Evidence for progression in frontal cortical pathology in late-stage Huntington's disease

Atrophy of the cerebral cortex in Huntington's disease is regionally heterogeneous and progressive, involving the entire cerebral mantle in terminal stages. Here, two areas (9 and 46) of the dorsolateral prefrontal cortex were analyzed in 11 late-stage (grades 3 or 4) Huntington's diseased patients and 8 normal control subjects. We used a 3-dimensional cell counting method to assess laminar cell density, number, and width. Reductions in overall cortical thickness in areas 9 (26%) and 46 (23%) were comparable. Area 9 exhibited loss of projection neurons in layers III (16%), V (31%), and VI (37%); these same layers were also reduced in width (25%, 34%, and 46%, respectively). In area 46, reductions in cortical width in layers II (18%) and VI (35%) were not accompanied by neuronal loss. Glial density was increased in deeper layers, reaching significance in layer VI (68%) of area 9 and in layer V (75%) of area 46; glial number was not altered. Thus, area 46 exhibited marked cortical thinning without apparent neuronal degeneration, whereas in area 9 neuronal loss was pronounced, consistent with an advanced phase of cortical pathology. Prominent involvement of corticothalamic neurons is discussed in the context of striatal loop circuitry and a possible pathologic cascade of cortical degeneration.     

Evolution of Alzheimer’s disease-related cytoskeletal changes in the basal nucleus of Meynert

This study examines the evolution of Alzheimer's disease (AD)-related pathology in a subcortical predilection site, the basal nucleus of Meynert (bnM), which is a major source of cortical cholinergic innervation. Brains of 51 autopsy cases were studied using silver techniques and immunostaining for tau-associated neurofibrillary pathology and for amyloid beta protein (Abeta) deposits. All cases are classified according to a procedure permitting differentiation of six stages of AD-related neurofibrillary changes in the cerebral cortex. Initial cytoskeletal abnormalities in the bnM are already noted in stage I of cortical neurofibrillary changes. The gradual development of the neurofibrillary pathology in the bnM parallels the progression of the AD-related stages in the cerebral cortex. A variety of morphologically distinguishable cytoskeletal alterations are observed in large nerve cells which predominate in the bnM. Based on these cellular alterations, a sequence of cytoskeletal deterioration is proposed. Initially, the abnormal tau protein is distributed diffusely throughout the cell body and the neuronal processes. Subsequently, it aggregates to form a neurofibrillary tangle, which appears as a spherical somatic inclusion. The cell processes gradually become fragmented. Finally the parent cell dies, leaving behind an extraneuronal "ghost tangle". With regard to the cortical stages of AD-related neurofibrillary changes, the initial forms of cytoskeletal changes in the bnM predominate in the transentorhinal AD stages (I and II), while "ghost tangles" preferentially occur in the neocortical stages (V and VI). The considerable morphological diversity of cytoskeletal alterations is typical of stages III and IV. These results indicate that individual neurons of the bnM enter the sequence of cytoskeletal deterioration at different times.     

The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia.

BACKGROUND: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development. METHODS: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. RESULTS: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D2 receptor availability in the striatum (n = 14, rho = -.64, p < .01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p < .05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. CONCLUSIONS: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.     

PET measures of benzodiazepine receptors in progressive supranuclear palsy

OBJECTIVE: To evaluate the integrity of neurons containing benzodiazepine receptors in metabolically affected regions of the brain in patients with clinically diagnosed progressive supranuclear palsy (PSP). METHODS: The cerebral distribution of [11C]flumazenil (FMZ), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor, and [18F]fluorodeoxyglucose (FDG), a measure of local cerebral glucose metabolism, was determined with PET in 12 patients with PSP and 10 normal control subjects. Tracer kinetic analysis was applied to quantify data and analysis was performed using three-dimensional stereotactic surface projections and stereotactically determined volumes of interest. RESULTS: There was a global reduction in FMZ binding of 13%, with a reduction in the anterior cingulate gyrus of 20% (p = 0.004), where glucose metabolic rates also showed the greatest reduction. CONCLUSIONS: PSP causes loss of benzodiazepine receptors in the cerebral cortex. Consistent with postmortem studies, the authors did not find significant changes in FMZ binding in subcortical nuclei that exhibit the most pathologic change. This study suggests that both loss of intrinsic neurons containing benzodiazepine receptors and deafferentation of the cerebral cortex from distant brain regions contribute to cerebral cortical hypometabolism in PSP.     

