TDP-43 pathologic lesions and clinical phenotype in fro...

TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions

ABSTRACT

Background: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U).

Objective: To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43).

Design: Retrospective clinical-pathologic study.

Setting: Academic medical center.

Patients : Twenty-three patients with histopathologically proven FTLD-U.

Main Outcome Measures: Demographic, symptom, neuropsychological, and autopsy characteristics.

Results: There are notably different clinical and neuropsychological patterns of impairment in FTLD-U subtypes. Patients with FTLD-U/TDP-43 characterized by numerous neuronal intracytoplasmic inclusions have shorter survival; patients with FTLD-U/TDP-43 featuring numerous neurites have difficulty with object naming; and patients with FTLD-U/TDP-43 in whom neuronal intranuclear inclusions are present have substantial executive deficits. There are also different anatomical distributions of ubiquitin pathologic features in FTLD-U subgroups, consistent with their cognitive deficits.

Conclusion: Distinct TDP-43 profiles may affect clinical phenotypes differentially in patients with FTLD-U.


Grossman M, Wood EM, Moore P, Neumann M, Kwong L, Forman MS, Clark CM, McCluskey LF, Miller BL, Lee VM, Trojanowski JQ. TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions. Arch Neurol. 2007 Oct;64(10):1449-54.


INTRODUCTION

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease manifesting as language dysfunction or as a disorder of social comportment and executive functioning.1-2 This condition is as common as Alzheimer disease in individuals younger than 65 years.3-5 The single most common histopathological diagnosis associated with FTD is frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U),6-8 characterized by ubiquitin-positive and tau-negative and {alpha}-synuclein–negative inclusions. Similar pathologic inclusions are seen in motor neuron disease (MND), a neurodegenerative disease affecting motor neurons in which a disorder of social, executive, or language functioning may co-occur in up to half of these patients.9-10

Until recently, the ubiquitinated protein in FTLD-U was unidentified. TDP-43 is now known to be a major disease protein in FTLD-U and MND, and pathologic TDP-43 is ubiquitinated, phosphorylated, and fragmented in these disorders.11-12 TDP-43 is specific to the ubiquitinated inclusions of FTLD-U, and the diagnostic inclusions in Parkinson disease (Lewy bodies) or in Alzheimer disease (neurofibrillary tangles and senile plaques) are not detected with antibodies to TDP-43. Several FTLD-U subtypes have been described using staining with antibodies to ubiquitin13-14 and TDP-43.11-12 As summarized in Table 1, FTLD-U1 (type 1 in the scheme by Sampathu et al,14 equivalent to type 2 in the study by Mackenzie et al13) is characterized by numerous neurites, few neuronal cytoplasmic inclusions (NCIs), and no neuronal intranuclear inclusions (NIIs). FTLD-U2 (type 2 in the scheme by Sampathu et al,14 equivalent to type 3 in the scheme by Mackenzie et al13) contains numerous NCIs, rare neurites, and no NIIs. FTLD-U3 (type 3 in the scheme by Sampathu et al,14 equivalent to type 1 in the study by Mackenzie et al13) consists of numerous NCIs and neurites, and NIIs are present. A previous study15 documented the clinical syndromes associated with these subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43), although descriptions such as semantic dementia, progressive nonfluent aphasia, and social-executive disorder can be unstable over time and difficult to distinguish later in the course of the disease. In this study, we report the clinical features of patients with subtypes of FTLD-U pathologic features as defined by immunostaining for TDP-43. We focus on quantitative neuropsychological performance, and we relate this to the neuroanatomical distribution of histopathological disease.


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Table 1. Schemes for Subclassifying TDP-43 Subtypes

TDP-43 Characteristics

++Neurites, +NCIs, and -NIIs
Type 1 (Sampathu et al 14)
Type 2 (Mackenzie et al 13)

+Neurites, ++NCIs, and -NIIs
Type 2 (Sampathu et al 14)
Type 3 (Mackenzie et al 13)

++Neurites, ++NCIs, and +NIIs
Type 3 (Sampathu et al 14)
Type 1 (Mackenzie et al 13)
___
NCIs, neuronal cytoplasmic inclusions
NIIs, neuronal intranuclear inclusions
+ present
++ abundant
- absent

Sampathu et al 14 observed prominent neurites, few NCIs and no NIIs (their type 1) in superficial frontal and temporal cortical layers, as well as in dentate gyrus and the striatum; prominent NCIs with few neurites and no NIIs (their type 2) in superficial and deep frontal and temporal cortical layers, as well as in dentate gyrus and the striatum; and the presence of NIIs together with NCIs and neurites in superficial frontal and temporal cortical layers and the dentate gyrus. Mackenzie et al 13 observed prominent neurites and NCIs with NIIs (their type 1) in layer II of frontal and temporal cortex and granule cells of the dentate gyrus; neurites, when present largely in isolation (their type 2), were evident in layer II of the cereral cortex; NCIs, when present largely in isolation (their type 3), were evident in corticl layer II or granule cells off the dentate gyrus.
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METHODS

