Clinicians' ability to diagnose dementia with Lewy bodies is not affected by ß-amyloid load.

OBJECTIVE: To investigate whether an increasing load of ß-amyloid and/or neuritic plaques influences the phenotype, and thus the clinical diagnostic accuracy, of dementia with Lewy bodies (DLB). METHODS: A series of 64 subjects with autopsy-proven DLB was studied. Last diagnosis before death was used to determine the clinical diagnostic accuracy of DLB in relation to Lewy body distribution and extent of Alzheimer ß-amyloid and/or neuritic pathology. DLB pathologic diagnosis was made according to consensus criteria, using α-synuclein immunostaining for Lewy body identification. ß-Amyloid immunostaining was used for quantifying ß-amyloid deposits. The Consortium to Establish a Registry for Alzheimer's Disease criteria and Braak stage were applied for semiquantitative grading of neuritic plaque and neurofibrillary tangle pathology. RESULTS: Overall clinical diagnostic accuracy for the entire DLB cohort was high (80%), reflecting the high prevalence of core clinical features (fluctuations [81%], parkinsonism [77%], visual hallucinations [70%]). Lower frequencies of core clinical features of DLB, resulting in lower accuracy of its clinical diagnosis, were associated with decreasing Lewy body distribution (p < 0.0001) and with increasing neuritic plaque pathology (p = 0.035), but not with the number of ß-amyloid plaque deposits. CONCLUSIONS: The likelihood of occurrence of the DLB clinical syndrome is positively related to the extent of Lewy body pathology and negatively related to the severity of Alzheimer neuritic pathology, while ß-amyloid load has no effect.

Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene.

AIMS: Frontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene. METHODS: Twenty-two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease. RESULTS: Three Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP-43 pathology was significantly less. CONCLUSION: Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72.

Frontotemporal dementia and its subtypes: a genome-wide association study.

BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. FUNDING: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

Anti-GQ1b ganglioside positive Miller Fisher syndrome - evidence of paranodal pathology on nerve biopsy.

BACKGROUND: Miller Fisher syndrome is a regional variant of Guillain-Barre syndrome with a characteristic clinical triad of ophthalmoplegia, areflexia and ataxia and occasionally distal limb sensory loss. 90% of patients have associated antibodies to the GQ1b ganglioside. The pathophysiology of antibody-mediated peripheral nerve impairment remains uncertain. This report includes the first description of a peripheral sensory nerve biopsy in Miller Fisher syndrome. RESULTS: A single case report is described of a 46 year old woman who presented with 2 weeks of distal glove and stocking sensory loss to both deep and superficial sensory modalities, areflexia and weight loss. This was followed by rapid onset of ataxia, ophthalmoplegia, and bulbar impairment. Peripheral neurophysiology showed reduced sensory nerve amplitudes with preserved conduction velocities in keeping with an axonal pattern of impairment. Clinical concerns of a systemic inflammatory disorder led to a diagnostic peripheral nerve biopsy from the sensory branch of the radial nerve. However she subsequently made a complete recovery over 5 weeks. Combinatorial glycoarrays confirmed restricted serum binding for GQ1b in acute serum which later resolved in a convalescent sample. The nerve biopsy showed lengthening of nodes of Ranvier, myelin splitting and macrophage internodal axonal invasion without any features of demyelination. CONCLUSIONS: The pathological features were strikingly similar to those found in acute motor axonal neuropathy and indicate the region of the node of Ranvier to be a primary focus of GQ1b induced damage in Miller Fisher syndrome, at least in this particular overlap syndrome with prominent sensory nerve involvement.

The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons.

Mitochondrial defects within substantia nigra (SN) neurons are implicated in the pathogenesis of Parkinson's disease. SN neurons show increased mitochondrial defects, mitochondrial DNA deletion levels, and susceptibility to such dysfunction, although the role of mitochondria in neuronal degeneration remains uncertain. In this study, we addressed this important question by exploring changes within the mitochondria of SN neurons from patients with primary mitochondrial diseases to determine whether mitochondrial dysfunction leads directly to neuronal cell loss. We counted the pigmented neurons and quantified mitochondrial respiratory activity, deficiencies in mitochondrial proteins, and the percentage of pathogenic mutations in single neurons. We found evidence of defects of both complex I and complex IV of the respiratory chain in all patients. We found that marked neuronal cell loss was only observed in a few patients with mitochondrial disease and that all these patients had mutations in polymerase gamma (POLG), which leads to the formation of multiple mitochondrial DNA deletions over time, similar to aging and Parkinson's disease. Interestingly, we detected α-synuclein pathology in two mitochondrial patients with POLG mutations. Our observations highlight the complex relationship between mitochondrial dysfunction and the susceptibility of SN neurons to degeneration and α-synuclein pathology. Our finding that the loss of SN neurons was only severe in patients with POLG mutations suggests that acquired mitochondrial defects may be less well tolerated by SN neurons than by inherited ones.

