OBJECTIVE: The aim of the study was to investigate the factors that underpin neuropsychiatric symptoms and how they might evolve over time in people with Mild Cognitive Impairment (MCI) and Alzheimer\'s disease (AD) dementia.
BACKGROUND: Neuropsychiatric symptoms are psychiatric and behavioural manifestations that occur in people with AD. These are highly prevalent along the continuum of the disease, including at the stage of MCI, as well as before cognitive decline. Various small- and large-scale projects have investigated the underlying factors that underpin these symptoms; however, the identification of clear clusters is still a matter of debate; furthermore, no study has investigated how the clusters might change across the development of AD pathology by comparing different time points.
OBJECTIVE: Our objective was to investigate the factors that underpin neuropsychiatric symptoms in Alzheimer\'s disease (AD) and Mild Cognitive Impairment (MCI) and to assess how the loadings might differ based on considerations such as the disease stage of the samples.
METHODS: Data was obtained from the Alzheimer\'s Disease Neuroimaging Initiative database (adni. loni.usc.edu), using scores from the Neuropsychiatric Inventory, followed up yearly from baseline until month 72. Participant groups included those with MCI or AD dementia, or a mixture of both, with all participants presenting with at least one neuropsychiatric symptom. A series of exploratory Principal Component and Factor (Principal Axis) Analyses were performed using Direct Oblimin rotation.
RESULTS: The best-fitting structure was interpreted for each time point. A consistent, unique structure could not be identified, as the factors were unstable over time, both within the MCI and AD groups. However, some symptoms showed a tendency to load on the same factors across most measurements (i.e., agitation with irritability, depression with anxiety, elation with disinhibition, delusions with hallucinations).
CONCLUSIONS: Although the analyses revealed some degree of co-occurrence of neuropsychiatric symptoms across time points/samples, there was also considerable variation. In the AD group, more discrete syndromes were evident at the early time points, whereas a more complex picture of co-occurring symptoms, with differences likely reflecting disease staging, was seen at later time points. As a clear and distinctive factor structure was not consistently identified across time points/ samples, this highlights the potential importance of sample selection (e.g., disease stage and/or heterogeneity) when studying, for example, the neurobiological underpinnings of neuropsychiatric symptoms.

OBJECTIVE: Posterior reversible encephalopathy syndrome (PRES) in systemic lupus erythematosus (SLE) is a challenging clinical dilemma. A retrospective single-center study was performed to investigate the clinical features, risk factors, outcomes, and clinical determinants of the prognosis of PRES in SLE.
METHODS: A retrospective study was performed from January 2015 to December 2020. 19 episodes of lupus PRES and 19 episodes of non-lupus PRES were identified. 38 cases of patients presenting with neuropsychiatric lupus (NPSLE) hospitalized during the same period were selected as controls. Survival status was acquired via outpatient and telephone follow-up in December 2022.
RESULTS: The clinical neurological presentation of PRES in lupus patients was similar to that of the non-SLE-related PRES and NPSLE populations. Nephritis-induced hypertension is the predominant trigger of PRES in SLE. Disease flare and renal failure-triggered PRES were identified in half of the patients with SLE. The mortality rate of lupus-related PRES during the 2‑year follow-up was 15.8%, the same as that of NPSLE. For patients with lupus-related PRES, multivariate analysis indicated that high diastolic blood pressure (OR =1.762, 95% CI: 1.031 ~ 3.012, p = 0.038), renal involvement (OR = 3.456, 95% CI: 0.894 ~ 14.012, p = 0.049), and positive proteinuria (OR = 1.231, 95% CI: 1.003 ~ 1.511, p = 0.047) were independent risk factors compared to NPSLE. A strong connection between the absolute counts of T and/or B cells and prognosis in lupus patients with neurological manifestations was found (p < 0.05). The lower the counts of T and/or B cells, the worse the prognosis.
CONCLUSIONS: Lupus patients with renal involvement and disease activity are more likely to develop PRES. The mortality rate of lupus-related PRES is similar to that of NPSLE. Focusing on immune balance might reduce mortality.
UNASSIGNED: HINTERGRUND UND ZIEL: Das Syndrom der posterioren reversiblen Enzephalopathie (PRES) bei systemischem Lupus erythematosus (SLE) stellt ein klinisches Dilemma und somit eine Herausforderung dar. In einer retrospektiven Einzelzentrumstudie wurden nun die klinischen Merkmale, Risikofaktoren, Ergebnisse und klinische Parameter für die Prognose des PRES bei SLE untersucht.
METHODS: Dazu wurde von Januar 2015 bis Dezember 2020 eine retrospektive Studie durchgeführt. Es wurden 19 Episoden von Lupus-PRES und 19 Episoden von Non-Lupus-PRES identifiziert. Als Kontrollen wurden 38 Fälle von Patienten ausgewählt, die sich mit neuropsychiatrischem Lupus (NPSLE) vorstellten und während des gleichen Zeitraums stationär aufgenommen wurden. Im Dezember 2022 wurde bei ambulanten und telefonischen Nachsorgeterminen der Überlebensstatus erhoben.
UNASSIGNED: Die klinisch-neurologischen Manifestationen des PRES bei Lupuspatienten waren ähnlich wie bei den Gruppen mit Non-Lupus-PRES und NPSLE. Vorherrschender Trigger des Lupus-PRES ist die nephritisinduzierte Hypertonie. Ein Schub der Erkrankung und ein durch Niereninsuffizienz getriggertes PRES wurden bei der Hälfte der Patienten mit SLE festgestellt. Die Mortalitätsrate des Lupus-PRES während des 2‑Jahres-Follow-up betrug 15,8%, der gleiche Wert wie bei NPSLE. Für Patienten mit Lupus-PRES zeigte die multivariate Analyse, dass ein hoher diastolischer Blutdruck (Odds Ratio, OR=1,762; 95%-Konfidenzintervall, 95%-KI: 1,031 ~ 3,012; p = 0,038), Nierenbeteiligung (OR = 3,456; 95%-KI: 0,894 ~ 14,012; p = 0,049) und Vorliegen einer Proteinurie (OR = 1,231; 95%-KI: 1,003 ~ 1,511; p = 0,047) unabhängige Risikofaktoren im Vergleich zum NPSLE darstellten. Es wurde ein starker Zusammenhang zwischen den absoluten Werten für T‑ und/oder B‑Zellen und der Prognose bei Lupuspatienten mit neurologischen Manifestationen festgestellt (p < 0,05). Je niedriger die Werte für T‑ und/oder B‑Zellen, umso schlechter die Prognose.
UNASSIGNED: Lupuspatienten mit Nierenbeteiligung und Krankheitsaktivität weisen eine höhere Wahrscheinlichkeit für die Entstehung eines PRES auf. Die Mortalitätsrate des Lupus-PRES ist ähnlich wie die des NPSLE. Eine Fokussierung auf das Immungleichgewicht könnte die Mortalität reduzieren.

