In this series of seventeen consecutive patients referred to a dementia specialty clinic who were later found to have CBD neuropathology, five presented with behavioral-variant frontotemporal dementia. The neuropsychological, neuropsychiatric, sensory/motor, and neuroanatomic features of this bvFTD(CBD) subgroup showed substantial overlap with findings in a comparison group of bvFTD patients with Pick’s disease neuropathology.
While CBD and Pick’s disease are both tauopathies, and can both result in a bvFTD clinical syndrome, they are neuropathologically distinct diseases. CBD is a 4-repeat (4R) tauopathy featuring swollen achromatic neurons, tau-positive neurofibrillary tangles, and tau-immunoreactive astrocytic plaques, coiled bodies, and threads unique to CBD, while Pick’s disease involves neuronal aggregates of hyperphosphorelated 3R tau known as Pick’s bodies (Dickson et al., 2002
; Cairns et al., 2007
; Ludolph et al., 2009
). Clinically, CBD is known to present as anatomically and behaviorally distinct syndromes, including classical CBS, PNFA, Alzheimer’s disease, and bvFTD. This demonstrates that CBD-related tau misfolding and aggregation can compromise and spread within several closely related networks, with preferred targets in the opercular and premotor cortices, but also involving divergent regions in both hemispheres. This flexibility in the neuronal vulnerability pattern drives the diverse clinical syndromes manifested in CBD. Preferred but flexible vulnerability is well-established for other neurodegenerative diseases, such as Alzheimer’s disease, in which patients most often develop an amnestic syndrome but can also present with predominant language, visuospatial, or even behavioral deficits (Alladi et al., 2007
). This ability of CBD to affect distinct networks implicated in other diseases raises the question of how closely CBD-based clinical syndromes mimic those resulting from non-CBD neuropathologies, because as treatments targeting specific neuropathological mechanisms appear, accurate prediction of underlying pathology from clinical syndrome becomes increasingly critical. Though CBD presenting as bvFTD has been described elsewhere (Kertesz et al., 2000
; Mathuranath et al., 2000
), cases occur infrequently enough to impede large scale studies of this subgroup.
Timing of disease onset and course did not help differentiate bvFTD patients with CBD versus Pick’s disease in our sample. In fact, the two bvFTD groups were nearly identical in age at symptom onset (CBD: median age 58, range 53–74; Pick’s: 60, 49–71), disease duration before presenting to a dementia specialist (CBD: 3.4 years ; Pick’s: 3.7 years), and disease duration at death (CBD: 7.6 years, range 3.8 – 12.7 ; Pick’s: 7.2, 3.3–9.8), emphasizing the similarity of the disease mechanism underlying these distinct tauopathies. Other studies have shown similar, fulminant courses from first symptom to death for patients with CBD pathology presenting with any clinical syndrome: 64.9 months (Murrary, et al., 2007); 6.1 years (Grimes, Lang, & Bergeron, 1999
); 7.0 years (SD 3.0) (Josephs, et al., 2006
); and 7.9 years (SD 2.6) (Wenning, et al., 1998
), though two studies report a slightly longer symptom duration (10±4 years (Llado, et al., 2008
), 11.8±3.9 years (Roberson, et al., 2005
Clinical asymmetry is a factor often hypothesized to differentiate patients with CBD from those with other underlying pathologies. Existing diagnostic criteria suggest that asymmetry tilts the scales towards a clinical diagnosis of CBD and away from PSP or another tauopathy (Litvan, et al., 2003
). While this has clearly been supported in the case of patients presenting with a PNFA syndrome (Gorno-Tempini et al., 2004
; Knibb et al., 2006
), results have been mixed for patients with CBS or AD syndromes. While some quantitative imaging studies report asymmetric (L>R) atrophy and hypoperfusion (Soliveri et al., 1999
; Boxer et al., 2006
), others have found nearly symmetric involvement of left and right hemispheres (Groschel et al., 2004
; Josephs et al., 2008
). One confound is that studies that rely on clinical, not pathological findings will tend to be biased towards finding asymmetry if a CBD diagnosis was made more likely by asymmetry. Also, these studies group together all clinical variants with either suspected or proven CBD pathology, essentially washing out right versus left differences.