Dementia with Lewy bodies: choline acetyltransferase parallels nucleus basalis pathology

Summary. The biological substrate underlying the reduced cortical choline acetyltransferase (ChAT) in dementia with Lewy bodies (DLB) is incompletely understood. We compared cortical ChAT levels with Lewy body densities and neuronal loss in the nucleus basalis of Meynert (nbM) and cerebral cortex in six DLB, seven Alzheimer's disease (AD), and six control cases. We found greater neuronal loss in the nbM in DLB compared to AD (U = 9.500, p = 0.049). Mean ChAT levels in the cortex were lower in dementia patients than controls (t = 17.500, p = 0.001), and DLB cases had slightly lower ChAT levels than AD cases, but this difference was not significant (t = −0.332, p = 0.746). Overall, cortical ChAT levels correlated inversely with neuronal loss in the nbM (Spearman rank correlation coefficient = −0.53). The correlation between ChAT level and the combined factor of nbM LBs and neuronal loss was −0.59. A similar correlation between ChAT level and the combined factor of nbM neurofibrillary tangles and neuronal loss was −0.72. The correlation between ChAT and the combined factor of nbM LBs and neuronal loss was −0.81 when AD cases were excluded from the analysis. Local cortical pathology was not related to ChAT level. We conclude that neuronal loss and Lewy body formation in the nbM may contribute to the reduction in cortical ChAT in DLB. Received September 1, 1998; accepted November 18, 1998     

A critical review of chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) has been described in the literature as a neurodegenerative disease with: (i) localized neuronal and glial accumulations of phosphorylated tau (p-tau) involving perivascular areas of the cerebral cortex, sulcal depths, and with a preference for neurons within superficial cortical laminae; (ii) multifocal axonal varicosities and axonal loss involving deep cortex and subcortical white matter; (iii) relative absence of beta-amyloid deposits; (iv) TDP-43 immunoreactive inclusions and neurites; and (v) broad and diverse clinical features. Some of the pathological findings reported in the literature may be encountered with age and other neurodegenerative diseases. However, the focality of the p-tau cortical findings in particular, and the regional distribution, are believed to be unique to CTE. The described clinical features in recent cases are very similar to how depression manifests in middle-aged men and with frontotemporal dementia as the disease progresses. It has not been established that the described tau pathology, especially in small amounts, can cause complex changes in behavior such as depression, substance abuse, suicidality, personality changes, or cognitive impairment. Future studies will help determine the extent to which the neuropathology is causally related to the diverse clinical features.     

Cerebellar involvement in progressive supranuclear palsy: A clinicopathological study

The clinical heterogeneity of progressive supranuclear palsy (PSP), which is classified as classic Richardson's syndrome (RS) and PSP‐Parkinsonism (PSP‐P), has been previously discussed. We retrospectively analyzed 22 consecutive Japanese patients with pathologically proven PSP to investigate the clinicopathological heterogeneity. We investigated the clinical features both early in and at any time during the disease course. The pathological severities of neuronal loss with gliosis and tau pathology were also evaluated. On the basis of the clinical features, 10 patients were categorized as having RS, and 8 were categorized as having PSP‐P. Four patients presenting with cerebellar ataxia or cerebral cortical signs were categorized as having unclassifiable PSP. Among them, 3 developed cerebellar ataxia as the initial and principal symptom. Notably, tau‐positive inclusion bodies in Purkinje cells were significantly more frequently observed in the patients with cerebellar ataxia than in those without cerebellar ataxia. All the patients with cerebellar ataxia exhibited more neuronal loss with gliosis and higher densities of coiled bodies in the cerebellar dentate nucleus than those without cerebellar ataxia. This study confirms the wide spectrum of clinicopathological manifestations associated with PSP regardless of different ethnic origin, and demonstrates that PSP patients manifest cerebellar ataxia. © 2009 Movement Disorder Society     

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 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 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 ≥ 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.     