The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined.
To identify brain-reactive autoantibodies possibly related to NPSLE, immunofluorescence (IF) and transmission electron microscopy (TEM) on rat and human brains were performed. ELISA was used to reveal the presence of known circulating autoantibodies, while western blot (WB) was applied to characterize potential unknown autoantigen(s).
We enrolled 209 subjects, including patients affected by SLE (n=69), NPSLE (n=36), Multiple Sclerosis (MS, n=22), and 82 age- and gender-matched healthy donors (HD). Autoantibody reactivity by IF was observed in almost the entire rat brain (cortex, hippocampus, and cerebellum) using sera from NPSLE and SLE patients and was virtually negative in MS and HD. NPSLE showed higher prevalence (OR 2.4; p = 0.047), intensity, and titer of brain-reactive autoantibodies than SLE patients. Most of the patient sera with brain-reactive autoantibodies (75%) also stained human brains. Double staining experiments on rat brains mixing patients\' sera with antibodies directed against neuronal (NeuN) or glial markers showed autoantibody reactivity restricted to NeuN-containing neurons. Using TEM, the targets of brain-reactive autoantibodies were located in the nuclei and, to a lesser extent, in the cytoplasm and mitochondria. Given the high degree of colocalization between NeuN and brain-reactive autoantibodies, we assumed NeuN was a possible autoantigen. However, WB analysis with HEK293T cell lysates expressing or not expressing the gene encoding for NeuN protein (RIBFOX3) showed that patients\' sera carrying brain-reactive autoantibodies did not recognize the NeuN corresponding band size. Among the panel of NPSLE-associated autoantibodies (e.g., anti-NR2, anti-P-ribosomal protein, antiphospholipid) investigated by ELISA assay, only the anti-β2-glycoprotein-I (aβ2GPI) IgG was exclusively found in those sera containing brain-reactive autoantibodies.
In conclusion, SLE and NPSLE patients possess brain-reactive autoantibodies but with higher frequency and titers found in NPSLE patients. Although many target antigens of brain-reactive autoantibodies are still undetermined, they likely include β2GPI.