In a recent study that carefully characterized the different clinical syndromes of CBD patients and performed a laterality analysis, PNFA patients showed marked L>R hemispheric asymmetry, but patients with executive-motor predominant and bvFTD behavior-dominant syndromes showed consistently bilateral damage [Lee et al, in press, Archives of Neurology]. Our study includes the same subset of bvFTD(CBD) patients, who might have been expected to demonstrate an asymmetrically right-predominant disease pattern, perhaps mirroring left-sided patients with predominantly language symptoms (Gorno-Tempini et al., 2004
). Yet the laterality analysis in Lee et al suggests that the relative degree of frontal asymmetry ranged widely in these bvFTD(CBD) patients.. Thus, asymmetric involvement of the language-dominant hemisphere may remain a useful diagnostic criterion for predicting CBD pathology in some clinical presentations like PNFA or CBS; however, the absence of asymmetry should not be used to rule out CBD, particularly in cases with a bvFTD syndrome. These data do suggest that bvFTD patients with greater than expected left-sided relative to right-sided atrophy may be more likely to have underlying CBD pathology, since this pattern was seen in two bvFTD(CBD) patients and in none of the bvFTD(Pick’s) patients.
Minimal Cognitive and Motor Distinctions
Standard neuropsychological testing revealed no clear differences between the two bvFTD groups. There was a wide range of performance on all tasks across patients in both groups. This pattern is frequently seen when bvFTD patients undergo cognitive testing, because behavior problems such as apathy, inattention, disorganization, and stimulus-boundedness can cause haphazard, artificially diminished scores on tasks in otherwise unaffected domains.
Constructional difficulty, i.e., difficulty copying or drawing, has long been associated with clinical CBS (Graham, Bak, & Hodges, 2003
). Preservation of visuospatial functioning, on the other hand, is a secondary, supportive diagnostic feature of bvFTD (Neary et al., 1998
). However, a recent study of FTD-spectrum disorders found that a group of patients with tauopathies, 55% of whom had CBD pathology, were more likely than other tau-negative subtypes to have visuospatial deficits (Grossman et al., 2007
). While it is notable that some patients in both bvFTD groups in the present study performed at an impaired level on visuoconstruction testing, the fact that only one patient failed to correctly copy the pentagons on the MMSE suggests that these patients’ constructional impairment was mild at best, and may have been attributable in part to the executive disorganization or behavioral impulsiveness often seen in bvFTD. Both bvFTD groups in this study demonstrated some scattered parietal damage on VBM analysis, though only the bvFTD(Pick’s) group showed significantly lower volumes in parietal ROIs than controls, specifically in the inferior parietal and paracentral regions. Other tests of parietal functions showed a similarly variable pattern; e.g., only the bvFTD(Pick’s) group showed even mild apraxia, but the bvFTD(CBD) group was more likely to exhibit early acalculia. These mixed results in this small sample suggest that additional study of the etiologic mechanisms underlying this tauopathy-related visuoconstruction deficit is warranted.
Our study obtained very detailed neuropsychological evaluation of speech and language symptoms, including examiner ratings of many elements of spontaneous speech. While some patients in both bvFTD groups performed normally on every other speech and language measure, all patients performed in the impaired range on both lexical and category verbal fluency tests. Four out of five CBD patients and 3/5 Pick’s patients had reduced overall speech output by history, and two of the bvFTD(CBD) patients, who exhibited very impoverished spontaneous speech at the time of the initial evaluation, typically spoke only in stereotyped phrases or using placeholder words. Though patients in the bvFTD(Pick’s) group also used pat phrases, none of them showed this level of impoverishment. The degree to which these language deficits were due to involvement of the motor speech system, versus other aspects of the language system, is unclear. A literature review by Graham (Graham, Bak, & Hodges, 2003
) suggests that 63% of pathologically-proven CBD patients, regardless of syndromic diagnosis, are aphasic at presentation. In one study of clinically diagnosed CBD patients, every patient performed in the impaired range on lexical and category fluency tests, and had significant deficits in spelling and oral phoneme blending and segmentation (Graham, Bak, Patterson, & Hodges, 2003
). Alternatively, poor performance on fluency tasks in these bvFTD patients may also have resulted from an apathy-related reduction of speech.
In a finding that may implicate the motor system in at least part of the bvFTD(CBD) patients’ impairment on language testing, some patients in both bvFTD groups were described as having difficulty writing by history, particularly with spelling and word retrieval. However, only the bvFTD(CBD) patients (2/5, compared to 0/5 in the Pick’s group) failed to correctly write a full sentence on the MMSE (which was given full credit if it had a subject and a verb, regardless of whether there were spelling or grammatical errors). Also, 3/5 bvFTD(CBD) patients were found to have micrographia, while no bvFTD(Pick’s) patients exhibited this symptom. Micrographia has been associated with white matter lesions (Scolding & Lees, 1994
; Ishihara et al., 2006
) and with basal ganglia lesions (Kuoppamaki et al., 2005
; Gangadhar, Joseph, & Chakravarthy, 2008
), though such lesions were seen in both bvFTD groups in this study. There was also a trend towards bvFTD(CBD) patients having more typical features of parkinsonism, but the numbers were so small it was not clear whether this was truly a signal.
