Assessing Nigrostriatal Dopaminergic Pathways via 123I-FP-CIT SPECT in Dementia With Lewy Bodies in a Psychiatric Patient Cohort

Background(123)-I-2-ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortro- pane single photon emission computed tomography (123I-FP-CIT SPECT) was validated to distinguish Alzheimer’s dementia from dementia with Lewy Bodies (DLB) by European medical agencies. Little evidence exists that validates 123 I-FP-CIT SPECT as a supplementary method to diagnose probable DLB in a psychiatric cohort of patients with psychiatric symptomatology and suspected DLB. We aim to elucidate differences in the clinical phenotype of DLB between those patients with and those without a positive 123 I-FP-CIT SPECT indicating a nigrostriatal deficit.MethodsTo investigate this, we included 67 patients from the Department of Psychiatry and Psychotherapy at University Medical Center Göttingen (UMG) in our study who had undergone 123I-FP-CIT SPECT in the Department of Nuclear Medicine (UMG) by evaluating their patient files.Results55% with a positive-123I-FP-CIT SPECT and probable DLB after the 123I-FP-CIT SPECT exhibited psychiatric features. The number of probable DLB patients in those exhibiting psychiatric symptoms was higher post-123I-FP-CIT SPECT than pre-123I-FP-CIT SPECT assessed cross-sectionally over a 6-year period (p < 0.05). In addition, prodromal DLB and prodromal DLB patients with a psychiatric-phenotype yielded higher numbers post-123I-FP-CIT SPECT than pre-123I-FP-CIT SPECT (p < 0.05). Furthermore, we discovered no phenotypical differences between those DLB patients with a positive and those with a negative 123I-FP-CIT SPECT. 123I-FP-CIT SPECT-positive DLB patients in our psychiatric cohort revealed a psychiatric onset more often (52%); DLB was less often characterized by an MCI onset (26%) (p < 0.005).ConclusionsOur findings support 123I-FP-CIT SPECT as an adjuvant tool for improving the diagnosis of probable DLB and prodromal DLB in a cohort of psychiatric patients with often concomitant psychiatric symptomatology. The psychiatric-onset is more frequent than an MCI-onset in DLB patients presenting nigrostriatal dysfunction, giving us an indication of the relevance of deep clinical phenotyping in memory clinics that includes the assessment of psychopathology

KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

Autoimmune dementia is a novel and expanding field which subsumes neuropsychiatric disorders with predominant cognitive impairments due to an underlying autoimmune etiology. Progressive dementias with atypical clinical presentation should trigger a thorough diagnostic approach including testing for neural surface and intracellular antibodies to avoid a delay in accurate diagnosis and initiating appropriate therapy. Here, we present two emerging cases of progressive dementia with co-existing serum autoantibodies against the KCNA2 (potassium voltage-gated channel subfamily A member 2) subunit. We found various cognitive deficits with dominant impairments in the memory domain, particularly in delayed recall. One patient presented a subacute onset of then-persisting cognitive deficits, while the other patient’s cognitive impairments progressed more chronically and fluctuated. Cognitive impairments coincided with additional neuropsychiatric symptoms. Both had a potential paraneoplastic background according to their medical history and diagnostic results. We discuss the potential role of KCNA2 autoantibodies in these patients and in general by reviewing the literature. The pathogenetic role of KCNA2 antibodies in cognitive impairment is not well delineated; clinical presentations are heterogeneous, and thus a causal link between antibodies remains questionable. Current evidence indicates an intracellular rather than extracellular epitope. We strongly suggest additional prospective studies to explore KCNA2 antibodies in specifically-defined cohorts of cognitively impaired patients via a systematic assessment of clinical, neuropsychological, neuroimaging, as well as laboratory and CSF (cerebrospinal fluid) parameters, and antibody studies to (1) determine the epitope’s location (intracellular vs. extracellular), (2) the mode of action, and (3) seek co-existing, novel pathogenetic autoantibodies in sera and CSF

Stem cell therapy in a parkinson animal model: tumorigenicity and functional integration.