Early-onset cataracts, spastic paraparesis, and ataxia caused by a novel mitochondrial tRNAGlu (MT-TE) gene mutation causing severe complex I deficiency: a clinical, molecular, and neuropathologic study.

Mitochondrial respiratory chain disease is associated with a spectrum of clinical presentations and considerable genetic heterogeneity. Here we report molecular genetic and neuropathologic findings from an adult with an unusual manifestation of mitochondrial DNA disease. Clinical features included early-onset cataracts, ataxia, and progressive paraparesis, with sequencing revealing the presence of a novel de novo m.14685G>A mitochondrial tRNA(Glu) (MT-TE) gene mutation. Muscle biopsy showed that 13% and 34% of muscle fibers lacked cytochrome c oxidase activity and complex I subunit expression, respectively. Biochemical studies confirmed a marked decrease in complex I activity. Neuropathologic investigation revealed a large cystic lesion affecting the left putamen, caudate nucleus, and internal capsule, with evidence of marked microvacuolation, neuron loss, perivascular lacunae, and blood vessel mineralization. The internal capsule showed focal axonal loss, whereas brainstem and spinal cord showed descending anterograde degeneration in medullary pyramids and corticospinal tracts. In agreement with muscle biopsy findings, reduced complex I immunoreactivity was detected in the remaining neuronal populations, particularly in the basal ganglia and cerebellum, correlating with the neurologic dysfunction exhibited by the patient. This study emphasizes the importance of molecular genetic and postmortem neuropathologic analyses for furthering our understanding of underlying mechanisms of mitochondrial disorders.

Synaptic proteins and choline acetyltransferase loss in visual cortex in dementia with Lewy bodies.

Functional neuroimaging studies have consistently reported abnormalities in the visual cortex in patients with dementia with Lewy bodies (DLB), but their neuropathologic substrates are poorly understood. We analyzed synaptic proteins and choline acetyltransferase (ChAT) in the primary (BA17) and association (BAs18/19) visual cortex in DLB and similar aged control and Alzheimer disease (AD) subjects. We found lower levels of synaptophysin, syntaxin, SNAP-25, and γ-synuclein in DLB subjects versus both aged control (68%-78% and 27%-72% for BA17 and BAs18/19, respectively) and AD cases (54%-67% and 10%-56% for BA17 and BAs18/19, respectively). The loss in ChAT activity in DLB cases was also greater in BA17 (72% and 87% vs AD and control values, respectively) than in BAs18/19 (52% and 65% vs AD and control groups, respectively). The observed synaptic and ChAT changes in the visual cortices were not associated with tau or ß-amyloid pathology in the occipital or the frontal, temporal, and parietal neocortex. However, the neocortical densities of LBs, particular those in BA17 and BAs18/19, correlated with lower synaptic and ChAT levels in these brain areas. These findings draw attention to molecular changes within the primary visual cortex in DLB and correlate with the neuroimaging findings within the occipital lobe in patients with this disorder.

Microangiopathy in the cerebellum of patients with mitochondrial DNA disease.

Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.3243A>G mutation in whom stroke-like events are part of the mitochondrial encephalopathy lactic acidosis and stroke-like episodes syndrome. We investigated microangiopathic changes in the cerebellum of 16 genetically and clinically well-defined patients. Respiratory chain deficiency, high levels of mutated mitochondrial DNA and increased mitochondrial mass were present within the smooth muscle cells and endothelial cells comprising the vessel wall in patients. These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations. In 8 of the 16 patients, multiple ischaemic-like lesions occurred in the cerebellar cortex suggestive of vascular smooth muscle cell dysfunction. Indeed, changes in vascular smooth muscle and endothelium distribution and cell size are indicative of vascular cell loss. We found evidence of blood-brain barrier breakdown characterized by plasma protein extravasation following fibrinogen and IgG immunohistochemistry. Reduced immunofluorescence was also observed using markers for endothelial tight junctions providing further evidence in support of blood-brain barrier breakdown. Understanding the structural and functional changes occurring in central nervous system microvessels in patients harbouring mitochondrial DNA defects will provide an important insight into mechanisms of neurodegeneration in mitochondrial DNA disease. Since therapeutic strategies targeting the central nervous system are limited, modulating vascular function presents an exciting opportunity to lessen the burden of disease in these patients.

