Alzheimer’s Disease and Neurosyphilis: Meaningful Commonalities and Differences of Clinical Phenotype and Pathophysiological Biomarkers

Abstract

Background:

Neurosyphilis-associated cognitive and behavioral impairment— historically coined as “general paralysis of the insane”— share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer’s disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss, fibrillary alterations, and local amyloid-β deposition. Consequently, accurate classification and timely differential diagnosis may be challenging.

Objective:

To describe clinical, bio-humoral, brain MRI, FDG-PET, and amyloid-PET features in cases of neurosyphilis with an AD-like phenotypical presentation, as well as clinical outcome in terms of response to antibiotic therapy.

Methods:

We selected the studies comparing patients with AD and with neurosyphilis associated cognitive impairment, to investigate candidate biomarkers classifying the two neurological diseases.

Results:

The neuropsychological phenotype of general paralysis, characterized by episodic memory impairment and executive disfunction, substantially mimics clinical AD features. Neuroimaging often shows diffuse or medial temporal cortical atrophy, thus contributing to a high rate of misdiagnosis. Cerebrospinal fluid (CSF)-based analysis may provide supportive diagnostic value, since increased proteins or cells are often found in neurosyphilis, while published data on pathophysiological AD candidate biomarkers are controversial. Finally, psychometric testing using cross-domain cognitive tests, may highlight a wider range of compromised functions in neurosyphilis, involving language, attention, executive function, and spatial ability, which are atypical for AD.

Conclusion:

Neurosyphilis should be considered a potential etiological differential diagnosis of cognitive impairment whenever imaging, neuropsychological or CSF features are atypical for AD, in order to promptly start antibiotic therapy and delay or halt cognitive decline and disease progression.

Keywords

Alzheimer’s disease biomarkers general paralysis neurosyphilis treatable dementia

INTRODUCTION

Syphilis is one of seven curable, sexually transmitted infections that is caused by a bacterial pathogen. There is still debate over the origin of syphilis and how it spread to different parts of the world. The most well-supported hypothesis, the Columbian Hypothesis, states that Columbus’ seamen, who first arrived in the Americas in 1492, brought the disease back to Europe following exploration of the Americas. Many of the crew members who served on this voyage later joined the army of King Charles VIII in his invasion of Italy in 1495, which some argue may have resulted in the spreading of the disease across Europe and as many as five million deaths (i.e., England’s King Edward IV). Later on, famous painters Henri de Toulouse-Lautrec, Paul Gaugin, and Edouard Manet are known to have died from syphilis as well as classic authors Oscar Wilde, Guy de Maupassant, and Charles Baudelaire, and famous composers like Franz Schubert, Hugo Wolf, and Robert Schumann. However, it took medicine centuries to understand, detect, and treat this devastating medical condition. In 1905, Fritz Richard Schaudinn (1871–1906), a German zoologist, and Erich Hoffman (1868–1959), a dermatologist, have discovered the etiologic agent of syphilis, whom they have named Spirochaeta pallida, composed by the bacterium called Treponema pallidum, on various syphilis lesions, proving its existence in both fresh and Giemsa colored specimens. While working at the Rockefeller Institute for Medical Research in 1913, Hideyo Noguchi (1876–1928), a Japanese bacteriologist, demonstrated the presence of the spirochete Treponema pallidum in the brain of a progressive paralysis patient, associating Treponema pallidum with neurosyphilis. In 1928, Alexander Fleming (1881–1955), a Scottish physician and microbiologist, discovered the world’s first broadly effective antibiotic substance, which he named penicillin, and since 1943, it has become the main treatment of syphilis.

WHO estimates that each year 11 million new cases of syphilis occur globally among adults aged 15–49 years [1]. Syphilis has re-emerged in several regions including North America, Western Europe, China, and Australia [1]. Host-associated factors that drive the re-emergence and spread of syphilis include high-risk sexual activity, migration and travel, and economic and social changes that limit access to health care.

Indeed, neurosyphilis is a central nervous system (CNS) infection caused by Treponema Pallidum, and represents a rare manifestation of tertiary syphilis [2]. It occurs in cases of untreated infection, when the presence of spirochetes in the brain triggers chronic inflammation and causes progressive cerebral atrophy with slowly progressive dementia [3]. Neurosyphilis related dementia, also called “general paralysis of the insane” (GPI), as indicated above was probably the most common type of dementia in the early 20th century [4], when life expectancy was below 65 years and neurodegenerative dementias associated with old age were less frequent [3]. With the discovery and the introduction of penicillin, the annual incidence of neurosyphilis dramatically reduced [5] and, as a result, nowadays many clinicians are not familiar with the disease [6].

Further, GPI can present with clinical, radiologic, and neuropsychological features resembling neurodegenerative diseases associated with cognitive impairment, in particular Alzheimer’s disease (AD) [3].

