-PAGE. The protein bands were transferred to nitrocellulose (NC) membranes (Whatman, USA) using the semi-90 dry method in transferring buffer. After blocking, the membranes were incubated for 2 h at room temperature with anti-14-3-3 polyclonal antibody (1:1000; Santa Cruz Biological, Santa Cruz, USA). The membranes were then incubated with goat anti-rabbit HRP-conjugated secondary antibody and the positive bands were detected using an enhanced chemiluminescence kit (Amersham-Pharmacia Biotech, USA). All CSF 14-3-3 result were verified by ELISA methods [31].

Statistical analysis

Continuous variables with normal distribution are presented as the mean±standard deviation (SD), and those not conforming to normal distribution as median and interquartile range (IQR). Categorical data are presented as the frequency (percentage). χ² test or Fisher exact test was used to compare categorical variables including the incidence of symptoms and signs. Mann-Whitney U test was used to compare continuous variables including age and Barthel Index. Forward stepwise logistic regression was used to adjust confounding variables (age, sex, and time from onset of the first symptom to LP). The Kaplan-Meier method was used to evaluate the association between onset to LP and the CSF 14-3-3 test. A two-sided p value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS, version 25.

RESULTS

The disease distribution of non-prion RPD patients with a positive CSF 14-3-3 test

The positive rate of the CSF 14-3-3 protein was 23.3% in the non-prion RPD patients. The percentage of patients that were positive for the 14-3-3 test across different disorders are summarized in Fig. 2. Autoimmune encephalitis (22.9%) and neurodegenerative disease (22.9%) were most common disorders with the CSF 14-3-3 positive result, followed by infectious diseases (11.4%), CNS neoplasm or paraneoplastic diseases (8.6%), inherited metabolic diseases (5.7%), cerebrovascular disease (2.9%), hypoxia-ischemic encephalopathy (2.9%), CNS demyelinating disease (2.9%), and normal pressure hydrocephalus (2.9%). In addition, 17.1% patients with positive 14-3-3 result had unclear diagnosis (Fig. 3). The specific distribution of the underlying diseases in the 14-3-3 positive group are shown in Table 1.

Fig. 2

The positive rate of CSF 14-3-3 test in the different disease subgroups in non-prion RPD patients.

Fig. 3

Distribution of non-prion pathologies among the RPD patients with positive 14-3-3 test.

Table 1

The 14-3-3 protein in CSF in non-prion RPD patients

Neurological disease	Positive/Total
	14-3-3 test (%)
	(n = 150)
Autoimmune encephalitis	8/38 (21.1%)
NMDAR	2/9
LGI1	5/18
AMPAR	0/1
GFAP	1/2
Hashimoto’s encephalopathy	0/5
Autoantibody-negative autoimmune encephalitis	0/1
Neurodegenerative disease	8/29 (27.6%)
AD	5/17
FTD	1/7
CBD	2/3
PSP	0/1
DLB	0/1
Infectious disease	4/17 (23.5%)
Neurosyphilis	1/5
Viral encephalitis	2/10
Brucellosis	0/1
Neurocysticercosis	1/1
CNS neoplasm or paraneoplastic disease	3/10 (30%)
Primary central nervous system lymphoma	1/2
Meningeal carcinomatosis	1/1
Brain metastasis of lung cancer	0/1
Paraneoplastic syndrome	1/6
Cerebrovascular disease	1/5 (20%)
Vascular dementia	1/4
Binswanger disease	0/1
Inherited metabolic disease	2/5 (40%)
Mitochondrial encephalomyopathy	2/4
Encephalofacial angiomatosis	0/1
Hypoxic-ischemic encephalopathy	1/5 (20%)
Other diagnosis	2/15 (13.3%)
Drug or alcoholic toxic encephalopathy	0/4
CNS demyelinating disease	1/3
Encephalitis with unknown cause	0/3
Nutritional Disorders	0/2
Myelodysplastic syndrome	0/1
Normal pressure hydrocephalus	1/1
Subdural effusion combined with FTD	0/1
Unknown	6/26 (23.1%)

AD, Alzheimer’s disease; FTD, frontotemporal degeneration; DLB, dementia with Lewy bodies; PSP, progressive supranuclear palsy; CBD, corticobasal degeneration; CNS, central nervous system

