Neurodegenerative Etiology Research Articles

Screening properties of the updated normative framework for the Italian MMSE in MCI and dementia.

This study aimed to assess the screening properties of Foderaro et al.s' updated normative framework for the Italian MMSE in detecting mild cognitive impairment (MCI) and dementia due to neurodegenerative, chronic cerebrovascular, and mixed etiologies, as well as in differentiating between these two syndromes. Data on 234 patients with either MCI (N = 83) or dementia (N = 151) due to Alzheimer's disease (N = 112), Lewy body disease (N = 11), frontotemporal lobar degeneration (N = 20), chronic cerebrovascular disease (N = 39), or mixed (N = 47) etiologies having been administered Foderaro et al.'s version of the MMSE were retrospectively recruited. Moreover, N = 247 healthy controls (HCs) with a normal Montreal Cognitive Assessment performance were prospectively recruited. Receiver-operating characteristics analyses were run to test the capability of both raw and demographically adjusted MMSE scores to discriminate both HCs from MCI/dementia and MCI from dementia. For these comparisons, screening metrics were also computed at Foderaro et al.'s cut-off (<26.02). The capability of demographically adjusted MMSE scores to discriminate both HCs from dementia and MCI from dementia was excellent (AUC = 0.91 and 0.93, respectively), whilst good for MCI case-finding (AUC = 0.85). Consistently, the screening metrics associated with the cut-off at hand were optimal-to-excellent for dementia case-finding (sensitivity = 0.95; specificity = 0.99) and for the differentiation between MCI and dementia (sensitivity = 0.95; specificity = 0.64), whilst imbalanced for detecting MCI (sensitivity = 0.35; specificity = 0.99). Foderaro et al.'s updated normative framework for the Italian MMSE has optimal screening properties for both dementia case-finding and the discrimination between MCI and dementia, being at variance unbalanced towards specificity when it comes to detecting MCI.

Adult-Onset Myoclonus in a Large Urban Inpatient Setting: A Retrospective Cohort Study.

Myoclonus is a hyperkinetic movement with various attributable etiologies, semiologies, and treatment outcomes. To our knowledge, few studies investigated adult-onset myoclonus in an inpatient setting. We retrospectively reviewed charts of adult inpatients with myoclonus at New York Presbyterian Brooklyn Methodist Hospital between 2011 and 2021. Data was analyzed with descriptive statistical methods to elucidate etiology-specific demographics and outcomes. 279 individuals, 56.63% female, were included in our study, aging at 70.61 + 15.76 years. More than 50% were not initially diagnosed with myoclonus by the admitting medical team, and more than 50% had 2 or more ascribable etiologies. Symptomatic myoclonus - mostly of toxic-metabolic or hypoxic-ischemic etiology - accounted for most cases. Hypoxic-ischemic etiologies had shorter durations prior to presentation and were also most resistant to treatment. Renal-associated myoclonus was most associated with asterixis, whereas stimulus-sensitive myoclonus was strongly associated with hypoxic-ischemic etiology. Mortality in-hospital was strongly associated with hypoxic-ischemic etiology and least associated with neurodegenerative and idiopathic etiologies. Treatment response rate diminished in patients who were tried on a second or third anti-seizure drug compared to those trialed on one. Myoclonus remains an underdiagnosed hyperkinetic movement disorder with various ascribable etiologies of varying demographic characteristics and treatment outcomes.

