Cognitive dysfunction and mortality in multiple sclerosis: Long-term retrospective review.

BACKGROUND: Cognitive dysfunction as a predictor of clinical progression and mortality in multiple sclerosis (MS) is still a matter of debate. OBJECTIVE: The aim of this study was to explore the long-term outcome associated with neuropsychological performance in a cohort of patients with MS. METHODS: A series of 408 MS patients had previously undergone a comprehensive neuropsychological assessment and a contemporaneous neurological evaluation (T1). A retrospective review of the clinical records was conducted 102-192 months after T1. Demographic and clinical data regarding the last clinical appointment with EDSS measurement (T2) were collected and the date of the last clinical contact or death (TS) was recorded. RESULTS: This review revealed that cognitive dysfunction (T1) was associated with higher odds of transitioning from relapsing-remitting course to a progressive disease course (adjusted odds ratio (OR) = 2.29, p = 0.043) and higher hazard of death in the total sample (adjusted hazard ratio (HR) = 3.07, p = 0.006) and the progressive disease course subgroup (adjusted HR = 3.68, p = 0.007), even when adjusting for other covariates. DISCUSSION: The study results demonstrate that cognitive dysfunction in MS is predictive of poorer prognosis and mortality.

Novel KMT2B mutation causes cerebellar ataxia: Expanding the clinical phenotype.

Hereditary cerebellar ataxias comprise a heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or cerebellar pathways. Next-generation sequencing techniques have contributed substantially to the expansion of ataxia-causing genes, including genes classically described in alternative phenotypes. Herein, we describe a patient with adult-onset cerebellar ataxia, minor dystonia, neuropathy, seizure and ophthalmological pathology, who bears a novel variant in KMT2B (NM_014727.2:c.3334 + 1G > A). Bioinformatic analysis suggested this variant completely abolished the splice-site at exon 8/intron 8, which was confirmed through analysis of mRNA extracted from fibroblasts. Exon 8 skipping would ultimately translate as an in-frame deletion at the protein level, corresponding to the loss of 91 aminoacids [p.(Gly1020_Asn1111del)]. So far, KMT2B disease causing variants have been described in patients with dystonia or neurodevelopmental delay, with no reports of a cerebellar predominant phenotype. Our findings highlight the possible role of KMT2B as a gene involved in hereditary cerebellar ataxias.

Congenital ataxia due to novel variant in ATP8A2.

Congenital ataxias are a heterogeneous group of disorders characterized by congenital or early-onset ataxia. Here, we describe two siblings with congenital ataxia, who acquired independent gait by age 4 years. After 16 years of follow-up they presented near normal cognition, cerebellar ataxia, mild pyramidal signs, and dystonia. On exome sequencing, a novel homozygous variant (c.1580-18C > G - intron 17) in ATP8A2 was identified. A new acceptor splice site was predicted by bioinformatics tools, and functionally characterized through a minigene assay. Minigene constructs were generated by PCR-amplification of genomic sequences surrounding the variant of interest and cloning into the pCMVdi vector. Altered splicing was evaluated by expressing these constructs in HEK293T cells. The construct with the c.1580-18C > G homozygous variant produced an aberrant transcript, leading to retention of 17 bp of intron 17, by the use of an alternative acceptor splice site, resulting in a premature stop codon by insertion of four amino acids. These results allowed us to establish this as a disease-causing variant and expand ATP8A2-related disorders to include less severe forms of congenital ataxia.

Past appendectomy may be related to early cognitive dysfunction in Parkinson's disease.

INTRODUCTION: The vermiform appendix is a potential site of initiation of Parkinson's disease (PD) pathology. We hypothesized that the appendectomy earlier in life may alter the clinical expression of PD. OBJECTIVE: To explore the effects of appendectomy prior to onset of PD motor symptoms on patients' symptoms, in particular on cognitive dysfunction. METHODS: Two hundred and sixty-two consecutive PD patients were asked about past history of appendectomy and underwent an evaluation, which included the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Schwab & England Independence Scale (S&E), Dementia Rating Scale-2 (DRS-2), Apathy Evaluation Scale, Hospital Anxiety and Depression Scale, and Brief Smell Identification Test. Motor symptoms were evaluated in OFF and ON states. Non-parametric group comparisons and logistic regressions were used for data analyses. RESULTS: Thirty-one patients (11.8%) had history of appendectomy prior to PD onset. These patients had more severe motor symptoms (UPDRS-III and H&Y) and lower functional independence (S&E) in ON and had higher frequency of cognitive dysfunction (DRS-2 Initiation/Perseveration, Conceptualization, and Memory subscales) (p < 0.05). The association between history of appendectomy and cognitive dysfunction was evident only in patients with late onset PD (≥ 55 years) and with disease duration ≤ 5 years. History of appendectomy remained statistically associated with impairment on DRS-2 Conceptualization and Memory subscales, when demographic and clinical variables were considered. CONCLUSION: History of appendectomy appears to alter the clinical expression of late onset PD, with early cognitive impairment, more severe motor symptoms in ON, and poorer functional independence under anti-parkinsonian medication.