Correlation between clinical features and CSF 14-3-3 status in non-prion RPD patients

Among the non-prion RPD patients, the median age of the patients with a positive 14-3-3 result [median (IQR):61 (53–67) year] was significantly higher than that of patients with a negative 14-3-3 result [median (IQR):57 (48–66) year, p = 0.028], while sex ratio was similar in both groups. Myoclonus was more frequently observed in 14-3-3-positive patients compared to the 14-3-3-negative patients (45.7% versus 22.6% respectively, p = 0.008), while the frequency of other symptoms and signs were similar in both groups. The results are summarized in Table 2. After adjusting for confounding variables including sex, age, and time from onset to LP, the patients with myoclonus still had higher positive rate of CSF 14-3-3 protein (OR = 3.079, 95% CI 1.355–6.998, p = 0.007).

Table 2

Clinical characteristics of non-prion RPD patients demarcated on the basis of CSF 14-3-3 results

	14-3-3(–)	14-3-3(+)	p
No, %	115 (76.7)	35 (23.3)
Sex (male/female)	83/32	21/14	0.171
Age, y, [median (IQR)]	57.0 (48.0–66.0)	61.0 (53.0–67.0)	0.028
Psychiatric, %	80 (69.6)	29 (82.9)	0.122
Visual disorder, %	11 (9.6)	3 (8.6)	1.000
Visual hallucination, %	11 (9.6)	4 (11.4)	0.751
Myoclonus, %	26 (22.6)	16 (45.7)	0.008
Epilepsy, %	27 (23.5)	9 (25.7)	0.786
Pyramidal sign, %	76 (66.1)	25 (71.4)	0.555
Extrapyramidal sign, %	56 (48.7)	19 (54.3)	0.562
Cerebellar sign, %	46 (40.0)	13 (37.1)	0.734
Sleep disorders, %	43 (37.4)	18 (51.4)	0.139
Weakness or sensory disturbance, %	31 (27.0)	14 (40.0)	0.140
Speech disorder, %	47 (40.9)	18 (51.4)	0.270
Akinetic mutism, %	5 (4.4)	1 (2.9)	1.000
Decorticate rigidity, %	2 (1.7)	1 (2.9)	0.552

Furthermore, the onset to LP was longer in 14-3-3-positive patients than that in 14-3-3-negative patients [median (IQR):24 (24–33.5) months and 12 (7–24) months respectively, p = 0.008] in the neurodegenerative subgroup, and Kaplan-Meier analysis also showed that the positive 14-3-3 test was associated with longer disease duration (p = 0.014) (Fig. 4). In AD subgroup, 14-3-3-positive patients had longer duration from onset to 14-3-3 protein test than that in 14-3-3-negative patients (23.0±2.24 versus 13.3±8.6 months respectively, p = 0.027). In the autoimmune subgroup, myoclonus was more frequently observed in 14-3-3-positive patients than in the 14-3-3-negative patients [6 (75%) versus 4 (18.2%) respectively, p = 0.002]. Other subgroups were not analyzed due to the small size. The data are summarized in Supplementary Tables 1 and 2.

Fig. 4

Kaplan-Meier curves of the disease duration in the CSF 14-3-3 positive and negative patients in the neurodegenerative subgroup.

Standard CSF analyses in patients with non-prion RPD

Various RPD were shown to have CSF pleocytosis and elevated total protein levels, with infectious illnesses being the most prevalent. Decreased glucose level mainly presented in parasitic and bacterial infections and some CSF neoplasm diseases such as CNS lymphoma and meningeal carcinomatosis. Oligoclonal bands could also be detected in various RPD. The detailed results of CSF analyses are shown in Table 3.