Efficacy of Antidepressants in Management of Depressive Symptoms in Dementia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: Dementia is associated with a complex array of neuropsychiatric manifestations which require consideration as they worsen the course of illness, especially in neurodegenerative etiologies. Depression and subsyndromal depressive symptoms are common in dementia, usually managed with antidepressants, but evidence is weak. Objective: The objective is to study the efficacy of antidepressants compared to placebo in management of depressive symptoms in dementia. Methodology: Electronic databases such as PubMed, MEDLINE, PsychINFO, ClinicalTrials.gov, BASE, and MedNar were searched from their date of inception to March 18, 2024, with appropriate search-terms. Randomized controlled trials (RCTs) that are double-blind in nature with placebo as comparator of dementia patients (Alzheimer’s disease [AD], Frontotemporal, Lewy body, and Parkinson disease dementia) treated with antidepressants for at least ≥ 4 weeks with severity of depressive symptoms measured on standardized rating scales were included. Studies with nonrandomized/nondouble-blind design, active drug or brain stimulation methods as comparator and nonneurodegenerative etiologies of dementia were excluded. Cochrane tool for risk of bias assessment, Covidence and Microsoft Excel for data extraction and review manager version 5.4.1 for data analysis were used. Results: Our search yielded 13(N) RCTs for systematic review, majority of which reported on AD (n = 12), selective serotonin reuptake inhibitors as intervention (n = 7), and high risk of bias (n = 9). Efficacy analysis using forest-plot with seven RCTs showed no statistically significant treatment effect (standardized mean differences [SMD] = −0.04, 95%confidence interval [−0.36, 0.27], Z = 0.26, P = 0.79) between intervention and placebo group. Substantial significant heterogeneity (I 2 = 74%, P &lt; 0.001) was noted across studies. Discussion: Antidepressants administered for 6–13 weeks and different rating scales used to measure outcome in RCTs were possible reasons for heterogeneity. We conclude that antidepressants have not been found to be efficacious compared to placebo in management of depressive symptoms in dementia. Findings cannot be generalized to other etiologies as our analysis found limited data majorly on AD and RCTs with high risk or some concerns in the bias, thus throws a light on need for robust RCTs in this area.

Efficacy of Transcranial Direct Current Stimulation on Cognitive Function in Dementia and Mild Cognitive Impairment Secondary to Neurodegenerative Etiology: A Systematic Review and Meta-Analysis

Background: Dementia is a chronic progressive illness with significant impairment in a person’s functioning ability. The currently available treatment options for dementia are limited in modifying disease progression. Non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) are emerging as potential treatment options for cognitive as well as behavioral symptoms in dementia. The objective of this systematic review and meta-analysis is to assess the efficacy of tDCS on cognitive function in mild cognitive impairment (MCI) and dementia due to neurodegenerative disorders to provide an update on the existing evidence considering an increasing number of trials using tDCS. Methods: The study was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines with a prespecified protocol registered in PROSPERO (CRD42024503852). The study selection was made through a search on databases such as PubMed, Ovid MEDLINE, APA PsycInfo, and Cochrane trials registry and a gray literature search on ClinicalTrials.gov. All randomized controlled trials that have used tDCS as a standalone intervention for cognitive impairment were included in the present study. Risk of bias (RoB) was assessed by the Cochrane RoB2 tool. Meta-analysis of outcomes was performed using RevMan software version 5.4. Pooled estimates of standardized mean difference (SMD) and 95% confidence interval (CI) were obtained for global cognition (primary outcome) and other domain-specific cognitive outcomes. Results: A total of 24 studies were finally included in the review. Most of the studies had “some concerns” with regard to the overall RoB. A total of 164 subjects in the true tDCS group and 151 subjects in the sham tDCS groups out of eight studies were analyzed for global cognitive outcome, giving a pooled SMD (95% CI) of 0.80 (0.35, 1.26), giving an overall effect of Z = 3.45 (P &lt; 0.001), with I2 value of 72%, favoring true tDCS. On a sub-group analysis, a significant improvement was noted in the Alzheimer’s dementia group but not MCI. Discussion: The study findings suggest that tDCS is effective in improving global cognition in participants with Alzheimer’s dementia but not MCI. Owing to a smaller number of studies, the domain-specific cognitive outcomes could not be assessed effectively. There was a wide heterogeneity in the included studies in terms of tDCS stimulation protocols.

EEG Functional Connectivity Differences Predict Future Conversion to Dementia in Mild Cognitive Impairment With Lewy Body or Alzheimer Disease.