Clinical spectrum of C9orf72 expansion in a cohort of Huntington's disease phenocopies.

The expansion in the C9orf72 gene has been recently reported as a genetic cause of Huntington's disease (HD) phenocopies. We aim to assess the frequency of the C9orf72 gene expansion in a Portuguese HD phenocopies cohort. Twenty HD phenotype-like patients without diagnosis were identified in our institutional database. C9orf72 gene expansion was detected using repeat-primed PCR. Clinical files were reviewed to characterize the phenotype of expansion-positive cases. One patient (5%) was positive for the C9orf72 expansion. A second patient presented 27 repeats-within the intermediate size interval. Both had familial neuropsychiatric disease characterized by diverse movement disorders, dementia, and psychiatric dysfunction that was distinct in severity and clinical expression. C9orf72 disease is clinically heterogeneous and without evident imaging markers. The definition of the role of intermediate alleles and of the pathological threshold for C9orf72 repeat expansions may have diagnostic implications.

Appendectomy may delay Parkinson's disease Onset.

BACKGROUND: Alpha-synuclein (α-Syn) is particularly abundant in the vermiform appendix, which makes this structure an anatomical candidate for the initiation of Parkinson's disease (PD) pathology. We hypothesized that history of appendectomy might affect PD clinical onset. METHODS: A total of 295 PD patients enrolled in a comprehensive observational study were asked about past history of appendectomy. Cox's regression, with a time-dependent covariate, explored the effects of appendectomy on age at PD onset. RESULTS: Thirty-four patients (11.5%) had appendectomy before PD onset. There was no significant effect of appendectomy on age at PD onset for the entire cohort (P = 0.153). However, among patients with late onset (≥55 years), we found evidence that those with past appendectomy had more years of life without PD symptoms than patients without appendectomy (P = 0.040). No association was found for the young-onset group (P = 0.663). CONCLUSIONS: An apparent relationship was observed between appendectomy and PD onset in the late PD cohort.

Cognitive reserve in multiple sclerosis: Protective effects of education.

BACKGROUND: Recent data suggest that cognitive reserve modulates the adverse effects of multiple sclerosis (MS) pathology on cognitive functioning; however, the protective effects of education in MS are still unclear. OBJECTIVE: To explore education as an indicator of cognitive reserve, while controlling for demographic, clinical and genetic features. METHODS: A total of 419 MS patients and 159 healthy comparison (HC) subjects underwent a comprehensive neuropsychological (NP) assessment, and answered the Hospital Anxiety and Depression Scale. Based on the HC data, MS patients' NP scores were adjusted for sex, age and education; and the estimated 5(th) percentile (or 95(th) percentile, when appropriate) was used to identify any deficits. Patients also performed the Mini-Mental State Examination (MMSE); and their human leucocyte antigen HLA-DRB1 and apolipoprotein E (ApoE) genotypes were investigated. RESULTS: Patients with higher education were less likely (p < 0.05) to have cognitive deficits than those with lower education, even when controlling for other covariates. Other significant predictors of cognitive deficit were: age, Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), and a progressive course. No significant association was found with the HLA-DRB1*15:01 or ApoE ε4 alleles. CONCLUSIONS: These results provide support to the use of education as a proxy of cognitive reserve in MS and stress the need to take into account education when approaching cognition in MS.

DRD3 Predicts Cognitive Impairment and Anxiety in Parkinson's Disease: Susceptibility and Protective Effects.