Overall, our data suggest that in a bvFTD patient, neither the absence of “typical” corticobasal symptoms (such as dystonia, alien limb, ideomotor apraxia, and myoclonus), nor even the absence of any motor symptoms at all, can rule out the presence of CBD pathology. However, they do suggest that suspicion of CBD in a bvFTD patient should increase with greater number and severity of symptoms consistent with parkinsonism.
Divergent neuroanatomic patterns in bvFTD
Both the CBD and Pick’s pathology groups met Neary clinical criteria for behavioral variant frontotemporal dementia (Neary, et al., 1998
), demonstrating a primarily behavioral syndrome consisting of apathy, disinhibition, aberrant personal behavior, and social behavior that was both insensitive and inappropriate. Quantitative neuroanatomic analysis demonstrated substantial overlap between bvFTD(CBD) and bvFTD(Pick’s) groups, and showed that the regions affected in bvFTD(CBD) patients are quite different from the left-sided, dorsolateral frontal-parietal pattern observed in studies of other CBD-based clinical syndromes. This involvement of “bvFTD-specific” networks in bvFTD(CBD) explains many of the behavioral features observed in this study. However, in both anatomy and quantitative neuropsychiatry, the overall clinical severity in the bvFTD(CBD) group appeared milder than that of the bvFTD(Pick’s) group, despite the fact that the two groups were nearly perfectly matched for disease duration, and there was an equal mix of mildly to severely impaired patients across both groups.
Close examination of atrophy patterns revealed that despite substantial damage to the inferior portions of the frontal cortex in bvFTD(CBD), the most medial and caudal portions of the OFC and subgenual cingulate, along with the ventral part of the insula and much of the frontoinsular rim, were relatively spared. This finding contrasts with the pattern observed in the bvFTD(Pick’s) patients, in which these regions were among the most severely affected, both in this study and in others (Brambati et al., 2007
; Seeley et al., 2008
). Many clinical researchers have noted that bvFTD patients can often be categorized into two groups: those with a predominantly disinhibited behavioral syndrome, with ventral > dorsal frontal atrophy, and those presenting with an apathy-predominant syndrome, typically involving dorsal > ventral frontal atrophy (Snowden et al., 2001
). In both anatomy and behavior, these bvFTD(CBD) patients uniformly present with the apathetic subtype of bvFTD. Apathy was their most severe symptom on the NPI, followed by motor, eating, and sleep disturbances. While all of the bvFTD(CBD) patients demonstrated some social disinhibition, caregivers rated these behaviors as relatively mild in comparison to those observed in the bvFTD(Pick’s) group. The relatively spared regions of the medial OFC are known to be involved in evaluation of both positive and negative reinforcers, emotion interpretation (Hornak et al., 2004
), and social disinhibition (Rosen et al., 2006
Despite the relative mildness of their disinhibition compared to the more florid bvFTD(Pick’s) patients, the bvFTD(CBD) patients did lose social comportment and the ability to recognize and adhere to social norms. This may be attributable to the substantial damage to other frontal structures seen in these bvFTD(CBD) patients, including the lateral orbitofrontal cortex and the most anterior, polar portions of the OFC. Damage to these regions has long been associated with bvFTD-like behavior change including decreased socialization, impulsivity, and impaired judgment (Rosen et al., 2005
). The lateral OFC is involved with assigning and evaluating negative behavioral reinforcers (Kringelbach & Rolls, 2004
). An inability to alter behavior to avoid potential punishment is consistent with the symptoms seen in the bvFTD(CBD) group, such as reckless driving, impulsive and irresponsible investments, spending, and donations, and extramarital promiscuity. Like the bvFTD(Pick’s) group, the bvFTD(CBD) group also showed substantial damage to more anterior structures, particularly the medial, polar regions of the OFC bilaterally. The frontal pole’s involvement in social cognition has been gaining recognition, and it has been implicated in complex processes such as interpersonal perspective taking (Gallagher & Frith, 2003
; Decety & Jackson, 2004
), goal-directed behavior (Kreuger, Barbey, & Grafman, 2009
), and prosocial cognition involving compassion, embarrassment, guilt, indignation, and emotional moral reasoning (Moll et al., 2007
; Moll, De Oliveira-Souza, & Zahn, 2008
). Failure to correctly reason about cognitive and emotional states of the self and other, coupled with a loss of automatic social sensitivity and responsiveness, are the hallmarks of the bvFTD syndrome. bvFTD results in such drastic, pervasive social and emotional deficits because brain regions mediating primitive emotionality and those mediating higher-order social cognition are both affected early in the disease. The bilateral damage to the frontal polar cortex seen in this study likely contributed to the impoverished social cognition seen in these bvFTD(CBD) patients, including loss of embarrassment over public incontinence and compulsive nose-picking, making rude and racially prejudiced observations in public, and habitually ignoring others in one’s social vicinity.
