Prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults: systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis on the prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults. METHODS: We systematically reviewed and performed a meta-analysis on the prevalence of TDP-43 proteinopathy in older adults with normal cognition, evaluated by the Mini-Mental State Examination or the Clinical Dementia Rating. We estimated the overall prevalence of TDP-43 using random-effect models, and stratified by age, sex, sample size, study quality, antibody used to assess TDP-43 aggregates, analysed brain regions, Braak stage, Consortium to Establish a Registry for Alzheimer's Disease score, hippocampal sclerosis and geographic location. RESULTS: A total of 505 articles were identified in the systematic review, and 7 were included in the meta-analysis with 1196 cognitively normal older adults. We found an overall prevalence of TDP-43 proteinopathy of 24%. Prevalence of TDP-43 proteinopathy varied widely across geographic location (North America: 37%, Asia: 29%, Europe: 14%, and Latin America: 11%). Estimated prevalence of TDP-43 proteinopathy also varied according to study quality (quality score >7: 22% vs. quality score <7: 42%), antibody used to assess TDP-43 proteinopathy (native: 18% vs. hyperphosphorylated: 24%) and presence of hippocampal sclerosis (without 24% vs. with hippocampal sclerosis: 48%). Other stratified analyses by age, sex, analysed brain regions, sample size and severity of AD neuropathology showed similar pooled TDP-43 prevalence. CONCLUSIONS: Different methodology to access TDP-43, and also differences in lifestyle and genetic factors across different populations could explain our results. Standardization of TDP-43 measurement, and future studies about the impact of genetic and lifestyle characteristics on the development of neurodegenerative diseases are needed.

Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease.

AIMS: Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages. METHODS: We utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-µm-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases. RESULTS: In Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9× between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN. CONCLUSIONS: LC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.

African ancestry protects against Alzheimer's disease-related neuropathology.

Previous studies in dementia epidemiology have reported higher Alzheimer's disease rates in African-Americans when compared with White Americans. To determine whether genetically determined African ancestry is associated with neuropathological changes commonly associated with dementia, we analyzed a population-based brain bank in the highly admixed city of São Paulo, Brazil. African ancestry was estimated through the use of previously described ancestry-informative markers. Risk of presence of neuritic plaques, neurofibrillary tangles, small vessel disease, brain infarcts and Lewy bodies in subjects with significant African ancestry versus those without was determined. Results were adjusted for multiple environmental risk factors, demographic variables and apolipoprotein E genotype. African ancestry was inversely correlated with neuritic plaques (P=0.03). Subjects with significant African ancestry (n=112, 55.4%) showed lower prevalence of neuritic plaques in the univariate analysis (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.55-0.95, P=0.01) and when adjusted for age, sex, APOE genotype and environmental risk factors (OR 0.43, 95% CI 0.21-0.89, P=0.02). There were no significant differences for the presence of other neuropathological alterations. We show for the first time, using genetically determined ancestry, that African ancestry may be highly protective of Alzheimer's disease neuropathology, functioning through either genetic variants or unknown environmental factors. Epidemiological studies correlating African-American race/ethnicity with increased Alzheimer's disease rates should not be interpreted as surrogates of genetic ancestry or considered to represent African-derived populations from the developing nations such as Brazil.

Cognitive-behavioural group therapy improves a psychophysiological marker of stress in caregivers of patients with Alzheimer's disease.

BACKGROUND: Family caregivers of patients with dementia frequently experience psychological stress, depression and disturbed psychophysiological activity, with increased levels of diurnal cortisol secretion. OBJECTIVES: To compare the effects of a cognitive-behavioural group therapy (CBT) to a psychoeducation group programme (EDUC) on cortisol secretion in caregivers of patients with moderate Alzheimer's disease (AD). METHOD: Caregivers of AD outpatients were semi-randomly allocated to one of two intervention programmes (CBT or EDUC) consisting of eight weekly sessions. Twenty-six participants completed the study. Before and after intervention, salivary cortisol was collected at four different times of the day. Effects of the interventions were evaluated with self-report psychological scales and questionnaires related to functional abilities and neuropsychiatric symptoms of the AD relative. RESULTS: Only in the CBT group did salivary cortisol levels significantly decrease after intervention, with a large effect size and high achieved power. Both groups reported a reduction of neuropsychiatric symptoms of their AD relative after intervention. CONCLUSION: Psychoeducation for caregivers may contribute to a reduction of neuropsychiatric symptoms of AD patients while CBT additionally attenuates psychophysiological responses to stressful situations in caregivers, by reducing diurnal cortisol levels. This may lead to a positive impact in the general health of the caregiver, eventually resulting in better care of the AD patient.

Phenotyping Superagers Using Resting-State fMRI.

