The Etiology of Rapidly Progressive Dementia: A 3-Year Retrospective Study in a Tertiary Hospital in China

INTRODUCTION

Rapidly progressive dementia (RPD) is a definition of the cognitive disorders with fast progression contributing to clinical syndrome of dementia within a relatively short period (less than 1 or 2 years) [1, 2]. In contrast to most dementias that progress in more than 10 years of time, a majority of RPDs would progress rapidly and even become fatal in a short period [3]. RPD displays a wide array of etiologies, encompassing neurodegenerative disorders, such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and prion disease, as well as non-neurodegenerative disorders, such as cerebrovascular diseases, central nervous system (CNS) infections, metabolic and toxic diseases, and brain tumors [2, 4]. Creutzfeldt-Jakob disease (CJD), arising from the aberrant conformational changes in the prion protein, stands as a prevalent manifestation within the spectrum of RPDs [2, 5]. The conditions of CJD usually deteriorate rapidly and can lead to irreversible disability and even mortality in a short period of time [5]. Unlike CJD and other neurodegenerative disorders contributing to RDP, some etiologies of RPD are treatable and reversible, including autoimmune encephalitis [2]. Therefore, the urgent and early assessment and differential diagnosis of patients with RPD are necessary and important for the subsequent treatment and prognosis.

The etiological factors contributing to RPD are multifaceted, rendering the prompt diagnosis and treatment of RPD challenging. Previous investigations have mainly focused on studying the etiologies of RPD among patients initially suspected of having prion diseases [6 –8]. Furthermore, past literature has documented the spectrum and etiologies of RPD in Western populations, with CJD and infectious or immune-mediated disorders being the most commonly observed causes [9, 10]. There are few reports in China summarizing the etiology of RPD from single centers, and the sample sizes are relatively small [11], or lack sufficient pathological data to make a definitive diagnosis of the causes [12]. The characterization and underlying causes of RPD in the Chinese Han population are still largely unexplored and poorly understood.

Here, we conducted a three-year retrospective study of 323 patients with RPD admitted to the department of neurology at Fudan University Huashan Hospital. In this study, we conducted a comprehensive analysis of the clinical and epidemiological data of patients to elucidate the disease profiles of individuals with RPD in our research center. Our investigation advances beyond preceding research through the inclusion of PET or CSF analysis, yielding enhanced accuracy and depth in the etiological assessment of RPDs. Through rigorous data collection and subsequent analysis, we aimed to gain valuable insights into the characteristics and patterns of RPD.

MATERIALS AND METHODS

RESULTS

The neurodegenerative and non-neurodegenerative causes of RPD

Overall, the proportion of neurodegenerative and non-neurodegenerative causes of RPD is about 48% (Fig. 1A). The various etiological factors within neurodegenerative and non-neurodegenerative categories of RPD are detailed in Fig. 1B and 1C. Of all patients, autoimmune encephalitis was the most common cause, followed by neurosyphilis, then by CJD (Table 3). Then based on whether the course of the disease is less than 6 months, our subgroup analysis of RPD etiology found that AD was the most common cause in neurodegenerative disorders, which accounted for 16.10% of all RPD cases, followed by CJD (8.98%) and frontotemporal dementia (FTD, 5.26%). Among non-neurodegenerative conditions, autoimmune encephalitis was the most common cause, which accounted for 16.72% of all RPD cases, followed by neurosyphilis (11.76%) and vascular cognitive impairment (8.05%). In neurodegenerative causes of RPD 64.10% had a course of 6 months or more, while in non-neurodegenerative causes, 73.44% had a course of less than 6 months (Table 3). However, some exceptions should be noticed. For instance, over a half of CJD cases presented with RPD less than 6 months. Moreover, there were a larger proportion of RPD more than 6 months in patients with neurosyphilis.

OPEN IN VIEWER

Fig. 1

Spectrum and frequency of rapid progressive dementia in current study. The pie chart showing the causes of rapidly progressive dementia in total participants (A), neurodegenerative causes of RPD (B), and non-neurodegenerative causes of RPD (C) causes of rapidly progressive dementia. # Others: the diseases that are rare or cannot be classified according to the current state of research, including chronic subdural hematoma, symptomatic epilepsy, mitochondrial disease, and leukodystrophy.