Background: A possible genetic contribution of dopamine D3 receptor (DRD3) to cognitive impairment in Parkinson's disease (PD) has yet to be investigated. Objective: To explore the effects of rs6280 (Ser9Gly) genotype on PD patients' cognitive performance and to clarify possible interactions with psychopathology. Methods: Two hundred and fifty-three consecutive PD patients underwent neurological and neuropsychological evaluations, which included: Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Dementia Rating Scale-2 (DRS-2), and Hospital Anxiety and Depression Scale (HADS). rs6280 polymorphism was genotyped for all PD patients and for 270 ethnically matched healthy volunteers (HC). Non-parametric group comparisons and logistic regressions were used for data analyses. Results: rs6280 genotype did not differ between PD and HC groups. PD patients with rs6280 CC genotype had more impaired cognitive performance (i.e., <1st percentile of demographically adjusted norms) on DRS-2 subscales Initiation/Perseveration and Construction than those with TT genotype. These associations remained statistically significant when other covariates (e.g., demographic features, disease duration, severity of motor symptoms in OFF and ON states, anti-parkinsonian medication, and psychopathology symptoms) were taken into consideration. PD patients with rs6280 TC had less anxiety (i.e., HADS Anxiety≥11) than those with TT (p = 0.012). This association was also independent of other covariates. Conclusions: Study findings suggest that rs6280 CC genotype predisposes to executive dysfunction and visuoconstructional deficits, whereas the heterozygous genotype protects from anxiety in PD. These effects do not appear to be dependent of one another. rs6280 is not a genotypic susceptibility factor for PD.

Predictors of cognitive dysfunction in hereditary transthyretin amyloidosis with liver transplant.

BACKGROUND: Cognitive dysfunction is part of the broad spectrum of clinical manifestations in older untreated hereditary transthyretin amyloidosis patients with peripheral polyneuropathy. OBJECTIVE: The objective of this study is to systematically explore cognitive dysfunction in ATTRV30M amyloidosis patients whose disease course was modified by liver transplant (LT). METHODS: A series of 269 carriers of TTRVal30Met mutation treated with LT underwent a neuropsychological assessment. Clinical charts were reviewed to identify focal neurological episodes (FNEs), cognitive complaints and laboratory results. Chi-square and Mann-Whitney tests explored potential predictors of cognitive dysfunction. RESULTS: Cognitive dysfunction was identified in 35 patients (13%)-14 (5%) had mild and 21 (8%) had moderate dysfunction. In comparison to normal cognition, both mild and moderate cognitive dysfunction patients had older age, higher mPND score and elevated NT-proBNP and Cystatin C values. Mild cognitive dysfunction was associated with longer disease duration and history of FNEs, whereas moderate dysfunction was related to older age at disease onset and more cognitive complaints and depression symptoms. CONCLUSIONS: Consistent with the natural history of the disease, older age and higher severity of the disease are significantly associated and potentially predictors of cognitive dysfunction in ATTRV30M patients treated with LT. The level of cognitive dysfunction may depend on some clinical variables.

Long-Term Headache and Cognitive Complaints Among Health Care Workers Who Acquired SARS-CoV-2.

Introduction Neurological manifestations are frequent after acquiring COVID-19 and may persist long-term as part of post-COVID-19 syndrome. Cognitive impairment, chronic fatigue, sleep disturbances, and headache complaints are the most reported neurological features. During the COVID-19 pandemic, health care workers were particularly vulnerable due to the high workload and levels of stress associated with this period, but acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may also contribute. The authors aimed to evaluate the neurological involvement of acquiring SARS-CoV-2 in a population of hospital health care workers and its impact on their personal and professional lives. Methods A sample of health care workers who did and did not acquire SARS-CoV-2 matched by age and sociodemographic variables was studied. Through an online questionnaire, data were collected regarding the symptoms in the acute phase of the disease (for those who acquired it) and for all in the last 6 months of the study period. Proportion of neurological complaints were compared between groups, adjusting for age, sex, and professional class (using a rate ratio (RR)). Results This study included 326 participants (174 cases and 152 controls). The mean age (standard deviation) was 39.7 (10.2) years, and the female:male ratio was 3:1. Headache and cognitive complaints were the most prevalent neurological complaints in the last 6 months of the study period. The health care workers who acquired SARS-CoV-2 were more likely to report headache and cognitive complaints than the control group (RR = 1.51, 95% confidence interval = 1.17-1.9 and RR = 2.02, 95% confidence interval = 1.53-2.65, respectively). Conclusion In a population of health care workers, those who acquired SARS-CoV-2 were more likely to have long-term cognitive complaints and persistent headaches.