Short-term memory impairment and mood-affective symptoms, followed by orientation difficulties, are typical clinical symptomatic features of AD, but characterize the onset of GPI as well. Neuroimaging in GPI most commonly shows cortical atrophy, either diffuse or located in one or more cortical areas, including temporal lobes, hippocampi, frontal lobes, parietal areas, and corpus callosum [7]. Therefore, it is not surprising that neuroimaging in GPI can mimic features of AD as well, in particular when atrophy involves mainly temporal regions.

Cases of hyperintensities in T2 and fluid attenuated inversion recovery (FLAIR) sequences have also been described, with hyperintense lesions often located in medial temporal lobes, bilaterally or unilaterally [8]. In these latter cases, where white matter abnormalities are predominant instead of atrophy, differential diagnosis include viral and autoimmune encephalitides [8].

The anatomopathological similarities between neurosyphilis and AD have been extensively analyzed, with several studies highlighting that in atrophic forms of GPI, inflammatory infiltrates are lacking, while cortical atrophy with neuronal loss, fibrillary alteration of neurons, local amyloid-β (Aβ) deposition, and severe microglia proliferation are evident [3 , 9–11]. Moreover, spirochetes accumulate in cerebral cortex and form cortical masses and plaques which are morphologically undistinguishable from perivascular senile plaques [3].

These findings led some authors to speculate that several types of bacterial infections, including spirochetes, may initiate a cascade of chronic inflammation and Aβ deposition leading to AD [3 , 13].

The Aβ pathway represents an initial pathophysiological change within the AD biological continuum alongside concomitant molecular pathways, including the neuroimmune and neuroinflammatory response (namely, neuroinflammation) [14]. Such evidence stems from genome-wide association studies and translational studies, which indicate that several AD-risk genes are linked to innate immune system functions [15], increased expression of proinflammatory pathways [16, 17], and microglia overactivation [14 , 19].

Neuroinflammation is implicated in CNS infective diseases, including neurosyphilis. In particular, treponemes can evade immune clearance and persist in the host, thus promoting chronic inflammation in the CNS through continual T-cell stimulation [3, 20]. Therefore, it is not unlikely that at least some shared inflammatory pathways are activated both in AD and neurosyphilis, leading to progressive tissue damaging and neurodegeneration.

Although their pathophysiological relationship remains to be elucidated, early detection and differential diagnosis are challenging in some cases. Nevertheless, the correct diagnosis is paramount in terms of successful treatment and patient outcome.

Here, we present an illustrative case report involving a man diagnosed with neurosyphilis with an AD-like phenotype (AD-NS) and we report the results of a systematic literature review identifying other paradigmatic cases of AD-NS. The purpose of this systematic review is to describe clinical, bio-humoral, brain magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), and amyloid-PET features in these individuals, as well as clinical outcome in terms of response to antibiotic therapy.

We also identified studies aimed at comparing neuropsychologic, bio-humoral, and imaging features of AD patients and of AD-NS patients. Ultimately, we tried to clarify the clinical and biomarker differences between AD and neurosyphilis manifesting with AD features, probably supportive of an optimized early diagnostic workup and pathophysiological classification.

ILLUSTRATIVE CASE

A 76-year-old man, smoker since young age, was referred to our university-based expert Neurology care unit presenting with cognitive impairment. His past medical history revealed hypertension and hypercholesterolemia as comorbidities. His symptoms started one year before referral, when he slowly developed memory impairment and difficulties in instrumental activities of daily life. He also complained of depressed mood. The neurological examination was normal except for partial disorientation in time and space.

During the previous months, he performed a neuropsychological evaluation that revealed deficits in working memory and executive functions, a cerebral FDG-PET with evidence of bilateral fronto-temporo-parietal hypometabolism, and a brain MRI with diffuse atrophy— more evident in bilateral temporo-parietal lobes— and widespread hemosiderin deposit.

A neurodegenerative cognitive decline was suspected and, when referred to our clinical center, we performed a lumbar puncture and cerebrospinal fluid (CSF) analysis, showing normal cells and increased proteins’ levels (104 mg/dl), one oligoclonal band, and negative neurotropic viruses and bacteria. CSF based pathophysiological biomarkers were consistent with a characteristic AD profile, showing a decreased amyloid-β₄₂ (Aβ₄₂)/amyloid-β₄₀ (Aβ₄₀) ratio (0.04, normal values >0.069), increased total tau protein (t-tau, 658 pg/ml, normal values <400 pg/ml) and phosphorylated tau protein 181 (p-tau181, 105 pg/ml, normal values <56.5 pg/ml).

In order to better characterize the widespread cerebral hemosiderin deposits, the patient underwent a brain magnetic resonance angiography proving reduced diameter of left sylvian artery and several fine widespread irregularities with a “rosary beads” pattern, initially interpreted as a result of a cerebral inflammatory vasculitis.