Subjects

Twenty-three patients with the pathological diagnosis of FTLD-U were investigated in this study. The brains were identified in the consecutive pathological series collected between 1995 and 2006 at the Center for Neurodegenerative Disease Research at the University of Pennsylvania School of Medicine and represent about 29% of a series of patients with the diagnosis of an FTD spectrum disorder.6 All patients were diagnosed by experienced neurologists in the departments of neurology at the University of Pennsylvania School of Medicine (M.G., C.M.C., and L.F.M.) or at the University of California, San Francisco (B.L.M.), according to published criteria.16-17 Subgroup diagnosis was assigned using a consensus mechanism based on a modification of published criteria.18-19 All cases were carefully screened for MND. Clinical diagnosis was based on informant interview, medical history, neurological examination, neuropsychological evaluation, laboratory screening, and brain imaging when available (including magnetic resonance imaging, single-photon emission computed tomography, or positron emission tomography). Because the patients came from multiple clinics by different investigators during a 10-year period, there was variability in the clinical data obtained and in the approach to clinical diagnosis. Clinical data were obtained from medical record review in patients in whom autopsy occurred before 2000 and were collected prospectively in patients with autopsy since 2000. Demographic characteristics are summarized in Table 1. Disease duration (survival) was computed from the time of symptom onset until death. Symptom onset was based on a family report of the earliest persistently abnormal clinical feature in the domains of language, memory, executive functioning, visual-spatial functioning, movement disorder or weakness, and social function or personality change.

Symptoms tabulated at presentation included focal weakness, language dysfunction, movement disorder, social or behavioral changes, and other cognitive complaints (eg, memory loss, inattention, planning disorder, or visual-spatial complaints). A limited battery of neuropsychological measures was obtained on a subset of patients as part of the routine evaluation at the University of Pennsylvania School of Medicine and at the University of California, San Francisco. This included the following 6 measures: (1) dementia (Mini-Mental State Examination [a 30-point scale surveying dementia severity]), (2) visual perceptual-spatial functioning (geometric design [copying geometric designs graded in difficulty]), (3) social functioning (social scale [a 6-point scale surveying disorders of social comportment and personality]), (4) language (confrontation naming [correct confrontation naming of black-and-white line drawings from an abbreviated version of the Boston Naming Test]), (5) memory (delayed recall [correct recall of 10 words after a brief delay following presentation during 3 learning trials] and recognition [correct recognition of the 10 words interspersed among 10 foils, probed following delayed recall]), and (6) executive functioning (digit span forward [the longest series of numbers repeated correctly in the presented order], digit span reverse [the longest series of numbers repeated correctly in an order reversing the order of presentation], and category naming fluency [the number of different animals named in 60 seconds]).

Neuropathological Evaluation

The neuropathological evaluations were performed as described previously.6 All cases were reviewed by 3 board-certified neuropathologists (M.N., M.S.F., and J.Q.T.) in a manner blinded to the clinical diagnoses. Using established criteria,17, 20-24 we identified brains with ubiquitin-positive and tau-negative and {alpha}-synuclein–negative inclusions (ie, FTLD-U). All cases without any inclusions were classified as dementia lacking distinctive histology and were excluded from this study. We analyzed 8 regions, including subcortical nuclei (striatum with nucleus basalis), limbic system (hippocampus and amygdala with entorhinal cortex), and cortex (midfrontal gyrus, inferoparietal lobule, superior and middle temporal gyri, anterior cingulate gyrus, and calcarine cortex). The spinal cord was not available in most of these cases, so we cannot exclude the possibility that clinically unapparent MND was underdiagnosed in this cohort. Semiquantitative methods were used to assess the density of immunostained ubiquitin lesions,25 and grading was assigned (0, no or rare pathologic findings; 1, low pathologic findings; 2, moderate pathologic findings; and 3, high pathologic findings) in each analyzed brain region. As described in detail elsewhere and as summarized in Table 1,14, 26 subtypes of FTLD-U were established on the basis of monoclonal antibodies. Frontotemporal lobar degeneration with ubiquitin-positive inclusions type 1 (FTLD-U1, equivalent to type 2 in the study by Mackenzie et al13) was recognized by monoclonal antibody 182 and consisted of frequent neurites and some NCIs but no NIIs; FTLD-U type 2 (FTLD-U2, equivalent to type 3 in the study by Mackenzie et al13) was recognized by monoclonal antibody 406 and was characterized by frequent NCIs and some neurites but no NIIs; and FTLD-U type 3 (FTLD-U3, equivalent to type 1 in the study by Mackenzie et al13) was identified by ubiquitin inclusions staining for neither of these monoclonal antibodies and contained NCIs, neurites, and NIIs. These analyses were based on an analysis of 1 section per region, and agreement between raters was good ({kappa} statistic, 0.75; 95% confidence interval, 0.52-0.98). The definition of these FTLD-U subtypes, all of which are characterized by TDP-43 pathologic lesions, also was confirmed using polyclonal antibodies to TDP-43.12

