Correlating quantitative MR imaging with histopathology in X-linked adrenoleukodystrophy.

BACKGROUND AND PURPOSE: Quantitative MR imaging techniques may improve the pathologic specificity of MR imaging regarding white matter abnormalities. Our purposes were to determine whether ADC, FA, MTR, and MRS metabolites correlate with the degree of white matter damage in patients with X-ALD; whether differences in ADC, FA, and MTR observed in vivo are retained in fresh and formalin-fixed postmortem brain tissue; and whether the differences predict histopathology. MATERIALS AND METHODS: MRS metabolites, MTR, ADC, and FA, were determined in 7 patients with X-ALD in 3 white matter areas (NAWM, active demyelination, and complete demyelination) and were compared with values obtained in 14 controls. MTR, ADC, and FA were assessed in postmortem brains from 15 patients with X-ALD and 5 controls. Values were correlated with the degree of astrogliosis and density of myelin, axons, and cells. Equations to estimate histopathology from MR imaging parameters were calculated by linear regression analysis. RESULTS: MRS showed increased mIns, Lac, and Cho and decreased tNAA in living patients with X-ALD; the values depended on the degree of demyelination. MTR, ADC, and FA values were different in postmortem than in vivo white matter, but differences related to degrees of white matter damage were retained. ADC was high and FA and MTR were low in abnormal white matter. Correlations between histopathologic findings and MR imaging parameters were strong. A combination of ADC and FA predicted pathologic parameters best. CONCLUSIONS: Changes in quantitative MR imaging parameters, present in living patients and related to the severity of white matter pathology, are retained in postmortem brain tissue. MR imaging parameters predict white matter histopathologic parameters.

Familial aggregation of parkinsonism in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Distinct genetic forms of frontotemporal dementia.

BACKGROUND: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. METHODS: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. RESULTS: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. CONCLUSION: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease.

Frontal presentation in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive hypokinetic rigid disorder with supranuclear gaze palsy and frequent falls. Although clinical consensus criteria are available, an atypical presentation may lead to clinical misdiagnosis in the initial phase. In the present study we investigated the clinical presentation of PSP and its relationship to initial clinical diagnosis and survival. METHODS: We ascertained patients with PSP in a prospective cohort by nationwide referral from neurologists and nursing home physicians. All patients underwent a structural interview and clinical examination before entering the study. Medical records were reviewed for the presence of symptoms during the first 2 years. RESULTS: A total of 152 patients ascertained between 2002 and 2005 fulfilled the international consensus criteria for PSP. Categorical principal component analysis of clinical symptoms within the first 2 years showed apart from a cluster of typical PSP symptoms, the clustering of cognitive dysfunction and behavioral changes. Further analysis showed that 20% of patients had a predominant frontal presentation with less than two other PSP symptoms. Survival analysis showed that this subgroup had a similar prognosis to that of the total group of patients with PSP. CONCLUSIONS: There exists a subgroup of patients with progressive supranuclear palsy (PSP) with a predominant frontal presentation, who progressed into typical PSP over the course of the disease.

Molecular misreading: the occurrence of frameshift proteins in different diseases.

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step.

Frameshift proteins in autosomal dominant forms of Alzheimer disease and other tauopathies.

Frameshift (+1) proteins such as APP(+1) and UBB(+1) accumulate in sporadic cases of Alzheimer disease (AD) and in older subjects with Down syndrome (DS). We investigated whether these proteins also accumulate at an early stage of neuropathogenesis in young DS individuals without neuropathology and in early-onset familial forms of AD (FAD), as well as in other tauopathies, such as Pick disease (PiD) or progressive supranuclear palsy (PSP). APP(+1) is present in many neurons and beaded neurites in very young cases of DS, which suggests that it is axonally transported. In older DS patients (>37 years), a mixed pattern of APP(+1) immunoreactivity was observed in healthy looking neurons and neurites, dystrophic neurites, in association with neuritic plaques, as well as neurofibrillary tangles. UBB(+1) immunoreactivity was exclusively present in AD type of neuropathology. A similar pattern of APP(+1) and UBB(+1) immunoreactivity was also observed for FAD and much less explicit in nondemented controls after the age of 51 years. Furthermore, we observed accumulation of +1 proteins in other types of tauopathies, such as PiD, frontotemporal dementia, PSP and argyrophylic grain disease. These data suggest that accumulation of +1 proteins contributes to the early stages of dementia and plays a pathogenic role in a number of diseases that involve the accumulation of tau.

Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology.

Frontotemporal dementia and parkinsonism linked to chromosome 17 have been associated with mutations in the microtubule associated protein tau (MAPT or tau) gene. This disorder is characterized by a large spectrum of neuronal and glial tau lesions in different brain regions. Pick bodies were found in a family with hereditary Pick's disease with the G272V mutation and in several families with other tau mutations in exons 9 and 11-13. The biochemical composition of Pick bodies varies between these mutations. Until recently, no detailed biochemical characterization of G272V brain material was done owing to unavailability of fresh frozen brain material. We now report a detailed study using the immunohistochemistry, western blots and electron microscopy of two brains with the G272V mutation that recently became available. Both brains showed severe neuronal loss in the temporal cortex, whereas in the frontal cortex the loss was less; and abundant Pick bodies in the dentate gyrus of the hippocampus, and caudate nucleus. The Pick bodies consisted exclusively of three-repeat (3R) isoforms, as was demonstrated by isoform-specific antibodies and supported by western blot analysis of sarkosyl-insoluble tau. These observations confirm that this family diagnosed with hereditary Pick disease meets all the criteria for this condition, including the presence of Pick bodies that are unphosphorylated at Ser262 and contain twisted filaments with long periodicity consisting only of 3R tau.

Selective deposition of mutant tau in the FTDP-17 brain affected by the P301L mutation.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a familial neurological disorder exhibiting autosomal dominant inheritance. Linkage analyses have led to the identification of many exonic and intronic mutations in the tau gene in affected families. Because FTDP- 17 causes extensive neuronal loss and intracellular tau deposits in affected regions, investigation of this disease should provide an important insight into the significance of tau deposits leading to neurodegeneration. Using site-specific antibodies that distinguish between wild-type and mutant tau, we have analyzed the proportions of wild-type and mutant tau in the soluble and insoluble fractions of the P301L brain. Western blotting showed that mutant tau was selectively deposited in the Sarkosyl-insoluble fraction. Consistent with this, immunocytochemistry showed that intraneuronal tau deposits consisted exclusively of mutant tau. In one case in which abundant senile plaques occurred, in addition to mutant tau, small amounts of wild-type tau were also deposited. On the other hand, the protein levels of mutant tau in the soluble fraction were selectively decreased despite no detectable decrease in the levels of mutant tau mRNA.

Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22.

Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases. However, most FTD families have no demonstrable tau mutations. Here we describe the clinical and neuropathological features of a large family with hereditary FTD. Genetic analysis showed strong evidence for linkage to chromosome 17q21-22 (maximum lod score 3.46, theta = 0 for marker D17S950), but mutations in the tau gene were not found. Clinical symptoms, neuropsychological deficits and neuroimaging findings of affected family members were similar to sporadic and tau-related FTD. The mean age at onset was 61.2 years, with loss of initiative and decreased spontaneous speech as the most prominent presenting symptoms. Pathological examination of the brains of two affected family members showed non-specific neuronal degeneration with dense cytoplasmic ubiquitin-positive inclusions in neurones of the second layer of the frontotemporal cortex and dentate gyrus of the hippocampus. In a number of neurones these inclusions appeared to be located inside the nucleus, although due to the small number of these inclusions this localization could not be confirmed by electron microscopy. The inclusions were not stained by tau, alpha-synuclein or polyglutamine antibodies. Biochemical analysis of soluble tau did not reveal abnormalities in tau isoform distribution and analysis of mRNA showed the presence of both three- and four-repeat transcripts. This is the first report of ubiquitin-positive, tau-negative inclusions in an FTD family with significant linkage to chromosome 17q21-22. Further characterization of the ubiquitin-positive inclusions may clarify the neurodegenerative pathways involved in this subtype of FTD.