Therefore, we performed an extensive screening for both autoimmune and infective vasculitis: among serological tests, Treponema Pallidum hemagglutination assay (TPHA) resulted positive at 1/20480 dilution and Rapid Plasma Reagin (RPR) test was positive too, whereas HIV serology was negative. Autoantibody screening, including antinuclear antibodies, extractable nuclear antigen antibodies, and antineutrophil cytoplasmic autoantibodies, did not show any abnormalities. CSF examination charted Fluorescent Treponemal Antibody Absorption and IgG to Treponema Pallidum positivity and TPHA positivity at 1/10240 dilutions, while RPR in CSF was negative.

A diagnosis of neurosyphilis was finally established and intravenous crystalized penicillin G (24 million units/day) was administered for 14days.

During hospitalization the neurological state remained substantially unchanged, with an acute isolated episode of confusion without psychomotor agitation, that was interpreted as a delirium due to the infection and the antibiotic therapy. At 6 months follow-up the patient had a partial restoration of instrumental activities of daily life, but a repeated neuropsychological evaluation confirmed a deficit in working memory and in executive functions, with a compromised Mini-Mental Score Examination (MMSE, 20.7/30, age and education adjusted score), a compromised Addenbrooke’s Cognitive Examination Revised (ACE-R, 71.29, age and education adjusted score), and a compromised Frontal Assessment Battery (FAB, 9.5, age and education adjusted score). Psychometric tests repeated at one-year follow up reported a substantially stable cognitive impairment (MMSE, 21.7/30, ACE-R 69.29, and FAB 8.5, age and education adjustedscores).

MATERIALS AND METHODS

We performed a systematic literature review to identify all well-documented cases of neurosyphilis mimicking AD, and all the studies in which features of patients with AD-NS were compared to AD patients. We followed guidelines for conducting systematic reviews set forth by Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) flow diagram.

Search strategy

A comprehensive search through PubMed was performed on August 16, 2022. The search strategy employed the use of the search terms: [“Alzheimer’s disease” or “cognitive decline” or “cognitive impairment” or “dementia”] AND [“neurosyphilis” or “CNS syphilis” or “neurolue” or “general paresis”]. Reference lists of relevant articles were also searched. Screening and eligibility assessment of articles was performed in Rayyan— a web and mobile app for systematic reviews (https://www.rayyan.ai).

Inclusion and exclusion criteria

Inclusion criteria were: 1) studies containing at least one well-described case of neurosyphilis mimicking AD, 2) comparative studies between patients with AD and patients with neurosyphilis presenting with dementia, and 3) English language publications.

We excluded: 1) studies not published in English language; 2) reviews on neurosyphilis in general; 3) preclinical or animal studies; 4) studies without detailed information about individual patients; 5) reports of patients with neurosyphilis but without AD phenotype (i.e., only other CNS involvement symptoms).

The diagnosis of neurosyphilis was based on positive serologies and one of the following criteria: a) a reactive venereal disease research laboratory (VDRL) in CSF or b) a negative VDRL in CSF with either elevated CSF protein (>45 mg/dl) or CSF white blood count (>5 cells/μL).

Criteria to define a case as AD mimic were the presence of long-lasting and persistent cognitive impairment eventually confirmed at neuropsychological evaluation and a) MRI with evidence of temporo-parietal atrophy, or b) PET-FDG documenting temporo-parietal hypometabolism, or c) CSF biomarkers consistent with a biological AD profile, i.e., reduced levels of Aβ₄₂ or Aβ₄₂/Aβ₄₀, and increased levels of t-tau and, especially, p-tau181.

Selection process

The selection was conducted by applying inclusion and exclusion criteria as stated above to every study or case series or case report. An article had to be included by at least two authors to be considered appropriate. In papers reporting more than one case, every single report was further analyzed in order to select only data from those cases fulfilling criteria for AD-Mimics.

Data extraction

From included case reports and case series, we extracted several variables, including age and sex, previous history of Treponema Pallidum infection, prevalent type of cognitive impairment, other neurologic signs/symptoms associated to cognitive impairment, MRI features, FDG-PET features, and CSF data including fluid AD biomarkers. We also extracted information on the treatment and outcome of patients in these studies.

RESULTS OF THE SYSTEMATIC REVIEW

The electronic literature search initially yielded 404 articles, of which 71 were excluded because they were published in language other than English and 199 were excluded by title and abstract evaluation (Fig. 1). The remaining articles were assessed for eligibility according to the criteria outlined above. Among the 134 full-text articles assessed for eligibility, 102 studies were excluded with reasons (Fig. 1). Twenty-five articles containing cases of neurosyphilis mimicking AD were included, of which 8 were case series and 17 case reports (Fig. 1) [21 –45]. A total of 34 patients with neurosyphilis mimicking AD were extracted.

Fig. 1

Flowchart showing the results of our literature search.

Additionally, 7 papers reporting comparisons between AD patients and AD-NS were included.