Der Morbus Parkinson ist die zweithäufigste neurodegenerative Erkrankung nach der Alzheimer-Demenz. Breites wissenschaftliches Interesse gilt dem gezielten Ersatz der von dem neurodegenerativem Prozess erfassten Zellen. Zielstrukturen bei der Parkinsonschen Erkrankung sind dopaminerge Neurone der Substantia nigra, deren Untergang das entscheidende Merkmal dieser fortschreitenden Bewegungsstörung ist. Experimentelle Zellersatzstrategien mit murinen und humanen Stammzelllinien in Tiermodellen weisen bis dato auf eine mögliche funktionelle Integration und eine gewisse Tumorigenität der transplantierten Gewebe hin. Gegenstand der vorliegenden Arbeit war es, verschiedene Stammzelllinien auf die Fähigkeit zur funktionellen Integration und auf die Bildung von Tumoren zu untersuchen. Undifferenzierte Stammzellen bzw. zu dopaminergen Neurone differenzierte Stammzellen wurden in ein unilaterales 6- Hydroxydopamin- Parkinsonmodell der Ratte transplantiert. Immunsuppression erfolgte mit täglichen Cyclosporin A- Injektion für 5 Wochen nach Transplantation. Verhaltensversuche umfassten einen Medikamenten- induzierten Rotationstest, Rotarodtest und Zylindertest. Histochemische und immunhistologische Untersuchungen dienten zum Nachweis von Dopamin produzierenden Neuronen und von Tumorgewebe. Von 91 transplantierten Tieren (18 Eras; 18 MPI1; 20 OS25; 35 HT2) wiesen 52 % eine Tumorbildung auf. Mit 70% zeigte die OS25-Zellinie die höchste Tumorigenität, gefolgt von der HT2-Zellinie (66%) sowie der Eras- und MPI1- Zelllinie (jeweils 28%). Tiere mit TH (Tyrosinhydroxylase)-positiven aber tumorfreien Transplantaten wiesen eine signifikante Verbesserung im Rotarodtest auf (p=0,009). Ebenso zeigten Tiere mit TH-positiven aber tumorfreien Transplantaten eine signifikante Reduktion der Rotationen nach Apomorphingabe im Vergleich zu den Tieren ohne Nachweis von TH (p=0,02). Die gefundene Tumorrate variierte von 28-70%, wobei differenzierte Stammzelllinien höhere Tumorraten aufwiesen als undifferenzierte murine Stammzellen. Eine funktionelle Integration der dopaminergen Neurone war nachweisbar, sofern eine Tumorbildung in den Transplantaten ausblieb. Neben undifferenzierte Stammzellen sind nicht endgültig differenzierte, noch pluripotente Zellen als möglicher Ursprung von Tumorgewebe anzunehmen. Die Identifikation, Charakterisierung und Eliminierung dieser Zellen scheinen für eine ausreichende Tumorreduktion und die klinische Anwendung der Stammzell- basierenden Zellersatztherapie unabdingbar

Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge

Our review aims to delineate the psychiatric spectrum of autoantibody-associated autoimmune encephalitis over time through its discoveries of antibodies. We searched in PubMed for appropriate articles depicting the first appearance and spectrum of psychiatric symptomatology in autoantibody-positive encephalitis for this narrative review. Memory impairment was first associated with autoantibodies against intracellular antigens such as anti-HuD antibodies in 1993. 8 years later, autoantibodies against cell membrane surface antigens such as voltage-gated potassium channels were described in conjunction with memory dysfunction. The spectrum of psychiatric syndromes was amplified between 1990 and 2020 to include disorientation, behavior, cognitive dysfunction, obsessive compulsive behavior and suicidality in encephalitis patients occurring together mainly with antibodies against surface antigens, less so against intracellular antigens. In general, we found no specific psychiatric symptoms underlying specific autoantibody-associated encephalitis. As fundamental data on this issue have not been systemically assessed to date, we cannot know whether our specific findings would remain from systematic studies, i.e., on the association between cerebrospinal fluid N-methyl-D-aspartate receptor antibodies in catatonia. The psychiatric symptomatology overlaps between psychiatric domains and occurs frequently in antibody-positive encephalitis. No specific psychiatric symptoms imply an underlying, specifically autoantibody-associated encephalitis. The psychiatric phenotypology associated with antibody-positive encephalitis has evolved tremendously recently, and this new evidence reveals its relevance for future diagnostic and treatment aspects of autoimmune encephalitis patients