OPEN IN VIEWER

Table 3

Spectrum and frequency of rapidly progressive dementia based on time course

RPD	RPD < 6 mo (%)	RPD≥6 mo (%)	Total (%)
Neurodegenerative causes of RPD	31 (24.22)	125 (64.10)	156 (48.30)
AD	1 (0.78)	51 (26.15)	52 (16.10)
CJD	16 (12.50)	13 (6.67)	29 (8.98)
FTD	1 (0.78)	16 (8.21)	17 (5.26)
DLB	2 (1.56)	10 (5.13)	12 (3.72)
PDD	4 (3.13)	4 (2.05)	8 (2.48)
MSA	0 (0.00)	8 (4.10)	8 (2.48)
AD, mixed pathology	3 (2.34)	5 (2.56)	8 (2.48)
NPH	3 (2.34)	4 (2.05)	7 (2.17)
PSP	0 (0.00)	5 (2.56)	5 (1.55)
CBS	0 (0.00)	3 (1.54)	3 (0.93)
MND	1 (0.78)	2 (1.03)	3 (0.93)
SCA	0 (0.00)	2 (1.03)	2 (0.62)
HD	0 (0.00)	1 (0.51)	1 (0.31)
NIID	0 (0.00)	1 (0.51)	1 (0.31)
Non-neurodegenerative causes of RPD	94 (73.44)	64 (32.82)	158 (48.92)
Autoimmune encephalitis	39 (30.47)	15 (7.69)	54 (16.72)
Neurosyphilis	15 (11.72)	23 (11.79)	38 (11.76)
Vascular cognitive impairment	14 (10.94)	12 (6.15)	26 (8.05)
Tumor	7 (5.47)	7 (3.59)	14 (4.33)
Toxic	8 (6.25)	1 (0.51)	9 (2.79)
Psychiatric	3 (2.34)	6 (3.08)	9 (2.79)
Viral encephalitis	8 (6.25)	0 (0.00)	8 (2.48)
Others	3 (2.34)	6 (3.08)	9 (2.79)

RPD, rapidly progressive dementia; AD, Alzheimer’s disease; CBD, cortical basal ganglia degeneration; CBS, cortico-basal syndrome; FTD, frontotemporal lobar degeneration; CJD, Creutzfeldt–Jakob disease; PDD, Parkinson’s disease; DLB, dementia with Lewy body; MSA, multiple system atrophy; PSP, progressive supranuclear palsy; NPH, normal pressure hydrocephalus; MND, motor neuron disease; SCA, spinocerebellar ataxia; HD, Huntington’s disease; NIID, neuronal intranuclear inclusion disease. # Others: the diseases that are rare or cannot be classified according to the current state of research, including 2 chronic subdural hematoma, 2 symptomatic epilepsy, 3 mitochondrial disease, and 2 leukodystrophy with uncertain causes.

DISCUSSION

This study aimed to provide a comprehensive profile of the clinical and etiological characteristics of RPD within Chinese Han population cohort, which consisted of 323 individuals. Our findings revealed that autoimmune encephalitis, AD, neurosyphilis, and CJD were among the major causes of RPD in our memory center. A significant proportion of RPD cases in this cohort were attributed to non-neurodegenerative causes. This suggests that RPD may be treatable and reversible in certain conditions, emphasizing the importance of timely identification and diagnosis of the underlying etiology associated with RPD.

Dementia, which is one of the leading causes of disability and dependency in older individuals [13, 14], often has an insidious onset and a chronic progression, whereas RPD usually has a rapid progression, peaking in even weeks or months [1]. RPD is a vague definition and was initially considered one of the typical clinical manifestations and diagnostic criteria of CJD [1]. In recent years, there were increasing observational studies suggesting that in addition to CJD, a variety of neurological conditions or secondary conditions led to RPD, and some of the causes were treatable, like immune-mediated diseases, metabolic and toxic conditions, and other secondary neurological disorders [15, 16]. The incidence of RPD among dementia patients varied from 3.7–27% based on different definitions [17, 18]. Owing to the great number of dementia patients, RPD posed a heavy socioeconomic burden on public health care and was regarded as a major challenge for the diagnosis and treatment of dementias [14]. Comprehensive profiling and in-depth analysis of the etiologies behind RPD will yield critical insights essential for accurate differential diagnosis. Our analysis suggested that reversible diseases accounted for a large proportion of RPD causes. It is thus important for neurologists to identify the underlying treatable causes of RPD timely.