Loss of myelin-associated glycoprotein in kearns-sayre syndrome.

OBJECTIVE: To explore myelin components and mitochondrial changes within the central nervous system in patients with well-characterized mitochondrial disorders due to nuclear DNA or mitochondrial DNA (mtDNA) mutations. DESIGN: Immunohistochemical analysis, histochemical analysis, mtDNA sequencing, and real-time and long-range polymerase chain reaction were used to determine the pathogenicity of mtDNA deletions. SETTING: Department of Clinical Pathology, Columbia University Medical Center, and Newcastle Brain Tissue Resource. PATIENTS: Seventeen patients with mitochondrial disorders and 7 controls were studied from August 1, 2009, to August 1, 2010. MAIN OUTCOME MEASURE: Regions of myelin-associated glycoprotein (MAG) loss. RESULTS: Myelin-associated glycoprotein loss in Kearns-Sayre syndrome was associated with oligodendrocyte loss and nuclear translocation of apoptosis-inducing factor, whereas inflammation, neuronal loss, and axonal injury were minimal. In a Kearns-Sayre syndrome MAG loss region, high levels of mtDNA deletions together with cytochrome- c oxidase-deficient cells and loss of mitochondrial respiratory chain subunits (more prominent in the white than gray matter and glia than axons) confirmed the pathogenicity of mtDNA deletions. CONCLUSION: Primary mitochondrial respiratory chain defects affecting the white matter, and unrelated to inflammation, are associated with MAG loss and central nervous system demyelination.

Frontotemporal dementia in elderly individuals.

OBJECTIVE: To determine whether cases of frontotemporal lobar degeneration (FTLD) do exist in elderly individuals and have clinical and neuropathological features distinct from those with presenile onset. DESIGN: Retrospective matched cohort study. SETTING: Regional Neuroscience Centre, North East England. PATIENTS: We compared clinicopathological features of 11 cases of FTLD in elderly individuals with 19 cases of presenile-onset FTLD. RESULTS: Retrospective case note analysis showed that most elderly patients with FTLD had behavioral features consistent with orbitofrontal and basofrontal involvement, similar to presenile-onset FTLD, though symptomatic memory loss was present in 91% (10 of 11) of elderly patients with FTLD compared with only 36% (7 of 19) of patients with presenile-onset FTLD. Neuropathologically, the group of elderly patients with FTLD comprised 7 with FTLD­TDP-43, 1 with ubiquitin-positive FTLD, 2 with FTLD-tau/Pick disease, and 1 with FTLD-tau/neurofibrillary tangle­predominant dementia with TDP-43, a composition similar to presenile-onset FTLD. However, hippocampal sclerosis was more common in elderly patients with FTLD than patients with presenile-onset FTLD (82% vs 37%) and more severe in elderly patients with FTLD (P < .05). By contrast, severe atrophy of the frontal and temporal lobes was less common in elderly patients with FTLD (frontal: 45%; temporal: 27%) than patients with presenile-onset FTLD (frontal: 63%; temporal: 78%). Elderly patients with FTLD represented 3.2% of all elderly patients with dementia autopsied at Newcastle General Hospital. CONCLUSIONS: Frontotemporal lobar degeneration in elderly patients does exist as a separate entity from presenile-onset FTLD. Its main features include (1) clinically frequent memory loss and behavioral change predominating over language and semantic dysfunction and (2) neuropathologically prominent hippocampal sclerosis but less pronounced cortical lobar atrophy. Clinically, FTLD in elderly patients is underrecognized and should be considered in the elderly subjects presenting with an "atypical Alzheimer disease" phenotype.

Relationship between mitochondria and α-synuclein: a study of single substantia nigra neurons.

