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.

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.

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.

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.

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.

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.

Does EEG montage influence Alzheimer's disease electroclinic diagnosis?

There is not a specific Alzheimer's disease (AD) diagnostic test. AD diagnosis relies on clinical history, neuropsychological, and laboratory tests, neuroimaging and electroencephalography. Therefore, new approaches are necessary to enable earlier and more accurate diagnosis and to measure treatment results. Quantitative EEG (qEEG) can be used as a diagnostic tool in selected cases. The aim of this study was to answer if distinct electrode montages have different sensitivity when differentiating controls from AD patients. We analyzed EEG spectral peaks (delta, theta, alpha, beta, and gamma bands), and we compared references (Biauricular, Longitudinal bipolar, Crossed bipolar, Counterpart bipolar, and Cz reference). Support Vector Machines and Logistic Regression classifiers showed Counterpart bipolar montage as the most sensitive electrode combination. Our results suggest that Counterpart bipolar montage is the best choice to study EEG spectral peaks of controls versus AD.

A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.

A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.

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.

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.

Spelling tasks and Alzheimer's disease staging.

Reading, writing and oral spelling were evaluated in 30 normal elderly individuals and 28 patients with probable Alzheimer's disease (AD). Significant differences between control and AD groups were found in all tasks. Oral spelling was the most impaired function in AD and the only one which differentiated mild and moderate dementia cases. This task is very sensitive to the disease's effects on working memory and may be included in batteries aimed at staging AD.

Incidence of dementia in a community-dwelling Brazilian population.

The authors report the incidence of dementia in a community-dwelling Brazilian population. In 1997, 1656 individuals aged 65 years or more, the majority being of very low educational level, were screened at their homes in Catanduva, Brazil, and dementia was diagnosed in 118 cases. The remaining 1538 individuals were rescreened 3.25 years later applying a health questionnaire, the Mini-Mental State Examination (MMSE) and the Pfeffer Functional Activities Questionnaire (PFAQ). According to PFAQ and MMSE scores, selected subjects were submitted to clinical, neurologic, and cognitive evaluations. The subjects diagnosed with dementia underwent laboratory tests and brain computed tomography. A total of 1119 individuals were rescreened and 50 incident cases of dementia (28 with Alzheimer disease [AD]) were identified. The incidence rate of dementia was 13.8 and of AD was 7.7 per 1000 person-years for individuals aged 65 years or older. The incidence rates of dementia almost doubled with every 5 years of age. There was no difference according to gender, but women had a higher incidence of dementia, predominantly AD, in very old age. There was a trend for higher incidence of dementia in illiterates (p = 0.07), but multivariate analysis disclosed significant association only between age and higher incidence of dementia. The incidence rates of dementia in this Brazilian community are comparable to those reported in Western and Asian studies.

14-3-3 protein in the CSF of patients with rapidly progressive dementia.

BACKGROUND: The presence of 14-3-3 protein in the CSF has been described to have high sensitivity and specificity for Creutzfeldt-Jakob disease (CJD). OBJECTIVE: To relate 14-3-3 protein in the CSF with the clinical diagnoses of diseases causing rapidly progressive dementia. METHODS: The authors studied 46 patients with rapidly progressive dementia that was classified into three diagnostic groups: definitive or probable CJD, possible CJD, and other diagnoses. The definitive or probable CJD group comprised 17 patients (3 definitive sporadic, 1 probable iatrogenic, 3 familial, and 10 probable sporadic CJD cases), the possible CJD group was composed of 7 patients, and the group with other diagnoses had 22 patients. Detection of the 14-3-3 protein was done by the immunoblotting method. RESULTS: In the definitive or probable CJD group, the test for 14-3-3 protein in CSF was positive in 14 (82%) cases, whereas 3 patients (1 probable sporadic and 2 familial cases) had negative results. CSF was positive for 14-3-3 protein in three of seven cases with possible CJD (42%). In the group with other diagnoses, three individuals had false-positive results (13%). Their diagnoses were definitive Alzheimer's disease, hypercalcemia, and multiple intracerebral hemorrhages. CONCLUSIONS: The detection of 14-3-3 protein in CSF is a useful in vivo diagnostic test for CJD and, when used in the appropriate clinical context, shows a good correlation to CJD. The presence of the 14-3-3 protein in the CSF reinforces the CJD clinical diagnosis but may not be able to differentiate CJD from other causes of rapidly progressive dementia in everyday clinical practice.

Familial Creutzfeldt-Jakob disease associated with a point mutation at codon 210 of the prion protein gene.

Creutzfeldt-Jakob disease (CJD), the most known human prion disease, is usually sporadic but approximately 15% of the cases are familial. To date, seven CJD cases with codon 210 mutation (GTT to ATT) have been reported in the literature. We describe a case of a 57 year-old woman who presented gait disturbances and rapidly progressive dementia, leading to death four months after onset. Electroencephalogram revealed periodic activity, diffusion-weighted magnetic resonance imaging showed hypersignal in basal ganglia, and test for 14-3-3 protein was strongly positive in the CSF. The complete prion protein gene coding region was sequenced after PCR amplification, showing a point mutation in codon 210. This is the first case of CJD with codon 210 mutation diagnosed in Brazil. We emphasize the role of genetic search for prion protein gene mutation, even in patients presenting clinical features resembling sporadic CJD.

Primary progressive aphasia: analisys of 16 cases.

Primary progressive aphasia (PPA) is an intriguing syndrome, showing some peculiar aspects that differentiate it from classical aphasic pictures caused by focal cerebral lesions or dementia. The slow and progressive deterioration of language occurring in these cases provides an interesting model to better understand the mechanisms involved in the linguistic process. We describe clinical and neuroimaging aspects found in 16 cases of PPA. Our patients underwent language and neuropsychological evaluation, magnetic resonance imaging (MRI) and single photon emission computerized tomography (SPECT). We observed a clear distinction in oral expression patterns; patients were classified as fluent and nonfluent. Anomia was the earliest and most evident symptom in both groups. Neuroimaging pointed to SPECT as a valuable instrument in guiding the differential diagnosis, as well as in making useful clinical and anatomical correlations. This report and a comparison to literature are an attempt to contribute to a better understanding of PPA.

Involuntary hand levitation associated with parietal damage: another alien hand syndrome.

The alien hand syndrome (AHS) usually consists of an autonomous motor activity perceived as an involuntary and purposeful movement, with a feeling of foreignness of the involved limb, commonly associated with a failure to recognise ownership of the limb in the absence of visual clues. It has been described in association to lesions of the frontal lobes and corpus callosum. However, parietal damage can promote an involuntary, but purposeless, hand levitation, which, sometimes, resembles AHS. In the present study, four patients (cortico-basal ganglionic degeneration - n=2; Alzheimer's disease - n=1 and parietal stroke - n=1) who developed alien hand motor behaviour and whose CT, MRI and/or SPECT have disclosed a major contralateral parietal damage or dysfunction are described. These results reinforce the idea that parietal lobe lesions may also play a role in some patients with purposeless involuntary limb levitation, which is different from the classic forms of AHS.

[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.