José Marcelo Farfel

Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain

The human brain is often considered to be the most cognitively capable among mammalian brains and to be much larger than expected for a mammal of our body size. Although the number of neurons is generally assumed to be a determinant of computational power, and despite the widespread quotes that the human brain contains 100 billion neurons and ten times more glial cells, the absolute number of neurons and glial cells in the human brain remains unknown. Here we determine these numbers by using the isotropic fractionator and compare them with the expected values for a human‐sized primate. We find that the adult male human brain contains on average 86.1 ± 8.1 billion NeuN‐positive cells (“neurons”) and 84.6 ± 9.8 billion NeuN‐negative (“nonneuronal”) cells. With only 19% of all neurons located in the cerebral cortex, greater cortical size (representing 82% of total brain mass) in humans compared with other primates does not reflect an increased relative number of cortical neurons. The ratios between glial cells and neurons in the human brain structures are similar to those found in other primates, and their numbers of cells match those expected for a primate of human proportions. These findings challenge the common view that humans stand out from other primates in their brain composition and indicate that, with regard to numbers of neuronal and nonneuronal cells, the human brain is an isometrically scaled‐up primate brain. J. Comp. Neurol. 513:532–541, 2009.

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

Aims: Alzheimers 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 β‐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 midbrains 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 ≥ 1. Results: In all of the BB ≥ 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.

Brain bank of the Brazilian aging brain study group—a milestone reached and more than 1,600 collected brains

IntroductionBrain banking remains a necessity for the study of aging brain processes and related neurodegenerative diseases. In the present paper, we report the methods applied at and the first results of the Brain Bank of the Brazilian Aging Brain Study Group (BBBABSG) which has two main aims: (1) To collect a large number of brains of elderly comprising non-demented subjects and a large spectrum of pathologies related to aging brain processes, (2) To provide quality material to a multidisciplinar research network unraveling multiple aspects of aging brain processes and related neurodegenerative diseases.MethodsThe subjects are selected from the Sao Paulo Autopsy Service. Brain parts are frozen and fixated. CSF, carotids, kidney, heart and blood are also collected and DNA is extracted. The neuropathological examinations are carried out based on accepted criteria, using immunohistochemistry. Functional status are assessed through a collateral source based on a clinical protocol. Protocols are approved by the local ethics committee and a written informed consent form is obtained.ResultsDuring the first 21 months, 1,602 samples were collected and were classified by Clinical Dementia Rating as CDR0: 65.7%; CDR0.5:12.6%, CDR1:8.2%, CDR2:5.4%, and CDR3:8.1%. On average, the cost for the processing each case stood at US

Very low levels of education and cognitive reserve A clinicopathologic study

400. To date, 14 laboratories have been benefited by the BBBABSG.ConclusionThe high percentage of non-demented subjects and the ethnic diversity of this series may be significantly contributive toward aging brain processes and related neurodegenerative diseases understanding since BBBABSG outcomes may provide investigators the answers to some additional questions.

Predictors of in-hospital mortality among older patients

Objective: We conducted a clinicopathologic study in a large population with very low levels of education to determine whether very few years of education could contribute to cognitive reserve and modify the relation of neuropathologic indices to dementia. Methods: In this cross-sectional study, we included 675 individuals 50 years of age or older from the Brazilian Aging Brain Study Group. Cognitive abilities were evaluated through a structured interview with an informant at the time of autopsy, including the Clinical Dementia Rating (CDR) scale. Neuropathologic examinations were performed using immunohistochemistry and following internationally accepted criteria. Multivariate linear regression models were conducted to determine whether the association between cognitive abilities (measured by CDR sum of boxes) and years of education was independent of sociodemographic variables and neuropathologic indices, including neuritic plaques, neurofibrillary tangles, lacunar infarctions, small-vessel disease, and Lewy bodies. In addition, interaction models were used to examine whether education modified the relation between neuropathologic indices and cognition. Results: Mean education was 3.9 ± 3.5 years. Formal education was associated with a lower CDR sum of boxes (β = −0.197; 95% confidence interval −0.343, −0.052; p = 0.008), after adjustment for sociodemographic variables and neuropathologic indices. Furthermore, education modified the relationship of lacunar infarcts with cognitive abilities (p = 0.04). Conclusions: Even a few years of formal education contributes to cognitive reserve.

