Re-investigating the effects of chronic smoking on the pathology of alcohol-related human brain damage.

Both pathological and neuroimaging studies have shown that chronic alcohol abuse causes generalized white matter, but limited gray matter, volume loss. Recent neuroimaging studies suggest that tobacco smoking also causes brain atrophy in both alcoholics and neurologically normal individuals. However, a recent pathological study, employing a manual technique to determine regional volumes, found no significant effects of smoking on either global or selected regional gray matter volumes in smokers or smoking alcoholics. Here a high-resolution computerized method was employed in the same cohort to evaluate four regions where neuroimaging studies have found atrophy in smokers and alcoholics: insula, thalamus, prefrontal cortex, and anterior cingulate cortex. Brain images from 44 cases comprising 16 non-smoking controls, nine smoking controls, eight non-smoking alcoholics, and 11 smoking alcoholics were quantified. No significant differences between the groups were found, although the alcoholic groups tended to have smaller volumes in most regions. Furthermore, there were no smoking or interactive effects, and no correlation between gray matter volumes and either tobacco pack-years or lifetime alcohol consumption. These results do not support the hypotheses that tobacco smoking causes gray matter loss or that smoking potentiates gray matter atrophy in chronic alcoholics.

Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation.

Cortical grey matter volume deficits and neuro-inflammation exist in patients with schizophrenia, although it is not clear whether elevated cytokines contribute to the cortical volume reduction. We quantified cortical and regional brain volumes in fixed postmortem brains from people with schizophrenia and matched controls using stereology. Interleukin (IL)-6, IL-1ß, IL-8 and SERPINA3 messenger RNAs (mRNAs) were quantified in the contralateral fresh frozen orbitofrontal cortex. We found a small, but significant reduction in cortical grey matter (1.3%; F(1,85)=4.478, P=0.037) and superior frontal gyrus (6.5%; F(1,80)=5.700, P=0.019) volumes in individuals with schizophrenia compared with controls. Significantly reduced cortical grey matter (9.2%; F(1,24)=8.272, P=0.008) and superior frontal gyrus (13.9%; F(1,20)=5.374, P=0.031) volumes were found in cases with schizophrenia and 'high inflammation' status relative to schizophrenia cases with 'low inflammation' status in the prefrontal cortex. The expression of inflammatory mRNAs in the orbitofrontal cortex was significantly correlated with those in dorsolateral prefrontal cortex (all r>0.417, all P<0.022), except for IL-8. Moreover, average daily and lifetime antipsychotic intake negatively correlated with cortical grey matter and superior frontal gyrus volumes (all r<-0.362, all P<0.05). The results suggest that the reduction in cortical grey matter volume in people with schizophrenia is exaggerated in those who have high expression of inflammatory cytokines. Further, antipsychotic medication intake does not appear to ameliorate the reduction in brain volume.

Human adult neurogenesis across the ages: An immunohistochemical study.

AIMS: Neurogenesis in the postnatal human brain occurs in two neurogenic niches; the subventricular zone (SVZ) in the wall of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. The extent to which this physiological process continues into adulthood is an area of ongoing research. This study aimed to characterize markers of cell proliferation and assess the efficacy of antibodies used to identify neurogenesis in both neurogenic niches of the human brain. METHODS: Cell proliferation and neurogenesis were simultaneously examined in the SVZ and SGZ of 23 individuals aged 0.2-59 years, using immunohistochemistry and immunofluorescence in combination with unbiased stereology. RESULTS: There was a marked decline in proliferating cells in both neurogenic niches in early infancy with levels reaching those seen in the adjacent parenchyma by 4 and 1 year of age, in the SVZ and SGZ, respectively. Furthermore, the phenotype of these proliferating cells in both niches changed with age. In infants, proliferating cells co-expressed neural progenitor (epidermal growth factor receptor), immature neuronal (doublecortin and beta III tubulin) and oligodendrocytic (Olig2) markers. However, after 3 years of age, microglia were the only proliferating cells found in either niche or in the adjacent parenchyma. CONCLUSIONS: This study demonstrates a marked decline in neurogenesis in both neurogenic niches in early childhood, and that the sparse proliferating cells in the adult brain are largely microglia.

The effects of chronic smoking on the pathology of alcohol-related brain damage.