Neuronal metabolic changes in the cortical region after subcortical infarction: a proton MR spectroscopy study

OBJECTIVES: To investigate whether proton magnetic resonance spectroscopy ((1)H MRS) can detect neuronal metabolic changes in the cortical region in patients with cortical dysfunction after subcortical infarction. METHODS: Fifteen patients with subcortical large (diameter>/=20 mm) infarcts were studied; nine patients with cortical dysfunction (group A), and six without (group B). Seven patients with lacunar infarction served as controls. Infarct volume was measured on T2 weighted images with an image analyser. (1)H MRS data were obtained in three regions; high signal intensity area on T2 weighted image, overlying cortex with a normal T2 MRI appearance, and contralateral homologous cortical region. RESULTS: Infarct volume was not different between groups A and B. N-acetylaspartate (NAA)/creatine+phosphocreatine (Cr) ratios in the cortical region overlying subcortical infarcts in group A were significantly lower than those in group B and the control group (p=0.002). The NAA/Cr ratios in the overlying cortex were significantly lower than those in the contralateral normal cortex in group A on the initial (p=0. 015) and follow up (p=0.028) (1)H MRS, but these differences were not found in group B and the control group. CONCLUSIONS: The results support the idea that the cerebral cortex is a responsible location for cortical dysfunction after subcortical infarctions. (1)H MRS can be used as a sensitive method for the detection of a neuronal metabolic damage, which is not demonstrated by conventional MRI.     

Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation

OBJECTIVE: To describe a family with chromosome 2p-linked hereditary spastic paraparesis (HSP) associated with dementia and illustrate the cerebral pathology associated with this disorder. BACKGROUND: HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe, progressive lower limb spasticity. Nongenetic classification relies on characteristics such as mode of inheritance, age at onset, and the presence or absence of additional neurologic features. Several loci have been identified for autosomal dominant pure HSP. The most common form, which links to chromosome 2p (SPG4), has recently been shown to be due to mutations in spastin, the gene encoding a novel AAA-containing protein. RESULTS: The authors report four generations of a British family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p. In addition, a missense mutation has been identified in exon 10 of the spastin gene (A1395G). Dementia was documented clinically in one member of the family, two other affected family members were reported to have had late onset memory loss, and a younger affected individual showed evidence of memory disturbance and learning difficulties. Autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology. There was neuronal depletion and tau-immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells were seen in the limbic and neocortex. The substantia nigra showed Lewy body formation. The pathologic findings are not typical of known tauopathies. CONCLUSIONS: The authors confirm that chromosome 2p-linked HSP can be associated with dementia and that this phenotype may be associated with a specific and unusual cortical pathology.     

Gerstmann-Sträussler syndrome — A variant type: amyloid plaques and Alzheimer's neurofibrillary tangles in cerebral cortex

Summary This report presents a variant of Gerstmann-Sträussler syndrome (GSS). A 53-year-old female had developed slowly progressive dementia and atactic gait since the age of 45. No myoclonic jerks and periodic synchronous discharges were observed throughout the illness. The neuropathological study revealed that many amyloid plaques and widespread Alzheimer's neurofibrillary tangles (NFTs) appeared in the cerebral cortex. Characteristically, the plaques reacted with anti-prion protein and none of them reacted with anti- protein, and they were made of many components, including amyloid cores, macrophages laden with lipid granules and/or degenerated neurites. Neuropil threads were seen mainly in amyloid plaques. Moreover, plaques appeared which were confluent and laminar in arrangement in the fifth and sixth cortical layers and had a close relationship to the neuronal loss. There was no spongiform change in the cerebral cortex or cerebellum. The cerebellum was almost intact except for a few amyloid plaques. Ultrastructurally, some of the plaques simulated kuru plaques and others had many degenerated neurites possessing paired helical filaments and other accumulated organelles. GSS has been proposed to include cases with progressive ataxia, dementia and massive multifocal plaques in the brain with or without cerebral spongiform changes. The case presented here is a very peculiar case of GSS. Recently, similar cases have been reported in some large families, diagnosed as familial Alzheimer's disease. These cases may be a telencephalic form with numerous NFTs of GSS.     

Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia

In clinical medicine, cerebral ischemia is frequently due to a focal, rather than global, insult. The effect of hyperglycemia in focal cerebral ischemia is not well defined. We studied the effect of hyperglycemia on neuropathologic changes in a rabbit model of focal cerebral ischemia. Rabbits were randomized to receive saline (n = 12) or glucose (n = 12) infusions. The left anterior cerebral and left internal carotid arteries were clipped after the infusion began. After 6 hours of occlusion, the area of severe ischemic neuronal damage in the left neocortex and striatum on two standard sections of brain was calculated and expressed as a percentage of the total area of the left cortex or striatum. The mean +/- SEM cortical area of severe ischemic neuronal damage was 22.1 +/- 2.8% in the glucose-treated rabbits and 34.0 +/- 4.6% in the saline-treated rabbits (p less than 0.05). The cortical area of severe ischemic neuronal damage was inversely correlated with plasma glucose concentration at the time of arterial clipping (p less than 0.05). We conclude that hyperglycemia is associated with decreased histologic neuronal injury in this model of focal cerebral ischemia and may be protective when cerebral ischemia occurs from a focal insult.     

Discrete glioneuronal malformative lesions in the foetal and infantile cerebral cortex

Microdysgenesis is a term describing microscopic cortical cytoarchitectural abnormalities. Histologically this change shows an irregular glioneuronal tissue combination forming an abnormal structure of the cortex. The pathological features of this malformation are subtle and less well defined than other more distinctive cortical malformations. The clinical significance of these discrete glioneuronal malformations is controversial. Microscopic dysgenetic changes have been reported in cases with intractable epilepsy but similar changes may be seen in neurologically normal adults. The purpose of our study was the investigation of microdysgenetic lesions in the developing nervous system with regard to normal neuronal migration, differentiation and maturation. The post-mortem routine investigated foetal and infantile brains which were analysed histologically for the presence of discrete cortical malformations. A wide spectrum of cytoarchitectural glioneuronal malformations was found in the investigated material. We observed leptomeningeal glioneuronal heterotopias, subpial bands of heterotopic neurones, nests of ectopic neurones in the first cortical layer, neuronal and glial clusters, small foci with irregularity of laminar structure of the cortex. Microdysgenetic changes arose from an insult occurring in the later stages of cortical development and influencing the normal fate of neuroglial cells. Various types of focal morphological and cytoarchitectonial developmental abnormalities have been associated with behavioural and neuropsychological deficits in older infants.     

Quantitative 1H MR spectroscopic imaging in early Rett syndrome

OBJECTIVE: To determine cerebral regional concentrations of N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cr) in Rett syndrome (RS) using 1H magnetic resonance spectroscopic imaging (MRSI). BACKGROUND: The biochemical defect underlying RS is unknown. Because in vivo MRSI can detect important cerebral metabolites, MRSI has a potential to reveal impairment of regional cerebral metabolism in RS noninvasively. METHODS: High-resolution, multislice 1H MRSI was carried out in 17 girls with RS. The control group consisted of nine healthy children. RESULTS: In patients with RS, average Cho concentration was 12% higher (p < 0.005) and average NAA concentration 11% lower (p < 0.0001) compared with the control group. Regional metabolic differences included significantly lower NAA concentration in the frontal gray and white matter, insula, and hippocampus in RS; no difference in regional Cho and Cr concentrations were found. A 20 to 38% higher Cho:NAA ratio in frontal and parietal gray and white matter, insular gray matter, and hippocampus (p < 0.05) and a 14 to 47% lower NAA:Cr ratio in frontal cortical gray matter, parietal and temporal white matter, insula, and putamen (p < 0.05) were found in subjects with RS compared with controls. Patients with seizures had higher average concentrations of Cho, Cr, and NAA compared with those without seizures (8-19%, p < 0.05). CONCLUSION: Metabolic impairment in RS involves both gray and white matter and particularly involves frontal and parietal lobes and the insular cortex. Loss of NAA most likely reflects reduced neuronal and dendritic tree size; increased Cho concentration may result from gliosis.     