Table 3

Basic CSF analyses in patients with non-prion RPD

Neurological diseases	CSF pleocytosis	Increased CSF total protein level	Decreased glucose level	Oligoclonal bands
Autoimmune encephalitis (n = 38)	26.3%	36.8%	2.6%	13.2%
Neurodegenerative disease (n = 29)	6.9%	17.2%	0%	3.4%
Viral infection (n = 10)	40%	50%	0%	20%
Neurosyphilis (n = 5)	80%	60%	0%	60%
Parasitic or bacterial infections (n = 2)	100%	100%	100%	0%
CNS neoplasm (n = 3)	66.6%	66.6%	66.6%	33.3%
Paraneoplastic disease (n = 7)	42.9%	42.9%	14.3%	28.6%
Cerebrovascular disease (n = 5)	0%	0%	0%	0%
Inherited metabolic disease (n = 5)	20%	20%	0%	0%

DISCUSSION

It was the first time to evaluate the relationship between CSF 14-3-3 protein and clinical features in non-prion diseases. Our results found that the CSF 14-3-3 protein was detected in a broad various of non-prion patients exhibiting RPD, and it was associated with older age and symptoms of myoclonus. In addition, in neurodegenerative disease, the positive 14-3-3 test was associated with longer duration from onset to LP, and in autoimmune encephalitis, myoclonus was more frequently observed in 14-3-3-positive patients.

Consistent with previous reports, we found that CSF 14-3-3 protein was present in various non-prion RPD disorders, including the incurable disorders caused by neurodegeneration and inherited metabolic abnormalities, as well as potentially treatable diseases such autoimmune and infectious encephalitis. Among them, autoimmune encephalitis and neurodegenerative diseases were the most frequent disorders with positive CSF 14-3-3 results. Bastiaansen et al. showed that the positive rate of CSF 14-3-3 protein in autoimmune encephalitis was 19% (8/42) and Freund et al. found that 3 out of 8 (37.5%) patients with autoimmune encephalitis were positive for 14-3-3 protein [32, 33]. Our results combined with previous studies remind clinicians that the positive rate of CSF 14-3-3 protein in patients with autoimmune encephalitis is not low. In addition, a previous study showed that CSF 14-3-3 was positive in 12/98 (12.2%) unselected patients with non-prion dementia [3]. All the patients included in our study presented with RPD, which indicated that the neuronal injury in these patients was more rapid and extensive than that in patients with typical clinical features. Thus, the positive rate of CSF 14-3-3 protein was higher. Another study also reported that among the patients that clinically mimic CJD, 32% of cases were negative for prion disease and 23% of patients were finally diagnosed with treatable neurological diseases [1, 4]. All these disorders are commonly mistaken for CJD due to the symptom of RPD plus pyramidal, extrapyramidal, or cerebellar signs, especially together with the positive 14-3-3 protein in CSF. Therefore, it is crucial to exclude curable diseases and avoid relying too heavily on CSF 14-3-3 testing for diagnosing CJD, since doctors or family members may choose to discontinue treatment in case of CJD diagnosis. Apart from the disorders and conditions reported previously, our study broadened the scope of treatable disorders with a positive 14-3-3 result to GFAP-related autoimmune encephalitis and brain cysticercosis.

In the non-prion RPD patients, CSF 14-3-3 protein results were associated with clinical features. The patients with positive CSF 14-3-3 protein were older and more likely present the symptom of myoclonus. Age-related changes in the morphology and function of neurons increase their susceptibility to toxins, infections, or inflammatory-induced damage, thereby resulting in the release of 14-3-3 protein into the CSF. Myoclonus is characterized by sudden, brief, shock-like involuntary movements. It is one of the major symptoms of CJD, but also present in various of other neurological diseases, such as neurodegenerative, metabolic-toxic, infectious, or autoimmune diseases [34]. The anatomical source and pathogenic mechanisms are ambiguous and complex in these disorders. The motor cortex is most commonly affected, although impairment of subcortical areas, brainstem, spinal, and peripheral nervous system also lead to myoclonus [34]. The correlation between 14-3-3 protein and myoclonus in non-prion RPD patients may be related to the acute and massive neuronal damage seen in these disorders. Iwasaki et al. also found that time from disease onset to first observation of myoclonus was significantly associated with survival duration, which suggested that the appearance of myoclonus indicated accelerated disease progression [35, 36]. In the subgroup analysis of autoimmune encephalitis in our study, patients with myoclonus also have a shorter disease duration than those without myoclonus, although the results did not reach statistical significance (the data were not shown).

