Biomedical subjects

Howard Feldman

Publications and source records attributed to Howard Feldman.

At least 19 recordsLinked to original sources

PubMed2006

Disease progression in vascular cognitive impairment: cognitive, functional and behavioural outcomes in the Consortium to Investigate Vascular Impairment of Cognition (CIVIC) cohort study.

BACKGROUND AND PURPOSE: Empirical studies to clarify the outcomes in Vascular Cognitive Impairment (VCI) are needed. We compared cognitive, functional, and behavioural outcomes in patients with VCI to patients with no cognitive impairment (NCI), and Alzheimer's disease (AD). METHODS: Secondary analysis of the Consortium to Investigate Vascular Impairment of Cognition (CIVIC), a multi-centre Canadian memory clinic 30-month cohort study. RESULTS: Of 1347 patients, 938 were eligible for follow-up, of whom 239 (24.5%) were lost and 29 (3%) had died. Of the remaining 697 patients, 125 had NCI, 229 had VCI, and 343 had AD at baseline. Compared to people with NCI, of whom 20-40% showed progression based on cognitive and functional measures, those with VCI were more likely to progress (50-65%), as were people with AD (50-80%) (p<0.01). More people with VCI showed progression of affective symptoms (30%) than those with NCI (12%) or AD (15% p<0.01). Progression of impaired judgment (rated clinically) in VCI (15%) was similar to AD (11%) but more common than in NCI (4%, p<0.01). CONCLUSIONS: Most people with VCI show readily detectable progression by 30 months. Depressive symptoms were more common and more progressive in VCI than in Alzheimer's disease, whereas clinical evidence of progressive executive dysfunction was common in both AD and VCI.

Aged↗

PubMed2006

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

Amino Acid Sequence↗

PubMed2006

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.

Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.

Adult↗

PubMed2006

Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease.

BACKGROUND: Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease. METHODS: We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII. RESULTS: No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity. CONCLUSION: We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.

Brain↗

PubMed2006

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

Cell Survival↗

PubMed2006

Mild cognitive impairment.

Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.

Aged↗

PubMed2006

A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.

Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-1 that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.

Aged↗

PubMed2006

Clinical practice with anti-dementia drugs: a consensus statement from British Association for Psychopharmacology.

The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review the evidence on the drug treatment for dementia. The level of evidence (types) was rated using a standard system: Types 1a and 1b (evidence from meta-analysis of randomised controlled trials or at least one controlled trial respectively); types 2a and 2b (one well-designed study or one other type of quasi experimental study respectively); type 3 (non-experimental descriptive studies); and type 4 (expert opinion). There is type 1a evidence for cholinesterase inhibitors (donepezil, rivastigmine and galantamine) for mild to moderate Alzheimer's disease; memantine for moderate to severe Alzheimer's disease; and for the use of bright light therapy and aromatherapy. There is type 1a evidence of no effect of anti inflammatory drugs or statins. There is conflicting evidence regarding oestrogens, with type 2a evidence of a protective effect of oestrogens but 1b evidence of a harmful effect. Type 1a evidence for any effect of B12 and folate will be forthcoming when current trials report. There is type 1b evidence for gingko biloba in producing a modest benefit of cognitive function; cholinesterase inhibitors for the treatment of people with Lewy body disease (particularly neuropsychiatric symptoms); cholinesterase inhibitors and memantine in treatment cognitive impairment associated with vascular dementia; and the effect of metal collating agents (although these should not be prescribed until more data on safety and efficacy are available). There is type 1b evidence to show that neither cholinesterase inhibitors nor vitamin E reduce the risk of developing Alzheimer's disease in people with mild cognitive impairment; and there is no evidence that there is any intervention that can prevent the onset of dementia. There is type 1b evidence for the beneficial effects of adding memantine to cholinesterase inhibitors, and type 2b evidence of positive switching outcomes from one cholinesterase inhibitor to another. There is type 2a evidence for a positive effect of reminiscence therapy, and type 2a evidence that cognitive training does not work. There is type 3 evidence to support the use of psychological interventions in dementia. There is type 2 evidence that a clinical diagnosis of dementia can be made accurately and that brain imaging increases that accuracy. Although the consensus statement dealt largely with medication, the role of dementia care in secondary services (geriatric medicine and old age psychiatry) and primary care, along with health economics, was discussed. There is ample evidence that there are effective treatments for people with dementia, and Alzheimer's disease in particular. Patients, their carers, and clinicians deserve to be optimistic in a field which often attracts therapeutic nihilism.