Supplementary Table 2 shows the distribution of RPD etiologies across different tertiary centers in multiple studies, and the observed frequencies are highly dependent on the study design. In our cohort, the most common cause of RPD was autoimmune encephalitis, followed by AD, neurosyphilis, and CJD. Immune-mediated encephalitis was one of the most important differential diagnoses for RPD [17 –19]. The typical symptoms of autoimmune encephalitis included early occurrence of altered consciousness and seizures [2]. Though immune-mediated encephalitis could be detected by certain antibodies, like the N-methyl-D-aspartate receptor (NMDAR) and leucine-rich glioma inactivated protein 1 (LGI1) [20], the diagnosis of immune-mediated encephalitis was challenging as the associated antibody could not be identified in some conditions [21]. Fortunately, once receiving appropriate treatment (i.e., corticosteroid and plasma exchange), the prognosis of immune-mediated encephalitis was usually better than other neurological disorders [22]. Our study showed that RPD due to autoimmune encephalitis tended to be younger and have a shorter time course of disease, which probably guide the differential diagnosis of RPD due to autoimmune encephalitis. In addition, CJD was the fourth common etiology for RPD in our cohort. Nevertheless, sporadic CJD was reported as the most common cause of RPD in another cohort at the University of California, San Francisco (UCSF) that included 178 cases in a period of six years [4, 23]. Our cohort was established within a diagnosis and treatment institution specializing in central nervous system diseases, with a primary focus on cognitive impairment as a complication, setting it apart from other referral hospital of certain diseases like CJD. Our study also indicated that non-neurodegenerative causes of RPD, including neurosyphilis and vascular cognitive impairment, contributed to a large proportion of RPD, suggesting that a lot of RPD patients were reversible with timely antisyphilitic treatment and controls of vascular risk factors, respectively. Another point worth noting is that leukodystrophy and mitochondrial disorders are also significant causes of RPD [24]. Early diagnosis of leukodystrophy offers patients potential treatment options, such as allogeneic hematopoietic stem cell transplantation and gene therapy, which hold promise [24 –26]. Overall, our study provided the memory diagnosis and treatment centers with reference for the differential diagnosis of RPD.

In our study, the most common neurodegenerative causes of RPD was AD, which was also the second most common cause of RPD. Consistent with our findings, Zhang et al. analyzed the major causes of RPD in the Chinese Han population and found that AD was the most common neurodegenerative cause [12]. Liu et al.’s findings echo our identification of neurodegenerative diseases and infectious as a leading cause of RPDs but note a higher incidence of toxic and metabolic conditions than we report [11]. The possible reasons for the difference among the studies were the differences in type of health-care system and ethnicities. Dementia due to neurodegenerative diseases, such as AD, FTD, dementia due to Lewy bodies, multiple system atrophy, or progressive supranuclear paralysis, was difficult to be found at the early stage and had a relatively slow progression of symptoms. Josephs et al. reported that AD, FTD, and DLB were all possible causes for RPD, particularly the patients with a disease duration beyond 12 months [27]. Likely, in another Western cohort of RPD patients, AD was reported to be one of the most common causes [19]. With the launch of anti-amyloid antibodies, such as lecanemab, new treatment options and opportunities for patients with AD have been provided [28, 29].

We also analyzed the etiology and spectrum of RPD in different courses of disease, which suggested that the most common disease of RPD with a duration of less than 6 months was autoimmune encephalitis, while AD was the most common etiology for RPD with a duration of more than 6 months. In addition, we found that neurosyphilis was one of the most common etiologies in RPD patients with a short or long course of disease. In China, the incidence of syphilis is increasing in recent years [30, 31]. However, the reported incidence of syphilis in China is dependent on case reporting, which may significantly underestimate the overall number of neurosyphilis. However, in our cohort, neurosyphilis accounted for a relatively higher proportion of RPD. The finding further highlighted the timely identification and diagnosis of RPD patients with short course and the subsequent etiological therapies.

The strength of this study was the relatively large number and complete clinical information of the RPD patients, but there were some limitations in our study. First, all RPD patients in the cohort came from the single center, which contributed to selection bias and an over-or under-representation of RPD patients. For instance, it was noted that a handful of RPD patients due to viral encephalitis were included in our study. Secondly, the observational design based on medical records made the clinical information limited, like the time of first symptoms and the onset.

AUTHOR CONTRIBUTIONS

Qin Shi (Data curation; Formal analysis; Investigation; Methodology; Writing – original draft); Wei-Shi Liu (Conceptualization; Investigation; Methodology; Writing – original draft); Fang Liu (Writing – review & editing); Yi-Xuan Zeng (Data curation; Formal analysis); Shu-Fen Chen (Data curation; Formal analysis; Investigation; Writing – original draft); Ke-Liang Chen (Investigation; Methodology; Resources); Jin-Tai Yu (Funding acquisition; Resources; Writing – review & editing); Yu-Yuan Huang (Writing – original draft; Writing – review & editing).