Clinical features, treatment, and outcomes of patients with neurosyphilis mimicking AD

The main results concerning demographic and clinical features, treatment and outcome of included patients are summarized in Table 1. All the included patients were negative to human immunodeficiency virus (HIV) test.

Table 1

Demographic and clinical features of included patients with neurosyphilis mimicking AD

Sex	Male (number, percentage)	27/34 (79.4%)
	Female (number, percentage)	7/34 (20.6%)
Age	Median value (range)	51 (30–90)
Previous diagnosis of syphilis	Number/total	0/34°
Prevalent type of cognitive impairment	Memory/attention impairment	18/34 (52.9%)
	Language impairment	2/34 (5.88%)
	Memory and Language impairment	4/34 (11.76%)
	Dysexecutive disturbance	1/34 (2.94%)
	Memory impairment and dysexecutive disturbance	1/34 (2.94%)
	Not specified/Other	8/34 (23.52%)
Months from cognitive symptoms onset to treatment	Median value (range)	12 (3–66)
Other neurological/psychiatric symptoms manifesting during the course of the disease	Behavioral disturbances/personality changes	23/34 (67.65%)
	Tremor and/or extrapyramidal symptoms	9/34 (26.47%)
	Gait disturbances	4/34 (11.76%)
	Argyll-Robertson Pupil	4/34 (11.76%)
	Sleep disorders	3/34 (8.82%)
	Pyramidal signs	3/34 (8.82%)
	Dysarthria	2/34 (5.88%)
	Urinary incontinence	2/34 (5.88%)
	Hemiparesis	2/34 (5.88%)
	Seizure	1/34 (2.94%)
	Headache	1/34 (2.94%)
MRI features before treatment^*	Diffuse atrophy	20/34 (58,82%)
	Medial temporal lobe atrophy	8/34 (23.52%)
	Fronto-temporal lobe atrophy	4/34 (11.76%)
	Other pattern of atrophy	1/34 (2.94%)
	Normal	1/34 (2.94%)
	Other additional findings	4/34 (14.71%)
	Diffuse multifocal hyperintensities	3/4
	Middle temporal lobe infarct	1/4
CSF features before treatment	Normal	5/34 (14,71%)
	Abnormal	29/34 (85,29%)
	Increased cells/mm³ (>5 cells/mm³)	21/34 (61,76%)
	Median value (range)	40 (4–290) cells/mm³^**
	Increased proteins (>45 mg/dl)	24/34 (70,59%)
	Median value (range)	86 (33–402)^**
CSF AD biomarkers	Patients with available result	4/34 (11,76%)
	Tau median value (range)	374.5 (19–1250) pg/mL
	Phospho-tau median value (range)	71 (18–181) pg/mL
	Aβ₄₂median value (range)	762 (690–1171) pg/mL
MMSE score before treatment	Patients with available result	21/34 (61.76%)
	Median value (range)	21 (0–28)
Molecular imaging features (Perfusional SPECT or FDG-PET)	Temporal hypometabolism or hypoperfusion:	5/5 (3 monolateral; 2 bilateral)
	Frontal hypometabolism or hypoperfusion	4/5 (1 monolateral, 3 bilateral)
	Parietal hypometabolism or hypoperfusion	3/5 (1 monolateral, 2 bilateral)
	Subcortical hypometabolism or hypoperfusion	1/5 (left caudate)
Antibiotic treatment	IV penicillin 16–24 mUI/die for 14 days	17/34 (50%)
	IV penicillin with more prolonged treatment	3/34 (8.82%)
	Ceftriaxone 2–4 g/die for 14 days	9/34 (26.47%)
	Other	3 /34 (8.82%)
	Unknown/not reported	2/34 (5.88%)
Follow-up after treatment (months)	Patients with available result	24/34 (70,59%)
	Median value (range)	6 (0.5–60)
Outcome	Worsened	4/34 (11.76%)
	Unchanged	4/34 (11.76%)
	Partial improvement	18/34 (52.94%)
	Full recovery	6/34 (17.64%)
	Not reported	2/34 (5.88%)
MRI features post treatment	Total patients with repeated imaging	10/34 (29,41%)
	Worsened	3/10
	Unchanged	5/10
	Partially improved	2/10
CSF features post treatment	Number of patients with repeated LP	12/34 (35,29%)
	Normal	6/12
	Abnormal	6/12
	Increased cells/mm³ (>5 cells/mm³)	2/6
	Increased proteins (>45 mg/dl)	4/6
MMSE score post treatment	Patients with available result	15/34 (44.12%)
	Median score (range)	26 (14–30)

CSF, cerebrospinal fluid; FDG-PET, fluorodeoxyglucose positron emission tomography; IV, intravenous; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; SPECT, single-photon emission computerized tomography. °Two patients had a history of urogenital lesions without being diagnosed with syphilis; ^*Two patients underwent brain CT scan instead of brain MRI; ^**Median score and range were calculated considering only pathological results.

