BACE1 and Other Alzheimer's-Related Biomarkers in Cerebrospinal Fluid and Plasma Distinguish Alzheimer's Disease Patients from Cognitively-Impaired Neurosyphilis Patients.

BACKGROUND: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer's disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. OBJECTIVE: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. METHODS: Levels of neurogranin (NGRN) and ß-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-ß 1-40 (Aß40), Aß42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. RESULTS: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. CONCLUSION: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

General paresis of insane: A forgotten entity.

The manifestations of CNS syphilis are unfamiliar to a differential of patients with dementia to many physicians today as of the relative rarity of this condition. This is a classical case report of a patient with syphilis and dementia in a 55-year-old female. General paresis of insane is a progressive disease of the brain leading to mental and physical worsening. It is important to consider tertiary syphilis in the differential diagnosis of dementia. Conventional presentations of neurosyphilis such as tabes dorsalis and general paresis of insane are read in textbooks only and rarely encountered in clinical practice in the 21st century.

Medial temporal lobe atrophy as a predictor of poor cognitive outcomes in general paresis.

BACKGROUND: The effect of penicillin therapy on clinical outcomes vary among patients with general paresis (GP). We sought to explore biomarkers that might serve as predictors of clinical outcomes in GP and identify patients requiring early intervention. METHODS: Thirty-five inpatients with GP were recruited. Each GP patient underwent comprehensive neuropsychological, neuroimaging and laboratory assessments before receiving penicillin therapy, and returned for follow-up evaluations after 6 months. The visual rating of medial temporal lobe atrophy (MTA) and the Fazekas scale was used to analyze the neuroimaging abnormalities. RESULTS: MTA scores were correlated with the pre-treatment cognitive scores and change in Mini Mental State Examination scores. GP patients with a Clinical Dementia Rating Scale (CDR) ≤1 or MTA scores ≤2 achieved significant improvement in neuropsychological test scores, as compared with patients with CDR >1 or MTA scores >2. Fazekas scale scores correlated with the pre-treatment attention scores. Significant improvements in cognitive test scores were observed in GP patients with normalization of serum rapid plasma regain (RPR) titers, but not those without normalization of RPR titers. CONCLUSIONS: Severe MTA may serve as a predictor of poor cognitive outcome and an indicator of severe cognitive impairment in GP patients. Thus, early interventions for improving cognitive function may be considered for GP patients with severe MTA. White matter hyperintensities may associated with attention impairment. Serum RPR titer may serve as a sensitive indicator of therapeutic effect in GP.

[Neurosyphilis: a historical disease with current relevance]. / Neurosyfilis: een historische ziekte met actueel belang.

In the last few years, an increasing worldwide incidence in syphilis has been reported, mostly in the United States and Western Europe. Neurosyphilis is characterized by a wide differential diagnosis, which too often causes the disease to remain undetected for a long time. We report a case of a male patient with manic psychotic symptoms, in whom neurosyphilis was identified after elaborate diagnostic investigations. We give an overview of the disease process and correlations with psychiatric symptoms, diagnostics, screening and treatment.

Stroke and syphilis: A retrospective study of 53 patients.

OBJECTIVE: The aim of this study was to describe the clinical, biological and radiological characteristics of patients with syphilitic vasculitis, and to assess the outcome after treatment. METHODOLOGY: A retrospective review was carried out based on the records of patients with ischemic stroke, and reactive CSF TPHA and VDRL results. None of these patients showed symptoms of any other diseases or had received high doses of penicillin. RESULTS: A total of 53 patients with stroke met the diagnostic criteria for syphilitic arteritis. Their average age was 41±12 years. Nine patients had a history of genital ulcer (17%), and the median duration of illness after presenting a chancre was 8 [range: 1-14] years. A prodromal syndrome was seen in 27 patients (50.9%) and included changes in mental status in 14 patients (26.4%), seizures in 10 cases (18.9%), headache in eight (15.1%) and memory loss in seven (13.2%). Neurological events included focal motor deficits in 29 cases (54.7%), ataxia in 11 (20.8%) and movement disorders in 15 (28.3%). HIV serology was performed in 31 patients and proved negative in every case. Disease evolution was generally favorable: 12 patients (22.6%) were autonomous at the time of hospital discharge; 29 (54.7%) had partially recovered; and only seven (13.2%) still had signs of severe sequelae. CONCLUSION: A diagnosis of syphilitic stroke should be suspected in young patients as a manifestation of syphilis, and tests for neurosyphilis should be routine in neurology departments to make a prompt diagnosis, thereby preventing psychological sequelae.

Historical reflections on neurosyphilis based on the 1826 treatise on general paralysis in demented patients by Louis Florentin Calmeil (1798-1895).