Statistical Analysis

Because of the few patients constituting the FTLD-U/TDP-43 subgroups, nonparametric statistical tests were used to evaluate the demographic characteristics, frequencies of clinical features, neuropsychological performance, and severity of the histopathological abnormalities. Neuropsychological measures were converted to z scores in each individual relative to 25 age-matched and education-matched healthy control subjects so that relative performance could be compared across measures with different numbers of items and different inherent levels of difficulty and so that statistically significant deficits could be identified in individuals constituting these small subgroups.


RESULTS

Clinical and demographic characteristics of patients with FTLD-U/TDP-43 are summarized in Table 2. Age at onset did not differ among patients with the FTLD-U/TDP-43 subtypes. The mean ± SD age at onset of patients with FTLD-U/TDP-43 was 61.5 ± 8.9 years (range, 46-78 years). This is similar to tauopathies (mean age at onset, 61.0 years)6 but is somewhat older than the mean age at onset of 54.8 years among patients with dementia lacking distinctive histopathology and is younger than the mean age at onset of 71.4 years among patients with Alzheimer disease.6 The mean ± SD survival in FTLD-U/TDP-43 is 87.3 ± 32.5 months (range, 20-156 months). The difference in survival among FTLD-U/TDP-43 subtypes approaches significance ({chi}22 = 4.81, P < .09). Although the small numbers of patients in these subgroups limit interpretation, survival among patients with FTLD-U2 is half as long as that among patients with FTLD-U1 and is substantially less than that among patients with FTLD-U3. This could not be entirely attributed to the presence of MND in 1 patient with FTLD-U2 because the disease duration associated with this TDP-43 subtype (20 months in the MND case and mean durations of 48 months and 84 months in the other 2 subtypes) was less than the disease duration of most patients with FTLD-U1 pathologic lesions (the disease duration in only 1 patient was <72 months). Disease duration in the MND case with FTLD-U3 was 24 months. PGRN mutations occurred only in association with FTLD-U3. A statistical comparison of patients with FTLD-U3 with PGRN mutations compared with those without PGRN mutations failed to reveal any differences. Likewise, comparisons of the clinical and pathological features associated with these FTLD-U3 subgroups (described herein) failed to reveal any differences.


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Table 2. Clinical and Demographic Characteristics of Patients With Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions (FTLD-U) and TDP-43 Inclusions(a)