Predicting which individuals may convert to dementia from mild cognitive impairment (MCI) remains difficult in clinical practice. Electroencephalography (EEG) is a widely available investigation but there is limited research exploring EEG connectivity differences in patients with MCI who convert to dementia. Participants with a diagnosis of MCI due to Alzheimer's disease (MCI-AD) or Lewy body disease (MCI-LB) underwent resting state EEG recording. They were followed up annually with a review of the clinical diagnosis (n=66). Participants with a diagnosis of dementia at year 1 or year 2 follow up were classed as converters (n=23) and those with a diagnosis of MCI at year 2 were classed as stable (n=43). We used phase lag index (PLI) to estimate functional connectivity as well as analysing dominant frequency (DF) and relative band power. The Network-based statistic (NBS) toolbox was used to assess differences in network topology. The converting group had reduced DF (U=285.5, p=0.005) and increased relative pre-alpha power (U=702, p=0.005) consistent with previous findings. PLI showed reduced average beta band synchrony in the converting group (U=311, p=0.014) as well as significant differences in alpha and beta network topology. Logistic regression models using regional beta PLI values revealed that right central to right lateral (Sens=56.5%, Spec=86.0%, -2LL=72.48, p=0.017) and left central to right lateral (Sens=47.8%, Spec=81.4%, -2LL=71.37, p=0.012) had the best classification accuracy and fit when adjusted for age and MMSE score. Patients with MCI who convert to dementia have significant differences in EEG frequency, average connectivity and network topology prior to the onset of dementia. The MCI group is clinically heterogeneous and have underlying physiological differences that may be driving the progression of cognitive symptoms. EEG connectivity could be useful to predict which patients with MCI-AD and MCI-LB convert to dementia, regardless of the neurodegenerative aetiology.

Presumed aetiologies and clinical outcomes of non-lesional late-onset epilepsy.

Our objective was to define phenotypes of non-lesional late-onset epilepsy (NLLOE) depending on its presumed aetiology and to determine their seizure and cognitive outcomes at 12 months. In all, 146 newly diagnosed NLLOE patients, >50 years old, were prospectively included and categorized by four presumed aetiological subtypes: neurodegenerative subtype (patients with a diagnosis of neurodegenerative disease) (n = 31), microvascular subtype (patients with three or more cardiovascular risk factors and two or more vascular lesions on MRI) (n = 39), inflammatory subtype (patient meeting international criteria for encephalitis) (n = 9) and unlabelled subtype (all individuals who did not meet the criteria for other subtypes) (n = 67). Cognitive outcome was determined by comparing for each patient the proportion of preserved/altered scores between initial and second neuropsychological assessment. The neurodegenerative subtype had the most severe cognitive profile at diagnosis with cognitive complaint dating back several years. The microvascular subtype was mainly evaluated through the neurovascular emergency pathway. Their seizures were characterized by transient phasic disorders. Inflammatory subtype patients were the youngest. They presented an acute epilepsy onset with high rate of focal status epilepticus. The unlabelled subtype presented fewer comorbidities with fewer lesions on brain imaging. The neurodegenerative subtype had the worst seizure and cognitive outcomes. In other groups, seizure control was good under antiseizure medication (94.7% seizure-free) and cognitive performance was stabilized or even improved. This new characterization of NLLOE phenotypes raises questions regarding the current International League Against Epilepsy aetiological classification which does not individualize neurodegenerative and microvascular aetiology per se.

A Case of Anti-IgLON5 Disease with Aplastic Anemia and review of the literature

Anti-IgLON5 is a neurological condition with neurodegenerative and autoimmune etiology. A 64-year-old man with a 2-year history of aplastic anemia presented with symmetrical parkinsonism, fluctuating consciousness, supranuclear gaze palsy, mild fasciculation, and muscular atrophy. He had disturbances in his sleep cycle and brain MRI. CSF analysis was positive for the IgLON5 antibody. We initiated immunotherapy with high-dose methylprednisolone, intravenous immunoglobulin, and rituximab. The patient showed a mild to moderate response to treatment. We reviewed 29 published case reports regarding anti-Iglon-5 and examined the clinical manifestation. None of the cases showed aplastic anemia, which was the main presentation in our case. All of the patients experienced sleep disturbances, while other symptoms were heterogeneous. Anti-Iglon-5 is usually diagnosed late, leading to a weak prognosis. This study helped us establish a better understanding of the correlation between antiIglon5 disease and other autoimmune disorders like anemia.