The median patients’ age was 51 years, ranging from 30 to 90 years. Sex was reported in all studies: 7 subjects were women and 27 were men. None had a previous diagnosis of syphilis, though in 2 cases a painless ulcer and a penile rash were retrospectively reported.

All patients presented with cognitive impairment as the first symptom, with the majority of them complaining about memory and/or attention impairment (23/34); other compromised domains involved language and executive functions. In eight cases, authors did not specify neuropsychological features indetail.

Most patients developed other subtle neurologic or psychiatric signs and symptoms during the course of the disease; the most common additional findings were behavioral symptoms or personality changes, with sometimes even acute psychotic phases. Other relatively common findings were subtle extrapyramidal or cerebellar signs, gait disorders, and Argyll-Robertson pupils.

Brain MRI revealed some degree of atrophy in 31 out of 34 patients, mainly with a diffuse pattern (18/34) or with prominent involvement of the medial temporal lobe (8/34). Collateral findings were vascular lesions (1/34) or hyperintensities in FLAIR sequences (3/34). Two patients underwent computed tomography scan instead of brain MRI, showing diffuse atrophy.

Molecular imaging, either perfusion single-photon emission computerized tomography (SPECT) or FDG-PET, was performed in five patients, with abnormal findings in all of them. More specifically, a temporal involvement was reported in all cases, followed by frontal hypometabolism or hypoperfusion.

CSF examination was reported in 32 out of 34 cases, resulting abnormal in 30 patients due to increase in cells, or protein, or both. CSF fluid biomarkers were available only for 4 patients.

Concerning treatment, all patients underwent antibiotic therapy, mainly with intravenous penicillin for a long period, or ceftriaxone if patient was known to have mild allergy to penicillin. In one case, penicillin was switched to ceftriaxone due to a reported Herxheimer reaction, a transient immunological phenomenon sometimes seen in patients infected by spirochetes who undergo antibiotic treatment, clinically manifesting with short-lasting constitutional symptoms, such as fever, headache, myalgias [46]. In two cases, antibiotic therapy was not detailed. Antibiotics administration was generally promptly initiated as soon as the diagnosis was confirmed by CSF examination.

Concerning outcome, for 6 patients a full recover was reported, while 18 patients experienced a partial cognitive recovery. In 4 cases the neurological conditions remained stable and in 4 cases they worsened. In 2 cases, follow-up data were not reported. A brain MRI was repeated during follow-up in 10 patients, showing some improvement in 2 cases, unchanged features in 5, and a worsening in 3 patients. Finally, a lumbar puncture was repeated after treatment ending in 12 subjects, resulting completely normal in 6 cases and still showing some abnormalities in the remaining patients.

All details about single cases are reported in Supplementary Table 1.

Comparison of neuropsychological features between AD and AD-NS

Three identified studies were focused on the comparison of neuropsychological features between AD-NS patients and AD patients. Two of these studies also involved a frontotemporal dementia (FTD) group. In particular, Wang and colleagues [47] found that 12 patients with GPI and 24 patients with AD showed a similar pattern of cognitive impairment compared to 36 healthy controls (HC), with compromised scores on memory tests. There were no significant differences between AD and GPI, except for the Clock-Drawing Test (CDT) [47]. Instead, compared to FTD group, GPI patients reported better language performances in Boston Naming and Verbal Fluency tests and worse performances on tests exploring visuospatial functions and delayed/cued recall of the Auditory Verbal Learning tests [47].

Zhao and colleagues [48] compared the cognitive functions and the neuropsychiatric behaviors in 30 patients with AD, 30 with GPI, and 30 with FTD, and found that MMSE scores were significantly higher in GPI patients compared to the other two groups, while Neuropsychiatric inventory (NPI) scores were significantly lower in GPI and AD patients compared to FTD [48].

Finally, the study by Zhong and colleagues [49] analyzed the severity of cognitive impairment between 91 patients with NS and 162 with AD, distinguishing different stages of dementia in both groups (mild cognitive impairment versus moderate dementia). By using NPI scale, a factor analysis on 12 items, they demonstrated that a frontal lobe syndrome is more evident and severe in neurosyphilis, compared to AD, from the early mild cognitive impairment to the moderate dementia stage [49].

Comparison of CSF AD biomarkers between AD and AD-NS

Four studies focused on the comparison of CSF AD biomarkers between patients with AD-NS and patients with AD (Table 2).