OBJECTIVE: To explore the relationship between α-synuclein pathology and mitochondrial respiratory chain protein levels within single substantia nigra neurons. DESIGN: We examined α-synuclein and mitochondrial protein expression in substantia nigra neurons of 8 patients with dementia with Lewy bodies, 5 patients with Parkinson disease, and 8 control subjects. Protein expression was determined using immunocytochemistry followed by densometric analysis. PATIENTS: We examined single substantia nigra neurons from 5 patients with idiopathic Parkinson disease (mean age, 81.2 years), 8 patients with dementia with Lewy bodies (mean age, 75 years), and 8 neurologically and pathologically normal control subjects (mean age, 74.5 years). The control cases showed minimal Lewy body pathology and cell loss. Patients with dementia with Lewy bodies and idiopathic Parkinson disease fulfilled the clinical and neuropathologic criteria for these diseases. RESULTS: Our results showed that mitochondrial density is the same in nigral neurons with and without α-synuclein pathology. However, there are significantly higher levels of the respiratory chain subunits in neurons containing α-synuclein pathology. CONCLUSIONS: The finding of increased levels of respiratory chain complex subunits within neurons containing α-synuclein does not support a direct association between mitochondrial respiratory chain dysfunction and the formation of α-synuclein pathology.

Cerebellar ataxia in patients with mitochondrial DNA disease: a molecular clinicopathological study.

Cerebellar ataxia is a prominent clinical symptom in patients with mitochondrial DNA (mtDNA) disease. This is often progressive with onset in young adulthood. We performed a detailed neuropathologic investigation of the olivary-cerebellum in 14 genetically and clinically well-defined patients with mtDNA disease. Quantitative neuropathologic investigation showed varying levels of loss of Purkinje cells and neurons of the dentate nucleus and inferior olivary nuclei. Typically, focal Purkinje cell loss was present in patients with the m.3243A>G mutation caused by the presence of microinfarcts, with relative preservation of neuronal cell populations in the olivary and dentate nuclei. In contrast, patients with the m.8344A>G mutation or recessive POLG mutations showed extensive and global neuronal cell loss in all 3 olivary-cerebellum areas examined. Molecular analysis of mutated mtDNA heteroplasmy levels revealed that neuronal cell loss occurred independently of the level of mutated mtDNA present within surviving neurons. High levels of neuronal respiratory chain deficiency, particularly of complex I, were detected in surviving cells; levels of deficiency were greater in regions with extensive cell loss. We found a relationship between respiratory deficiency and neuronal cell density, indicating that neuronal cell death correlates with respiratory deficiency. These findings highlight the vulnerability of the olivary-cerebellum to mtDNA defects.

Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, increasing in prevalence with age. Most patients who develop AD have an unknown cause, but characteristic neuropathological features include the deposition of extracellular amyloid beta and of intraneuronal hyperphosphorylated tau protein. Researchers have previously implicated mitochondrial dysfunction in AD. We previously showed an increase in neurons displaying a mitochondrial biochemical defect-cytochrome-c oxidase (COX) deficiency-in the hippocampus in patients with sporadic AD compared with age-matched controls. COX deficiency is well described as a marker of mitochondrial (mt) DNA dysfunction. This present study analyzed the mtDNA in single neurons from both COX normal and COX-deficient cells. Analysis of the mtDNA revealed that COX deficiency is caused by high levels of mtDNA deletions which accumulate with age. Future research is needed to clarify the role mtDNA deletions have in normal aging and investigate the relationship between mtDNA deletions and the pathogenesis of sporadic AD.

Sensory neuronopathy in patients harbouring recessive polymerase γ mutations.

Defects in the mitochondrial DNA replication enzyme, polymerase γ, are an important cause of mitochondrial disease with ∼25% of all adult diagnoses attributed to mutations in the POLG gene. Peripheral neuronopathy is often part of the clinical syndrome and can represent the most disabling feature. In spite of this, the molecular mechanisms underlying the neuronopathy remain to be elucidated and treatment strategies are limited. In the present study, we use a combined approach comprising clinical, electrophysiological, neuropathological and molecular genetic investigations to unravel the mechanisms underpinning peripheral neuronopathy in autosomal recessive polymerase γ-related disease. Electrophysiological assessments documented a dorsal root ganglionopathy in all 11 cases. Of the 11 cases, eight also showed changes consistent with motor fibre loss. Detailed neuropathological investigation of two patients confirmed the electrophysiological findings, revealing atrophy of posterior columns and striking neuronal cell loss from the dorsal root ganglia, which was accompanied by severe mitochondrial biochemical abnormalities involving respiratory chain complexes I and IV due to clonally-expanded mitochondrial DNA deletions and a significant reduction in mitochondrial DNA copy number in affected neurons. We propose that the respiratory chain defects, secondary to mitochondrial DNA deletion and depletion, are likely to be responsible for pathology observed in the dorsal root ganglion and the sensory ganglionopathy documented electrophysiologically.