Both pathological and neuroimaging studies demonstrate that chronic alcohol abuse causes brain atrophy with widespread white matter loss limited gray matter loss. Recent neuroimaging studies suggest that tobacco smoking also causes brain atrophy in both alcoholics and neurologically normal individuals; however, this has not been confirmed pathologically. In this study, the effects of smoking and the potential additive effects of concomitant alcohol and tobacco consumption were investigated in autopsied human brains. A total of 44 cases and controls were divided into four groups: 16 non-smoking controls, nine smoking controls, eight non-smoking alcoholics, and 11 smoking alcoholics. The volumes of 26 gray and white matter regions were measured using an established point-counting technique. The results showed trends for widespread white matter loss in alcoholics (p < 0.007) but no effect on gray matter regions. In contrast, smoking alone had no effect on brain atrophy and the combination of smoking and alcohol showed no additional effect. Neuronal density was analyzed as a more sensitive assay of gray matter integrity. Similar to the volumetric analysis, there was a reduction in neurons (29%) in the prefrontal cortex of alcoholics, albeit this was only a trend when adjusted for potential confounders (p < 0.06). There were no smoking or combinatorial effects on neuronal density in any of the three regions examined. These results do not support the hypothesis that smoking exacerbates alcohol-related brain damage. The trends here support previous studies that alcohol-related brain damage is characterized by focal neuronal loss and generalized white matter atrophy. These disparate effects suggest that two different pathogenic mechanisms may be operating in the alcoholic brain. Future studies using ultrastructural or molecular techniques will be required to determine if smoking has more subtle effects on the brain and how chronic alcohol consumption leads to widespread white matter loss.

The NSW brain tissue resource centre: Banking for alcohol and major neuropsychiatric disorders research.

The New South Wales Brain Tissue Resource Centre (NSWBTRC) at the University of Sydney (Australia) is an established human brain bank providing tissue to the neuroscience research community for investigations on alcohol-related brain damage and major psychiatric illnesses such as schizophrenia. The NSWBTRC relies on wide community engagement to encourage those with and without neuropsychiatric illness to consent to donation through its allied research programs. The subsequent provision of high-quality samples relies on standardized operational protocols, associated clinical data, quality control measures, integrated information systems, robust infrastructure, and governance. These processes are continually augmented to complement the changes in internal and external governance as well as the complexity and diversity of advanced investigation techniques. This report provides an overview of the dynamic process of brain banking and discusses the challenges of meeting the future needs of researchers, including synchronicity with other disease-focus collections.

The effects of chronic alcoholism on cell proliferation in the human brain.

Neurogenesis continues in the human subventricular zone and to a lesser extent in the hippocampal subgranular zone throughout life. Subventricular zone-derived neuroblasts migrate to the olfactory bulb where survivors become integrated as interneurons and are postulated to contribute to odor discrimination. Adult neurogenesis is dysregulated in many neurological, neurovascular and neurodegenerative diseases. Alcohol abuse can result in a neurodegenerative condition called alcohol-related brain damage. Alcohol-related brain damage manifests clinically as cognitive dysfunction and the loss of smell sensation (hyposmia) and pathologically as generalized white matter atrophy and focal neuronal loss. The exact mechanism linking chronic alcohol intoxication with alcohol-related brain damage remains largely unknown but rodent models suggest that decreased neurogenesis is an important component. We investigated this idea by comparing proliferative events in the subventricular zone and olfactory bulb of a well-characterized cohort of 15 chronic alcoholics and 16 age-matched controls. In contrast to the findings in animal models there was no difference in the number of proliferative cell nuclear antigen-positive cells in the subventricular zone of alcoholics (mean±SD=28.7±20.0) and controls (27.6±18.9, p=1.0). There were also no differences in either the total (p=0.89) or proliferative cells (p=0.98) in the granular cell layer of the olfactory bulb. Our findings show that chronic alcohol consumption does not affect cell proliferation in the human SVZ or olfactory bulb. In fact only microglial proliferation could be demonstrated in the latter. Therefore neurogenic deficits are unlikely to contribute to hyposmia in chronic alcoholics.

Clinical phenotypes in autopsy-confirmed Pick disease.