Twin neurological enigmas radiological and medical insight into a dual encounter with metformin induced encephalopathy

Metformin induced encephalopathy is an infrequent but critical neurological complication associated with metformin therapy. Lentiform fork sign, an infrequent radiological imaging (MRI), presents a distinctive image in basal ganglia pathology. It manifests as a V-shaped or fork-like hyperintensity in the globus pallidus and putamen regions. While it has been associated with various conditions like diabetic uremic encephalopathy, toxins like methanol and ethylene glycol, Neurodegenerative etiologies. Its occurrence following metformin administration remains rare because of contraindication of prescribing metformin in a hemodialysis patient due to its well-known side of lactic acidosis. This abstract aims to report and discuss two cases presenting the lentiform forks sign following metformin administration in patients undergoing hemodialysis due to end-stage renal disease. Symptomatic involvement of basal ganglia as metformin induced encephalopathy and resolution with clinical recovery following hemodialysis are rarely reported. We hereby report two such cases which shows symptomatic improvement clinically as well as radiologically following hemodialysis

Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.

Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited. A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared. Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement. BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.

A scoping review of mathematical models covering Alzheimer's disease progression.

Alzheimer's disease is a complex, multi-factorial, and multi-parametric neurodegenerative etiology. Mathematical models can help understand such a complex problem by providing a way to explore and conceptualize principles, merging biological knowledge with experimental data into a model amenable to simulation and external validation, all without the need for extensive clinical trials. We performed a scoping review of mathematical models describing the onset and evolution of Alzheimer's disease as a result of biophysical factors following the PRISMA standard. Our search strategy applied to the PubMed database yielded 846 entries. After using our exclusion criteria, only 17 studies remained from which we extracted data, which focused on three aspects of mathematical modeling: how authors addressed continuous time (since even when the measurements are punctual, the biological processes underlying Alzheimer's disease evolve continuously), how models were solved, and how the high dimensionality and non-linearity of models were managed. Most articles modeled Alzheimer's disease at the cellular level, operating on a short time scale (e.g., minutes or hours), i.e., the micro view (12/17); the rest considered regional or brain-level processes with longer timescales (e.g., years or decades) (the macro view). Most papers were concerned primarily with amyloid beta (n = 8), few described both amyloid beta and tau proteins (n = 3), while some considered more than these two factors (n = 6). Models used partial differential equations (n = 3), ordinary differential equations (n = 7), and both partial differential equations and ordinary differential equations (n = 3). Some did not specify their mathematical formalism (n = 4). Sensitivity analyses were performed in only a small number of papers (4/17). Overall, we found that only two studies could be considered valid in terms of parameters and conclusions, and two more were partially valid. This puts the majority (n = 13) as being either invalid or with insufficient information to ascertain their status. This was the main finding of our paper, in that serious shortcomings make their results invalid or non-reproducible. These shortcomings come from insufficient methodological description, poor calibration, or the impossibility of experimentally validating or calibrating the model. Those shortcomings should be addressed by future authors to unlock the usefulness of mathematical models in Alzheimer's disease.

Classification of patients with dementia in a late life depression cohort using structural MRI