Thalamic form of Creutzfeldt-Jakob disease or fatal insomnia? Report of a sporadic case with normal prion protein genotype

We describe a 68-year-old man with a 53-month history of progressive dementia and clinical features of a progressive supranuclear palsy-like syndrome and dysautonomia. In the late stage of his illness, the patient also developed generalized myoclonic seizures. There was no family history of similar disorders. Histological examination revealed neuronal loss and gliosis with spongiosis in the cerebral cortex. In addition, more severe neuronal loss and gliosis without spongiosis were observed in the thalamus, especially in the anterior ventral and mediodorsal nuclei, and the inferior olivary nucleus. There was also obvious loss of Purkinje cells. Immunohistochemically, no protease-resistant prion protein (PrP^res)-positive structures were demonstrated. However, Western blotting revealed the presence of PrP^res in the cerebral cortex. This patient had a wild type of PrP genotype. We initially considered this to be a case of the thalamic form of Creutzfeldt-Jakob disease (CJD) with a long duration. However, it is noteworthy that essentially similar pathology, albeit with less severe cerebral cortical changes, has also been reported in fatal familial insomnia, a newly identified phenotypically different prion disease with a mutation in the PrP gene. On the basis of clinicopathological features, we eventually felt that this patient was more likely to have been a sporadic case of fatal insomnia (FI) of long duration. The present case appears to draw further attention to the possible relationship between CJD and FI. Received: 18 July 1996 / Revised, accepted: 3 October 1996     

Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia

BACKGROUND: The orbitofrontal cortex is involved in the monitoring of reward and in judgement. Lesion studies and functional neuroimaging investigations implicate this region in affective disorders, and altered neuronal and glial cell composition have been observed in this region in subjects with major depressive disorder (MDD). AIMS: Stereologically based investigation of caudal orbitofrontal cortex (cOFC), in 60 postmortem brains from four groups of 14 subjects each with bipolar disorder (BPD), schizophrenia and MDD. METHODS: Glial cell and neuronal size and density were examined in all subjects using stereological probes such as the nucleator and the optical disector. RESULTS: We found statistical evidence for a neuronal size reduction in BPD in layer 1 (21%, p=0.007) and a trend for a reduction in layer 5 (20%, p=0.05). There was a significant interaction effect of brain hemisphere and group on neuronal size in layer 3 (p=0.001), with evidence for reduced layer 3 neuronal sizes in MDD (30%, p<0.001). We found no evidence for group differences in glial cell size nor for differences in glial or neuronal density. CONCLUSIONS: These findings provide preliminary evidence that neuronal size reduction in cOFC is a component of the pathology of BPD. Overall, the data implicate this cortical region in affective disorders, but provide no evidence for neuronal or glial pathology in this region in schizophrenia.     

Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review

Thirty-two autopsied cases of progressive neuronal degeneration of childhood with liver disease are reviewed. The typical clinical course is intractable seizures and liver failure following a period of developmental delay and failure to thrive in early infancy, but some children first present with seizures. Characteristic changes on the electroencephalogram, loss of visual-evoked potentials, occipital atrophy on computed tomographic scan, and particular changes on liver biopsy may assist diagnosis. Most patients succumb in less than 3 years, but some have a protracted survival into their teens, and very rarely they may present in early adulthood. Liver pathology comprises fatty change, hepatocyte loss, bile duct proliferation, fibrosis, and often cirrhosis. Gradual progression can be followed in sequential biopsies. Macroscopically, the cerebral cortex is variably involved, but usually there is patchy thinning and discoloration, with a striking predilection for the striate cortex. Microscopic changes include spongiosis, neuronal loss, and astrocytosis, which progresses down through the cortical layers. All areas may be affected but the calcarine cortex is usually most affected. Etiology is still obscure, though mitochondrial and slow viral disorders have been postulated.     