Table 2

Summary of included studies comparing patients with AD and patients with neurosyphilis presenting with dementia

Study	Objective	Patients included	Results
Neuropsychological comparison
Wang et al. 2011 [47]	To investigate cognitive features of patients with GPI compared to HC, AD, and FTD patients	24 AD patients, 12 GPI patients, 11 FTD patients, 36 HC	Patients with GPI and with AD showed a similar pattern of cognitive impairment compared to HC, mainly involving memory impairment.
			No significant differences between AD and GPI patients, except for the Clock-Drawing Test (better performance of AD versus GPI). Compared to FTD, GPI patients showed better language performances (Boston Naming and Verbal Fluency tests) and worse visuospatial structure imitation, and delayed and cued recall of the Auditory Verbal Learning tests.
Zhao et al. 2016 [48]	To compare and analyze differences in cognitive functions and neuropsychiatric behaviors between AD, GPI and FTD	30 AD patients, 30 GPI patients, 30 FTD patients	MMSE scores were significantly higher in GPI compared to AD and FTD groups.
			NPI scores were significantly higher in FTD group than GPI and AD groups.
Zhong et al. 2017 [51]	To compare the severity of cognitive impairment between NS and AD	162 AD patients, 91 NS patients (21 NS-MCI and 70 NS-dementia), 157 MCI patients, 139 HC	MMSE and total NPI scores showed significant differences between groups: factor analysis on 12 NPI items showed that frontal lobe syndrome was more severe in patients with NS compared to AD from the early MCI stage to the moderate dementia stage.
CSF fluid biomarkers comparison
Paraskevas et al. 2007 [53]	To investigate the levels of tau protein in neurosyphilis	14 AD patients, 12 NS patients, 17 patients with syphilis without CNS involvement, 14 HC	T-tau: increased levels in neurosyphilis (median 349 pg/mL, range [312–429]) and in AD (543 pg/mL [441–1017]) compared to HC (189 pg/mL [106–220]) and syphilis without CNS involvement (190 pg/mL [160–223]).
Zhong et al. 2013 [51]	To assess the levels of Aβ40 and Aβ₄₂ in patients with GPI compared to HC, AD and DLB patients	51 AD patients, 43 GPI patients, 26 DLB patients, 30 HC	Aβ₄₂: levels significantly lower in AD (p < 0.001), DLB (p < 0.001) and GPI (p < 0.001) groups than in HC.
			Aβ₄₀: levels significantly lower in AD (p = 0.001) and DLB (p < 0.001) than in HC. GPI group showed a trend towards decreased levels (p = 0.075) compared to HC.
Luo et al. 2015 [50]	To explore the amyloid and tau metabolism in GPI and ANS patients compared with AD and HC	53 AD patients, 44 GPI patients, 10 ANS patients, 36 HC	Aβ₄₂: levels significantly lower in AD group than in the other three groups (p < 0.001).
			Aβ₄₀: no differences between groups (p = 0.053).
			T-tau and p-tau: levels significantly lower in GPI, ANS and HC compared to AD group (all p < 0.001). No differences between GPI, ANS and HC.
Zhang et al. 2020 [52]	To explore biomarker levels in NS and GPI compared with those in AD	23 AD patients, 55 GPI patients and 13 NS patients without GPI	Aβ₄₂: no differences between groups.
			T-tau: levels significantly higher in AD patients than in GPI (p = 0.003) and NS (p = 0.002) patients.
			BACE1: plasma levels higher in AD patients than in GPI (p = 0.001) and NS (p = 0.042) patients, while CSF levels higher in AD patients than in GPI patients (p = 0.005) and no difference between GPI and NS.

AD, Alzheimer’s disease; ANS, asymptomatic neurosyphilis; BACE1, β-amyloid precursor protein cleaving enzyme; CNS, central nervous system; CSF, cerebrospinal fluid; DLB, dementia with Lewy bodies; GPI, general paralysis of the insane; HC, healthy controls; MCI, mild cognitive impairment; NPI, neuropsychiatric inventory; NS, neurosyphilis.

Three out of four studies presented Aβ₄₂ and Aβ₄₀ levels for AD patients and GPI patients. Luo and colleagues [50] found that CSF Aβ₄₂ values were significantly lower in 53 AD patients compared to 44 GPI patients and 36 HC (p < 0.001), but also that Aβ₄₂ levels in GPI group were significantly lower than in HC (p < 0.001), while CSF levels of Aβ₄₀ were not significantly different between the groups [50]. In the study by Zhong and colleagues [51], the authors found that the AD group (n = 51) had lower CSF levels of Aβ₄₂ (p < 0.001) and Aβ₄₀ (p = 0.001) compared to HC (n = 30), while the GPI group (n = 43) displayed lower CSF Aβ₄₂ levels (p < 0.001) with a trend towards decreased CSF Aβ₄₀ levels (p = 0.075) [51].

Finally, Zhang and colleagues [52] found no differences between CSF Aβ₄₂ and Aβ₄₀ values between AD and GPI, but they analyzed plasma and CSF levels of Beta-secretase 1 (BACE1) and found a significant increase in 23 AD patients compared to 55 GPI patients (p = 0.001 and p = 0.005 respectively) [52]. No HC were included in this study.