General paralysis is a neurological symptom of tertiary syphilis that was first identified in asylums as paralytic madness. The enlightened discussion of 60 clinicopathological cases provided by Louis Florentin Calmeil in his 1826 treatise greatly improved our knowledge of general paralysis. However, Calmeil was unable to relate this symptom to syphilis, although the latter was quite widespread at that time. Following a detailed reanalysis of Calmeil's observations with special attention to his clinical and demographic data, we conclude that this eminent clinician was unable to define the cause of general paralysis because his early 19th century mind was still under the influence of traditional knowledge and moral prejudices. For Calmeil, general paralysis belonged entirely to the realm of psychiatry.

Neuropsychiatric Features of Neurosyphilis: Frequency, Relationship with the Severity of Cognitive Impairment and Comparison with Alzheimer Disease.

BACKGROUND: The pattern of neuropsychiatric features of patients with neurosyphilis and the impact of the severity of cognitive impairment on neuropsychiatric syndromes are unknown. OBJECTIVE: We aim to assess the neuropsychiatric features of patients with neurosyphilis, and compare the impact of the severity of cognitive impairment on the neuropsychiatric syndromes between neurosyphilis and Alzheimer disease (AD). METHODS: Neuropsychiatric symptoms and the degree of cognitive impairment were assessed in a case-control study of 91 neurosyphilis, 162 AD, 157 mild cognitive impairment, and 139 normal controls by the Neuropsychiatric Inventory (NPI) scale and Clinical Dementia Rating scale, respectively. Factor analysis was performed on the 12 NPI items. RESULTS: Factor analysis showed that patients with neurosyphilis showed more severe neuropsychiatric syndromes at the dementia stage than those neurosyphilis patients at the mild cognitive impairment stage, while neuropsychiatric manifestations were equally common among the different stages of dementia (all p < 0.05). Frontal lobe syndrome was more severe in patients with neurosyphilis than in patients with AD from the early mild cognitive impairment stage to the moderate dementia stage (all p < 0.01). CONCLUSIONS: Patients with neurosyphilis show different patterns of neuropsychiatric syndromes at the mild cognitive impairment and dementia stages, and differ from patients with AD.

[Neurosyphilis in Psychiatric Settings: Three Case Reports]. / Psikiyatri Kliniginde Nörosifiliz: Üç Olgu Bildirimi.

Syphilis is a generally sexually transmitted and multisystem disease caused by the spirochete Treponema pallidum. All of the organs of the body may be involved during the course of the disease. Neurosyphilis is a clinical form of syphilis with the central nervous system (CNS) involvement. While primarily meningeal and vascular structures are involved in early neurosyphilis, a parenchymal affection of the brain and spinal cord emerges at later stages of neurosyphilis. It presents with symptoms of meningitis, meningovasculitis and parenchymal neurosyphilis (presenting as tabes dorsalis and general paresis). Clinically, it can mimic a variety of psychiatric disorders such as depression, psychosis, mania, delirium, personality changes and dementia. During its progression making presentations similar to many systemic or neuropsychiatric diseases, syphilis is defined as "great imitator". Nowadays, neurosyphilis is a rare disease as a result of the widespread use of antibiotics that must be kept in mind in the differential diagnosis of neurological and psychiatric disorders. In this article, three neurosyphilis cases with different psychiatric presentations are reported and literature relevant to syphilis are reviewed.

Revisiting an old foe: The face of psychosis in neurosyphilis.

A delusional, agitated middle-aged man presented to hospital with a tenacious psychotic episode. Upon appropriate therapy for neurosyphilis, dramatic resolution of this brief episode ensued, prompting a literature review of psychosis associated with neurosyphilis.

Diagnosing neurosyphilis: a case of confusion.

A Pakistani man aged 60 years presented with personality change, aggression, paranoid delusions and sexual disinhibition while being treated for severe chest sepsis in intensive care. Collateral history confirmed that these personality changes had been developing over the course of the previous 2 years. He was found to have positive syphilis serology during a routine confusion screen, and the possibility of neurosyphilis was raised. Cerebrospinal fluid examination revealed elevated protein but negative syphilis testing. Following multidisciplinary discussion, the decision was made to treat as neurosyphilis, which resulted in a significant improvement in symptoms. The genitourinary department was able to carry out thorough contact tracing. This case demonstrates the importance of including syphilis in a confusion screen as this patient was diagnosed following a low clinical suspicion. It also highlights some potential pitfalls and difficulties in the diagnosis of neurosyphilis and the importance of the use of a multidisciplinary team.

Neurosyphilis Is a Long-forgotten Disease but Still a Possible Etiology for Dementia.

We herein report a heterosexual Japanese man in his forties who had been suffering from advanced dementia and personality change for 4 years. Positive results of a serological test for syphilis, Treponema pallidum hemagglutination assay, and fluorescent treponemal antibody-absorption test of both serum and cerebral spinal fluid led to the diagnosis of neurosyphilis. Jarisch-Herxheimer reaction was seen shortly after the first dose of penicillin was administered to the patient. His cognitive function did not recover after treatment. The incidence of syphilis has been reported to be increasing. Neurosyphilis should not be overlooked as an etiology for progressive dementia even in this post-antibiotic era.