Neural cell-surface and intracellular autoantibodies in patients with cognitive impairment from a memory clinic cohort

Autoantibody-associated cognitive impairment is an expanding field in geriatric psychiatry. We aim to assess the association between the presence of specific neural autoantibodies and cognitive performance in a memory clinic cohort. 154 patients with cognitive impairment were included between 2019 and 2020 presenting initially in a memory clinic. We evaluated their patient files retrospectively applying epidemiologic parameters, psychopathology, neuropsychology, intracellular and membrane-surface autoantibodies in serum and cerebrospinal fluid (CSF) and markers of neurodegeneration in CSF. In 26 of 154 patients, we searched for neural autoantibodies due to indicators for autoimmunity. In 15/26 (58%) of patients we detected serum and/or CSF autoantibodies. We identified autoantibodies against intracellular or cell-surface antigens in 7 of all 26 (27%) patients with cognitive dysfunction, although we cannot exclude patients with potential specific autoantibodies lacking autoimmune indicators. There were no significant differences between psychopathological and neuropsychological profiles in groups of patients with cognitive impairment comprising patients with autoantibodies (ABS + COG), no autoantibodies (ABS - COG), and Alzheimer's disease (ADCOG). Concerning our CSF parameters, we detected intrathecal IgG synthesis in 14% of ABS + COG and in 13% of ABS - COG patients, whereas no intrathecal IgG synthesis was found in ADCOG patients. Furthermore, CSF Aß42 was significantly diminished in the ADCOG compared to the ABS + COG group (p < 0.05). In addition, the Aß42/40 ratio was lower in ADCOG patients than in the ABS + COG or ABS - COG group (p < 0.05). Our findings reveal the underestimated occurrence and autoantibodies' potential role in patients presenting cognitive impairment. Furthermore, the patients with possible Alzheimer's disease might be differentiated from autoantibody-positive patients via a reduced Aß42 and Aß42/40 ratio in the CSF. The antibody-type varies between patients to a relevant degree, thus demonstrating the need for more research to identify subgroup-specific phenotypes. These pilot study results open an avenue for improving diagnosis and treatment in a memory clinic

KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

Autoimmune dementia is a novel and expanding field which subsumes neuropsychiatric disorders with predominant cognitive impairments due to an underlying autoimmune etiology. Progressive dementias with atypical clinical presentation should trigger a thorough diagnostic approach including testing for neural surface and intracellular antibodies to avoid a delay in accurate diagnosis and initiating appropriate therapy. Here, we present two emerging cases of progressive dementia with co-existing serum autoantibodies against the KCNA2 (potassium voltage-gated channel subfamily A member 2) subunit. We found various cognitive deficits with dominant impairments in the memory domain, particularly in delayed recall. One patient presented a subacute onset of then-persisting cognitive deficits, while the other patient’s cognitive impairments progressed more chronically and fluctuated. Cognitive impairments coincided with additional neuropsychiatric symptoms. Both had a potential paraneoplastic background according to their medical history and diagnostic results. We discuss the potential role of KCNA2 autoantibodies in these patients and in general by reviewing the literature. The pathogenetic role of KCNA2 antibodies in cognitive impairment is not well delineated; clinical presentations are heterogeneous, and thus a causal link between antibodies remains questionable. Current evidence indicates an intracellular rather than extracellular epitope. We strongly suggest additional prospective studies to explore KCNA2 antibodies in specifically-defined cohorts of cognitively impaired patients via a systematic assessment of clinical, neuropsychological, neuroimaging, as well as laboratory and CSF (cerebrospinal fluid) parameters, and antibody studies to (1) determine the epitope’s location (intracellular vs. extracellular), (2) the mode of action, and (3) seek co-existing, novel pathogenetic autoantibodies in sera and CSF