Three out of four studies analyzed CSF t-tau values, and only in one study levels of CSF p-tau were reported. Luo and colleagues [50] found that CSF t-tau and p-tau values were significantly higher in 53 AD compared to 44 GPI patients and 36 HC (p < 0.001), while no differences were seen between GPI and HC [50]. In the study by Zhang and colleagues [52] levels of CSF tau were significantly higher in 23 AD patients than in 55 GPI patients (p = 0.003) [52]. Paraskevas and colleagues [53] demonstrated, instead, that 12 patients with neurosyphilis had increased CSF levels of t-tau compared to 14 HC (p < 0.01), though in 14 AD patients the increase in t-tau levels was even higher (p < 0.001) [53].

DISCUSSION

Often defined as a “great imitator”, it is undeniable that several clinical features of neurosyphilis, particularly in its late form of GPI, can overlap with those of AD. Here, we report a case of neurosyphilis showing clinical signs, brain imaging and CSF profiles consistent with AD. We also identified other similar reported cases presenting with an AD clinical phenotype, thus confirming that diagnosis and classification can sometimes be challenging.

The initial clinical pictures— characterized by an insidious onset of memory impairment and cognitive disfunctions, together with nonspecific personality changes— can be very difficult to distinguish from primary neurodegenerative diseases, leading to a high rate of misdiagnosis [54 –56]. During the course of the disease, other neurological signs and symptoms may appear, that lead to rediscuss the diagnosis, such as early pyramidal or extrapyramidal signs, gait disturbances or Argyll-Robertson pupils.

Structural neuroimaging cannot differentiate as well, since isolated cortical atrophy, more often diffuse and less frequently involving only mesial temporal lobes as in AD, was the most common findings, also in our illustrative case. Indeed, the additional presence of vasculitis-like lesions or large T2/FLAIR hyperintensities could help to rule out a primary neurodegenerative cause of cognitive impairment [7, 57], and could prompt further investigations, as occurred in our case. Few studies suggested that iron depositions in microglia of frontal and temporal lobes, seen as hypointensities in susceptibility-weighted brain MRI sequences, may represent a peculiar radiological findings of GPI [58]. However, no pathognomonic MRI lesions have been described in neurosyphilis.

As for nuclear medicine imaging, and despite FDG-PET is a commonly used technique for the diagnosis of AD and for the differential diagnosis with other neurodegenerative diseases, very few data are available about its use in neurosyphilis, mainly showing conflicting results [59].

For instance, a small Austrian study analyzed FDG-PET features in neurosyphilis and documented a global reduction in glucose consumption, more pronounced in frontal lobes and with sparing of basal ganglia and thalamus [60]. However, other reports described more various FDG-PET patterns in AD-NS, ranging from hypermetabolic temporal lobes to focal temporal hypometabolism [61, 62]. All the patients with neurosyphilis showed hypometabolism involving one or both temporal and parietal lobes. Indeed, this feature represents a possible pitfall leading to misdiagnosis of AD. Actually, FDG-PET in typical AD shows middle/lateral temporal and parietal hypometabolism with relative sparing of basal ganglia, primary motor cortex and thalamus [63, 64]. Precuneus and posterior cingulate are among the most sensitive regions affected in the early stages of AD [64], but they are not specific, since there are reports of AD-NS with hypometabolism and sparing in the same regions [59].

Even less information are available regarding SPECT imaging in GPI, with some studies reporting increased cerebral perfusion and the majority indicating diffuse hypoperfusion [65].

CSF examination may certainly provide some clues, even if syphilis tests are not performed. We report abnormal CSF in more than 85% of cases, with increased cells and/or proteins.

Data on fluid biomarkers in CSF are more controversial. Some comparative studies reported increased levels of t-tau both in AD and in GPI compared to HC, without significant differences between the two conditions [53], while other studies found that t-tau only increased in AD but not in GPI [50, 52]. The same applied to Aβ₄₂ concentrations, that were comparable in GPI and AD in some studies [51, 52], whereas significantly higher results were reported in GPI patients compared to AD patients in other studies [50]. Concentrations of p-tau181 were analyzed only in one study, in which they resulted significantly higher in AD compared to GPI patients and HC [50]. Since these biomarkers may not be sufficient to accurately discriminate between the two pathological entities, other candidate biomarkers reflecting neurodegenerative diseases and AD pathophysiology may enrich the panel and optimize performance [66]. For instance, BACE1, the key enzyme responsible for the pathologic amyloidogenic cleavage of the Aβ protein precursor, has shown promising results as a plasma biomarker candidate for different contexts-of-use [66, 67]. BACE1 concentrations are significantly higher in AD patients compared to GPI patients [52]. However, these results warrant confirmation with further investigations.

Other critical pathophysiological pathways occurring in infectious diseases of the CNS, such as neuroinflammation and blood-brain-barrier disruption, are reported to happen in AD as well [68 –73], thus making nonspecific inflammatory biomarkers (i.e., cytokines, reactive oxygen species, activated microglia) unable to discriminate between the two diseases.