Neuropathological correlates of volumetric MRI in autopsy-confirmed Lewy body dementia.

The objective of this study was to determine the neuropathological correlates of regional medial temporal lobe volume measures on magnetic resonance imaging (MRI) in subjects with Lewy body dementia (LBD). Twenty-three autopsy-confirmed LBD cases with an MRI scan close to death (mean 1.5 years) were studied. MRI-based volumetric measures were calculated for total intracranial volume, hippocampus, entorhinal cortex, and amygdala. Quantitative neuropathological analysis of plaques, tangles, and Lewy bodies were carried out in the same regions. Spearman's rho was used to examine correlations between MRI volumes and neuropathology measures and linear regression to assess the relationship between neuropathology and MRI volumes. A significant inverse correlation was observed between normalized amygdala volume and percent area of Lewy bodies in the amygdala (r = -0.461, p = 0.035). There were no other significant correlations between regional MRI volume and measures of neuropathology. Lewy body, but not Alzheimer's disease (AD) pathology was associated with reduced amygdala volume in pathologically-verified LBD cases but neither Lewy body nor Alzheimer's disease pathology was associated with volume loss in the hippocampus or entorhinal cortex, suggesting other neuropathological factors account for atrophy in these structures in LBD.

Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death.

Dopaminergic (DA) neuron degeneration is a feature of brain aging but is markedly increased in patients with Parkinson's disease (PD). Recent data indicate elevated metabolic stress as a possible explanation for DA neuron vulnerability. Using laser capture microdissection, we isolated DA neurons from the substantia nigra pars compacta of PD patients, age-matched and young controls to determine transcriptional changes by expression profiling and pathway analysis. We verified our findings by comparison to a published dataset. Parallel processing of isolated neurons and bulk tissue allowed the discrimination of neuronal and glial transcription signals. Our data show that genes known to be involved in neural plasticity, axon and synaptic function, as well as cell fate are differentially regulated in aging DA neurons. The transcription patterns in aging suggest a largely maintained expression of genes in energy-related pathways in surviving neurons, possibly supported by the mediation of PPAR/RAR and CREB signaling. In contrast, a profound down-regulation of genes coding for mitochondrial and ubiquitin--proteasome system proteins was seen in PD when compared to the age-matched controls. This is in accordance with the established mitochondrial dysfunction in PD and provides evidence for mitochondrial impairment at the transcriptional level. In addition, the PD neurons had disrupted pathways that comprise a network involved in the control of energy metabolism and cell survival in response to growth factors, oxidative stress, and nutrient deprivation (PI3K/Akt, mTOR, eIF4/p70S6K and Hif-1α). PI3K/Akt and mTOR signaling are central hubs of this network which is of relevance to longevity and--together with induction of mitochondrial biogenesis--may constitute potential targets for therapeutic intervention.

The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene.

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.

Pathological correlates of frontotemporal lobar degeneration in the elderly.

Frontotemporal lobar degeneration (FTLD) is generally recognised as a disorder with presenile onset (that is before 65 years of age) with only occasional cases presenting later than this. We set out to determine what proportion of cases of FTLD had late onset of disease and whether such cases of FTLD had distinctive clinical and neuropathological features as compared to cases with presenile onset. Within a combined Manchester and Newcastle autopsy series of 117 cases with pathologically confirmed FTLD (109/117 cases also met Lund Manchester clinical criteria for FTLD), we identified 30 cases (onset age range 65-86 years), comprising 25% of all FTLD cases ascertained in these two centres over a 25-year period. Neuropathologically, the 30 elderly cases presented features of several FTLD histological subgroups [FTLD-TDP (types 1, 2 and 3, 19 cases (63%)], FLTD-tau [MAPT, PiD and CBD, 10 cases (33%)] and FTLD-UPS (1 case), similar in range of phenotypes to that seen in the presenile group, though patients with MAPT, but not PGRN, mutation, or FUS pathology, were notably absent or fewer in the elderly group. Hippocampal sclerosis (HS) was present in 13/30 of the elderly FTLD cases (43%) compared with 14/79 (18%) (P = 0.012) in the presenile FTLD patients. Lobar atrophy present in most of the younger patients was prominent in only 25% of the elderly subjects. Prospective and retrospective psychiatric and medical case note analysis showed that the majority of the elderly FTLD patients, like their younger counterparts, had behavioural features consistent with frontotemporal dementia. FTLD is common amongst elderly persons and all or most of the major clinical and histological subtypes present in younger individuals can be seen in the older group.