Study of neuropathological changes and dementia in 100 centenarians in The 90+ Study.

INTRODUCTION: The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. METHODS: We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. RESULTS: A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. DISCUSSION: Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. HIGHLIGHTS: Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

Combined Alzheimer's disease and cerebrovascular staging explains advanced dementia cognition.

INTRODUCTION: The absence of a consensus system for full neuropathological evaluation limits clinicopathological studies and comparability between laboratories. Combined staging for Alzheimer's type and cerebral vascular pathology may allow a better classification of cases for clinical and cognitive correlation. METHODS: Cognitive and postmortem neuropathological data were obtained from 70 brains donated to the Tissue Bank of the Centro de Investigación de Enfermedades Neurológicas (CIEN) Foundation according to recently developed staging schemes for Alzheimer's type and vascular pathology. Subjects belonged to a cohort of institutionalized patients with moderate or severe dementia and a mean follow-up period of 7 years. RESULTS: Cases were classified into three groups: Alzheimer's predominant (64.1%), vascular predominant (6.3%) and mixed pathology (29.6%). Significant differences were observed in Severe Mini-Mental State Examination and verbal fluency between the vascular predominant and the other groups of patients. DISCUSSION: The combination of scales measuring cerebral vascular and Alzheimer's type pathology allowed a classification of patients that reveals differences between groups in premortem cognitive features.

In vivo cortical diffusion imaging relates to Alzheimer's disease neuropathology.

BACKGROUND: There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. METHODS: Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC-the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies-Lewy body disease and TAR DNA-binding protein 43 (TDP-43)-on cortical microstructure was assessed. RESULTS: Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. CONCLUSIONS: Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.

Neuropathological Changes in the Brains of Suicide Killers.

BACKGROUND: Homicide combined with subsequent suicide of the perpetrator is a particular form of interpersonal violence and, at the same time, a manifestation of extreme aggression directed against oneself. Despite the relatively well-described individual acts of homicide and suicide, both in terms of psychopathology and law, acts of homicide and subsequent suicide committed by the same person are not well-studied phenomena. The importance of emotional factors, including the influence of mental state deviations (psychopathology), on this phenomenon, is discussed in the literature, but still there is relatively little data with which to attempt neuropathological assessments of the brains of suicide killers. This paper is dedicated to the issue based on the neuropathological studies performed. METHODS: We analyzed a group of murder-suicides using histochemical and immunohistochemical methods. RESULTS: The results of our research indicate the presence of neurodegenerative changes including multiple deposits of ß-amyloid in the form of senile/amyloid plaques and perivascular diffuse plaques. CONCLUSIONS: Neurodegenerative changes found in the analyzed brains of suicide killers may provide an interesting starting point for a number of analyses. The presence of neurodegenerative changes at such a young age in some murderers may suggest preclinical lesions that affect cognitive functions and are associated with depressed moods.

Neuropathologic correlates of trial-related instruments for Alzheimer's disease.

To advance disease-modifying therapies, it is critical to understand the relationship between the neuropathological changes of Alzheimer's Disease (AD) and the clinical measures used in therapeutic trials. We reviewed neuropathologically proven cases of AD from the National Alzheimer's Coordinating Center (NACC) and examined correlations between neuropathological changes and clinical-trial related instruments collected as part of the Uniform Dataset (UDS). We explored the relationships between neurofibrillary tangles, neuritic plaques, and total pathology burden with immediate and delayed recall, Clinical Dementia Rating-Sum of Boxes, Functional Activity Questionnaire, Neuropsychiatric Inventory Questionnaire, and Mini-Mental State Examination scores. 169 patients in NACC database had appropriate neuropathological and clinical data. All instruments correlated highly with neuritic plaques, Braak staging, and total pathology. Correlation coefficients for the relationships were relatively modest, suggesting that the pathologic burden examined accounts for between 13 and 40% of the variance of each of the instruments assessed. We conclude that there is a strong correlation between clinical trial-related measures and neuropathology identified at autopsy in AD. The amount of variance explained by the pathology is limited and other factors, both disease- and measurement-related, contribute to the variability observed in clinical measurements.