Aged↗

PubMed2005

Clinical and radiographic subtypes of vascular cognitive impairment in a clinic-based cohort study.

BACKGROUND AND PURPOSE: There is a need for empirical studies to define criteria for vascular cognitive impairment (VCI) subtypes. In this paper, we report the predictive validity of a subtype classification scheme based on clinical and radiographic features. METHODS: Nine Canadian memory clinics participated in the Consortium to Investigate Vascular Impairment of Cognition. This cohort consisted of 1347 patients, of whom 324 had VCI, and was followed for up to 30 months. RESULTS: Clinical and neuroimaging features defined three subtypes: vascular cognitive impairment, no dementia, (n=97), vascular dementia (n=101) and mixed neurodegenerative/vascular dementia (n=126). Any ischemic lesion on neuroimaging increased the odds (odds ratio=9.31; 95% confidence interval 6.46, 13.39) of a VCI diagnosis. No VCI subtype, however, was associated with a specific neuroimaging abnormality. Compared to those with no cognitive impairment, patients with each VCI subtype had higher rates of death and institutionalization (hazard ratio for combined adverse events=6.08, p<0.001). CONCLUSIONS: Both clinical features and radiographic features help establish a diagnosis of VCI. The outcomes of VCI subtypes, however, are more strongly associated with clinical features than with radiographic ones.

Aged↗

PubMed2005

Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial.

BACKGROUND: There have been very limited investigations of cholinesterase inhibitor therapy in more advanced stages of Alzheimer's disease (AD). The efficacy and safety of donepezil were evaluated in post hoc analyses of a subgroup of patients with more severe AD (standardized Mini-Mental State Examination [sMMSE] score 5-12) within a randomized, placebo-controlled trial in moderate to severe AD (MSAD study). Additional analyses examined whether donepezil's treatment effects were consistent across the full range of baseline AD severity studied (sMMSE score 5-17). METHODS: Patients with moderate to severe AD (n = 290) who were living in the community or in assisted living facilities received donepezil or placebo for 24 weeks; n = 145 in the more severe AD subgroup. The primary outcome measure was the Clinician's Interview-Based Impression of Change (CIBIC-plus) with secondary outcomes including the sMMSE, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia. Analysis of Variance and Analysis of Covariance models tested for treatment x disease severity interaction in the full MSAD study sample. RESULTS: CIBIC-plus scores for donepezil patients were significantly improved compared with placebo for each time-point, with a 0.70 mean treatment difference at Week 24 last observation carried forward (LOCF; p = 0.0002). Significant differences favoring donepezil were noted at Week 24 LOCF for all secondary measures. There were no treatment x severity interactions for any of the efficacy measures. CONCLUSIONS: In this analysis, donepezil had significant benefits over placebo on global, cognitive, functional, and behavioral measures in a subgroup of patients with more severe AD. Furthermore, the treatment effects of donepezil were not driven by a particular stratum within the moderate to severe dementia range.

Aged↗

PubMed2005

Neuropsychological subgroups of cognitively-impaired-not-demented (CIND) individuals: delineation, reliability, and predictive validity.

The objectives of the present investigation were to determine whether subgroups of Cognitively-Impaired-Not-Demented (CIND) individuals with distinct neuropsychological profiles exist in two independent samples, and whether subgroup membership is related to diagnostic outcome over periods of 2 to 5 years. A series of cluster analyses was performed on ipsative factor z-scores derived from principal component analyses. Five subgroups were identified in the Base Sample (n = 461): Verbal Dysfunction, Verbal/Visuospatial Dysfunction, Memory/Verbal Dysfunction, Memory Dysfunction, and Visuospatial Dysfunction. This five-cluster solution was replicated in an independent sample of CIND individuals (n = 166). The highest rates of conversion to dementia were observed in the Memory Dysfunction and Memory/Verbal Dysfunction subgroups. The Verbal Dysfunction subgroup was most likely to show improvement in cognitive status. The cognitive heterogeneity of the CIND condition must be taken into account in future research focusing on the early identification of dementia.