Sporadic Creutzfeldt-Jakob disease in a young Dutch valine homozygote: atypical molecular phenotype.

A case of sporadic Creutzfeldt-Jakob disease (sCJD) is described in a young Dutch protein prion gene (PRNP) codon 129 valine homozygote. Certain clinical and molecular features of this case overlap those of variant CJD. The case highlights possible difficulties in the differential diagnosis of vCJD and the more rare sCJD subtypes based on molecular features alone.

Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions.

Macroscopic sampling of multiple sclerosis lesions in the brain tends to find chronic lesions. For a better understanding of the dynamics of the multiple sclerosis disease process, research into new and developing lesions is of great interest. As MRI in vivo effectively demonstrates lesions in multiple sclerosis patients, we have applied it to unfixed post-mortem brain slices to identify abnormalities, in order to obtain a higher yield of active lesions. The Netherlands Brain Bank organized the rapid autopsy of 29 multiple sclerosis patients. The brain was cut in 1 cm coronal slices. One or two slices were subjected to T(1)- and T(2)-weighted MRI, and then cut at the plane of the MRI scan into 5 mm thick opposing sections. Areas of interest were identified based on the MRI findings and excised. One half was fixed in 10% formalin and paraffin-embedded, and the corresponding area in the adjacent half was snap-frozen in liquid nitrogen. In total, 136 out of 174 brain tissue samples could be matched with the abnormalities seen on T(2)-weighted MRIs. The stage of lesional development was determined (immuno) histochemically. For 54 MRI-detectable samples, it was recorded whether they were macroscopically detectable, i.e. visible and/or palpable. Histopathological analysis revealed that 48% of the hyperintense areas seen on T(2)-weighted images represented active lesions, including lesions localized in the normal appearing white matter, without apparent loss of myelin but nevertheless showing a variable degree of oedema, small clusters of microglial cells with enhanced major histocompatibility complex class II antigen, CD45 and CD68 antigen expression and a variable number of perivascular lymphocytes around small blood vessels [designated as (p)reactive lesions]. From the macroscopically not-visible/not-palpable MRI-detected abnormalities, 58% were (p)reactive lesions and 21% contained active demyelinating lesions. In contrast, visible and/or palpable brain tissue samples mainly contained chronic inactive lesions. We conclude that MRI-guided sampling of brain tissue increases the yield of active multiple sclerosis lesions, including active demyelinating and (p)reactive lesions.

[Increased activity of stress-regulating systems in Alzheimer disease]. / Verhoogde activiteit van stressregulerende systemen bij de ziekte van Alzheimer.

Behavioral, i.e. non-cognitive, disturbances, such as anxiety, agitation, sleep disturbances and depression occur in the majority of Alzheimer's disease (AD) patients, but their neurobiological basis is unknown. Disturbance of stress regulating systems, like the locus coeruleus, could play an important role. The locus coeruleus, the main production site of noradrenaline in the central nervous system, is involved in phenomena like attention, arousal and the response to the environment. In Alzheimer's disease, there is a marked reduction of noradrenergic neurons in the locus coeruleus. We studied the activity in the remaining locus coeruleus neurons and found an inverse relationship between the number of remaining neurons and the noradrenergic activity. This could indicate compensatory activity and loss of flexibility of this system. Clinically, the loss of flexibility could result in an impairment to focus attention and to respond to the environment. These results can be related to another stress related system, the hypothalamo-pituitary-adrenal-(HPA)axis. This means that further evaluation of both of these systems is necessary.

Post-mortem high-resolution MRI of the spinal cord in multiple sclerosis: a correlative study with conventional MRI, histopathology and clinical phenotype.