Neuroprotective effect of paeonol on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat.

Diabetic encephalopathy (DE) has been characterized by the impaired cognition and the abnormalities of neurochemistry and neurostructure. The study was conducted to evaluate the neuroprotective effect of paeonol on STZ-induced DE rats. Paeonol of 25, 50, 100mg/kg (p.o.) could decrease the latency time and path length, and enhance significantly the spent time in the target quadrant and platform crossings in Morris water maze test. The treatment with paeonol could also increase significantly Na(+)-K(+)-ATP enzyme and ChAT activities, as well as decreasing significantly AchE activity in hippocampal tissue. Immunohistochemistry and TUNEL staining showed that paeonol could attenuate apoptosis of neurons and caspase 3 expression, improve two neurotrophic factors BDNF and IGF expressions, and also ameliorate Aß deposition in the hippocampus and cerebral cortex. In conclusion, the present study demonstrated diabetic rats treated with paeonol could ameliorate the cognition deficits. These findings indicated paeonol might act as a beneficial agent for the prevention and treatment of DE.

Neuroprotective effect of Liuwei Dihuang decoction on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Liuwei Dihuang decoction (LWDHD) is a well-known prescription of traditional Chinese medicine (TCM) and consists of six crude drugs including Rehmannia glutinosa Libosch. (family: Scrophulariaceae), Cornus officinalis Sieb. (family: Cornaceae), Dioscorea oppositifolia L. (family: Dioscoreaceae), Paoenia ostii (family: Paeoniaceae), Alisma orientale (G. Samuelsson) Juz (family: Alismataceae) and Poria cocos (Schw.) Wolf (family: Polyporaceae). It has been used for the treatment of "Kidney-Yin" deficiency syndrome in clinic in China for a long time. Recent studies found that LWDHD had a potential benefit for the treatment of diabetic complications. The aim of the present study is to investigate the neuroprotective effect of LWDHD on memory and cognition deficits in streptozotocin (STZ)-induced diabetic encephalopathy (DE) rats. MATERIALS AND METHODS: Adult male Sprague Dawley (SD) rats were fed with high-glucose-fat diet for 50 days and then received an intraperitoneal injection of STZ (40 mg/kg) to induce DE model. Morris water maze test was used to evaluate the memory and cognition capability of DE rats. Choline acetyltransferase (ChAT), acetylcholinesterase (AChE), Na(+)-K(+)-ATP enzyme, iNOS and GSH kits were used to determine their activities or content in hippocampus. TUNEL staining, immunohistochemistry and Congo red staining were conducted to evaluate the apoptosis, caspase-3 protein expression, insulin-like growth factors 1 (IGF-1) and brain derived neurophic factor (BDNF) expressions, as well as Aß deposition. RESULTS: The treatment with LWDHD (1 and 2g/kg, p.o., once daily, 30 days) could significantly reduce the escape latency time and path length, and obviously enhance the spent time in the target quadrant and platform crossings in Morris water maze test compared with model group (P<0.05, P<0.01). LWDHD could also significantly decrease the level of fasting blood glucose, increase Na(+)-K(+)-ATP enzyme and ChAT activities, enhance remarkedly GSH level while decrease significantly AChE and iNOS activities in hippocampus (P<0.05, P<0.01). Furthermore, TUNEL staining, Congo red staining and immunohistochemistry showed that LWDHD significantly improved the expressions of IGF-1 and BDNF, attenuated the neural apoptosis, overexpression of caspase-3 and Aß deposition in the hippocampus and cerebral cortex of STZ-induced DE rats (P<0.01). CONCLUSION: Our findings suggested that LWDHD had a neuroprotective effect on DE rats. LWDHD may be of benefit in the treatment of DE.

Neuropathological changes in brain cortex and hippocampus in a rat model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. METHODS: Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and Beta amyloid (ABeta) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 muL of ABeta (1-40) into the hippocampal fissure. RESULTS: In the present study, ABeta (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. ABeta injection CA1 caused ABeta deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. CONCLUSION: We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group.