BACKGROUND: Neuropathology of frontotemporal lobar degeneration is variable and relationship between the pathology and the clinical presentation remains uncertain. Abnormal deposits of hyperphosphorylated and ubiquitinated tau protein are present in 30% of cases, which include the classic presentation of Pick disease with argyrophilic, intraneuronal inclusions known as Pick bodies. This study aimed to improve sensitivity of clinicopathologic relations in cases with neuropathologically confirmed Pick disease and to identify clinical symptoms and signs predictive of disease progression. METHODS: This was a retrospective analysis of 21 cases with a pathologic diagnosis of Pick disease and sufficient clinical information to establish early presenting clinical features from 2 specialist centers, representing 70% of all cases of Pick disease identified between 1998 and 2007 in these centers. RESULTS: At presentation, 13/21 cases (62%) were clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 8/21 (38%) with language variant frontotemporal dementia (lvFTD) including 2 with mixed syndromes. Patients with bvFTD died on average 5 years earlier than those with lvFTD (7 years vs 12 years after disease onset). Pathologically, fewer Pick bodies were present in the frontal and inferior temporal cortices of bvFTD than lvFTD cases. In contrast, both groups showed decreased neuronal density in the dentate gyrus with increasing disease duration. CONCLUSIONS: The pathologic course of the disease in FTLD cases with Pick bodies is not uniform and disease duration can be estimated based on early clinical features. These findings have relevance as treatment options, which are likely to be pathology specific, are developed.

White matter loss in healthy ageing: a postmortem analysis.

Age-related brain changes are widely documented. Because of differences in measurement methods and case selection, the reported effects of age on regional grey and white matter brain volumes, however, are much more pronounced and widespread in neuroimaging than in postmortem studies. Consequently, the magnitude of the effect that is specific to chronological age remains unresolved. We present postmortem volume measurements for 26 cortical, subcortical and white matter regions, in 24 human brains aged 46-92 years, free of neuropathological abnormalities. Significant age-related loss was observed in anterior and posterior white matter but not in total grey matter volumes. Further analyses on five cortical subregions previously reported to exhibit large age-related loss on MRI yielded negative results. These analyses demonstrate smaller changes with age than those reported in imaging studies. Although this discrepancy between postmortem and imaging studies may partly be explained by the increase in noise of the neuroimaging data with age, our results suggest that healthy brain ageing is a process affecting predominantly white matter not grey matter.

Ubiquitin-positive inclusions and progression of pathology in frontotemporal dementia and motor neurone disease identifies a group with mainly early pathology.

Frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions has been a topic of major interest in recent years, with this group now accounting for the majority of tau-negative cases of frontotemporal degeneration. The severity of neurodegeneration in FTLD is dependent on the stage of disease and is substantial even in the earliest stages. Elucidating the pathogenesis of FTLD requires evaluation of changes during the earliest possible stage of disease. However, the long survival of most frontotemporal dementia cases means that cases with early neuropathology are not frequently encountered. Cases of FTLD with the shortest survival are those with coexisting motor neurone disease (FTLD + MND), making these the ideal group for studying early FTLD pathology. It is not clear, however, what the pathological contribution of MND is in these cases. This study evaluates the pathology of 20 cases of FTLD (11 with no clinical signs of MND and nine with FTLD + MND) as well as 10 cases of MND without dementia. Our findings indicate that the deposition of ubiquitin does not play a key role in the neurodegenerative process in FTLD, and that the severity of neurodegeneration in FTLD is similar in cases with and without clinical MND.

Predicting memory performance in normal ageing using different measures of hippocampal size.

A number of different methods have been employed to correct hippocampal volumes for individual variation in head size. Researchers have previously used qualitative visual inspection to gauge hippocampal atrophy. The purpose of this study was to determine the best measure(s) of hippocampal size for predicting memory functioning in 102 community-dwelling individuals over 80 years of age. Hippocampal size was estimated using magnetic resonance imaging (MRI) volumetry and qualitative visual assessment. Right and left hippocampal volumes were adjusted by three different estimates of head size: total intracranial volume (TICV), whole-brain volume including ventricles (WB+V) and a more refined measure of whole-brain volume with ventricles extracted (WB). We compared the relative efficacy of these three volumetric adjustment methods and visual ratings of hippocampal size in predicting memory performance using linear regression. All four measures of hippocampal size were significant predictors of memory performance. TICV-adjusted volumes performed most poorly in accounting for variance in memory scores. Hippocampal volumes adjusted by either measure of whole-brain volume performed equally well, although qualitative visual ratings of the hippocampus were at least as effective as the volumetric measures in predicting memory performance in community-dwelling individuals in the ninth or tenth decade of life.