We used high-resolution MRI to study the post-mortem appearance of spinal cord multiple sclerosis in relation to histopathology and low-resolution images. Fifty-nine 3 cm long formalin-fixed spinal cord specimens from 19 multiple sclerosis patients and three controls were studied. Clinical characteristics of each patient were reviewed. High-field MRI consisted of proton-density weighted spin-echo imaging with an in-plane resolution of 80 microm. Specimens were also imaged at 1.0 T, with 1 mm pixel resolution. After MRI, the specimens were cut at 5 mm intervals and stained for myelin (Luxol fast blue/cresyl violet) and axons (Bodian method). Two observers scored the MRIs for abnormalities and divided them into (i) well-delineated areas of high signal intensity (SI) and (ii) poorly defined areas of mildly increased SI. Abnormalities were scored semiquantitatively, white matter and grey matter separately. In 81 sections the total area of abnormalities per section was measured on both histopathology sections and on matched high-field MRIs. Abnormalities ranged from just a few abnormal areas to complete involvement of the spinal cord specimen. Patients with an aggressive disease course had more abnormalities than patients with a mild or intermediate disease course. Areas of mildly increased SI were seen in all specimens, and were often found around focal high-SI lesions. However, in six patients, areas of mildly increased SI were the predominant finding on the MRIs, correlating with a primary progressive disease course. Histopathologically, high-SI areas correlated with complete demyelination, while mildly increased SI corresponded with partial demyelination. All areas scored as abnormal by the neuropathologist were also found on the MRIs, and sizes measured using both methods correlated well (r = 0.85, P<0.01). On conventional MRIs, abnormalities could be recognized fairly well. However, better differentiation could be made between high-SI and mildly increased SI abnormalities on the 4.7 T images. In conclusion, high-resolution MRI revealed a great range of abnormalities in spinal cord multiple sclerosis, which related to disease course during life. Furthermore, we found very good correlation between the extent of abnormalities shown by histopathology and the SI changes on proton-density MRIs, mainly relating to demyelination revealed histopathologically.

Complex compulsive behaviour in the temporal variant of frontotemporal dementia.

OBJECTIVE: As metabolic and structural changes in frontotemporal-subcortical pathways have been reported in patients with obsessive-compulsive disorders, we investigated the correlation between complex compulsive behaviour (CCB) and the distribution of atrophy in a group of 90 patients with frontotemporal dementia (FTD). METHODS: CCB was defined as complex, intentional, and time consuming repetitive behaviour, which was distinguished from simple compulsive behaviour (SCB), such as verbal and motor repetitions and utilisation behaviour. Cortical atrophy on CT and/or MRI was semi-quantitatively assessed in frontal, temporal, parietal and occipital regions, and the pattern of atrophy was compared between patients with and without CCB or SCB. Linear measures were used to establish the presence of caudate atrophy (bicaudate ratio) and ventricular enlargement (bifrontal ratio). RESULTS: CCB was reported in 18 (21%) and SCB in 53 (61%) FTD patients. Frontotemporal atrophy was present in 64 patients (74%), and predominant temporal atrophy in 23 (26%). The pattern of atrophy was asymmetric in 25 patients (29%). Logistic regression analysis showed that temporal lobe atrophy (p < 0.005), as well as asymmetry of atrophy (p < 0.05) were independently associated with CCB, after adjusting for age at onset, gender, duration of symptoms at the time of imaging, severity of atrophy, and bicaudate and bifrontal ratio. No relationship was found between the presence of SCB and the distribution of atrophy, although patients with SCB tended to have more caudate atrophy (p < 0.1). CONCLUSION: Temporal lobe atrophy appears to mediate CCB in patients with FTD, especially if asymmetry of atrophy is present. Future studies with quantitative and volumetric measurements of the cortical and subcortical structures may further clarify the aetiology of CCB in FTD.

Hypothalamic lesions in multiple sclerosis.