AbstractBackgroundLate life depression (LLD) is a risk factor for cognitive impairment, with up to 40% of depressed older adults showing persistent cognitive deficits even after symptom remission. Over 20% of Alzheimer’s disease patients exhibit depression‐like symptoms which can represent an early marker of disease (Tsuno et Homma., 2009). We hypothesized that automated classification algorithms trained on structural MRI could predict adjudicated diagnosis of cognitive impairment (CI) in this cohort.MethodOur study evaluated 295 patients with LLD. An adjudication committee consisting of two board‐certified psychiatrists and a clinical neuropsychologist determined ground‐truth labels for patient diagnostic results of CI (N = 145) or No CI (N = 150). Patients underwent T1‐weighted scans, which were segmented with Freesurfer 6.0.1 (freesurfer.net) packaged with fMRIPrep 1.5.8 (fmriprep.org) using the Desikan‐Killiany atlas. Cortical thickness and volumetric data were obtained along with demographic parameters. Freesurfer data was then regressed against estimated total intracranial volume. 11 classifications algorithms implemented in R were trained and tested on 209 and 88 patients, respectively, to classify if a patient has CI. All continuous‐valued data were normalized with respect to the training set mean and standard deviation.ResultTable 1 shows results from multiple classifications algorithms, including high sensitivity, specificity, and accuracy from adaptive boosting algorithms. The latter algorithms iteratively optimize a set of binary classification tree algorithms (Freund et Schapire., 1996).ConclusionVolumetric structural MRI biomarkers trained with machine learning classifiers can adequately categorize depressed older adults with CI which could assist the adjudication process. Future work incorporating structural MRI biomarkers with gold standard clinical data may improve earlier detection of cognitive impairment stemming from a neurodegenerative etiology.

Neural Correlates of Mild Behavioral Impairment in older adults across the neurodegenerative spectrum

AbstractBackgroundMild behavioral impairment (MBI) is a syndrome characterized by later life onset, persistent neuropsychiatric symptoms (NPS) in non‐demented older adults. MBI can co‐occur with Mild Cognitive Impairment (MCI) and has a range of neurodegenerative etiologies including Alzheimer’s disease (AD), Cerebrovascular Disease (CVD), and Parkinson’s disease (PD). MBI is associated with poorer cognitive and psychosocial function and an increased risk of developing dementia. Thus, we aimed to explore the structural neural correlates of MBI, specifically in the regions known to be associated with cognitive impairment (i.e., corticolimbic and frontal‐executive circuits), across multiple neurodegenerative diagnoses from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).MethodWe assessed the association between MBI and brain structural alterations via T1‐weighted imaging in three groups with Montreal Cognitive Assessment scores ³19: individuals with MCI (due to AD; n = 37), CVD (n = 129), and PD (n = 127). NPS scores were derived from the Neuropsychiatric Inventory (NPI‐Q) domains, and categorized as NPS+ (i.e., NPI score&gt;0); and NPS‐ (NPI score = 0). We selected regions of interest from the corticolimbic and frontal‐executive circuits to measure brain structure using cortical thickness and subcortical volume. Partial correlation, corrected for age, sex, and education was used to assess the association between MBI and brain structural alterations.ResultOverall, apathy, depression, and anxiety, which map to the decreased motivation and emotional dysregulation MBI domains, had a high prevalence across all the groups. In the brain‐MBI association analysis, apathy was associated with decreased thickness of the l‐rostral middle frontal, r‐superior temporal, and frontal pole in the PD and CVD (but not MCI) groups. Anxiety was associated with decreased volume of the right hippocampus and amygdala in the MCI group, but not CVD or PD (FDR p&lt; 0.05). No structural correlates were found for depression.ConclusionOur findings provide evidence of a specific association between apathy and reduced efficiency of the frontal‐executive system in individuals with PD and CVD. In addition, the well‐established AD corticolimbic atrophy patterns (e.g., hippocampus and amygdala) seen in MCI are prominent in the presence of anxiety. Overall, the relatively distinct brain‐MBI associations across neurodegenerative disorders suggest that pathological substrates may alter MBI neural correlates.