Characteristic

Male sex
* FTLD-U1: 5
* FTLD-U2: 2
* FTLD-U3: 4

Clinical diagnosis

- Motor neuron disease
* FTLD-U1: 0
* FTLD-U2: 1
* FTLD-U3: 1

- Other(b)
* FTLD-U1: 1
* FTLD-U2: 0
* FTLD-U3: 4

- FTD
* FTLD-U1: 8
* FTLD-U2: 2
* FTLD-U3: 6


Clinical FTD phenotype

- Progressive nonfluent aphasia
* FTLD-U1: 1
* FTLD-U2: 0
* FTLD-U3: 2

- Semantic dementia
* FTLD-U1: 3
* FTLD-U2: 0
* FTLD-U3: 0

- Social-executive disorder
* FTLD-U1: 4
* FTLD-U2: 2
* FTLD-U3: 4

- PGRN mutation present
* FTLD-U1: 0
* FTLD-U2: 0
* FTLD-U3: 4

Age at onset, y
* FTLD-U1: 61.6±9.0
* FTLD-U2: 57.6±13.9
* FTLD-U3: 60.5±8.9

Age at testing, y
* FTLD-U1: 66.2±9.0
* FTLD-U2: 60.7±13.6
* FTLD-U3: 63.0±9.3

Education, y
* FTLD-U1: 13.7±2.2
* FTLD-U2: 14.7±2.3
* FTLD-U3: 15.2±2.9

Disease duration, mo
* FTLD-U1: 100.3±39.0
* FTLD-U2: 50.7±32.1
* FTLD-U3: 74.8±29.5
___
FTD = frontotemporal dementia
(a) Data are given as number of patients or as mean±SD
(b) Three patients were given the clinical diagnosis of Alzheimer disease, and 2 patients were given the clinical diagnosis of Lewy body disease.
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Table 3 summarizes the initial clinical features of patients with FTLD-U/TDP-43. Symptoms at onset involved many domains of cognitive and motor functioning, but these complaints were not identical across FTLD-U/TDP-43 subgroups ({chi}26 = 52.9, P < .001). These differences remained even if patients with MND were removed from the analysis ({chi}26 = 45.3, P < .001). Although we were able to observe only a few patients, we found that social complaints were present in all patient subgroups, that patients with FTLD-U1 also have an equivalent amount of language complaints, and that patients with FTLD-U3 have language and memory complaints that are less prominent. Visual-perceptual and motor complaints are rare at presentation in these patients.


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Table 3. Clinical Symptoms at Onset in Patients With Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions (FTLD-U) and TDP-43 Inclusions

Symptom: Number of patients (%)

Social
* FTLD-U1: 6 (66.7)
* FTLD-U2: 2 (66.7)
* FTLD-U3: 10 (90.9)

Language (a)
* FTLD-U1: 6 (66.7)
* FTLD-U2: 1 (33.3)
* FTLD-U3: 6 (54.5)

Memory
* FTLD-U1: 3 (33.3)
* FTLD-U2: 0
* FTLD-U3: 6 (54.5)

Executive
* FTLD-U1: 2 (22.2)
* FTLD-U2: 1 (33.3)
* FTLD-U3: 3 (27.3)

Visual-perceptual
* FTLD-U1: 0
* FTLD-U2: 0
* FTLD-U3: 0

Motor-pyramidal
* FTLD-U1: 0
* FTLD-U2: 0
* FTLD-U3: 1 (9.1)

Motor-extrapyramidal
* FTLD-U1: 0
* FTLD-U2: 1 (33.3)
* FTLD-U3: 1 (9.1)

___
(a) The primary initial symptom in both cases of motor neuron disease was speech difficulty.
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Table 4 summarizes the neuropsychological assessment of patients in whom scores are available. The FTLD-U/TDP-43 subgroups differed in their neuropsychological profiles ({chi}27 = 20.6, P < .002), although the Mini-Mental State Examination scores did not differ across FTLD-U/TDP-43 subtypes ({chi}22 = 2.4, P = .12). Although our findings must be interpreted cautiously because of the small numbers of patients, subgroup differences were seen for digit span forward ({chi}22 = 7.2, P < .03) and for digit span reverse ({chi}22 = 5.6, P < .06). Using a z score criterion of –2.32 (equivalent to P < .01, 2-tailed) to evaluate subgroup performance, only patients with FTLD-U3 were statistically significantly impaired on measures of executive functioning such as digit span. Using a z score criterion of less than –1.96 (P < .05, 2-tailed) to assess individual patient performance on these 2 tasks, we found that 60% of scores were statistically significantly impaired in individual patients with FTLD-U3 who were assessed, while none of the scores were impaired in patients with FTLD-U1, and only 1 of the scores was impaired in patients with FTLD-U2. A subgroup difference was also seen for confrontation naming ({chi}22 = 5.7, P < .05). The greatest naming deficit was in patients with FTLD-U1; every individual patient with FTLD-U1 who was tested had statistically significant naming difficulty (using a z score criterion of less than –1.96), although this deficit was present in 1 patient with FTLD-U2 and in 1 patient with FTLD-U3. Category naming fluency, a language-mediated executive measure, was statistically significantly impaired in all 3 of the FTLD-U/TDP-43 subgroups. A statistically significant deficit was present in all but 1 of the patients with FTLD-U1 and in only 1 of the patients with FTLD-U3 who were tested. Memory recall was statistically significantly impaired in 3 patients with FTLD-U1, in 1 patient with FTLD-U2, and in 2 patients with FTLD-U3 who were tested. All subgroups showed a statistically significant deficit for memory recognition according to z scores. However, this seemed to be due to a large deficit in 2 individual patients in each subgroup. All patient subgroups showed a moderate level of social disorder.