Predictors of cognitive dysfunction one-year post COVID-19.

OBJECTIVES: (a) To characterize the frequency of objective cognitive deficits and self-perceived cognitive difficulties and (b) to explore demographic and clinical predictors of cognitive dysfunction and cognitive complaints. METHOD: One hundred and ten adults diagnosed with COVID-19 between March and November 2020, aged ≤ 74 years underwent a brief neuropsychological evaluation 12 months after infection, which included: Brief Visuospatial Memory Test-Revised, California Verbal Learning Test, and Symbol Digit Modalities Test. T scores < 38 were considered abnormal performance; cognitive dysfunction was defined as ≥ 2 abnormal tests. Participants also completed Broadbent's Cognitive Failure Questionnaires (CFQ), Hospital Anxiety and Depression Scale, Modified Fatigue Impact Scale, and Short-Form Health Survey. CFQ ≥ 43 was considered indicative of cognitive complaints. RESULTS: Twenty participants (18.2%) had cognitive dysfunction and 36 (33.3%) had cognitive complaints. Cognitive dysfunction was related to lower education, preinfection history of headache/migraine, and acute COVID-19 symptoms of headache and sleep disturbance. Cognitive complaints were more likely to occur in women, those with fewer years of education, and acute COVID-19 symptoms of headache and sleep disturbance. Cognitive complaints were also significantly related to symptoms of anxiety, depression, and fatigue. Sex and psychopathology were not significant predictors of cognitive dysfunction. Modest associations were found between CFQ total score and cognitive test performance. DISCUSSION: A subset of individuals develops cognitive difficulties in the context of post-COVID syndrome. Results may support the protective effect of education, a known proxy of cognitive reserve. COVID-19 infection symptoms of headache and sleep disturbance appear to be risk factors for long-term cognitive difficulties. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Trace Element Imbalances in Acquired Hepatocerebral Degeneration and Changes after Liver Transplant.

Brain manganese (Mn) accumulation is a key feature in patients with acquired hepatocerebral degeneration (AHD). The role of trace elements other than Mn in AHD needs to be clarified. In this study, using inductively coupled plasma mass spectrometry, we aimed to evaluate blood levels of trace elements in patients with AHD before and after liver transplantation (LT). Trace element levels in the AHD group were also compared with those of healthy controls (blood donors, n = 51). Fifty-one AHD patients were included in the study (mean age: 59.2 ± 10.6 years; men: 72.5%). AHD patients had higher levels of Mn, Li, B, Ni, As, Sr, Mo, Cd, Sb, Tl and Pb and a higher Cu/Se ratio, and lower levels of Se and Rb. Six patients (two women; mean age 55 ± 8.7 years) underwent LT, and there was an improvement in neurological symptoms, a significant increase in the Zn, Se and Sr levels, and a decrease in the Cu/Zn and Cu/Se ratios. In summary, several trace element imbalances were identified in AHD patients. Liver transplantation resulted in the improvement of neurological manifestations and the oxidant/inflammatory status. It is possible that observed changes in trace element levels may play a role in the pathophysiology and symptomatology of AHD.

Olfactory dysfunction in multiple sclerosis: association with secondary progression.

OBJECTIVE: The Brief Smell Identification Test (B-SIT) was used to explore odour identification capacities in multiple sclerosis (MS). METHODS: In total, 153 consecutive patients with MS and 165 healthy controls (HC) participated in the study. All participants were asked to answer the B-SIT and the Hospital Anxiety and Depression Scale (HADS). The Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Scale (MSSS), and the Mini-Mental State Examination (MMSE) were used for patients' clinical and cognitive characterization. RESULTS: Patients with MS (11.1%) were more impaired on the B-SIT than HC participants (3%). The frequency of impairment was higher for patients with secondary progressive (SPMS; 11/16, 68.8%) than relapsing-remitting (RRMS; 4/121, 3.3%) or primary progressive (2/16, 12.5%) courses. A threshold score of ≤ 8 on the B-SIT provided a sensitivity of 69% and a specificity of 97% in the identification of SPMS among patients with relapsing onset. The association between SPMS and impaired B-SIT remained statistically significant after adjusting for demographic (i.e. age and education), clinical (i.e. disease duration, EDSS, and MSSS), psychopathological (i.e. HADS anxiety and depression scores), and cognitive (i.e. MMSE) variables. CONCLUSIONS: A brief odour identification measure provided a good discrimination between SPMS and RRMS courses. A systematic assessment of olfactory functions may contribute to the development of clinical markers of SPMS.

Auditory verbal learning test can lateralize hippocampal sclerosis.

The ability of the Auditory Verbal Learning Test (AVLT) to lateralize hippocampal sclerosis (HS) in mesial temporal lobe epilepsy (MTLE) was explored in a sample of 50 patients with MTLE-HS (23 right and 27 left). Patients' AVLT scores were adjusted to the demographic characteristics of each individual in accordance with the Portuguese normative data. The laterality of the HS was determined by consensus by two neuroradiologists. ROC curves were used to identify the best AVLT cutoff scores to differentiate right vs. left HS. Diagnostic statistics were applied to different AVLT measures. The study results revealed that four AVLT scores can correctly classify the laterality of HS in the total sample and a sub-group of 39 right-handed patients (Edinburgh Laterality Inventory +100): delayed recall trial (76 and 80%, respectively), delayed recognition trial (64 and 67%, respectively), learning over trials index (64 and 74%, respectively), and long-term percent retention index (68 and 72%, respectively). In right-handed patients, the diagnostic capability of the delayed recall trial was improved by pairing it with the learning over trials index (accuracy of 85%). In sum, AVLT measures of verbal memory differentiate left from right HS in MTLE. The delayed recall trial demonstrated good diagnostic capacity.

Medulloblastoma and gliomatosis cerebri: rare brain tumors in multiple sclerosis patients.

The simultaneous appearance of both multiple sclerosis (MS) and central nervous system (CNS) tumors is relatively uncommon. Whether the co-existence of two diseases is due to chance alone or the result of a causal relationship is still a matter of debate. There is also controversy about the effect of long-term exposure of MS patients to immunomodulatory drugs on the incidence of cancer. This paper reports two cases of rare CNS tumors (i.e., medulloblastoma and gliomatosis cerebri) in adult MS patients. Our cases emphasize that when uncommon neurological features appear in patients with MS, brain magnetic resonance imaging (MRI) ought to be done and brain biopsy should be considered to exclude a concomitant CNS disorder. These procedures are essential for the differential diagnosis and early treatment.

Early graft patency after off-pump and on-pump coronary bypass surgery: a prospective randomized study.

AIMS: Uncertainty persists regarding the impact of the off-pump technique on coronary bypass graft patency. The primary objective of this study was to assess coronary artery bypass graft patency in patients randomized to off-pump and on-pump multivessel coronary artery bypass grafting (CABG). Secondary objectives were clinical outcomes and neuropsychological functioning. METHODS AND RESULTS: One hundred and fifty patients were randomized to off-pump (n = 75) or on-pump CABG (n = 75). Graft patency was assessed by multidetector computed tomography 5 weeks after surgery. The two groups were similar regarding patients' characteristics and logistic Euroscore (3.6 vs. 3.7%). Mean number of grafts performed was 3.5 ± 0.6 and 3.5 ± 0.6 in off-pump and on-pump, respectively (P = 0.7). Raw graft patency rate was 89.9% in off-pump and 95.0% in on-pump (OR 2.2, 95% CI 1.07-4.44; P = 0.03). Nineteen (27%) off-pump and 9 (13%) on-pump patients had at least one occluded graft (P = 0.04) and the proportion of patent grafts per patient was 0.91 ± 0.2 in off-pump vs. 0.96 ± 0.1 in on-pump (P = 0.06). However, after adjusting by heparin dose, graft patency was not statistically different between groups (OR 0.87, 95% CI 0.25-2.98, P = 0.83). At 30 days, there was no statistically significant difference in major adverse events and neuropsychological functioning between off-pump and on-pump groups. One-year follow-up showed similar functional class and positive treadmill exercise tests. CONCLUSIONS: Under the conditions this trial was conducted, CABG performed off-pump had lower overall graft patency rate than on-pump, which was not statistically different after controlling for total heparin dose. Thirty-day complications, neuropsychological functioning, and one-year clinical and functional outcomes were not statistically different between the two techniques.

Depression and anxiety in multiple sclerosis patients: The role of genetic variability of interleukin 1ß.

BACKGROUND: Mood disorders, as depression and anxiety, are frequent in Multiple Sclerosis (MS) patients. High pro-inflammatory cytokine levels (e.g. IL-1ß) have been reported in depressed individuals. OBJECTIVE: We aimed to investigate the role of the rs16944 (IL-1ß-511 C>T) polymorphism in the development of anxiety and depression symptoms in a Portuguese cohort of MS patients. METHODS: 393 MS patients answered the Hospital Anxiety and Depression Scale (HADS) at T1. This questionnaire was reapplied to a subgroup of 175 MS patients approximately three years later (T2). HADS cut-off scores for anxiety and depression were respectively ≥11 and ≥8. RESULTS: At T1, anxiety was found in 106 MS patients (27.0%) and 11 controls (16.7%); whereas depression was identified in 116 (29.5%) MS patients and 9 controls (13.6%). Persistent anxiety and depression were respectively recorded in 12% and 20% of MS patients. The rs16944TT genotype was found to be a susceptibility factor for the occurrence of depression at T1 (OR = 3.16, p=0.002) and the development of persistent depression (OR = 5.63, p=0.003) in MS. CONCLUSION: Study results support the hypothesis that inflammation is a significant factor in psychopathology development.

Unveiling the relationship between central parkinsonian pain and motor symptoms in Parkinson's disease.

BACKGROUND: Pain in Parkinson's disease (PD) is a common and heterogeneous non-motor symptom. Although the characteristics and predictors of pain in general and of central pain in particular are still largely unknown. METHODS: A semi-structured interview, the Brief Pain Inventory and the Pain Disability Index were used to identify and characterize pain in a consecutive series of 292 PD patients. Unified PD Rating Scale-III, Hoehn & Yahr, Schwab and England Independence Scale and Freezing of Gait Questionnaire were applied to assess motor symptoms and functional independence in off and on conditions. Hospital Anxiety and Depression Scale and Questionnaire of Impulsive-Compulsive Control Disorders were used to screen for anxiety, depression and impulse control disorders. RESULTS: Two hundred and twelve patients (73%) reported pain, which was classified as: musculoskeletal (63%), dystonia-related (27%), central parkinsonian (22%) and/or radicular or neuropathic (9%). Patients with pain had more comorbidities and more severe motor symptoms. Patients with central parkinsonian pain were significantly younger, had earlier disease onset, fewer comorbidities, greater non-axial motor symptom severity in on, more pain-related disability and more relief of pain with antiparkinsonian medication than patients with non-central parkinsonian pain. CONCLUSIONS: PD patients with central parkinsonian pain have some distinctive demographic and clinical features, including lower levodopa responsiveness of motor appendicular/limb symptoms to levodopa, associated with greater responsiveness of pain symptoms to these same medications. These findings suggest the need for a more integrated approach to motor and non-motor symptoms in these patients' clinical care. SIGNIFICANCE: In a consecutive series of 292 patients with PD, almost three quarters of patients with PD reported pain. The study results revealed that pain was related to more severe motor symptoms, anxiety symptoms and comorbidities. Among patients with pain, those with central parkinsonian subtype had distinct demographic and clinical features, including lower levodopa responsiveness for non-axial motor symptoms and greater responsiveness of pain to antiparkinsonian treatment.

Proinflammatory and anti-inflammatory cytokines in the CSF of patients with Alzheimer's disease and their correlation with cognitive decline.

Cumulative data suggest that neuroinflammation plays a prominent role in Alzheimer's disease (AD) pathogenesis. The purpose of this work was to assess if patients with AD present a specific cerebrospinal fluid (CSF) cytokine profile and if it correlates to disease progression. We determined the levels of 27 cytokines in CSF of patients with AD and compared them with patients with frontotemporal dementia and nondemented controls. In addition, we correlated the cytokine levels with cognitive status and disease progression after 12 months. Patients with AD had higher levels of proinflammatory and anti-inflammatory cytokines (eotaxin, interleukin [IL]-1ra, IL-4, IL-7, IL-8, IL-9, IL-10, IL-15, granulocyte colony-stimulating factor, monocyte chemotactic protein 1, platelet-derived growth factor, tumor necrosis factor alfa) compared to nondemented controls. There was a negative correlation between the disease progression and the levels of several cytokines (IL-1ß, IL-4, IL-6, IL-9, IL-17A, basic fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon gamma, macrophage inflammatory proteins-1ß). To the best of our knowledge, this is the first study reporting a "protective" role of the upregulation of specific intrathecal cytokine levels in AD. This finding supports that a fine "rebalancing" of the immune system represents a new target in AD therapeutic approach.