Histocompatibility antigens, aspirin use and cognitive performance in non-demented elderly subjects.

HLA genotype and anti-inflammatory drug use have independently been associated with a lower risk of Alzheimer's disease (AD). We recently reported a negative association between aspirin use and AD. To investigate this further, we performed a cross-sectional study to investigate cognitive performance in 151 non-demented individuals in relation to HLA-DRB1 genotype and aspirin use. Aspirin and HLA-DRB1*01 were positive predictors of performance on logical memory (aspirin, p=0.04) and verbal fluency tests (HLA-DRB1*01, p=0.018), respectively. HLA-DRB1*05 had a negative impact on the Boston naming test (p=0.002). Our results suggest that aspirin use and inflammatory genotype may influence cognition in non-demented subjects.

Identifying severely atrophic cortical subregions in Alzheimer's disease.

The present study analyses the pattern of atrophy in anatomically discrete brain regions in prospectively-studied pathologically-confirmed patients with Alzheimer's disease (AD) and controls. Standard volumetric measurements were made of the entire cortex subdivided into 23 anatomical regions. Analyses determined regions of significant atrophy in AD and differences between the severity and rates of atrophy. Two levels of severity were found. Atrophy concentrated in medial temporal lobe structures as well as in inferior temporal and superior and middle frontal cortices. The degree of atrophy in these regions related to disease duration, consistent with an early and sustained disease process. The rate of atrophy was significantly greater for the fusiform gyrus. The inferior frontal lobes were entirely spared at all AD stages, while atrophy of other cortical regions was less marked and not related to disease duration, suggesting late involvement. Our findings show that the fusiform gyrus is particularly affected by AD, and suggest two levels of atrophy that correspond with published neurofibrillary tangle (most atrophic) and senile plaque (less atrophic) densities.

Staging disease severity in pathologically confirmed cases of frontotemporal dementia.

OBJECTIVE: To devise a staging scheme for addressing the severity of atrophy in patients with pathologically proven frontotemporal dementia (FTD) and determine any relationship with clinical indices. METHODS: Twenty-four cases with clinical and pathologic features of FTD were selected using standard inclusion and exclusion criteria from 125 dementia cases collected in Sydney, Australia, over an 8.5-year period. Patterns of gross atrophy were determined in two coronal brain slices. Reproducibility of a four-stage severity scheme was tested. Nonparametric statistics were used to determine relationships between the stage of atrophy and clinical indices (age at death, duration from diagnosis, and clinical severity at death). RESULTS: The FTD cases studied could be reliably grouped (kappa = 0.97) into four progressively severe stages of global atrophy. Initial mild atrophy occurred in the orbital and superior medial frontal cortices and hippocampus (stage 1), progressed to involve the other anterior frontal regions, temporal cortices, and basal ganglia (stage 2), then involved all remaining tissue in these coronal slices (stage 3), until very marked atrophy was observed in all areas (stage 4). These stages correlated with disease duration and clinical dementia severity, lending validity to the progressive nature of the staging scheme. CONCLUSIONS: The authors have identified a reproducible staging system for the severity of gross atrophy in cases of FTD. This staging scheme provides the required framework to compare different research indices and determine correlates relating to time and disease progression in FTD-information necessary to determine core disease processes and etiologic factors.

Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss.

BACKGROUND: Alzheimer's disease (AD) is characterised by functional impairment, cerebral atrophy, and degeneration of specific neuronal populations, especially pyramidal neurones of the cerebral cortex and hippocampal formation. Although patients with subcortical vascular dementia have been shown to have similar metabolic and volumetric deficits to those with AD, the underlying pathogenesis of these changes is poorly understood. OBJECTIVE: To determine whether pyramidal cell loss occurs in small vessel disease (SVD) dementia by quantifying hippocampal volume and CA1 neurone number. METHODS: Fifty four prospectively studied patients with dementia were screened, and four patients fulfilling criteria for SVD with no other significant neuropathological abnormality were identified. These were compared with five patients fulfilling criteria for AD and seven controls matched for age and sex. The hippocampal formation was serially sectioned, and the number of CA1 pyramidal neurones estimated using the optical dissector technique. Analysis of variance was used to evaluate group differences. RESULTS: Patients in both the AD and SVD groups showed a substantial loss of pyramidal neurones from the CA1 region. The pattern of hippocampal atrophy and the degree of CA1 neuronal loss were similar in the two dementia groups. CONCLUSIONS: These findings support recent in vivo studies showing similar metabolic deficits and atrophy in AD and subcortical vascular dementia. In addition, they provide evidence that the underlying cause of these abnormalities is a similar loss of neurones. Whereas the cause of the neuronal loss in AD is related to the deposition of abnormal proteins, the cause in SVD is unknown. In the absence of other pathologies, damage to cerebral microvasculature should be considered a likely candidate.