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Table 4. Neuropsychological Performance of Patients With Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions (FTLD-U) and TDP-43 Inclusions(a)

* FTLD-U1: n=9
* FTLD-U2: n=3(b)
* FTLD-U3: n=11

Task

Mini-Mental State Exam (n=20)
* FTLD-U1: 22.4±7.9
* FTLD-U2: 18,7±7.1
* FTLD-U3: 24.8±6.2

Digits forward (n=10)c
* FTLD-U1: 0.46±0.6
* FTLD-U2: -1.0
* FTLD-U3: -2.24±0.9

Digits reverse (n=9)c
* FTLD-U1: 0.98±1.3
* FTLD-U2: -2.1
* FTLD-U3: -2.38±1.2

Category naming fluency (n=15)
* FTLD-U1: -2.99±0.6
* FTLD-U2: -2.95±1.5
* FTLD-U3: -2.57±0.7

Confrontation naming (n=11)b
* FTLD-U1: -6.59±1.7
* FTLD-U2: -2.35±1.1
* FTLD-U3: -2.61±3.1

Memory recall (n=13)
* FTLD-U1: -2.00±1.6
* FTLD-U2: -3.9
* FTLD-U3: -1.89±1.6

Geometric design (n=12)
* FTLD-U1: -0.07±1.4
* FTLD-U2: -0.3
* FTLD-U3: -0.80±1.8

Social scale (n=12)
* FTLD-U1: 0.43±0.3
* FTLD-U2: 0.3
* FTLD-U3: 0.48±0.3
___
(a) Data are given as mean±SD z scores relative to 25 age-matched and education -matched healthy control subjects except for the raw score of the Mini-Mental State Examination (maximum score 30) and the social scale (maximum score, 1.00). The statistical threshold for the groupwise deficit was set at a z score of less than -2.32 (P<0.01). The disease duration at the time of testing (FTLD-U1, 51.8 months, FTLD-U2, 37.0 months; and FTLD-U3, 36.6 months) did not statistically significantly differ across subgroups.
(b) Values without a standard deviation are for a single case.
(c) Between-group differences were present for these measures according to the Kruskal-Wallis test.
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The pathological assessment of these patients is summarized in Table 5. Ubiquitin and TDP-43 pathologic lesions differed in their anatomical distribution across FTLD-U/TDP-43 subgroups ({chi}27 = 14.7, P < .04), although the overall histopathological burden did not differ between subgroups ({chi}22 = 3.33, P = .07). Pathologic lesions were dense in lateral temporal cortex and entorhinal portions of the medial temporal lobe in patients with FTLD-U1, while the densest pathologic change in FTLD-U3 was in midfrontal cortex. Ubiquitin and TDP-43 pathologic findings differed statistically significantly across subgroups in the hippocampal region ({chi}22 = 6.2, P < .05) because of substantial disease in FTLD-U1 and FTLD-U2. Ubiquitin and TDP-43 pathologic lesions were also moderately dense in the amygdala region in all subgroups but were less dense in parietal, cingulate, and deep gray regions, including the striatum. These findings must be interpreted cautiously because of the small numbers of samples in each subgroup.


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Table 5. Grading of Ubiquitin Pathologic Findings in Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions (FTLD-U) and TDP-43 Inclusions(a)

* FTLD-U1: n=9
* FTLD-U2: n=3
* FTLD-U3: n=11

Region

Overall ubiquitin burden
* FTLD-U1: 1.5±0.5
* FTLD-U2: 1.6±0.3
* FTLD-U3: 1.1±0.6

Midtemporal cortex (n=23)
* FTLD-U1: 2.2±0.8
* FTLD-U2: 1.0±0.0
* FTLD-U3: 1.5±1.0

Entorhinal cortex (n=23)
* FTLD-U1: 2.2±0.7
* FTLD-U2: 2.0±1.0
* FTLD-U3: 1.5±1.4

Hippocampus (n=23)
* FTLD-U1: 1.8±0.8
* FTLD-U2: 2.0±1.0
* FTLD-U3: 0.8±1.0

Amygdala (n=19)
* FTLD-U1: 1.4±1.1
* FTLD-U2: 2.5±0.7
* FTLD-U3: 1.3±1.1

Midfrontal cortex (n=23)
* FTLD-U1: 1.3±0.9
* FTLD-U2: 1.3±0.6
* FTLD-U3: 1.6±1.2

Parietal cortex (n=20)
* FTLD-U1: 1.1±0.8
* FTLD-U2: 1.3±0.6
* FTLD-U3: 1.1±1.1

Cingulate cortex (n=12)
* FTLD-U1: 1.3±1.5
* FTLD-U2: 1.5±0.7
* FTLD-U3: 0.7±1.0

Striatum (n=19)
* FTLD-U1: 0.8±1.0
* FTLD-U2: 2.0±0.0
* FTLD-U3: 0.8±0.7
---
(a) Daa are given as mean±SD semiquantitative score on a scale of 0 (none) to 3 (dense)
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COMMENT

We examined the clinical phenotypes associated with subtypes of FTLD-U defined by immunostaining for pathologic TDP-43. Differences were found in the clinical characteristics of FTLD-U/TDP-43 subtypes, implicating pathologic TDP-43 in the phenotype associated with patients with FTLD-U. Patients with FTLD-U3 seem to have executive dysfunction, and their pathologic lesions are dense in midfrontal cortex. By comparison, patients with FTLD-U1 have statistically significant impairment with naming, and their pathologic lesions are dense in temporal cortex. Therefore, distinct phenotypes are evident in FTLD-U/TDP-43 subgroups, and these seem to be determined at least in part by the distribution of their pathologic lesions.