Neuropsychiatric symptoms of neurocognitive disorders have been classified into higher-order constructs, often called neuropsychiatric syndromes. As with the general psychopathology literature, these classifications have been achieved through two approaches: empirical and authoritative. The authoritative approach relies on expert panels that condense the available evidence into operational criteria, whereas the empirical approach uses statistical methods to discover symptom patterns and possible hierarchies formed by them. In this article, the author reviews the strengths and weaknesses of both approaches using general psychopathology literature as a reference point. The authoritative approach, influenced by the DSM, has led to several sets of criteria, which could aid clinical trials, diagnostics, and communication. However, unknown reliability and the complex relationships between empirical evidence and published criteria may limit the utility of current criteria. The empirical approach has been used to explore syndrome structures on the basis of rating scales for neuropsychiatric symptoms. The structures suggested in these studies have not been replicated easily and have been limited by either small sample sizes, restricted breadth of neuropsychiatric assessment, or both. Suggestions for further development of both approaches are offered. First, neuropsychiatric symptoms and syndromes need to be studied with measures of broad scope and in large samples. These requirements are prerequisites not only for eliciting highly informative empirical classifications but also for understanding these symptoms at a more nuanced level. Second, both approaches could benefit from more transparency. Finally, the reliability of the available authoritative criteria should be examined.

Neuropsychiatric syndromes and symptoms play increasingly important roles in research diagnostic criteria for neurodegenerative disorders. Diagnostic criteria were reviewed including those for dementia, Alzheimer\'s disease, mild cognitive impairment, mild behavioral impairment, prodromal Alzheimer\'s disease, dementia with Lewy bodies, prodromal dementia with Lewy bodies, Parkinson\'s disease, multiple system atrophy, frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy, corticobasal degeneration, traumatic encephalopathy syndrome, Huntington\' disease, amyotrophic lateral sclerorsis. All contemporary research diagnostic criteria for neurodegenerative disorders expect those for Parkinson\'s disease, primary progressive aphasia, multisystem atrophy and amyotrophic lateral sclerosis include neuropsychiatric phenomena as core diagnostic criteria. There are no disease-specific neuropsychiatric symptoms; apathy and disinhibition are common in tauopathies, and rapid-eye-movement sleep behavioral disorder occurs almost exclusively in synucleinopathies. Neuropsychiatric symptoms and syndromes are increasingly integrated into research diagnostic criteria for neurodegenerative disorders; they require clinician skills for recognition; their biology is better understood as their relationships to cognitive, motor, and autonomic symptoms of neurodegenerative disorders are studied.

The aim of the present study was to assess the effects of nutritional supplementation on neuropsychiatric symptoms among people with dementia.
Randomized controlled trials (RCTs) were searched in the Databases PubMed, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials and Clinicaltrials.gov from inception until January 31, 2020. Studies of RCTs carried out on people with any type of dementia who were taking nutritional supplements and had neuropsychiatric symptoms were included in this systematic review and meta-analysis. Neuropsychiatric symptoms were assessed with the validated Neuropsychiatric Inventory (NPI). Effect sizes were calculated with standardized mean differences (SMD) and 95% confidence intervals (95%CI), applying a random effect model.
The search yielded 1034 studies with four studies being included in the meta-analysis with a total of 377 people with dementia (mean age 69.3 [SD: 7.7] years). The diagnoses comprised mild to late Alzheimer\'s disease and frontotemporal dementia. Two studies included a multicomponent supplementation, one an omega-3, and one a special supplement tailored for cognitive impairment. The median follow-up was 18 weeks, with a range from 12 to 24 weeks. Pooled data showed that nutritional supplementation did not improve NPI (SMD = -0.33; [95%CI: -0.74 to 0.08]; P = 0.11; I2 = 45%).
The findings of this meta-analysis demonstrated no significant impact on NPI through nutritional supplementation. However, the generalization of the results is limited, as different supplements were used in different stages of dementia with a short follow-up time.

Neuropsychiatric syndromes (NPS) are common in neurodegenerative disorders (NDD). This review describes the role of NPS in the diagnosis of NDD, criteria for the diagnosis of NPS, management of NPS, and agents in clinical trials for NPS.
NPS play an increasingly important role in the diagnosis of NDD. Consensus diagnostic criteria have evolved for psychosis, depression, agitation, and apathy in NDD. With one exception-pimavanserin is approved for the treatment of hallucinations and delusions in Parkinson\'s disease-there are no drugs approved by the FDA for treatment of NPS in NDD. Trials show that atypical antipsychotics reduce psychosis in AD and in Parkinson\'s disease, although side effect concerns have constrained their use. Antidepressants show benefit in treatment of Parkinson\'s disease with depression. Several agents are in clinical trials for treatment of NPS in NDD. Neuropsychiatric syndromes play a major role in NDD diagnosis. Clinical criteria allow recognition of NPS in NDD. Psychotropic medications are often useful in the treatment of NPS in NDD; efficacious, safe, and approved agents are needed.

