William G. Ellis

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10−11; odds ratio, minor allele (C) 0.61, 95% CI 0.53–0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10−4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Neuropathological basis of magnetic resonance images in aging and dementia

Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.

What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia

Background: Few studies have compared the accuracy of [18F]fluorodeoxyglucose (FDG) PET to the accuracy of clinical and pathologic diagnosis in dementia patients. Methods: Forty-four individuals with dementia, cognitive impairment, or normal cognitive function underwent clinical initial evaluation (IE) and PET scanning and were followed up for approximately 4 years until a final evaluation (FE) and 5 years until death and autopsy. Clinical, pathologic, and imaging diagnoses were categorized as Alzheimer disease (AD) or not AD. Results: Sensitivity of the IE for the pathologic diagnosis of AD was 0.76, and specificity was 0.58; PET had values of 0.84 and 0.74, and FE had values of 0.88 and 0.63. Positive predictive values for IE, PET, and FE were 0.70, 0.81, and 0.76. Negative predictive values were 0.65, 0.78, and 0.80. The diagnosis of AD was associated with a 70% probability of detecting AD pathology; with a positive PET scan this increased to 84%, and with a negative PET scan this decreased to 31%. A diagnosis of not AD at IE was associated with a 35% probability of AD pathology, increasing to 70% with a positive PET scan. Conclusions: As a diagnostic tool, PET is superior to a baseline clinical evaluation and similar to an evaluation performed 4 years later. Although the addition of [18F]fluorodeoxyglucose PET to a clinical diagnosis provides useful information that can affect the likelihood of detecting Alzheimer disease pathology, the value of this technique in the current clinical environment with limited therapeutic options is likely to be modest.

Cognitive impact of subcortical vascular and Alzheimer's disease pathology

To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimers disease [AD]), cognitive status, and apolipoprotein E genotype.

Presenile dementia in Down's syndrome Ultrastructural identity with Alzheimer's disease

Light and electron microscopic features in the presenile dementia that occurred in a 54 year old woman with Downs syndrome were identical to those of Alzheimers presenile dementia. In both diseases, senile plaques and Alzheimers neurofibrillary tangles fill the cerebral cortex and are scattered through subcortical and brainstem nuclei. Although presenile dementia of Downs syndrome is ill-defined clinically, the marked histologic changes are so predictably age-related that this condition offers many insights into sequences of aging and degeneration in the human brain.

Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia

The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimers disease (AD)‐type neurofibrillary degeneration and anoxia–ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy‐derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5–7 slabs/case), cut into 50μm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging–derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging–derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons. Ann Neurol 2005;57:896–903

Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD

Objective To assess the ability of the current diagnostic criteria for frontotemporal lobar degeneration (FTLD) to differentiate FTLD from AD. Methods Thirty cases with autopsy-proven FTLD and 30 cases of AD, matched for Mini-Mental State Examination score, were identified from the clinical databases of three dementia subspecialty centers, and their charts were reviewed for the presence of clinical features described in the current criteria for FTLD. The proportion of patients with each clinical feature at the first clinical presentation was compared across groups. Results A significantly larger proportion of patients with FTLD showed behavioral abnormalities, particularly social and personal conduct disorders and emotional blunting, than patients with AD. Few differences in language features were seen between the groups, and many of the language features detailed in the criteria were found in only a small proportion of patients. In both groups, many patients showed neuropsychological abnormalities, except for perceptual difficulties, which were present in many patients with AD but only in a few patients with FTLD. Extrapyramidal motor symptoms were more likely to be present in FTLD. Logistic regression revealed that five features—social conduct disorders, hyperorality, akinesia, absence of amnesia, and the absence of a perceptual disorder—correctly classified 93% of patients with FTLD and 97% of patients with AD. Conclusion A combination of behavioral, neuropsychological, and physical findings is most useful in distinguishing FTLD from AD. Future studies should be directed at establishing more objective methods of identifying these clinical features.