Catalan Early Onset Dementia Network 2021 Report

AbstractBackgroundThe Catalan Early Onset Neurodegenerative Dementia Network is a multicenter project launched in 2020 with the aim of understanding the epidemiology and clinical care of people with early‐onset neurodegenerative dementia and their caregivers.MethodsNeurologists and geriatricians visiting patients with cognitive impairment in Catalonia were invited to prospectively collect demographical and clinical data from patients with age at onset (AAO) less than 65 years visited during the year 2021.ResultWe registered information of 1221 subjects from 14 centers. Mean age was 56,2 years (SD 8.7), 64% were woman. Mean age at symptom onset was 53,9 years (SD 9.1). The most frequent cognitive symptoms at onset were memory impairment (72,9%) and dysexecutive difficulties (21,8%). Mean Mini Mental State Examination (MMSE) score was 26,7 (range 7‐30). Initial clinical diagnose was a non‐neurodegenerative disorder in 81,4% of cases and a neurodegenerative disorder in 17,81%. Genetic counseling accounted for 0,8% of visits. The suspected non‐neurodegenerative and neurodegenerative patients were studied with a neuropsychological test (85,5% vs 86,7%, respectively), magnetic resonance imaging (MRI) (39,9% vs 55,6%), computerized tomography (CT) scan (33,2% vs 34,4%), fluorodeoxyglucose positron emission tomography (FDG‐PET) (6,8% vs 39,0%), amyloid‐PET (3,9% vs 34,4%) and lumbar puncture (7,1%, vs 44,8%). 16,6% of participants had a final diagnose of a neurodegenerative cognitive disorder (10,9% Alzheimer’s disease, 2,3% frontotemporal lobular degeneration, 2,1% MCI of suspected neurodegenerative etiology, 0,58% other neurodegenerative dementias); 83,4% were diagnosed with a non‐degenerative disorder (28,4% subjective cognitive decline (SCD), 25,0% mild cognitive impairment of non‐neurodegenerative etiology, 19,8% cognitive impairment after Covid‐19, 10,2% other dementias). Diagnostic delay was higher for neurodegenerative disorders (17 months: median 12 months (interquartile range (IQR) 19) between AAO and first visit +5 months (IQR 8) between first visit and diagnose) than non‐degenerative disorders (12 months: 9 months (IQR 19,6) + 3 months (IQR 7) respectively).ConclusionOf 1221 patients under 65 years old visited in cognitive disorders units, only 16,6% had a final diagnose of neurodegenerative cognitive disorder. More than a quarter of subjects were diagnosed as SCD and a fifth as cognitive impairment after Covid‐19. In 2021, diagnosis delay was higher in neurodegenerative disorders (median 17 months).

An imaging review of the hippocampus and its common pathologies.

The hippocampus is a complex structure located in the mesial temporal lobe that plays a critical role in cognitive and memory-related processes. The hippocampal formation consists of the dentate gyrus, hippocampus proper, and subiculum, and its importance in the neural circuitry makes it a key anatomic structure to evaluate in neuroimaging studies. Advancements in imaging techniques now allow detailed assessment of hippocampus internal architecture and signal features that has improved identification and characterization of hippocampal abnormalities. This review aims to summarize the neuroimaging features of the hippocampus and its common pathologies. It provides an overview of the hippocampal anatomy on magnetic resonance imaging and discusses how various imaging techniques can be used to assess the hippocampus. The review explores neuroimaging findings related to hippocampal variants (incomplete hippocampal inversion, sulcal remnant and choroidal fissure cysts), and pathologies of neoplastic (astrocytoma and glioma, ganglioglioma, dysembryoplastic neuroepithelial tumor, multinodular and vacuolating neuronal tumor, and metastasis), epileptic (mesial temporal sclerosis and focal cortical dysplasia), neurodegenerative (Alzheimer's disease, progressive primary aphasia, and frontotemporal dementia), infectious (Herpes simplex virus and limbic encephalitis), vascular (ischemic stroke, arteriovenous malformation, and cerebral cavernous malformations), and toxic-metabolic (transient global amnesia and opioid-associated amnestic syndrome) etiologies.

Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases.