Alzheimer's disease: its diagnosis and pathogenesis.

A hypothesis has been presented that links many of the identified and putative risk factors for AD and suggests a mechanism for their action. Crawford (1996, 1998) proposes an association between AD and cerebral blood flow (CBF) by citing evidence that many of the factors that are linked with an increased risk of AD also decrease CBF (e.g., old age, depression, underactivity, head trauma). Similarly, it is suggested factors that increase CBF are associated with a decreased risk of AD (e.g., education, exercise, smoking, NSAIDs). Although the authors acknowledge that reduced CBF is not sufficient to cause AD, the reported positive and negative associations provide tantalizing evidence for a common mode of action for many of the equivocal risk factors reported to date. This hypothesis is also consistent with other data that links microvascular damage and impaired blood flow (de la Torre, 1997, 2000) and low education with increased cerebrovascular disease (Del Ser et al., 1999). Gaining a better understanding of the interaction between AD and vascular disease is of great importance. Not only will it provide insights into the pathogenesis of AD, but it may also provide us with a rare opportunity for the treatment and possible prevention of AD. A great many risk factors for vascular disease have been identified and intervention programs have successfully reduced the incidence of heart disease and stroke. The potential exists to provide the same level of success with AD.

Variable phenotype of Alzheimer's disease with spastic paraparesis.

A variant form of Alzheimer's disease (AD), in which spastic paraparesis (SP) precedes dementia, is characterised by large, noncored, weakly neuritic Abeta-amyloid plaques resembling cotton wool balls and is caused by genomic deletion of presenilin 1 exon 9. A pedigree with a 5.9 kb exon 9 deletion shows a phenotypic spectrum including subjects with typical AD or with SP and numerous cotton wool plaques. In SP subjects, dementia onset is delayed and modified. This phenotypic variation suggests that modifying factors are associated with exon 9 deletions.

Effect of anti-inflammatory medications on neuropathological findings in Alzheimer disease.

BACKGROUND: There has been no analysis of brain tissue from longitudinally observed, cognitively tested patients to validate whether anti-inflammatory medications protect against the pathological changes of Alzheimer disease. OBJECTIVE: To investigate the role of anti-inflammatory medications in alleviating the pathological features of Alzheimer disease. DESIGN AND MAIN OUTCOME MEASURES: A 5-year postmortem tissue collection was performed after a case-control study of Alzheimer disease (approximately 90 [30%] of patients died during follow-up, of whom consent for autopsy was obtained in 44 [50%]). Cases were selected on the basis of (1) adequate clinical histories of nonsteroidal anti-inflammatory drug usage, (2) no neuropathological findings other than Alzheimer disease, and (3) no generalized sepsis at death. Variables analyzed included neuropsychological test scores and amount of tissue inflammation and Alzheimer-type pathological changes. Two-way analysis of variance was used to determine whether drug usage significantly affected these variables. SETTING: The Centre for Education and Research on Ageing and the Prince of Wales Medical Research Institute, Sydney, Australia. PATIENTS: Twelve patients with Alzheimer disease (5 taking anti-inflammatory drugs) and 10 nondemented controls (3 taking anti-inflammatory drugs) were selected (50% of available sample). RESULTS: Of the patients with Alzheimer disease, anti-inflammatory drug users performed better on neuropsychological test scores than did nonusers. However, there were no significant differences in the amount of inflammatory glia, plaques, or tangles in either diagnostic group. CONCLUSION: Long-term anti-inflammatory medications in patients with Alzheimer disease enhanced cognitive performance but did not alleviate the progression of the pathological changes. Arch Neurol. 2000.