In addition, in the subgroup of neurodegenerative diseases, the disease duration was longer in the 14-3-3-positive as opposed to the 14-3-3 negative patients. In our study, all the patients with neurodegenerative diseases were characterized by RPD and the rate of cognitive decline was similar. The long duration from disease onset to LP could indicate that patients had progressed to an advanced stage of disease, during which the neuronal injury was more extensive. This could lead to the increase of CSF 14-3-3 positive rate. Our results remind clinicians that CSF 14-3-3 protein might be positive in patients with advanced non-prion neurodegeneration patients. Further research with large sample size as well as studies targeting the association of CSF 14-3-3 protein and biomarkers of neuronal injury such as CSF tau protein levels and brain structural and metabolic changes should be conducted to verify our findings. In addition, previous studies also found that the sensitivity of CSF 14-3-3 protein for CJD diagnosis increased during disease progression. In CJD patients who had more than one LP performed, the sensitivity of CSF 14-3-3 protein increased in the second LP when compared to the first LP [37].

Basic CSF analyses including white blood cells, total protein levels, glucose levels, and oligoclonal bands are routinely performed in clinical practice and could provide the early clue for the diagnosis of RPD. CSF pleocytosis and increased total protein levels are usually clear signs of CNS inflammation. Decreased CSF glucose levels were more common in infectious diseases and certain CNS neoplasms such as lymphoma and meningeal carcinomatosis. However, around 20% of patients with immune-mediated encephalitis could lack inflammatory signs in the CSF, and noninflammatory CSF may be more common in patients over sixty [38, 39]. In addition, a slight increase in CSF white blood cell and total protein levels was also observed in patients with various noninflammatory/infectious diseases, such as CNS lymphoma or neoplastic meningitis. Thus, considering the atypical CSF presentations, we recommend that the specific protein biomarkers such as CSF autoimmune antibodies should be tested in all unclear RPD patients, even in those with a positive 14-3-3 protein result who was easily diagnosed with CJD. Real-time quaking-induced conversion (RT-QuIC) assay for prion should be carried out if 14-3-3 protein was positive, and the diagnosis of prion diseases was suspected.

Our study also has some limitations that ought to be considered. First, there is a lack of consensus on the definition of RPD. The assessment of RPD was complicated. Compared with the definition which stresses the performance on cognitive/neuropsychological testing, which could overstate impairment in patients with visual or language impairment, the criteria that incorporates measures of function are preferred. Thus, we adopted the generally accepted definition, which states that patients with RPD progressed from independence to complete (or nearly complete) dependence within 1 to 2 years. It is necessary to develop a more reasonable and unified diagnostic criterion for RPD in the future to investigate RPD systematically. Second, due to the traditional ethical values of China, autopsy is very rare in China and none of the patients in our study were autopsied. These increased the difficulty in distinguishing prion disease from non-prion disease, especially for MM2C type prion disease which is characterized by relatively slow progression and long disease duration. However, MM2C type prion disease is rarer and accounted for only 2% in a previous study involving 300 CJD cases [40]. In our study, the majority of non-prion patients were with a definite diagnosis. Thus, although we could not exclude the presence of concurrent CJD in these patients, it should be very rare. Third, CSF 14-3-3 protein isotypes may be differently involved between different diseases, but we only examined CSF total 14-3-3 protein and did not examine 14-3-3 isotypes. Further study should be done to explore the differences of CSF 14-3-3 protein isotypes in different diseases. Fourth, the number of patients included in this study was relatively small, and these findings should be verified by further research with large samples.

Conclusions

CSF 14-3-3 protein is present in a broad spectrum of non-prion RPD disorders, especially in autoimmune encephalitis, rapidly progressive neurodegenerative diseases, and those patients with the symptom of myoclonus. These results could help clinicians interpret the results of CSF 14-3-3 protein more reasonably and make the correct diagnosis.

Footnotes

ACKNOWLEDGMENTS

This work was supported by grants from the Ministry of Science and Technology of China (2019YFC0118600), National Natural Science Foundation of China (81971011), Beijing Municipal Science and Technology Committee (D171100008217005, 7202060) and the Xuanwu Hospital Science Program for Fostering Yong Scholars (QNPY2021001).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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