BACKGROUND AND PURPOSE: Superagers are defined as older adults with episodic memory performance similar or superior to that in middle-aged adults. This study aimed to investigate the key differences in discriminative networks and their main nodes between superagers and cognitively average elderly controls. In addition, we sought to explore differences in sensitivity in detecting these functional activities across the networks at 3T and 7T MR imaging fields. MATERIALS AND METHODS: Fifty-five subjects 80 years of age or older were screened using a detailed neuropsychological protocol, and 31 participants, comprising 14 superagers and 17 cognitively average elderly controls, were included for analysis. Participants underwent resting-state-fMRI at 3T and 7T MR imaging. A prediction classification algorithm using a penalized regression model on the measurements of the network was used to calculate the probabilities of a healthy older adult being a superager. Additionally, ORs quantified the influence of each node across preselected networks. RESULTS: The key networks that differentiated superagers and elderly controls were the default mode, salience, and language networks. The most discriminative nodes (ORs > 1) in superagers encompassed areas in the precuneus posterior cingulate cortex, prefrontal cortex, temporoparietal junction, temporal pole, extrastriate superior cortex, and insula. The prediction classification model for being a superager showed better performance using the 7T compared with 3T resting-state-fMRI data set. CONCLUSIONS: Our findings suggest that the functional connectivity in the default mode, salience, and language networks can provide potential imaging biomarkers for predicting superagers. The 7T field holds promise for the most appropriate study setting to accurately detect the functional connectivity patterns in superagers.

The Brain Metabolic Signature in Superagers Using In Vivo 1H-MRS: A Pilot Study.

BACKGROUND AND PURPOSE: Youthful memory performance in older adults may reflect an underlying resilience to the conventional pathways of aging. Subjects having this unusual characteristic have been recently termed "superagers." This study aimed to explore the significance of imaging biomarkers acquired by 1H-MRS to characterize superagers and to differentiate them from their normal-aging peers. MATERIALS AND METHODS: Fifty-five patients older than 80 years of age were screened using a detailed neuropsychological protocol, and 25 participants, comprising 12 superagers and 13 age-matched controls, were statistically analyzed. We used state-of-the-art 3T 1H-MR spectroscopy to quantify 18 neurochemicals in the posterior cingulate cortex of our subjects. All 1H-MR spectroscopy data were analyzed using LCModel. Results were further processed using 2 approaches to investigate the technique accuracy: 1) comparison of the average concentration of metabolites estimated with Cramer-Rao lower bounds <20%; and 2) calculation and comparison of the weighted means of metabolites' concentrations. RESULTS: The main finding observed was a higher total N-acetyl aspartate concentration in superagers than in age-matched controls using both approaches (P = .02 and P = .03 for the weighted means), reflecting a positive association of total N-acetyl aspartate with higher cognitive performance. CONCLUSIONS: 1H-MR spectroscopy emerges as a promising technique to unravel neurochemical mechanisms related to cognitive aging in vivo and providing a brain metabolic signature in superagers. This may contribute to monitoring future interventional therapies to avoid or postpone the pathologic processes of aging.

The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer's disease. A precocious onset?

AIMS: Alzheimer's disease (AD) is a progressive and irreversible disease. There is strong evidence that the progression of the phospho-tau neurofibrillary cytoskeletal changes, rather than the beta-amyloid burden, is crucial in determining the severity of the dementia in AD. The Braak and Braak staging system (BB) focuses mainly on the cortical cytoskeletal pathology and classifies this progressive pathology into six stages, spreading from the transentorhinal region to primary cortices. Although it is reported elsewhere that the midbrain's dorsal raphe nucleus (DR), which is connected with those areas of the cerebral cortex undergoing early changes during BB I and II, exhibits AD-related cytoskeletal pathology, this nucleus has not been considered by the BB. METHODS: To determine during which BB stage and how frequently the DR is affected by AD-related neurofibrillary changes, we studied the DR of 118 well-characterized individuals of the Brain Bank of the Brazilian Aging Brain Study Group categorized according to the BB. Thirty-eight of these individuals were staged as BB = 0, and 80 as BB >or= 1. RESULTS: In all of the BB >or= 1 individuals (cortical neurofibrillary changes were present at least in the transentorhinal region) and in more than 1/5 of the BB = 0 individuals neurofibrillary changes were detected in the supratrochlear subnucleus of the DR. CONCLUSIONS: These observations: (i) support the hypothesis of transneuronal spread of neurofibrillary changes from the DR to its interconnected cortical brain areas; and (ii) indicate that the supratrochlear subnucleus of the DR is affected by neurofibrillary changes before the transentorhinal cortex during the disease process underlying AD.