A possible explanation for this finding is that specific conformations of pathologic TDP-43 or the extent of its abnormal ubiquitination, phosphorylation, or cleavage has a predilection for a particular anatomical distribution or differentially affects neuronal function or viability in a specific brain region. For example, the dense lateral temporal pathologic lesions in patients with FTLD-U1 who have the greatest naming difficulty is consistent with this possibility. This may be related in part to the increased frequency of the semantic dementia phenotype in this FTLD-U/TDP-43 subgroup. Findings from another study13 associated the form of pathologic lesion seen in this subgroup with semantic dementia. Likewise, prefrontal pathologic lesions were abundant in the patients with FTLD-U3 with executive limitations in the present study, and Mackenzie and coworkers13 observed a disorder of social comportment and executive functioning in patients with these pathologic findings. We also found that episodic memory is most impaired in patients with FTLD-U1 and FTLD-U2, who have more extensive hippocampal pathologic findings than patients with FTLD-U3. Our use of quantitative observations allowed us to establish a direct relationship between clinical impairment and the neuroanatomical distribution of disease burden that is less sensitive to the shifting syndromic diagnoses known to occur in FTD.15 This is consistent with an extensive literature implicating regional disease burden in the cognitive profiles of patients with neurodegeneration.6, 27-30 Our observations must be tempered by the fact that small numbers of patients were investigated in this study and that clinical evaluation was separated from the time of death by many months. Nevertheless, groupwise statistical contrasts seem to reflect individual patient performance profiles. Cognitive differences in FTLD-U/TDP-43 subgroups are unlikely to be due to the age at onset, the age at the time of testing, overall dementia severity, or overall histopathological burden because the subgroups were matched on these factors. These clinical differences are unlikely to reflect differences in disease duration between FTLD-U/TDP-43 subgroups. There may be greater naming difficulty in FTLD-U1 because these patients have longer disease duration, allowing the disease to compromise temporal cortical functioning for a longer period. However, this would not explain the statistically significantly greater executive difficulty in FTLD-U3 (ie, cognitive difficulties in patients with briefer survival). PGRN mutations were observed only in FTLD-U3, but a direct statistical comparison of FTLD-U cases with PGRN mutations compared with FTLD-U cases without PGRN mutations did not reveal regional or overall differences in histopathological severity.31 Although findings from previous studies32-33 associate more severe language difficulty with PGRN mutations, a recent series of patients with FTLD-U with PGRN mutations did not show more severe language difficulty than patients with FTLD-U without PGRN mutations.31 Regardless of the basis for cognitive difficulties associated with FTLD-U subtypes, selective impairment in specific cognitive domains suggests that TDP-43 pathologic lesions have a substantial effect on the clinical phenotype in FTLD-U/TDP-43. This emphasizes the disease-causing importance of this protein in FTD and underlines TDP-43 as an important target for drug development.

There has been considerable controversy in the literature examining survival in FTD. Some work suggests that tau-negative pathologic conditions such as FTLD-U are associated with a briefer survival.34-35 This finding persists after excluding cases with clinical MND, a condition with tau-negative pathologic lesions known to have a poor prognosis.36-37 We and others13 found a statistically significant difference in survival among subgroups of patients with different FTLD-U/TDP-43 pathologic patterns. This observation should be interpreted cautiously because of the difficulty in establishing the onset of a neurodegenerative disease with any precision. Nevertheless, patients with FTLD-U1 seemed to have longer disease duration than patients with FTLD-U2 and FTLD-U3 in the present study. This is unlikely to be entirely because of the poor survival in MND because of the small number of participants with MND in our study. A previous study13 described briefer survival in the subgroup of patients with FTLD-U/TDP-43 with numerous NCIs, few neurites, and no NIIs, consistent with the pathologic profile seen in FTLD-U2, although this may have been confounded in part by the large number of patients with clinical features of MND in this subgroup. Additional work with larger numbers of patients is needed to assess the role of FTLD-U/TDP-43 pathologic lesions on survival. Investigations found no difference in the survival of individuals with tau-negative pathologic conditions compared with tau-positive pathologic conditions such as Pick disease,15, 38-39 but other work demonstrated that tau-negative pathologic conditions are associated with longer survival than tau-positive pathologic conditions.40 Some of these discrepancies seem in part to be related to the different kinds of pathologic lesions contributing to the tau-positive subgroups in these studies. Therefore, studies15, 40 with larger numbers of patients with corticobasal degeneration seem to be associated with briefer survival in tau-positive patient subgroups. Findings from the present study suggest that an additional source of variability in the survival of patients with FTD is the specific type of TDP-43 pathologic lesion seen in patients with FTLD-U with tau-negative pathologic findings. Indeed, this may represent a notable confound in previous studies6, 8 investigating survival because FTLD-U/TDP-43 represents such a large proportion of the cases in tau-negative subgroups.