Antiglutamate decarboxylase (anti-GAD) antibodies are associated with several neurological manifestations, like epilepsy and movement disorders. However, in daily neurological practice, it remains hard to define when to test for anti-GAD antibodies in patients with neurologic and/or psychiatric symptoms. Therefore, here, we report the patient characteristics of a large retrospective cohort of patients tested for anti-GAD antibodies in clinical practice and compare the characteristics of anti-GAD positive and anti-GAD negative patients.
We blindly assessed relevant clinical symptoms and comorbidities and functional outcome with the modified Rankin Scale (mRS) in a retrospective observational cohort of all patients in which the decision to assess anti-GAD levels had been made based solely on the presence of possible associated neurological and/or psychiatric symptoms (N=119).
Out of 119 patients, 17 (14.3%) were anti-GAD positive. The anti-GAD positive patients had a median age of 30years (range: 3-64; 2 children). They all had epilepsy, with 8 (47%) patients reporting cognitive complaints. Psychiatric symptoms were less prevalent in anti-GAD positive patients, only 1 anti-GAD positive patient (6%) versus 34 anti-GAD negative patients (33%) reported psychiatric symptoms (p=0.021). The most frequent comorbidity of anti-GAD positive patients was diabetes mellitus type 1 (n=8). Twelve (71%) and 13 (78%) of the anti-GAD positive patients were functionally independent at the time of diagnosis and after one year, respectively (mRS score: 0 to 2). There was no significant difference in functional status at any time during follow-up compared with the anti-GAD negative group.
Antiglutamate decarboxylase (anti-GAD) antibodies relate to epilepsy with or without cognitive complaints. However, psychiatric symptoms were almost absent in anti-GAD positive patients, and the presence of anti-GAD antibodies contributed little to the prognosis in our cohort.

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OBJECTIVE: Neuropsychiatric (NP) events are found in patients with rheumatic diseases, commonly in systemic lupus erythematosus (SLE) and Sjögren\'s syndrome (SS). The standard nomenclature and case definitions for 19 NPSLE syndromes by the American College of Rheumatology (ACR) Committee on Research cover a wide range of NP events seen in both SLE and SS. Despite advances in the understanding of SLE and SS, NP syndromes continue to pose diagnostic challenges. Correct attribution of NP events is critical in determining the correct treatment and prognosis. Anti-N-methyl-d-aspartate receptor subunits NR2A/B (anti-NR2A/B) antibodies have been demonstrated in the sera of SLE and SS patients and have been associated with collective or specific NP syndromes, though not consistently. Interpretation of anti-NR2A/B antibody data in the medical literature is rendered difficult by small sample size of patient groups. By combining different studies to generate a pooled effect size, a meta-analysis can increase the power to detect differences in the presence or absence of NP syndromes. Hence, we set out to perform a meta-analysis to assess the association between anti-NR2A/B antibodies and NP syndromes in SLE and SS.
METHODS: A literature search was conducted using PubMed and other databases from inception to June 2016. We abstracted data relating to anti-NR2A/B antibodies from the identified studies. The random effects model was used to calculate overall combined odds ratio (OD) with its corresponding 95% confidence interval (CI) to evaluate the relationship between anti-NR2A/B antibodies and NP syndromes in SLE and SS patients with and without NP events. We also included our own cohort of 57 SLE patients fulfilling the ACR 1997 revised classification criteria and 58 healthy controls (HCs).
RESULTS: In total, 17 studies with data on anti-NR2A/B antibodies in 2212 SLE patients, 66 SS patients, 99 disease controls (DCs) (e.g. antiphospholipid syndrome, myasthenia gravis and autoimmune polyendocrine syndrome I) and 538 HCs were used in this analysis. Overall pooled prevalence of serum/plasma anti-NR2A/B antibodies was higher in SLE patients [24.6% (95% CI 18.5-32.0%)] and SS patients [19.7% (95% CI 11.8-31.0%)] compared to DCs [14.8% (95% CI 2.2-56.9)] and HCs [7.6% (95% CI 4.6-12.4%)] (p=0.001). There was a significantly greater proportion of SLE and SS patients with NP syndromes who demonstrated positivity for serum/plasma anti-NR2A/B antibody [pooled OR=1.607 (95% CI 1.041-2.479), p=0.032] as compared to SLE and SS patients without NP syndromes in 13 studies. Usable data for cerebrospinal fluid anti-NR2A/B antibodies were available in only 4 studies [pooled OR=0.831 (95% CI 0.365-1.888), p=0.658]. Among the 19 NP syndromes, serum/plasma anti-NR2A/B antibodies were not specifically associated with any NP syndrome, including cognitive dysfunction (p=0.259) and mood disorder (p=0.503). Meta-regression identified proportion of anti-double-stranded deoxyribonucleic acid antibody positivity (p=0.009) and SLE Disease Activity Index (p=0.028) as moderators for the heterogeneity of serum/plasma anti-NR2A/B antibodies.
CONCLUSIONS: Circulating anti-NR2A/B antibody testing has a diagnostic value for NP syndromes in SLE and SS collectively. However, the evidence to date suggests that anti-NR2A/B antibody positivity cannot distinguish specific NP syndromes.