The human cerebral cortex is neither one nor many: neuronal distribution reveals two quantitatively different zones in the gray matter, three in the white matter, and explains local variations in cortical folding

OBJECTIVE: The objective of this study was to determine predictors of in-hospital mortality among older patients admitted to a geriatric care unit. INTRODUCTION: The growing number of older individuals among hospitalized patients demands a thorough investigation of the factors that contribute to their mortality. METHODS: This was a prospective observational study implemented from February 2004 to October 2007 in a tertiary university hospital. A consecutive sample of 922 patients was evaluated for possible inclusion in this study. Patients hospitalized for palliative care, those who declined to participate, and those with incomplete data were excluded, resulting in a group of 856 patients aged 60 to 104 years. Bivariate and multivariate analyses were performed to determine associations between in-patient mortality and gender, age, length of stay, number of prescribed medications and diagnoses at admission, history of heart failure, neoplastic disease, immobility syndrome, delirium, infectious disease, and laboratory tests at admission (serum albumin and creatinine). RESULTS: The overall mortality rate was 16.4%. The following factors were associated with higher in-hospital mortality: delirium (OR=4.13, CI=2.65–6.44, P<.001), neoplastic disease (OR=3.38, CI=2.11–5.42, P<.001), serum albumin levels at admission <3.3mg/dL (OR=3.23, CI=2.03–5.13, P<.001), serum creatinine levels at admission ≥ 1.3mg/dL (OR=2.39, CI=1.53–3.72, P<.001), history of heart failure (OR=1.97, CI=1.20–3.22, P=.007), immobility (OR=1.84, CI=1.16–2.92, P =.009), and advanced age (OR=1.03, CI=1.01–1.06, P=.019). CONCLUSIONS: This study strengthens the perception of delirium as a mortality predictor among older inpatients. Cancer, immobility, low albumin levels, elevated creatinine levels, history of heart failure and advanced age were also related to higher mortality rates in this population.

Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer's disease.

The human prefrontal cortex has been considered different in several aspects and relatively enlarged compared to the rest of the cortical areas. Here we determine whether the white and gray matter of the prefrontal portion of the human cerebral cortex have similar or different cellular compositions relative to the rest of the cortical regions by applying the Isotropic Fractionator to analyze the distribution of neurons along the entire anteroposterior axis of the cortex, and its relationship with the degree of gyrification, number of neurons under the cortical surface, and other parameters. The prefrontal region shares with the remainder of the cerebral cortex (except for occipital cortex) the same relationship between cortical volume and number of neurons. In contrast, both occipital and prefrontal areas vary from other cortical areas in their connectivity through the white matter, with a systematic reduction of cortical connectivity through the white matter and an increase of the mean axon caliber along the anteroposterior axis. These two parameters explain local differences in the distribution of neurons underneath the cortical surface. We also show that local variations in cortical folding are neither a function of local numbers of neurons nor of cortical thickness, but correlate with properties of the white matter, and are best explained by the folding of the white matter surface. Our results suggest that the human cerebral cortex is divided in two zones (occipital and non-occipital) that differ in how neurons are distributed across their gray matter volume and in three zones (prefrontal, occipital, and non-occipital) that differ in how neurons are connected through the white matter. Thus, the human prefrontal cortex has the largest fraction of neuronal connectivity through the white matter and the smallest average axonal caliber in the white matter within the cortex, although its neuronal composition fits the pattern found for other, non-occipital areas.