AUTHOR INFORMATION

Correspondence: Murray Grossman, MD, Department of Neurology, University of Pennsylvania School of Medicine, 2 Gibson, 3400 Spruce St, Philadelphia, PA 19104-4283 (mgrossma@mail.med.upenn.edu).

Accepted for Publication: April 8, 2007.

Author Contributions: Study concept and design: Grossman, Lee, and Trojanowski. Acquisition of data: Grossman, Wood, Moore, Neumann, Kwong, Forman, Clark, McCluskey, Miller, Lee, and Trojanowski. Analysis and interpretation of data: Grossman, Wood, Moore, Neumann, and Forman. Drafting of the manuscript: Grossman, Lee, and Trojanowski. Critical revision of the manuscript for important intellectual content: Wood, Moore, Neumann, Kwong, Forman, Clark, McCluskey, Miller, Lee, and Trojanowski. Statistical analysis: Lee. Obtained funding: Grossman, Miller, Lee, and Trojanowski. Administrative, technical, and material support: Wood, Moore, Kwong, Forman, McCluskey, Lee, and Trojanowski. Study supervision: Trojanowski.

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by grants AG17586 (Dr Lee), AG15116 (Dr Grossman), AG20073 (Dr Miller), and NS44266 (Dr Grossman) from the National Institutes of Health and the Dana Foundation (Dr Grossman).

Author Affiliations: Departments of Neurology (Drs Grossman, Clark, and McCluskey and Ms Moore) and Pathology and Laboratory Medicine (Ms Wood and Drs Kwong, Forman, Lee, and Trojanowski), Center for Neurodegenerative Disease Research (Ms Wood and Drs Neumann, Kwong, Forman, Lee, and Trojanowski), and Alzheimer's Disease Center (Dr Clark), University of Pennsylvania School of Medicine, Philadelphia; Center for Neuropathology and Prion Research, Ludwig Maximilian University of Munich, Munich, Germany (Dr Neumann); and Department of Neurology, University of California, San Francisco (Dr Miller).