Morvan’s fibrillary chorea: a paraneoplastic manifestation of thymoma

Morvan’s fibrillary chorea is a rare disease characterised by symptoms which include neuromyotonia, cramping, weakness, pruritis, hyperhidrosis, insomnia, and delirium. The first case of Morvan’s fibrillary chorea to be associated with clinical manifestations of myasthenia gravis with thymoma, psoriasis, and atopic dermatitis is reported. Muscle histopathology disclosed chronic denervation and myopathic changes and in vitro electrophysiology demonstrated both presynaptic and postsynaptic defects in neuromuscular transmission. Serum antibodies to acetylcholine receptors, titin, N-type calcium channels, and voltage gated potassium channels were detected. Plasmapheresis, thymectomy, and long term immunosuppression induced a dramatic resolution of symptoms. The association of thymoma with other autoimmune disorders and autoantibodies, and prolonged and sustained remission with chronic immunosuppression, place Morvan’s fibrillary chorea on the range of neurological diseases arising as a paraneoplastic complication of cortical thymomas.

A Magnetic Resonance Template for Normal Neuronal Migration in the Fetus

OBJECTIVE Although the features of neuronal migration have been known since the turn of the century, the serial features of neuronal migration as seen with magnetic resonance imaging (MRI) have not been described. Our objective was to provide a template of the normal appearance and the temporal pattern of neuronal migration in the human fetal brain early in the second trimester as seen with MR imaging and to correlate our findings with histological sections and atlases. METHODS Twenty-eight normal fetal specimens, which ranged from 9 to 24 weeks of gestational age, were imaged with a 1.5 T clinical MRI unit by use of conventional spin echo, fast spin echo, and three-dimensional Fourier transformation spoiled gradient refocussed pulse sequences. RESULTS The three-dimensional Fourier transformation spoiled gradient refocussed pulse sequence provided the highest resolution images of neuronal migration. At 13 weeks of gestational age, the germinal matrix was identified. A five-layer pattern of the fetal forebrain, which included layers of neuroblast formation and migration, could be identified at 16 to 18 weeks by MRI. The germinal matrix and layers of migrating neurons diminished considerably in size by 21 weeks. Histological studies and correlation with anatomic atlases confirmed the MRI findings. CONCLUSION Images obtained by use of MRI with standard clinical pulse sequences can document the appearance and the temporal patterns of neuronal migration in postmortem fetal specimens. With the evolution of high-resolution MRI and faster scanning techniques, these findings may serve as a template for the in utero MRI appearance of neuronal migration and thereby compliment the antenatal ultrasonic investigation of congenital anomalies.

Astrocyte hypertrophy in the Alzheimer's disease hippocampal formation

In Alzheimers disease (AD), neuritic plaques are often found in the hippocampal dentate gyrus along the boundary between inner and outer molecular layers. The dentate outer molecular layer in AD also exhibits axon sprouting in response to an early loss of entorhinal neurons. The relationship between the laminar arrangement of plaques and the sprouting remains unclear. In experimental entorhinal lesions in the rat, the denervated dentate outer molecular layer demonstrates hypertrophic astrocytes which may provide trophic support for the sprouting response. It is not known whether an equivalent astrocyte response occurs in AD or whether this response is related to the distribution of plaques. We used immunohistochemical staining for glial fibrillary acidic protein (GFAP) to demonstrate reactive astrocytes in the hippocampus in AD patients and age-matched controls. These results were compared to the astrocyte response to an experimental entorhinal lesion in the rat. Quantitative and qualitative analyses demonstrated a significant increase in GFAP-positive hypertrophic astrocytes in the dentate outer molecular layer in AD compared to controls. These astrocytes were randomly distributed within the outer layer and did not parallel the distribution of neuritic plaques. In the entorhinal-lesioned rat, reactive hypertrophied astrocytes also showed a selective distribution within the denervated outer molecular layer. Our results further support the similarity of the hippocampal response in AD and experimental entorhinal lesion but do not explain the laminar distribution of neuritic plaques along the denervated zone.