Aged↗

PubMed2004

Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging.

BACKGROUND: Apolipoprotein E (ApoE) epsilon4 genotype is a well-established risk factor for Alzheimer's disease (AD). However, its effect on predicting conversion from normal to "cognitive impairment, no dementia" (CIND) and from CIND to AD is less clear. METHODS: We used a nested case-control design from the population-based Canadian Study of Health and Aging (CSHA) to examine the effect of ApoE epsilon4 genotype on the conversion of subjects from normal to CIND and from CIND to AD. We also contrasted these findings with incident cases of AD and vascular dementia (VaD) in the CSHA cohort. RESULTS: The ApoE epsilon4 genotype was a significant risk factor for conversion from CIND to AD and from normal to AD and VaD. However, it was not a significant risk factor for conversion from normal to CIND. This effect is robust to adjustment for age, sex and education level. There is significant interaction between the ApoE epsilon4 genotype and age for AD and for conversion from CIND to AD. No interaction between ApoE epsilon4 genotype, sex, age, ethnicity and education level was found in other subgroup analyses. The positive predictive value of ApoE epsilon4 for predicting CIND conversion to AD was 0.48, and the negative predictive value was 0.65. INTERPRETATION: Possession of an ApoE epsilon4 allele increases the risk of AD developing from CIND. It is also associated with a decrease in the age at onset of AD. Its predictive values do not support its utility as a diagnostic test for predicting progression from CIND to AD, but it may be useful in research studies to enrich study samples that have a higher rate of progression to AD.

Aged↗

PubMed2004

Emerging therapies for vascular dementia and vascular cognitive impairment.

BACKGROUND: Cerebrovascular disease (CVD) and ischemic brain injury secondary to cardiovascular disease are common causes of dementia and cognitive decline in the elderly. CVD also contributes to cognitive loss in Alzheimer disease (AD). SUMMARY: Progress in understanding vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising symptomatic and preventive treatments. Cholinergic deficits in VaD due to ischemia of basal forebrain nuclei and cholinergic pathways can be treated with cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil and galantamine in patients with VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior, and activities of daily living. The N-methyl-D-aspartate receptor antagonist memantine stabilized progression of VaD compared with placebo. Primary and secondary stroke prevention, in particular with control of hypertension and hyperlipidemia, can decrease VaD incidence. CONCLUSIONS: From a public health viewpoint, recognition of VCI before the development of dementia and correction of vascular burden on the brain may lead to a global decrease of incident dementia.

Carbamates↗

PubMed2004

Extrapyramidal features in patients with motor neuron disease and dementia; a clinicopathological correlative study.

Motor neuron disease (MND) may be complicated by frontotemporal dementia and/or an extrapyramidal movement disorder. Several studies have identified the pathological substrate for dementia in MND as being ubiquitin-immunoreactive inclusions and dystrophic neurites in the extramotor neocortex and hippocampus. Although degenerative changes have previously been noted in the basal ganglia and substantia nigra in MND, detailed pathological studies with clinical correlation are lacking. We examined postmortem material from eight patients with a history of MND and dementia, four of whom also had prominent extrapyramidal features. All cases showed the expected degenerative changes in the pyramidal motor system and ubiquitin-positive inclusions in the extramotor cortex. In addition, the cases with a history of extrapyramidal features had striking pathology in the basal ganglia and substantia nigra; neuronal loss and gliosis ranged from moderate to severe and immunohistochemistry demonstrated numerous neuronal inclusions and dystrophic neurites, which were reactive for ubiquitin, but not tau or alpha-synuclein. Similar pathology was either absent or much milder in cases without extrapyramidal features. This study illustrates the utility of ubiquitin immunohistochemistry in demonstrating the range of pathology in MND and provides a neuropathological correlate for the extrapyramidal features which may occur in MND with dementia.