Emerging methodological, technical, design, and conceptual paradigms in AD screening and diagnostics, such as the use of the ATN-biomarker classification system [74] and liquid biopsy (i.e., a non-invasive, blood-based biomarker panel) [75 –78], hold the promise to facilitate practical and actionable solutions for precision medicine-oriented practice [76]. Such biomarker panels could be extended by indicators reflecting first-level inflammation-infection screening providing a fast-track characterization across the single patient’s physiology and pathophysiology [76, 79].

Finally, a careful and thorough neuropsychological examination can evidence alterations across cognitive domains atypical for AD. GPI patients tend to have a wider range of compromised functions, involving not only memory but also language, attention, executive function, and spatial ability [47]. Some studies showed that in psychometric tests like MMSE and Montreal Cognitive Assessment, patients with GPI performed significantly better than patients with AD [48, 49], while the CDT, which measures multiple cognitive functions all together, appeared more compromised in GPI patients compared to AD patients [47]. This finding indicated that a cross-domain cognitive test might be more sensitive in differentiating patients with AD-NS from patients with AD.

However, it is known that AD with positive pathophysiological biomarkers could present atypical features leading to frequent misdiagnoses in case diagnoses are purely clinically based [80].

In addition, patients with GPI early exhibited a different range of neuropsychiatric symptoms than AD, such as hallucinations, mood disorders, personality changes, and apathy, thus highlighting a disfunction in frontal lobe at disease onset [54]. Conversely, in patients with AD, there are different pattern of early symptomatic presentations (i.e., spectrum of atypical AD subtypes), but generally the severity of neuropsychiatric symptoms increases as the severity of dementia worsens [81]. The different timing in the involvement of frontal lobes in AD and AD-NS is likely related to the different pathological progression: in AD the Aβ deposition follows a limbic-to-frontal sequence [82], while the distribution of neuropathology in neurosyphilis does not seem to have spatio-temporal characteristics [83].

However, milder and often under-recognized neuropsychiatric symptoms may precede overt cognitive decline in AD, causing substantial distress for both people with dementia and their caregivers [84, 85]. Of note, in a subgroup of people with AD, memory problems are not the first symptoms. This is called atypical AD [80]. AD usually presents with progressive episodic memory loss. Atypical presentations of AD occur and involve non-amnestic and early-onset forms of the disease. Posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA) are two well-described syndromes that are most commonly due to atypical presentations of AD. PCA is a higher-order disturbance of vision whilst lvPPA is characterized by hesitant speech with word-finding difficulties and problems with repetition of words and phrases. Therefore, the differential diagnosis between AD (typical and atypical spectrum) and neurosyphilis should also be considered when neuropsychiatric symptoms are present, irrespectively of the cognitive stage, since these symptoms have a high socio-economic burden and negatively impact long-term prognosis [84].

In summary, despite many difficulties in the differential diagnosis, early detection, and identification of neurosyphilis mimicking AD is paramount in order to start an appropriate antibiotic therapy and avoid neurological sequalae. In our systematic review, 17% of patients experienced a full recovery after antibiotic therapy, while 52% showed some degrees of improvement. Of the remaining cases, 11% experienced symptomatic stabilization, and only in 11% of cases worsening and decline was reported.

Thus, the possibility of neurosyphilis as a cause of cognitive impairment, especially in young patients, or when atypical imaging or CSF features are present [86 –88], needs to be taken into account to avoid unnecessary and deleterious delays.

The molecular, cellular, and network dynamics underlying clinical recovery in several CNS disease, including NS, are still unknown [89]. In addition, no predictors of clinical trajectories in AD-NS individuals have been identified so far. A recent study [90] suggests that severe mesial temporal lobe atrophy may serve as a predictor of poor cognitive outcome in GPI despite appropriate treatment.

Finally, because of the highlighted clinical and biological commonalities, AD-NS may represent a viable clinical construct to investigate in-vivo pathophysiological changes occurring in the early prodromal stages of AD.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgements to report.

FUNDING

The authors have no funding to report.

CONFLICT OF INTEREST

AV declares no competing financial interests related to the present article, and his contribution to this article reflects only and exclusively his own academic expertise on the matter. This work is linked to his previous academic position at Sorbonne University, Paris, France. AV was an employee of Eisai Inc. [Nov 2019 – June 2021]. AV has not received any fees or honoraria since November 2019. Before November 2019 he received lecture honoraria from Roche, MagQu LLC, and Servier.

HH is an employee of Eisai Inc. The present article has been initiated and prepared as part of his academic position at Sorbonne University, Paris, France, and reflects entirely and exclusively his own opinion. He serves as Senior Associate Editor for Alzheimer’s & Dementia and did not receive any fees or honoraria since May 2019.

He is inventor of 11 patents and has received no royalties:

In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388

In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784

Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300

In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463

In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286

In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822

In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553

CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797

In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966

Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921

Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: Publication number: United States Patent 10921330.

DATA AVAILABILITY

The data supporting the findings of this study are available within the article and its .

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

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