Frederick Delius: controversies regarding his neurological disorder and its impact on his compositional output.

Frederick Delius was born in Yorkshire, England, on June 29, 1862, the son of German immigrants. He showed early musical talent but his father, a wealthy wool merchant, insisted he pursue a business career. After several failures, including an assignment managing an orange grove near Jacksonville, Florida, his father agreed to support his musical studies in Leipzig, assuming he would then become self-sufficient. Delius spent most of his adult life in France, living with and ultimately marrying Jelka Rosen, a painter of independent means, composing prolifically, and being sexually promiscuous both before and after starting life with Jelka. He contracted syphilis in 1895 and manifestations of neurosyphilis appeared in 1910. Despite periods of relative good health over the ensuing 10 years, he became progressively disabled from 1920 on, ultimately quadriparetic and blind but with preserved cognition and musical inspiration. In his final years, he completed several compositions aided by a young British musician, Eric Fenby, who served as his amanuensis and caregiver, along with Jelka, to his death on June 10, 1934.

Neurocognitive changes in tertiary neurosyphilis: a retrospective chart review.

CONTEXT: Since the beginning of the new millennium, prevalence of syphilis has re-increased and is once again, a major public health problem. Neurosyphilis is the extension of syphilitic infection to the nervous system. It is considered by many as a cause of reversible dementia, when treated early. However, scarce data exist on the evolution of cognitive and behavioral impairments in patients affected by tertiary neurosyphilis. OBJECTIVES: The aim of this study was to explore the cognitive and behavioral changes in a cohort of patients diagnosed with neurosyphilis. DESIGN: A retrospective study based on systematized chart review between 2000 and 2012 in a large neurological tertiary care facility. OUTCOME MEASURE: Clinical evaluations by treating physicians. RESULTS: Eighteen patients were identified with tertiary neurosyphilis. Out of this group, only two had systematic neuropsychological follow-up despite physician reports of significant and persistent cognitive and psychiatric changes. For these two cases, only slight improvements were noted in memory and executive skills while improvements in attention were marked. None of our patients had previous psychiatric history yet a large proportion developed symptoms after the infection. CONCLUSION: Although neurosyphilis is traditionally considered a reversible form of dementia, we found limited support for this claim in our two patients with close follow-up. Quality data on the cognitive and psychiatric changes in the rest of our cohort was dramatically lacking, and this could not be explained by absence of symptoms at presentation. Given the recrudescence of syphilis, we propose a systematic approach to the evaluation and follow-up of this disorder.

Psychosis in neurosyphilis -- clinical aspects and implications.

BACKGROUND: The World Health Organization estimates that 10-12 million new syphilis infections occur each year. Without treatment, years to decades after initial infection, 30% of affected individuals may develop tertiary syphilis, which can manifest as neurosyphilis. The aim of this review is to evaluate the research literature examining the psychopathological manifestations of psychosis in association with neurosyphilis. METHOD: The authors performed a systematic electronic search for published studies (1995-2012). The following databases were used: Medline, Embase and the Cochrane Library as well as the search engines Scopus and Google Scholar. RESULTS: 61 articles were used for detailed analysis. Psychotic symptoms due to neurosyphilis are numerous and can inform differential diagnosis for many psychotic manifestations according to ICD-10 or DSM-IV. CONCLUSION: Due to our results, current epidemiological data, and the difficulties in differential diagnosis of neurosyphilis, routine screening tests are still recommended in the psychiatric field. Long-term psychiatric input, with periodic syphilis titre controls, seems indicated in individuals affected by neurosyphilis with psychiatric symptoms. Furthermore, individuals with mental health problems may be at higher risk of acquiring syphilis.

A fatal fall associated with undiagnosed parenchymatous neurosyphilis.

A fall from a great height is often associated with altered mental status. Aside from the usual contributing factors, for example, alcohol consumption or mental illness, natural disease leading to a fatal fall is seldom identified by autopsy. The case described in this report is that of a 57-year-old man who had been clinically diagnosed with presenile Alzheimer disease and fell head first into a river from the bridge. These events were captured by a surveillance camera on the bridge; an acquaintance reported that he had previous suicidal ideation. At autopsy, the cervical spinal cord was determined to have been severely injured, and the sixth cervical vertebra was observed to have been fractured. Histological examination showed chronic meningoencephalitis including neuronal loss, perivascular cuffing, and the proliferation of microglia and astrocytes in the cerebral cortex. Serologic evaluation consisting of the nontreponemal antigen test (rapid plasma reagin [RPR]) and treponemal antibody test (Treponema pallidum latex agglutination) was positive in both cases (RPR: 18.2 RPR units, T. pallidum latex agglutination: 7718 U/mL). These findings suggested that the patient had been affected by a syphilis infection and that his suicidal behavior was associated with parenchymatous neurosyphilis.