Demyelinating lesions of fiber bundles in and adjacent to the hypothalamus (i.e. the fornix. anterior commissure, internal capsule, and optic system) may be the basis for autonomic and endocrine alterations in multiple sclerosis (MS) patients. Therefore we investigated the presence and immunological activity of lesions in hypothalamic fiber bundles of 17 MS patients and 14 controls. In the MS group, 16 of 17 patients showed demyelinated lesions. The incidence of active lesions was high (60%) and outnumbered chronic inactive lesions in the internal capsule (p = 0.005). In 4 of 17 MS patients, axonal damage was observed and in 3 of 17 MS patients grey matter lesions were apparent. Duration of MS was inversely related to the active hypothalamic MS lesion score (r = -0.72, p = 0.001). Since comparison of hypothalamic lesions with MS lesions in other areas of the brain in the same patients (n = 7) showed a great similarity both as stage and appearance was concerned, this negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole brain. In controls no demyelinating lesions were seen but in 11 control cases HLA expression was observed that was lower than that present in MS patients (p = 0.02). In the median eminence region that lacks a blood-brain barrier, all controls showed a strong HLA expression around the blood vessels. We conclude that systematic pathological investigation of the hypothalamus in MS patients reveals an unexpected high incidence of active lesions that may impact on hypothalamic functioning.

Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients.

Mutations in the gene for the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In this study we compared the presence of the P301L mutated tau protein from brain material of patients with that of the normal 4-repeat, using polyclonal antibodies specific for the P301L point mutation and its normal counterpart. We determined the relative ratio of mutated versus normal tau protein in the sarkosyl-soluble and -insoluble protein fractions from several brain regions. Although mutated and normal tau proteins are both present in the sarkosyl-insoluble deposits, quantitative analysis showed that the mutated protein is the major component. In the sarkosyl-soluble fraction of frontal and temporal cortex the overall ratio of 3-repeat versus 4-repeat tau isoforms is unchanged but there is a dramatic depletion of mutant tau protein. Furthermore, we observed an increase in tau-immunoreactive cleavage products with the P301L antibody, suggesting that the mutant protein is partly resistant to degradation and this is confirmed by pulse-chase experiments. This is the first direct evidence using patient material that shows a selective aggregation of mutant tau protein resulting in sarkosyl-insoluble deposits and the specific depletion of mutated tau protein in the soluble fraction.

A histopathological contribution to supratentorial glioma grading, definition of mixed gliomas and recognition of low grade glioma with Rosenthal fibers.

BACKGROUND: Previous glioma studies have described separate grading systems for oligodendrogliomas and astrocytomas. Many of these gliomas contain mixtures of neoplastic astrocytes and oligodendrocytes. Prognosis may be related to the percentages of these neoplastic components. Previous survival/grading studies have been limited to histopathological features but have not evaluated the importance of percentages of neoplastic components. This study attempted to perceive the relative importance of percentages of neoplastic astrocytes and oligodendrocytes for definition of astroglial, oligodendroglial and mixed oligoastroglial tumors. After determination of these limits we explored the possibility to develop a grading system for common supratentorial gliomas based on reproducible histopathological features. METHODS: A retrospective study was performed of 362 cases of unselected supratentorial glioma. One hundred and thirty-eight binary and nine continuous histopathological variables, amongst which percentages of neoplastic astrocytes and oligodendrocytes, were scored and related to survival. Only well reproducible histological features were accepted in Cox regression to define glioma grades. RESULTS AND CONCLUSIONS: Supratentorial gliomas appeared to be composed of variable percentages of neoplastic oligodendrocytes and astrocytes, but this spectrum did not correspond to a continuous change in prognosis. Gliomas containing 30% or more neoplastic oligodendrocytes had a slightly better outcome (p < 0.0432) but higher percentages did not further improve prognosis. Percentages of neoplastic astrocytes were not correlated to survival. We therefore propose to designate gliomas containing 30% or more neoplastic oligodendrocytes as oligodendroglial tumors, and others as astroglial tumors. From a prognostic point of view there is no need to recognize mixed oligoastrocytomas. An interesting finding was the recognition of a low grade glioma group with Rosenthal fibers, which had the longest postoperative survival. Another prognosticator of interest concerns the mitotic rate as a continuous variable. Atypical mitoses indicated the worst survival, after necrosis. It was possible to develop a grading system for all supratentorial gliomas using six reproducible histological parameters: necrosis, atypical mitoses, the mitotic rate, endothelial proliferative activity, percentage of neoplastic oligodendrocytes and Rosenthal fibers. This resulted in four grades for astroglial tumors (p < 0.002) and three grades for oligodendroglial tumors (p < 0.008) which differed significantly within each group with respect to survival.