Current clinical practice of electroconvulsive therapy and repetitive transcranial magnetic stimulation in psychiatry, a German sample

The purpose of the study was to evaluate the current clinical practice of Electroconvulsive Therapy and Repetitive Transcranial Magnetic Stimulation in German psychiatry. Case-based data (> 1.000.000 cases) were collected according to §21 of the German hospital remuneration law from January 2015 to December 2017. The study cohort comprises approximately 35-40% of the annual psychiatric cases and hospitals in Germany. Frequency of ECT and rTMS cases were investigated considering main diagnoses according to ICD-10 and treatment settings (inpatient vs. day-care). ECT cases with short-term hospitalization (≤ 4 days) were supposed to be maintenance ECT cases. A linear regression analysis was conducted to estimate trends in the use of ECT and rTMS. Different groups were compared using Chi-square tests. ECT and rTMS cases appear to increase in total during the observation period possibly due to facilities newly introducing ECT and rTMS but also to increased frequency of treatments. Both treatments were rarely performed in day-care settings (0.89% and 11.25%). ECT was performed in 1.72% of all cases with affective disorders and in 1.48% with major depressions, respectively. Age ≥ 65 years, females, severe and psychotic depression were significantly associated with a higher rate of ECT cases. > 40% of all ECT cases were possibly maintenance ECT cases. Only 0.60% of these were performed in day- care settings. rTMS was primarily performed in major depression (86,7% of all rTMS cases). This study suggests a growing demand for ECT and rTMS. Nevertheless, the use of ECT is still low compared to the high prevalence of treatment resistant depression. The use of rTMS is even lower and seems to be restricted to specialized institutions. Maintenance ECT is frequently carried out in an inpatient setting. Limitations of this study are the case- and group-based analysis, missing data on outpatient services and treatment sessions per case. Therefore, the database is not necessarily representative for the entire German healthcare system. Further studies are needed to verify the presented findings and should address the feasibility of ambulatory and day-care ECT services

Establishment of a teaching hospital-based dementia consultation service for rurally-based regional district general hospitals

OBJECTIVE: The treatment of patients with dementia poses a considerable challenge to regional district general hospitals, particularly in rural areas. Here we report the establishment and initial evaluation of a dementia-specific consultation service provided by a teaching hospital-based Psychiatry Department to regional district general hospitals in surrounding smaller towns. METHODS:: The consultation service was provided to patients with pre-existing or newly suspected dementia, who were in acute hospital care for concurrent conditions. An evaluation of 61 consultations - 49 on-site and 12 via telemedicine - was performed to assess the needs of the participating hospitals and the specific nature of the referrals to the consultation service. RESULTS: Suspected dementia or cognitive dysfunction was the primary reason for consultation requests (>50% of cases). Other common requests concerned suspected delirium, behavioral symptoms, and therapeutic recommendations. During the consultations, a diagnosis of dementia was reached in 52.5% of cases, with other common diagnoses including delirium and depression. Recommendations related to pharmacotherapy were given in 54.1% of consultations. Other recommendations included referral for outpatient neurological or psychiatric follow-up, further diagnostic assessment, or assessment in a memory clinic. Geriatric psychiatric inpatient treatment was recommended in only seven cases (11.5 %). CONCLUSION: Our initial evaluation demonstrates the feasibility of providing a dementia-specific consultation service in rural areas. The service has the potential to reduce acute transfers to inpatient geriatric psychiatry and enables older patients with dementia or delirium to be treated locally by helping and empowering rurally-based regional hospitals to manage these problems and associated complications

Autoantibody-associated psychiatric syndromes in children: link to adult psychiatry

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-d-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines