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INTRODUCTION: Patients with subjective memory complaints (SMC) may include subgroups with different neuropsychological profiles and risks of cognitive impairment. METHODS: Cluster analysis was performed on two datasets (n: 630 and 734) comprising demographic and neuropsychological data from SMC and healthy controls (HC). Survival analyses were conducted on clusters. Bayesian model averaging assessed the predictive utility of clusters and other biomarkers. RESULTS: Two clusters with higher and lower than average cognitive performance were detected in SMC and HC. Assignment to the lower performance cluster increased the risk of cognitive impairment in both datasets (hazard ratios: 1.78 and 2.96; Plog‐rank: 0.04 and <0.001) and was associated with lower hippocampal volumes and higher tau/amyloid beta 42 ratios in cerebrospinal fluid. The effect of SMC was small and confounded by mood. DISCUSSION: This study provides evidence of the presence of cognitive clusters that hold biological significance and predictive value for cognitive decline in SMC and HC. Highlights: Patients with subjective memory complaints include two cognitive clusters.Assignment to the lower performance cluster increases risk of cognitive impairment.This cluster shows a pattern of biomarkers consistent with incipient Alzheimer's disease pathology.The same cognitive cluster structure is found in healthy controls.The effect of memory complaints on risk of cognitive decline is small and confounded. [ABSTRACT FROM AUTHOR]

Background: Factors predicting clinical outcomes after MR‐guided focused ultrasound (MRgFUS)‐thalamotomy in patients with essential tremor (ET) are not well known. Objective: To examine the clinical outcomes and their relationship with patients' baseline demographic and clinical features and lesion characteristics at 6‐month follow‐up in ET patients. Methods: A total of 127 patients were prospectively evaluated at 1 (n = 122), 3 (n = 102), and 6 months (n = 78) after MRgFUS‐thalamotomy. Magnetic resonance imaging (MRI) was obtained at 6 months (n = 60). Primary outcomes included: (1) change in the Clinical Rating Scale of Tremor (CRST)‐A+B score in the treated hand and (2) frequency and severity of adverse events (AEs) at 6 months. Secondary outcomes included changes in all subitems of the CRST scale in the treated hand, CRST‐C, axial tremor (face, head, voice, tongue), AEs, and correlation of primary outcomes at 6 months with lesion characteristics. Statistical analysis included linear mixed, standard, and logistic regression models. Results: Scores for CRST‐A+B, CRST‐A, CRST‐B in the treated hand, CRST‐C, and axial tremor were improved at each evaluation (P < 0.001). Five patients had severe AEs at 1 month that became mild throughout the follow‐up. Mild AEs occurred in 71%, 45%, and 34% of patients at 1, 3, and 6 months, respectively. Lesion volume was associated with the reduction in the CRST‐A (P = 0.003) and its overlapping with the ventralis intermedius nucleus (Vim) nucleus with the reduction in CRST‐A+B (P = 0.02) and CRST‐B (P = 0.008) at 6 months. Conclusions: MRgFUS‐thalamotomy improves hand and axial tremor in ET patients. Transient and mild AEs are frequent. Lesion volume and location are associated with tremor reduction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) is the most common cause of dementia worldwide. It is known that cerebral amyloid aggregation and neurodegeneration are first steps in the physiopathology of AD. In the prodromal phase, a clinical diagnosis of amnesic mild cognitive impairment (aMCI) can be stablished, but not all subjects with MCI have a prodromal AD. The objective of this study was to determinate the impact of amyloid and FDG PET on the progression from aMCI to AD dementia. Methods: From October 2013 to March 2021, we prospectively selected 145 patients with a diagnosis aMCI. We excluded subjects older than 85 and those with structural brain lesion on brain MRI. Participants went through an amyloid and an FDG‐PET scans and were classified as positive or negative for amyloid and neurodegeneration. Patients were followed to stablish progression to AD dementia, 118 patients were followed up more than 36 months. Statistical analyses were done with STATA with significance set at p<0.05. All analyses were adjusted by age, gender, and education. Results: Demographics are shown on table 1. Sensibility, specificity, negative predictive value, and positive predictive value during the 4 years are shown on table 2. 88 patients were A+ and 74 patients were A‐. We divided the patients in 4 groups: A+/FDG+ (n:54), A+/FDG‐ (n:34), A‐/FDG‐ (40), A‐/FDG+(4). The mean of conversion were 39.95 months, this time depends on the result of the biomarkers. A‐ patients converted less and latter with a mean of 75.07 (IC 56.54→81) month, than A+ patients, that converted earlier (chi2 = 20.37 Pr>chi2 = 0.0000). A+/FDG+ converted with a mean of 27.79 (20.40‐33.21) months while A+/FDG‐ converted earlier with a mean of 37.38 (20.73‐48.26) month. (chi2 = 4.16 Pr>chi2 = 0.0415). Conclusions: Amyloid and FDG PET can help us to stablish prognosis in aMCI patients. We have observed that a positive amyloid PET is associated with an increased risk of progression to AD dementia. Even more, aMCI patients with both, amyloid PET and FDG, positive PETs progressed more often and earlier to AD dementia than those who have a positive amyloid PET but a negative FDG‐PET. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) may represent a preclinical stage of Alzheimer's disease (AD). Predicting progression of SCD patients is of great importance in AD-related research but remains a challenge. Objective: To develop and implement an ensemble machine learning (ML) algorithm to identify SCD subjects at risk of conversion to mild cognitive impairment (MCI) or AD. Methods: Ninety-nine SCD patients were included. Thirty-two progressed to MCI/AD, while 67 remained stable. To minimize the effect of class imbalance, both classes were balanced, and sensitivity was taken as evaluation metric. Bagging and boosting ML models were developed by using socio-demographic and clinical information, Mini-Mental State Examination and Geriatric Depression Scale (GDS) scores (feature-set 1a); socio-demographic characteristics and neuropsychological tests scores (feature-set 1b) and regional magnetic resonance imaging grey matter volumes (feature-set 2). The most relevant variables were combined to find the best model. Results: Good prediction performances were obtained with feature-sets 1a and 2. The most relevant variables (variable importance exceeding 20%) were: Age, GDS, and grey matter volumes measured in four cortical regions of interests. Their combination provided the optimal classification performance (highest sensitivity and specificity) ensemble ML model, Extreme Gradient Boosting with over-sampling of the minority class, with performance metrics: sensitivity = 1.00, specificity = 0.92 and area-under-the-curve = 0.96. The median values based on fifty random train/test splits were sensitivity = 0.83 (interquartile range (IQR) = 0.17), specificity = 0.77 (IQR = 0.23) and area-under-the-curve = 0.75 (IQR = 0.11). Conclusion: A high-performance algorithm that could be translatable into practice was able to predict SCD conversion to MCI/AD by using only six predictive variables. [ABSTRACT FROM AUTHOR]

Background: There is a need to better understand the experience of patients living with Alzheimer's disease (AD) in the early stages.Objective: The aim of the study was to evaluate the perception of quality of life in patients with early-stage AD.Methods: A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD, a Mini-Mental State Examination (MMSE) score ≥22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5.-1.0. The Quality of Life in Alzheimer 's Disease (QoL-AD) questionnaire was used to assess health-related quality of life. A battery of self-report instruments was used to evaluate different psychological and behavioral domains. Associations between the QoL-AD and other outcome measures were analyzed using Spearman's rank correlations.Results: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years and mean disease duration was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1). The mean QoL-AD score was 37.9 (4.5). Eighty-three percent (n = 124) of patients had moderate-to-severe hopelessness, 22.1% (n = 33) had depressive symptoms, and 36.9% (n = 55) felt stigmatized. The quality of life showed a significant positive correlation with self-efficacy and negative correlations with depression, emotional and practical consequences, stigma, and hopelessness.Conclusion: Stigma, depressive symptoms, and hopelessness are frequent scenarios in AD negatively impacting quality of life, even in a population with short disease duration and minimal cognitive impairment. [ABSTRACT FROM AUTHOR]

Psychosocial adjustment to a complex and disabling long‐term condition like Parkinson´s disease is a complex, dynamic, cyclical and interactive process. Family caregivers, face multiple challenges that require a significant effort in terms of psychosocial adjustment, which must be considered by healthcare professionals in order to provide a holistic care. The patients' self‐report version of the Psychosocial Adjustment to Illness Scale (PAIS‐SR), which has been validated in Spain for use in Parkinson's disease, is designed to evaluate the psychosocial adjustment of patients. Our purpose was to validate the Spanish PAIS‐SR version for caregivers of patients with Parkinson's disease. An open, national cross‐sectional study with one point‐in‐time evaluation and retest was carried out in 450 family caregivers of patients with Parkinson's disease. Data were collected in Spain from April 2016 to September 2017. The psychometric analysis performed showed that the Spanish version of the PAIS‐SR for caregivers presents adequate indicators of reliability, internal and external validity, and is structured according to the seven‐domain model proposed by the author of the instrument. [ABSTRACT FROM AUTHOR]

Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow‐up in European expert centers diagnosing patients with MCI. Methods: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow‐up in MCI. Results: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre‐ and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. Conclusions: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning. [ABSTRACT FROM AUTHOR]

It remains unclear whether the supportive imaging features described in the diagnostic criteria for progressive supranuclear palsy (PSP) are suitable for the full clinical spectrum. The aim of the current study was to define and cross‐validate the pattern of glucose metabolism in the brain associated with a diagnosis of different PSP variants. A retrospective multicenter cohort study performed on 73 PSP patients who were referred for a fluorodeoxyglucose positron emission tomography PET scan: PSP–Richardson's syndrome, n = 47; PSP–parkinsonian variant, n = 18; and progressive gait freezing, n = 8. In addition, we included 55 healthy controls and 58 Parkinson's disease (PD) patients. Scans were normalized by global mean activity. We analyzed the regional differences in metabolism between the groups. Moreover, we applied a multivariate analysis to obtain a PSP‐related pattern that was cross‐validated in independent populations at the individual level. Group analysis showed relative hypometabolism in the midbrain, basal ganglia, thalamus, and frontoinsular cortices and hypermetabolism in the cerebellum and sensorimotor cortices in PSP patients compared with healthy controls and PD patients, the latter with more severe involvement in the basal ganglia and occipital cortices. The PSP‐related pattern obtained confirmed the regions described above. At the individual level, the PSP‐related pattern showed optimal diagnostic accuracy to distinguish between PSP and healthy controls (sensitivity, 80.4%; specificity, 96.9%) and between PSP and PD (sensitivity, 80.4%; specificity, 90.7%). Moreover, PSP–Richardson's syndrome and PSP–parkinsonian variant patients showed significantly more PSP‐related pattern expression than PD patients and healthy controls. The glucose metabolism assessed by fluorodeoxyglucose PET is a useful and reproducible supportive diagnostic tool for PSP–Richardson's syndrome and PSP–parkinsonian variant. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effects of a psychoeducational intervention compared with an education programme to strengthen quality of life, psychosocial adjustment, and coping in people with Parkinson's disease and their informal caregivers. Design: A quasi‐experimental study was performed with repeated measures at baseline, after the intervention and 6 months post‐intervention. Methods: The study was carried out at seven primary care centres from 2015‐2017. A total of 140 people with Parkinson's and 127 informal caregivers were allocated to the experimental and the control groups. The experimental group received a 9‐week psychoeducational intervention, whereas the control group received a 5‐week education programme. Repeated measures ANOVA were used to test differences in quality of life, psychosocial adjustment, and coping between the experimental and control groups and over time. Results: Patients and informal caregivers in both the experimental and control groups showed significantly better psychosocial adjustment at the post‐intervention measurement compared with baseline data. We also found significantly greater quality of life in patients and coping skills in caregivers after the end of the interventions in the experimental and control groups. Nevertheless, no significant differences were identified on the outcomes at the 6‐month post‐intervention measurement. Conclusion: The effect of the psychoeducational intervention was not different from the effect of the education programme. The strategies applied in both interventions followed a group approach led by a multidisciplinary team covering information about PD, healthy lifestyles, and social resources. They might be easily sustained in Primary Care to improve care for people with Parkinson's and informal caregivers. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and β-amyloid (Aβ) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients.Methods: We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aβ and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aβ interact with amylin in either the pancreas or brain of these subjects.Results: Cytoplasmic tau and Aβ protein deposits were detected in pancreatic β cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aβ and tau in both the pancreas and hippocampus.Interpretation: The presence of both tau and Aβ inclusions in pancreatic β cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539-551. [ABSTRACT FROM AUTHOR]

There is increasing evidence of a vascular contribution to Alzheimer's disease (AD). In some cases, prior work suggests that chronic brain hypoperfusion could play a prime pathogenic role contributing to the accumulation of amyloid-β,while other studies favor the hypothesis that vascular dysfunction and amyloid pathology are independent, although synergistic, mechanisms contributing to cognitive impairment. Vascular dysfunction can be evaluated by assessing cerebral blood flow impairment. Phase contrast velocity mapping by MRI offers a non-invasive means of quantifying the total inflow of blood to the brain. This quantitative parameter could be a sensitive indicator of vascular disease at early stages of AD. In this work, phase contrast MRI was used to evaluate cerebral hemodynamics in patients with subjective memory complaints, amnestic mild cognitive impairment, and mild to moderate AD, and compare them with control subjects. Results showed that blood flow and velocity were decreased in the patients with cognitive dysfunction and the decrease correlated with the degree of cognitive impairment as assessed by means of neuropsychological tests. Total cerebral blood flow measurements were clearly reduced in AD patients, but more importantly appeared to be sensitive enough to distinguish between healthy subjects and those with mild cognitive impairment. A quantitative measurement of total brain blood flow could potentially predict vascular dysfunction and compromised brain perfusion in early stages of AD. [ABSTRACT FROM AUTHOR]

Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline. [ABSTRACT FROM AUTHOR]

In addition to the medium spiny neurons the mammalian striatum contains a small population of GABAergic interneurons that are immunoreactive for tyrosine hydroxylase (TH), which dramatically increases after lesions to the nigrostriatal pathway and striatal delivery of neurotrophic factors. The regulatory effect of levodopa (L-Dopa) on the number and phenotype of these cells is less well understood. Eleven macaques (Macaca fascicularis) were included. Group I (n = 4) received 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and L-Dopa; Group II (n = 4) was treated with MPTP plus vehicle and Group III (n = 3) consist of intact animals (control group). L-Dopa and vehicle were given for 1 year and animals sacrificed 6 months later. Immunohistochemistry against TH was used to identify striatal and nigral dopaminergic cells. Double and triple labeling immunofluorescence was performed to detect the neurochemical characteristics of the striatal TH-ir cells using antibodies against: TH, anti-glutamate decarboxylase (GAD67) anti-calretinin (CR) anti-dopa decarboxylase (DDC) and anti-dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32). The greatest density of TH-ir striatal cells was detected in the striatum of the L-Dopa treated monkeys and particularly in its associative territory. None of the striatal TH-ir cell expressed DARPP-32 indicating they are interneurons. The percentages of TH-ir cells that expressed GAD67 and DDC was approximately 50%. Interestingly, we found that in the L-Dopa group the number of TH/CR expressing cells was significantly reduced. We conclude that chronic L-Dopa administration produced a long-lasting increase in the number of TH-ir cells, even after a washout period of 6 months. L-Dopa also modified the phenotype of these cells with a significant reduction of the TH/CR phenotype in favor of an increased number of TH/GAD cells that do not express CR. We suggest that the increased number of striatal TH-ir cells might be involved in the development of aberrant striatal circuits and the appearance of L-Dopa induced dyskinesias. [ABSTRACT FROM AUTHOR]

Abstract: A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75±7.1years) scanned with brain MRI and genotyped as part of Alzheimer''s Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76±5.5years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR ‘T’ alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2–8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5–1.5% per T allele at 1year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5–12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI. [Copyright &y& Elsevier]

(1) Background: Both cerebral vascular disorders and cognitive decline increase in incidence with age. The role of cerebral vascular disease and hemodynamic changes in the development of cognitive deficits is controversial. The objective of this study was to assess the cardiovascular response during cardiac stress testing in neurologically asymptomatic individuals who developed cognitive impairment several years after previous cardiac stress testing. (2) Methods: This was a retrospective cohort study of patients who underwent cardiac stress testing between January 2001 and December 2010. Patients were followed up until May 2015, and we selected those who developed cognitive dysfunction including dementia, mild cognitive impairment, and subjective cognitive decline, after the stress test. Heart rate and blood pressure both at rest and at peak exercise, and the mean R-R interval at rest were recorded. For each patient who developed cognitive impairment, we selected one matched control who did not show cognitive decline by the end of the follow-up period. (3) Results: From the cohort of 7224 patients, 371 developed cognitive impairment; of these, 186 (124 men) met the inclusion criteria, and 186 of the other patients were selected as matched controls. During follow-up, cognitive impairment appeared 6.2 ± 4.7 years after the cardiac stress test. These patients who had subsequently developed cognitive impairment had significantly lower at-rest systolic, diastolic, and mean blood pressure than controls (p < 0.05). Further, compared with controls, their maximum heart rate was significantly higher at peak exercise. (4) Conclusion: The results from this study suggest that differences in cardiovascular response to stress might be present in individuals who develop cognitive decline. These findings challenge the possibility of assessing blood pressure and heart rate variability at rest and during cardiac stress as potential risk factors associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose (FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or assisted image reading is not well established to evaluate hypometabolism/hypermetabolism. We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018. Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard visual reading and assisted by voxel-based analyses, compared to a normal database. For the latter, three different methods were performed: two based on statistical surface projections (Siemens syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative. 18F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis. Medial–temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive and localized larger hypermetabolic areas. As it may lead to comparable and accurate results, visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG. [ABSTRACT FROM AUTHOR]

Introduction: Patients with subjective memory complaints (SMC) may include subgroups with different neuropsychological profiles and risks of cognitive impairment., Methods: Cluster analysis was performed on two datasets (n: 630 and 734) comprising demographic and neuropsychological data from SMC and healthy controls (HC). Survival analyses were conducted on clusters. Bayesian model averaging assessed the predictive utility of clusters and other biomarkers., Results: Two clusters with higher and lower than average cognitive performance were detected in SMC and HC. Assignment to the lower performance cluster increased the risk of cognitive impairment in both datasets (hazard ratios: 1.78 and 2.96; P log-rank : 0.04 and <0.001) and was associated with lower hippocampal volumes and higher tau/amyloid beta 42 ratios in cerebrospinal fluid. The effect of SMC was small and confounded by mood., Discussion: This study provides evidence of the presence of cognitive clusters that hold biological significance and predictive value for cognitive decline in SMC and HC., Highlights: Patients with subjective memory complaints include two cognitive clusters. Assignment to the lower performance cluster increases risk of cognitive impairment. This cluster shows a pattern of biomarkers consistent with incipient Alzheimer's disease pathology. The same cognitive cluster structure is found in healthy controls. The effect of memory complaints on risk of cognitive decline is small and confounded., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Limited information is available on the active process of seeking medical help in patients with Alzheimer's disease (AD) at early stages. The aim of this study was to assess the phenomenon of medical help-seeking in early AD and to identify associated factors., Methods: A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD (National Institute on Aging/Alzheimer's Association criteria), a Mini-Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5-1.0. A multivariate logistic regression analysis was conducted., Results: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years, 50.3% were female, and 87.2% had a CDR-GS score of 0.5. Mean disease duration was 1.4 (1.8) years. Ninety-four (63.1%) patients sought medical help, mostly from neurologists. Patients with help-seeking intentions were mostly female (60.6%) with a CDR-GS score of 0.5 (91.5%) and had a greater awareness of diagnosis, poorer quality of life, more depressive symptoms, and a more severe perception of their condition than their counterparts. Lack of help-seeking intentions was associated with male sex ( p  = 0.003), fewer years of education ( p  = 0.005), a low awareness of diagnosis ( p  = 0.005), and a low emotional consequence of the condition ( p  = 0.016)., Conclusion: Understanding the phenomenon of active medical help-seeking may facilitate the design of specific strategies to improve the detection of cognitive impairment, especially in patients with a lower level of educational attainment and poor awareness of their condition., Competing Interests: EG-A and JM are employees of Roche Farma Spain. AV-G discloses honoraria from a consulting/advisory role with KRKA, Kern Pharma, Exeltis, Esteve, Roche, AbbVie, Schwabe, Neuraxpharm, Nutricia, and Alter. AO-R discloses honoraria from a consulting/advisory role with Alter, Biocross, Biogen, KRKA, Esteve, Schwabe, Nutricia, and Lilly. EF-M discloses honoraria from a consulting/advisory role with Kern Pharma, Esteve, Roche, and Neuraxpharm. MeB discloses honoraria from a consulting/advisory role with Grifols, Araclon Biotech, Roche, Lilly, Merck, Biogen, Zambon, Novo-Nordisk, Bioiberica, Biogen, Eisai, Servier, and Schwabe Pharma. RA discloses their participation on an advisory board and having received speaking fees from Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva. AL discloses honoraria from a consulting/advisory role with Grifols, Fujirebio-Europe, Novartis, Roche, Otsuka, Nutricia, Zambón, Biogen, Lilly, and KRKA. A preliminary report of this data was presented as an eposter at the 9th Congress of the European Academy of Neurology (EPO-187, Budapest, Hungary; July 1–4, 2023). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Villarejo-Galende, García-Arcelay, Piñol-Ripoll, del Olmo-Rodríguez, Viñuela, Boada, Franco-Macías, Ibañez de la Peña, Riverol, Puig-Pijoan, Abizanda-Soler, Arroyo, Baquero-Toledo, Feria-Vilar, Balasa, Berbel, Rodríguez-Rodríguez, Vieira-Campos, Garcia-Ribas, Rodrigo-Herrero, Lleó and Maurino.)

Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose (FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or assisted image reading is not well established to evaluate hypometabolism/hypermetabolism. We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018. Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard visual reading and assisted by voxel-based analyses, compared to a normal database. For the latter, three different methods were performed: two based on statistical surface projections (Siemens syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative. 18 F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis. Medial-temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive and localized larger hypermetabolic areas. As it may lead to comparable and accurate results, visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG.

PET using 18F-2-fluoro-2-deoxy-D-glucose (FDG-PET) has been gradually introduced in the diagnostic clinical criteria of the most prevalent neurodegenerative diseases. Moreover, an increasing amount of literature has shown that the information provided by FDG-PET enhances the sensitivity of standard imaging biomarkers in less frequent disorders in which an early differential diagnosis can be of paramount relevance for patient management and outcome. Therefore emerging uses of FDG-PET may be important in prion diseases, autoimmune encephalitis (AE) and amyotrophic lateral sclerosis. Interestingly, FDG-PET findings can also be observed in the early phases of these conditions, even in the presence of normal magnetic resonance imaging scans. Thalamic hypometabolism is a common finding in sporadic Creutzfeldt-Jacob disease and fatal familiar insomnia patients, with further cortical synaptic dysfunction in the former. Limbic and extra-limbic metabolic abnormalities (more often hypermetabolism) can be observed in AE, although specific patterns may be seen within different syndromes associated with antibodies that target neuronal surface or synaptic antigens. FDG-PET shows its usefulness by discriminating patients with amyotrophic lateral sclerosis associated to upper motor neuron onset that evolve to frontotemporal dementia. Besides visual and voxel based image analysis, multivariate analysis as interregional correlation analysis and independent/principal component analysis have been successfully implemented to PET images increasing the accuracy of the discrimination of neurodegenerative diseases. The clinical presentation and current diagnostic criteria of these neurologic disorders as well as the emerging usefulness of FDG-PET in the diagnostic workup are presented and discussed in this review.

A 70-year-old woman with a history of autoimmune hepatitis and renal cell carcinoma presented with subacute cognitive impairment. A brain MRI revealed mild leukoaraiosis, whereas brain F-FDG PET/CT showed diffuse cerebral hypometabolism that resembled some of the patterns described in limbic encephalitis and neurodegenerative diseases. With the suspicion of autoimmune encephalitis, the patient received immunotherapy with dramatic improvement of cognitive function and metabolic normalization at the 2-month follow-up on brain F-FDG PET/CT. Our results demonstrate that brain F-FDG PET/CT might be a useful tool in the assessment of patients with autoimmune encephalitis.

Alzheimer's disease (AD) is the most common form of dementia in the elderly, and it is characterized by progressive impairment in multiple cognitive domains of sufficient severity to interfere with individuals' daily living activities. Historically, the diagnosis of AD has been based on the identification of a clinical syndrome, and accuracy studies of the current clinical criteria conducted in referral clinics have shown high sensitivity for AD. However, the identification of the disease is still not perfect, and there is growing evidence that the use of biomarkers will increase our ability to better indentify the underlying biology of AD, especially in its early stages. These biomarkers will improve the detection of the patients suitable for research studies and drug trials, and they will contribute to a better management of the disease in the clinical practice. In this review, we discuss the most studied biomarkers in AD: cerebrospinal fluid proteins, structural magnetic resonance imaging, functional neuroimaging techniques, and amyloid imaging.

Introduction: Two types of drugs have been approved for the symptomatic treatment of Alzheimer's disease (AD): the cholinesterase inhibitors (ChEIs) and memantine. There is a growing interest to know whether the combination of these drugs is safe and if it adds any clinical benefit to patients., Objective: To systematically review published medical literature assessing the efficacy and tolerability of a combination treatment of memantine and donepezil in AD patients., Methods: We searched PubMed for English and Spanish-language literature, using the terms "Alzheimer's disease," "cholinesterase inhibitors," "donepezil," and "memantine." Our review focused on clinical trials and observational studies., Results: Eleven publications representing seven unique studies were selected for this review. Three were randomized double-blind, placebo-controlled trials and four were observational studies., Conclusions: Available data revealed that the combination of memantine and donepezil slowed down cognitive decline, prolonged functional independence, and improved behavioral symptoms in patients with moderate to severe AD. The long-term use of the dual therapy decreased the risk of nursing home admission. More longitudinal studies are needed to further examine the role of combined therapy in the management of AD patients.