Basal Ganglia Diseases↗

PubMed2004

Fatal familial insomnia: the first account in a family of Chinese descent.

BACKGROUND: Fatal familial insomnia (FFI) is an autosomal dominant disease linked to a mutation in the prion protein gene. Fatal familial insomnia is characterized by sleep disturbance and loss of neurons, with gliosis in the thalamic nuclei. OBJECTIVE: To describe the clinical, neurophysiological, radiological, and neuropathological data in a Chinese family with FFI. SETTING: Tertiary referral university hospital setting. PATIENTS: Patient 1 was a 36-year-old man who presented with insomnia and myoclonus. In the subsequent 9 months, he developed ataxia and dementia, followed by death. Patient 2 was the aunt of patient 1, and presented at the age of 47 years with insomnia, myoclonus, and dementia; her condition declined during a 12-month period. Genetic analysis was performed, followed by neuropathological and biochemical analysis of the disease-associated form of the prion protein PrPSc on the postmortem brain specimen. RESULTS: Molecular analysis demonstrated an aspartic acid to asparagine mutation at codon 178 and homozygosity for methionine at codon 129. Both patients showed severe neuronal loss and prominent gliosis in the thalamus and brainstem involvement, with evidence of astrogliosis in the inferior olivary nucleus. Patient 1 also had neuronal loss and astrogliosis in the region of the superior colliculus and in the periaqueductal region. PrPSc was detected on Western blot analysis, and had a wide distribution. The strongest signals were present in the amygdala, hypothalamus, caudate, parahippocampal gyrus, periaqueductal gray matter, and mediodorsal thalamus. CONCLUSIONS: To our knowledge, this is the first report of FFI in a family of Chinese descent. This supports the worldwide distribution of FFI, and despite differences in genetic background, the clinical and pathological findings are similar to those found in white patients with FFI.

Adult↗

PubMed2004

Dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Alzheimer Disease↗

PubMed2004

Neuropsychological characterization of cognitively-impaired-not-demented (CIND) individuals: clinical comparison data.

The primary objective of the present investigation was to characterize the neuropsychological test performance of a large sample of clinic-referred individuals diagnosed as Cognitively-Impaired-Not-Demented (CIND). Participants classified as Not-Cognitively-Impaired (NCI; n = 68) differed from CIND individuals (n = 205) on a number of demographic, clinical, and neuropsychological measures. A backward stepwise logistic regression analysis revealed that measures of learning and memory, visuoconstruction abilities, and cognitive flexibility provided the best discrimination between NCI and CIND participants. Clinical comparison data for CIND participants were generated for various demographically defined groups. The amount of inter-test scatter (highest minus lowest sample-based z-score) and the overall number of cognitive impairments (impairment being defined as performance equal to or greater than 1 standard deviation below the sample mean) in CIND individuals are reported. The results support the impression that CIND is a cognitively heterogeneous condition.

Adult↗

PubMed2004

Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic cases.

Ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions are characteristically found in the extramotor cortex in patients with motor neuron disease (MND) and dementia (MND-dementia) and in a subset of patients with frontotemporal dementia (FTD) without motor symptoms (FTD-MND type). Recently, ub-ir neuronal intranuclear inclusions have been described in a small number of patients with familial FTD-MND type. To better define the sensitivity and specificity of this pathological change, we examined postmortem tissue from 14 patients with FTD-MND type (8 familial, 6 sporadic), 10 cases of MND-dementia (5 familial, 5 sporadic) and 19 cases of MND with no history of cognitive dysfunction (2 familial, 17 sporadic). Numerous intranuclear inclusions were found in multiple anatomic sites in 6/8 cases of familial FTD-MND. Rare intranuclear inclusions were present in the hippocampal dentate granule cells in 1 case of familial MND-dementia. No sporadic cases had intranuclear inclusions. These findings suggest that intranuclear inclusions are specific for familial FTD and may identify a subset of families with a common genetic basis. Although intranuclear inclusions are most characteristic of families with pure FTD, they may also be found in some pedigrees with both FTD and MND, further supporting the hypothesis that FTD-MND type and MND-dementia represent a clinicopathological spectrum of disease.

Cell Nucleus↗