Post-Mortem diagnosis of dementia by informant interview

Alzheimer’s disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cell-cycle (Cdk1, Cdk4, Cdk5, Cyclin B1, Cyclin D1, p27Kip1, phospho-Rb and E2F1) through immunohistochemistry and cell death through TUNEL in autopsy hippocampal tissue samples arrayed in a tissue microarray (TMA) composed of three groups: I) “clinical-pathological AD” (CP-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and clinical dementia (CDR≥2, IQCODE>3.8); II) “pathological AD” (P-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and without cognitive impairment (CDR 0, IQCODE<3.2); and III) “normal aging” (N) - subjects without neuropathological AD (Braak≤II and CERAD 0 or A) and with normal cognitive function (CDR 0, IQCODE<3.2). Our results show that high levels of oxidative DNA damage are present in all groups. However, significant reductions in DNA repair and cell-cycle inhibition markers and increases in cell-cycle progression and cell death markers in subjects with CP-AD were detected when compared to both P-AD and N groups, whereas there were no significant differences in the studied markers between P-AD individuals and N subjects. This study indicates that, even in the setting of pathological AD, healthy cognition may be associated with a preserved repair to DNA damage, cell-cycle regulation, and cell death in post-mitotic neurons.

Sexual Dimorphism in the Human Olfactory Bulb: Females Have More Neurons and Glial Cells than Males

The diagnosis of normal cognition or dementia in the Brazilian Brain Bank of the Aging Brain Study Group (BBBABSG) has relied on postmortem interview with an informant. Objectives To ascertain the sensitivity and specificity of postmortem diagnosis based on informant interview compared against the diagnosis established at a memory clinic. Methods A prospective study was conducted at the BBBABSG and at the Reference Center for Cognitive Disorders (RCCD), a specialized memory clinic of the Hospital das Clínicas, University of São Paulo Medical School. Control subjects and cognitively impaired subjects were referred from the Hospital das Clínicas to the RCCD where subjects and their informants were assessed. The same informant was then interviewed at the BBBABSG. Specialists’ panel consensus, in each group, determined the final diagnosis of the case, blind to other center’s diagnosis. Data was compared for frequency of diagnostic equivalence. For this study, the diagnosis established at the RCCD was accepted as the gold standard. Sensitivity and specificity were computed. Results Ninety individuals were included, 45 with dementia and 45 without dementia (26 cognitively normal and 19 cognitively impaired but non-demented). The informant interview at the BBBABSG had a sensitivity of 86.6% and specificity of 84.4% for the diagnosis of dementia, and a sensitivity of 65.3% and specificity of 93.7% for the diagnosis of normal cognition. Conclusions The informant interview used at the BBBABSG has a high specificity and sensitivity for the diagnosis of dementia as well as a high specificity for the diagnosis of normal cognition.

Prevalence of dementia subtypes in a developing country: a clinicopathological study

Sex differences in the human olfactory function reportedly exist for olfactory sensitivity, odorant identification and memory, and tasks in which odors are rated based on psychological features such as familiarity, intensity, pleasantness, and others. Which might be the neural bases for these behavioral differences? The number of cells in olfactory regions, and especially the number of neurons, may represent a more accurate indicator of the neural machinery than volume or weight, but besides gross volume measures of the human olfactory bulb, no systematic study of sex differences in the absolute number of cells has yet been undertaken. In this work, we investigate a possible sexual dimorphism in the olfactory bulb, by quantifying postmortem material from 7 men and 11 women (ages 55–94 years) with the isotropic fractionator, an unbiased and accurate method to estimate absolute cell numbers in brain regions. Female bulbs weighed 0.132 g in average, while male bulbs weighed 0.137 g, a non-significant difference; however, the total number of cells was 16.2 million in females, and 9.2 million in males, a significant difference of 43.2%. The number of neurons in females reached 6.9 million, being no more than 3.5 million in males, a difference of 49.3%. The number of non-neuronal cells also proved higher in women than in men: 9.3 million and 5.7 million, respectively, a significant difference of 38.7%. The same differences remained when corrected for mass. Results demonstrate a sex-related difference in the absolute number of total, neuronal and non-neuronal cells, favoring women by 40–50%. It is conceivable that these differences in quantitative cellularity may have functional impact, albeit difficult to infer how exactly this would be, without knowing the specific circuits cells make. However, the reported advantage of women as compared to men may stimulate future work on sex dimorphism of synaptic microcircuitry in the olfactory bulb.