A hallmark of aging and neurodegenerative diseases is a disruption of proteome homeostasis ("proteostasis") that is caused to a considerable extent by a decrease in the efficiency of protein degradation systems. The ubiquitin proteasome system (UPS) is the major cellular pathway involved in the clearance of small, short-lived proteins, including amyloidogenic proteins that form aggregates in neurodegenerative diseases. Age-dependent decreases in proteasome subunit expression coupled with the inhibition of proteasome function by aggregated UPS substrates result in a feedforward loop that accelerates disease progression. Nuclear factor erythroid 2- like 1 (NFE2L1) is a transcription factor primarily responsible for the proteasome inhibitor-induced "bounce-back effect" regulating the expression of proteasome subunits. NFE2L1 is localized to the endoplasmic reticulum (ER), where it is rapidly degraded under basal conditions by the ER-associated degradation (ERAD) pathway. Under conditions leading to proteasome impairment, NFE2L1 is cleaved and transported to the nucleus, where it binds to antioxidant response elements (AREs) in the promoter region of proteasome subunit genes, thereby stimulating their transcription. In this review, we summarize the role of UPS impairment in aging and neurodegenerative disease etiology and consider the potential benefit of enhancing NFE2L1 function as a strategy to upregulate proteasome function and alleviate pathology in neurodegenerative diseases.

Mouse models of cerebral injury and cognitive impairment in hypertension.

Hypertension is a major risk factor for dementia, including both vascular and neurodegenerative etiologies. With the original aim of studying the effect of blood pressure elevation on canonical target organs of hypertension as the heart, the vasculature or the kidneys, several experimental models of hypertension have sprouted during the years. With the more recent interest of understanding the cerebral injury burden caused by hypertension, it is worth understanding how the main models of hypertension or localized cerebral hypertension stand in the field of hypertension-induced cerebral injury and cognitive impairment. With this review we will report main genetic, pharmacological and surgical models of cognitive impairment induced by hypertension, summarizing how each specific category and model can improve our understanding of the complex phenomenon of cognitive loss of vascular etiology.

Cervical myelitis: a practical approach to its differential diagnosis on MR imaging.

Differential diagnosis of non-compressive cervical myelopathy encompasses a broad spectrum of inflammatory, infectious, vascular, neoplastic, neurodegenerative, and metabolic etiologies. Although the speed of symptom onset and clinical course seem to be specific for certain neurological diseases, lesion pattern on MR imaging is a key player to confirm diagnostic considerations. The differentiation between acute complete transverse myelitis and acute partial transverse myelitis makes it possible to distinguish between certain entities, with the latter often being the onset of multiple sclerosis. Typical medullary MRI lesion patterns include a) longitudinal extensive transverse myelitis, b) short-range ovoid and peripheral lesions, c) polio-like appearance with involvement of the anterior horns, and d) granulomatous nodular enhancement prototypes. Cerebrospinal fluid analysis, blood culture tests, and autoimmune antibody testing are crucial for the correct interpretation of imaging findings. The combination of neuroradiological features and neurological and laboratory findings including cerebrospinal fluid analysis improves diagnostic accuracy. · The differentiation of medullary lesion patterns, i. e., longitudinal extensive transverse, short ovoid and peripheral, polio-like, and granulomatous nodular, facilitates the diagnosis of myelitis.. · Discrimination of acute complete and acute partial transverse myelitis makes it possible to categorize different entities, with the latter frequently being the overture of multiple sclerosis (MS).. · Neuromyelitis optica spectrum disorders (NMOSD) may start as short transverse myelitis and should not be mistaken for MS.. · The combination of imaging features and neurological and laboratory findings including cerebrospinal fluid analysis improves diagnostic accuracy.. · Additional brain imaging is mandatory in suspected demyelinating, systemic autoimmune, infectious, paraneoplastic, and metabolic diseases..