Chronic stress is associated with high cortisol levels and emotional coping mechanisms in amnestic mild cognitive impairment.

BACKGROUND/AIMS: To investigate the association between cortisol levels, chronic stress and coping in subjects with amnestic-type mild cognitive impairment (aMCI). METHODS: Cortisol levels were measured using morning saliva samples from 33 individuals with aMCI and from 41 healthy elderly. Chronic stress was evaluated with the Stress Symptoms List (SSL), whereas coping strategies were assessed using the Jalowiec Coping Scale. RESULTS: aMCI subjects with high SSL scores presented higher cortisol levels (p = 0.045). Furthermore, aMCI subjects who employed emotion-focused coping had higher SSL scores (p = 0.023). CONCLUSION: The association between increased cortisol secretion, chronic stress and coping strategies may be modulated by the presence or absence of cognitive impairment, where memory defi- cit awareness constitutes an additional potential factor involved in high stress severity.

Concomitant Transverse Myelitis and Acute Axonal Sensory-Motor Neuropathy in an Elderly Patient.

Diagnosing concomitant transverse myelitis (TM) and Guillain-Barré syndrome (GBS) can be challenging. We report a case of an elderly patient presenting with acute sensory and motor disturbances in the four limbs, associated with urinary retention, ophthalmoparesis, facial weakness, and dysarthria. Electrodiagnostic studies were consistent with acute motor sensory axonal neuropathy (AMSAN), and imaging showed a longitudinally extensive tumefactive contrast-enhancing hyperintense spinal cord lesion extending from T6 to the cone. Concomitant AMSAN and TM have not been previously reported in the elderly. Comorbid TM and other GBS variants have been previously reported. Intravenous methylprednisolone, plasma exchange, cyclophosphamide, or combination therapies are usually used, although there are no randomized controlled studies regarding treatment choices.

The history of tabes dorsalis and the impact of observational studies in neurology.

It is common for a particular aspect of scientific knowledge to undergo a great advance in a brief period of time after the discovery of new investigational procedures that broaden research horizons. Knowledge of neurosyphilis increased markedly during the second half of the 19th century. As revealed by the example of tabes dorsalis, this progress was not related to new research methods but instead to the impetus of careful clinical observations.

Diffusion-weighted MRI in two cases of familial Creutzfeldt--Jakob disease.

Diffusion-weighted magnetic resonance imaging (DWI) has been described as a useful tool for the diagnosis of sporadic Creutzfeldt--Jakob disease (CJD). To our knowledge, DWI abnormalities have not previously been reported in familial CJD. In two patients with familial CJD associated with distinct mutations at codon 183 and at codon 210 of the prion protein gene, DWI showed a high signal in the basal ganglia and in the cerebral cortex. These abnormalities are similar to those described in sporadic CJD. This observation expands the value of DWI for the diagnosis of some forms of familial CJD. It remains to be investigated whether this finding also holds for CJD associated with other mutations of the prion protein gene.

Brain metastasis of a malignant fibrous histiocytoma of the lung.

Sarcomas metastatic to the brain as well as primary malignant fibrous histiocytomas of the lung are very unusual tumors. The authors report a case of a 52-year-old man who presented with neurological symptoms due to cerebral metastasis of a malignant fibrous histiocytoma of the lung and provide a review of the literature on the subject.

Elementary motor perseveration in early diagnosis of progressive supranuclear palsy.

Three patients with progressive supranuclear palsy (PSP) with different symptoms at onset presented intense elementary motor perseveration before the appearance of the distinctive features of the illness. In elementary motor perseveration once an element of a movement has begun it is no longer inhibited at the right time and continues unchecked. Perseverations were observed in these patients during tests for dysdiadochokinesia, for reproduction of rhythmic structures and during the drawing of simple geometric shapes. Though this sign has not yet been described in PSP it is possible that an adequate search for its occurrence may show it to be an important sign for early diagnosis and an element for the clinical characterization of PSP.

[Clinical subtypes of frontotemporal dementia]. / Subtipos clínicos da demência frontotemporal.

Three distinctive clinical presentations can occur in frontotemporal dementia (FTD): disinhibited, apathetic and stereotypic subtypes. Each one shows a specific pattern of clinical, neuropsychological and neuroimaging findings, besides manifesting the core features of this form of dementia. We report three clinical cases, each one an example of a subtype of FTD, that were evaluated by neuropsychological and neuroimaging methods. Even the reported cases being a prototype of a specific subgroup, they can share some features with the others subtypes. According to this, patients with predominantly disinhibited or stereotypic behavior can also show apathy, in much the same way as predominantly apathetic or disinhibited patients can manifest stereotypic ritualistic behavior. The final stage of FTD is generally dominated by apathetic behavior.