Decreased hippocampal metabolic activity in Alzheimer patients is not reflected in the immunoreactivity of cytochrome oxidase subunits.

In the present study we have compared histochemically determined cytochrome oxidase activity with the levels of immunocytochemically stained cytochrome oxidase subunits (CO II and CO IV) and ATP synthase in the human hippocampus in relation with Alzheimer's disease. Cytochrome oxidase activity was significantly reduced in all hippocampal areas of Alzheimer patients. The protein levels of subunits II and IV were not different between control subjects and Alzheimer patients. Additionally, it was observed that the active cytochrome oxidase is evenly distributed over both cell bodies and neuropil, while a relatively large pool of inactive enzyme or precursors is limited to the neuronal somata. Further, in Alzheimer patients the CO IV immunoreactivity decreased with age, whereas in control subjects it increased with age. Our results suggest that the assembly of cytochrome oxidase or the processing of its subunits may be impaired.

Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression.

Circadian rhythm disturbances are frequently present in Alzheimer disease (AD). In the present study, we investigated the expression of vasopressin (AVP) mRNA in the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on formalin-fixed paraffin-embedded material was improved to such a degree that we could, for the first time, visualize AVP mRNA expressing neurons in the human SCN and carry out quantitative measurements. The total amount of AVP mRNA expressed as masked silver grains in the SCN was 3 times lower in AD patients (n = 14; 2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11; 6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the amount of AVP mRNA between AD patients with depression (n = 7) and without depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2, respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons showed a marked day-night difference in controls under 80 years of age. The amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/- 1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02), whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD patients. There was no relationship between the amount of AVP mRNA in the SCN and age at onset of dementia, duration of AD and the neuropathological changes in the cerebral cortex. These findings suggest that the neurobiological basis of the circadian rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. It also explains the beneficial effects of light therapy on nightly restlessness in AD patients.

Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids.

OBJECTIVE: To provide clinical, MRI, and histopathologic findings in a rare white matter disorder with autosomal dominant inheritance, so-called hereditary diffuse leukoencephalopathy with spheroids (HDLS). BACKGROUND: Progressive leukoencephalopathies often constitute a diagnostic dilemma in both children and adults. In some cases, histopathologic examination of brain tissue is required for a classifying diagnosis. METHODS: Clinical history, MRI, and autopsy findings were reviewed in three patients with HDLS: a father, his daughter, and an unrelated patient. RESULTS: Clinical history consisted of an adult-onset neurologic deterioration with signs of frontal lobe dysfunction, epilepsy, spasticity, ataxia, and mild extrapyramidal disturbances. MRI findings included cerebral atrophy and patchy white matter changes, most pronounced in the frontal and frontoparietal area with extension through the posterior limb of the internal capsule into the pyramidal tracts of the brainstem. Autopsy in two patients revealed a leukoencephalopathy with frontoparietal and frontal preponderance and numerous neuroaxonal spheroids in the abnormal white matter. The pyramidal tracts were affected throughout the brainstem. CONCLUSION: Similar clinical and histopathologic findings have been reported in members of a Swedish pedigree. The homogeneity of the findings strongly suggests that HDLS is a distinct disease entity. In the absence of a biochemical or genetic marker, a definitive diagnosis requires histopathologic confirmation in one of the affected family members. Neuroaxonal spheroids.