Cognitive Stimulation Therapy in a Veteran Sample: A Program Evaluation Study

ABSTRACT Objectives Cognitive stimulation therapy (CST) is an evidence-based intervention for dementia. This program evaluation examined the outcomes of a modified CST program in a veteran sample. Methods Twenty-five veterans who participated in a once-weekly, 7-week CST program and completed pre/post-group assessments were selected for inclusion in this chart review study. In this diverse sample (Mage = 74.40; 44% White, 44% Hispanic/Latinx, 8% Black, 4% multiracial), most had a suspected neurodegenerative etiology. Paired-samples t-test examined QoL and cognitive pre/post-intervention scores. Results Statistically significant improvements were observed in RBANS total index scores (Cohen’s d = 0.46). Although there was not a statistically significant change in MoCA scores or patient QoL-AD ratings, there were small effects in the predicted direction (Cohen’s d = 0.29 and 0.30, respectively). There was no significant change or effect on caregiver QoL-AD ratings (Cohen’s d = .09). Conclusions A modified, once-weekly 7-week CST program for veterans was feasible and demonstrated positive outcomes. Improvements were observed in global cognition and there was a small, positive effect on patient-rated QoL. Given that dementia is often progressive, stability of cognition and QoL are suggestive of the protective effects of CST. Clinical implications CST is feasible and beneficial as a once-weekly brief group intervention for veterans with cognitive impairment.

Diagnosis across a cohort of “atypical” atypical and complex parkinsonism

IntroductionThe diagnostic approach for adulthood parkinsonism can be challenging when atypical features hamper its classification in one of the two main parkinsonian groups: Parkinson's disease or atypical parkinsonian syndromes (APS). Atypical features are usually associated with non-sporadic neurodegenerative causes. MethodsRetrospective analysis of patients with a working clinical diagnosis of “atypical” APS and complex parkinsonism. “Atypical” APS were classified according to the diagnostic research criteria and the “4-step diagnostic approach” (Stamelou et al. 2013). When not indicated, the final aetiological diagnosis was prospectively assessed. Brain MRI of progressive supranuclear palsy (PSP) look-alikes was reviewed by a neuroradiologist. ResultsAmong 18 patients enrolled, ten were assigned to the “atypical” APS and eight to the complex parkinsonism group. In the “atypical” APS group, nine patients had PSP and one had corticobasal degeneration. In the PSP group the median magnetic resonance parkinsonism index was 17.1. A final aetiological diagnosis was established for 11 patients, four from the complex parkinsonism (L-2-hidroxiglutaric aciduria and DiGeorge syndrome) and seven from the “atypical” APS (Perry syndrome, postencephalitic PSP, vascular PSP, and MTP-AT6 mitochondrial disease) group. ConclusionsIn this study, the identification of atypical APS features, as proposed in the “4-step diagnostic approach”, successfully guided the investigation of alternative diagnoses. Distinctive non-neurodegenerative etiologies causing “atypical” atypical and complex parkinsonism were uncovered, including acquired (post-encephalitis and vascular) and genetic (MTP-AT6 mitochondrial disease mimicking PSP, described for the first time) ones. In the future, accurate clinical identification and distinction between neurodegenerative and non-neurodegenerative parkinsonism etiologies will allow for refining clinical trials.

Distinguishing apathy from depression: A review differentiating the behavioral, neuroanatomic, and treatment-related aspects of apathy from depression in neurocognitive disorders.

This narrative review describes the clinical features of apathy and depression in individuals with neurocognitive disorders (NCDs), with the goal of differentiating the two syndromes on the basis of clinical presentation, diagnostic criteria, neuropathological features, and contrasting responses to treatments. Literature was identified using PubMed, with search terms to capture medical conditions of interest; additional references were also included based on our collective experience and knowledge of the literature. Evidence from current literature supports the distinction between the two disorders; apathy and depression occur with varying prevalence in individuals with NCDs, pose different risks of progression to dementia, and have distinct, if overlapping, neurobiological underpinnings. Although apathy is a distinct neuropsychiatric syndrome, distinguishing apathy from depression can be challenging, as both conditions may occur concurrently and share several overlapping features. Apathy is associated with unfavorable outcomes, especially those with neurodegenerative etiologies (e.g., Alzheimer's disease) and is associated with an increased burden for both patients and caregivers. Diagnosing apathy is important not only to serve as the basis for appropriate treatment, but also for the development of novel targeted interventions for this condition. Although there are currently no approved pharmacologic treatments for apathy, the research described in this review supports apathy as a distinct neuropsychiatric condition that warrants specific treatments aimed at alleviating patient disability. Despite differences between these disorders, both apathy and depression pose significant challenges to patients, their families, and caregivers; better diagnostics are needed to develop more tailored treatment and support.