[High-dose intravenous penicillin therapy in neurosyphilis: study of 62 cases. II. Evaluation of cerebrospinal fluid]. / Penicilinoterapia intravenosa em altas doses na neurossífilis: Estudo de 62 casos. II. Avaliação do líqüido cefalorraqueano.

Sixty-two patients with symptomatic neurosyphilis were treated with 20 or 24 megaunits of intravenous penicillin G daily for 15 to 30 days. The mean follow-up time after the treatment was 30 months. Forty-one patients had pleocytosis in the CSF before treatment. Six months and twelve or more months later, abnormal cell count was observed in 4 (9.8%) and in 3 patients (7.3%), respectively. The CSF protein level and the titers of Wassermann reaction in the CSF decreased slowly after treatment. The gammaglobulin concentration of the CSF and the immunoglobulin production inside the blood-brain barrier were still increased beyond the first year after treatment. The results of the treatment of these patients with high doses of intravenous penicillin G were not different from the results verified with lesser doses of intramuscular penicillin that were reported in the literature.

[Intravenous penicillin therapy in high doses in neurosyphilis: study of 62 cases. I. Clinical evaluation]. / Penicilinoterapia intravenosa em altas doses na neurossífilis: estudo de 62 casos. I. Avaliação clínica.

Sixty-two patients with symptomatic neurosyphilis were treated with 20 or 24 megaunits of intravenous penicillin G daily for 15 to 30 days. The mean follow-up time after the treatment was 30 months. Thirteen patients developed new neurological signs after the treatment. Their diagnosis were: general paresis (9), taboparesis (2), tabes dorsalis (1) and meningovascular neurosyphilis (1). After the treatment, thirty-six patients (58.1%) improved, 22 patients (35.5%) were unchanged and 4 patients (6.4%) deteriorated on clinical grounds. In two patients there was a progression to other forms of neurosyphilis. The results of the treatment of these patients with high doses of intravenous penicillin G were not different from the results verified with classical intramuscular penicillin that were reported in the literature, from the clinical standpoint.

[Neuropsychological semiology]. / Semiologia neuropsicológica.

The authors present a version of the Luria's neuropsychological investigation from an initial battery comprising all the Luria's items, and according to Christensen. It is not an standardized procedure but the investigation of each area of the brain that can be regarded as a supplement to classical neurology. Each of the areas makes a highly specific contribution to ensure the operation of the functional system.

[Arachnoid cyst and pseudotumor cerebri: case report]. / Cisto de aracnóide e pseudotumor cerebral.

Report on a 12 years old patient with an arachnoid cyst of posterior cranial fossa and pseudotumor cerebri. This patient is a shunt dependent of his cyst-peritoneal shunt. This association and evolution of this pacient suggest a common and specifical pathogenic mechanism of these two pathologies based in a disturbance of the cerebral fluid circulation.

[Which patients does the neurologist assist? Basis for a curriculum in neurology]. / Que pacientes atende um neurologista? Alicerce de um currículo em neurologia.

OBJECTIVE: To present the most frequent diagnosis of patients referred to a neurologist and to discuss the importance of this finding for the definition of the curriculum in Neurology. BACKGROUND: The development of subspecialties of Neurology is interfering in the definition of what should be taught to train a physician or a neurologist. The knowledge of which are the most common neurological diseases may contribute to construct these curricula. METHOD: The initial diagnosis in 1815 outpatients referred to the neurologic service of an university-affiliated public hospital in São Paulo, Brazil, were analyzed. RESULTS: The most common diagnosis, in decreasing order of frequency were: headache, epilepsy, mental disorders, cerebrovascular disease, head injury, polyneuropathy, vestibular syndrome, spastic crural paraparesis, extrapyramidal syndrome, dementia, intracranial hypertension and facial palsy. CONCLUSION: The importance of the subspecialties in the curriculum should be related to the frequency of the neurologic diseases in the community.

Encoding process in delayed recall impairment and rate of forgetting in Alzheimer's disease.

OBJECTIVE: To assess the role of impaired encoding in learning and in delayed recall disturbances, and to evaluate the rate of forgetting in AD. METHOD: Fifteen AD patients with mild or moderate dementia and 15 normal matched controls were assessed with the Buschke Selective Reminding Test. Delayed recall was evaluated after 30 minutes and after 24 hours. RESULTS: AD patients had a poorer performance across the six trials of the learning phase as well as in both delayed recall evaluations, with no difference between recall at 30 minutes and at 24 hours. CONCLUSION: Performance in the learning phase was as specific and almost as sensitive as the performance in delayed recall for AD diagnosis. Encoding impairment was responsible for poorer learning and rapid displacement of previous learned material in the AD group. Finally, we did not find a higher rate of forgetting in AD patients.