REFERENCES

1. Grossman M. Frontotemporal dementia: a review. J Int Neuropsychol Soc. 2002;8(4):566-583. FULL TEXT | ISI | PUBMED
2. Snowden JS, Neary D, Mann DM. Fronto-temporal Lobar Degeneration: Fronto-temporal Dementia, Progressive Aphasia, Semantic Dementia. New York, NY: Churchill Livingstone; 1996.
3. Knopman DS, Petersen RC, Edland SD, Cha RH, Rocca WA. The incidence of frontotemporal lobar degeneration in Rochester, Minnesota, 1990 through 1994. Neurology. 2004;62(3):506-508. FREE FULL TEXT
4. Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology. 2002;58(11):1615-1621. FREE FULL TEXT
5. Rosso SM, Kaat LD, Baks T; et al. Frontotemporal dementia in the Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003;126(pt 9):2016-2022. FREE FULL TEXT
6. Forman MS, Farmer J, Johnson JK; et al. Frontotemporal dementia: clinicopathological correlations. Ann Neurol. 2006;59(6):952-962. FULL TEXT | ISI | PUBMED
7. Hodges JR, Davies RR, Xuereb J; et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol. 2004;56(3):399-406. FULL TEXT | ISI | PUBMED
8. Lipton AM, White CL, Bigio EH. Frontotemporal lobar degeneration with motor neuron disease–type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol (Berl). 2004;108(5):379-385. FULL TEXT | PUBMED
9. Lomen-Hoerth C, Anderson T, Miller BL. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002;59(7):1077-1079. FREE FULL TEXT
10. Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology. 2003;60(7):1094-1097. FREE FULL TEXT
11. Davidson Y, Kelley T, Mackenzie IR; et al. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl). 2007;113(5):521-533. FULL TEXT | PUBMED
12. Neumann M, Sampathu DM, Kwong LK; et al. Ubiquinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-133. FREE FULL TEXT
13. Mackenzie IR, Baborie A, Pickering-Brown S; et al. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl). 2006;112(5):539-549. FULL TEXT | PUBMED
14. Sampathu DM, Neumann M, Kwong LK; et al. Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol. 2006;169(4):1343-1352. FREE FULL TEXT
15. Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain. 2005;128(pt 9):1996-2005. FREE FULL TEXT
16. Lund and Manchester Groups. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry. 1994;57(4):416-418. FREE FULL TEXT
17. McKhann GM, Trojanowski JQ, Grossman M, Miller BL, Dickson D, Albert M. Clinical and pathological diagnosis of frontotemporal dementia: report of a work group on frontotemporal dementia and Pick's disease. Arch Neurol. 2001;58(11):1803-1809. FREE FULL TEXT
18. Grossman M, Ash S. Primary progressive aphasia: a review. Neurocase. 2004;10(1):3-18. FULL TEXT | ISI | PUBMED
19. Neary D, Snowden JS, Gustafson L; et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546-1554. FREE FULL TEXT
20. National Institute on Aging; and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging. 1997;18(4)(suppl):S1-S2. FULL TEXT | ISI | PUBMED
21. Dickson DW, Bergeron C, Chin SS; et al. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol. 2002;61(11):935-946. ISI | PUBMED
22. Gilman S, Low PA, Quinn N; et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. 1999;163(1):94-98. FULL TEXT | ISI | PUBMED
23. Hauw JJ, Daniel SE, Dickson D, Horoupian D, Jellinger K, Lantos P. Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994;44(11):2015-2019. FREE FULL TEXT
24. McKeith IG, Fairbairn AF, Bothwell RA; et al. An evaluation of the predictive validity and inter-rater reliability of clinical diagnostic criteria for senile dementia of the Lewy body type. Neurology. 1994;44(5):872-877. FREE FULL TEXT
25. Forman MS, Mackenzie IR, Cairns NJ; et al. Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol. 2006;65(6):571-581. PUBMED
26. Cairns NJ, Neumann M, Mackenzie IR; et al. Neuropathologic heterogeneity in familial and sporadic TDP-43 proteinopathy. Am J Pathol. In press.
27. Fleischman DA, Wilson RS, Gabrieli JDE, Schneider JA, Bienias JL, Bennett DA. Implicit memory and Alzheimer's disease neuropathology. Brain. 2005;128(pt 9):2006-2015. FREE FULL TEXT
28. Grossman M, Libon DJ, Forman MS; et al. Distinct antemortem profiles in pathologically defined patients with frontotemporal dementia. Arch Neurol. In press.
29. Harasty JA, Halliday GM, Xuereb J, Croot K, Bennett H, Hodges JR. Cortical degeneration associated with phonologic and semantic language impairments in AD. Neurology. 2001;56(7):944-950. FREE FULL TEXT
30. Lipton AM, Cullum CM, Satumtira S; et al. Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias. Arch Neurol. 2001;58(8):1233-1239. FREE FULL TEXT
31. Van Deerlin VMD, Wood EM, Moore P; et al. Clinical, genetic, and pathological characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol. 2007;64(8):1148-1153. FREE FULL TEXT
32. Gass J, Cannon A, Mackenzie IR; et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006;15(20):2988-3001. FREE FULL TEXT
33. Mesulam M, Johnson N, Krefft TA; et al. Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol. 2007;64(1):43-47. FREE FULL TEXT
34. Hodges JR, Davies R, Xuereb J, Kril JJ, Halliday GM. Survival in frontotemporal dementia. Neurology. 2003;61(3):349-354. FREE FULL TEXT
35. Roberson ED, Hesse JH, Rose KD; et al. Frontotemporal dementia progresses to death faster than Alzheimer disease. Neurology. 2005;65(5):719-725. FREE FULL TEXT
36. del Aguila MA, Longstreth WT, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology. 2003;60(5):813-819. FREE FULL TEXT
37. Sorenson EJ, Stalker AP, Kurland LT, Windebank AJ. Amyotrophic lateral sclerosis in Olmsted County, Minnesota, 1925 to 1998. Neurology. 2002;59(2):280-282. FREE FULL TEXT
38. Josephs KA, Knopman DS, Whitwell JL; et al. Survival in two variants of tau-negative frontotemporal lobar degeneration: FTLD-U vs FTLD-MND. Neurology. 2005;65(4):645-647. FREE FULL TEXT
39. Rascovsky K, Salmon DP, Lipton AM; et al. Rate of progression differs in frontotemporal dementia and Alzheimer disease. Neurology. 2005;65(3):397-403. FREE FULL TEXT
40. Xie SX, Forman MS, Farmer J; et al. Factors associated with survival probability in autopsy-proven frontotemporal dementia. J Neurol Neurosurg Psychiatry. In press.