Pattern of brain destruction in Parkinson's and Alzheimer's diseases

Summary Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related degenerative disorders of the human brain. Both diseases involve multiple neuronal systems and are the consequences of cytoskeletal abnormalities which gradually develop in only a small number of neuronal types. In AD, susceptible neurons produce neurofibrillary tangles (NFTs) and neuropil threads (NTs), while in PD, they develop Lewy bodies (LBs) and Lewy neurites (LNs). The specific lesional pattern of both illnesses accrues slowly over time and remains remarkably consistent across cases.In AD, six developmental stages can be distinguished on account of the predictable manner in which the neurofibrillary changes spread across the cerebral cortex. The pathologic process commences in the transentorhinal region (clinically silent stages I and II), then proceeds into adjoining cortical and subcortical components of the limbic system (stages III and IV — incipient AD), and eventually extends into association areas of the neocortex (stages V and VI — fully developed AD).During the course of PD, important components of the limbic system undergo specific lesions as well. The predilection sites include the entorhinal region, the CA2-sector of the hippocampal formation, the limbic nuclei of the thalamus, anterior cingulate areas, agranular insular cortex (layer VI), and — within the amygdala — the accessory cortical nucleus, the ventromedial divisions both of the basal and accessory basal nuclei, and the central nucleus. The amygdala not only generates important projections to the prefrental association areas but also exerts influence upon all non-thalamic nuclei which in a non-specific manner project upon the cerebral cortex and upon the nuclei regulating endocrine and autonomie functions. All these amygdala-dependent structures themselves exhibit severe PD-specific lesions. In general, the extranigral destructions are in themselves not sufficient to produce overt intellectual deterioration. Similarly, AD-related pathology up to stage III may be asymptomatic as well. Fully developed PD with concurring incipient AD, however, is likely to cause impaired cognition. Presently available data support the view that the occurrence of additional lesions in the form of AD stage III (or more) destruction is the most common cause of intellectual decline in PD.     

Elevated immunoreactivity for glutamic acid decarboxylase in the rat cerebral cortex following transient middle cerebral artery occlusion

We investigated the expression of glutamic acid decarboxylase (molecular weight 67,000; GAD67) immunohistochemically in the rat cerebral cortex following transient middle cereral artery occlusion (MCAO) capable of producing slowly progressive neuronal damage. An increase in GAD67 immunoreactivity was observed in the cerebral cortex ipsilateral to the ischemic insult, most prominent in lamina IV, 3 to 14 days after MCAO. At this stage, light microscopy showed GAD67-positive puncta to be larger and more strongly immunoreactive in the ipsilateral cortex than those in the contralateral side. The elevated expression of GAD67 in the insulted cortex may reflect part of the adaptive functional changes in GABA transmission with slowly progressive cortical ischemic damage.Supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan     

Somatotopic astrocytic activity in the somatosensory cortex

Astrocytes play a crucial role in maintaining neuronal function and monitoring their activity. According to neuronal activity maps, the body is represented topographically in the somatosensory cortex. In rats, neighboring cortical areas receive forelimb (FL) and hindlimb (HL) sensory inputs. Whether astrocytic activity is also restricted to the cortical area receiving the respective peripheral sensory inputs is not known. Using wide field optical imaging we measured changes in the concentration of astrocytic calcium within the FL and HL sensorimotor cortex in response to peripheral sensory inputs. Mapping the calcium signals upon electrical stimulation of the forepaw and hindpaw we found activity largely restricted to the FL and HL area, respectively. In comparison to neuronal activity the time course of the astrocytic calcium activity was considerably slower. The signal took 6 s to peak after the onset of a 2 Hz and 2 s long electrical stimulation of the hindpaw and 8 s for a 4 s stimulation. The astrocytic signals were delayed relative to cerebral blood flow measured using laser speckle imaging. The intensity of both the astrocytic and neuronal signals in the HL sensorimotor cortex declined with increase in stimulation frequency. Moreover, blocking neuronal input by tetrodotoxin abolished astrocytic calcium signals. We suggest that the topographical representation of the body is not only true for cortical neurons but also for astrocytes. The maps and the frequency‐dependent activations reflect strong reciprocal neuroglial communication and provide a new experimental approach to explore the role of astrocytes in health and disease. © 2013 Wiley Periodicals, Inc.