The fact that these bvFTD(CBD) patients demonstrate ventral < dorsal damage may also help explain the milder eating disturbances seen in the bvFTD(CBD) group relative to the bvFTD(Pick’s) patients. The region most directly associated with binge eating in bvFTD patients is the ventral portion of the anterior insula (Woolley et al., 2007
), a region showing significantly greater damage in bvFTD(Pick’s) patients than in bvFTD(CBD). Review of the bvFTD(CBD) cases suggests that only two of the four cases engaged in binge eating, and that it was rated as severe only in one of these patients at the time of the initial evaluation. While 4/5 of the bvFTD(Pick’s) patients’ altered eating behavior had resulted in substantial weight gain, this was true of only 2/5 of the bvFTD(CBD) patients. The anterior insula contains primary and secondary gustatory cortices and is connected with the olfactory bulb and OFC, implicating it in taste preference (Mesulam, 1991
; Rousseaux, Godefroy, Cabaret, & Bernati, 1996
). Increased propensity for sweet foods may also correspond to the decreased function of deep structures like the ventral hypothalamus (Sparks et al., 1994
Though the ventral insula was comparatively spared, bvFTD(CBD) patients did evidence significant early damage to the right dorsal insula. While the posterior portion of the insula is a terminal part of the pathway receiving bodily sensations, the more anterior portions of the insula integrate those sensations into conscious awareness (i.e., interoception) (Craig, 2009
). The frontal insula participates in emotional processing and leads the brain’s response to salient emotional stimuli (Sridharan, Levitin, & Menon, 2008
), functions critical to adaptive behavior in social contexts. Disproportionate right insular involvement may also explain why a number of these bvFTD(CBD) patients had obsessions, compulsions, or delusions involving their own bodies, particularly involving urination and sexual behavior. One bvFTD(CBD) patient had compulsions involving repeated toilet flushing, hand washing, and showering, and vacillated between thinking he was constipated or had diarrhea. He had delusions and complex visual hallucinations that were focused upon his genitalia. A second case also exhibited highly excessive trips to the restroom as well as eating compulsions, which continued despite emesis. Damage to the right insula may have interfered with patients’ ability to perceive and correctly process visceral, autonomic information (Craig, 2002
; Critchley, Wiens, Rotshtein, Ohman, & Dolan, 2004
), which in turn may have led to disturbed and at times delusional beliefs about bodily functions, a finding also common in bvFTD patients with other neuropathologies. When these disturbed somatic signals became the object of patients’ obsessive-compulsive behavior, they formed rigid dysfunctional behavior patterns centered on hygiene, voiding, and sexual behavior (Perneczky et al., 2008
Striatal structures, including the head of the caudate, were damaged early in these bvFTD(CBD) patients, similar to other varieties of bvFTD patients. There is evidence that the right caudate and putamen are integrally involved in social and emotional behaviors, including empathy (Rankin et al., 2007
), emotion processing (Phan, Wager, Taylor, & Liberzon, 2002
), and interpretation of emotional voice prosody (Cancelliere & Kertesz, 1990
). At a lower threshold medial temporal structures such as the amygdala were also significantly atrophied in the bvFTD(CBD) patients. Bilateral damage to this structure can result in a Kluver-Bucy syndrome involving symptoms such as hyperorality, changes in sexual behavior or diet, and docility (Hayman, Rexer, Pavol, Strite, & Meyers, 1998
). With their connections to the hypothalamus, insula, and OFC, these subcortical structures play a key role in emotion processing and are likely involved in many bvFTD-like behaviors.
Almost every behavioral symptom that appeared in the bvFTD(Pick’s) group also appeared in the bvFTD(CBD) group, if to a milder degree. The one apparent exception was that more of the bvFTD(CBD) patients exhibited a greater degree of anxious self-concern than was seen in the bvFTD(Pick’s) patients. This distinction was seen on quantitative ratings of anxiety, including the caregiver-rated NPI and the patient self-reported GDS, on which bvFTD(CBD) patients were much more likely than bvFTD(Pick’s) patients to personally endorse feeling fearful, worried, or dysphoric. Review of the clinical reports also supports this distinction, suggesting that 4/5 of the bvFTD(CBD) patients often experienced heightened anxiety, which at times was specific but sometimes took on a more generalized form. Even the bvFTD(CBD) patient who presented quite late in her course was described as often “frightened,” and intermittently recognized that something was wrong with her, occasionally saying vaguely, “I think I’m in trouble.” In contrast, despite mention of a phase of increased anxiety in one bvFTD(Pick’s) patient at initial symptom onset, none of the bvFTD(Pick’s) patients demonstrated the capacity for fearfulness and anxious self-concern at the time of their initial evaluation. This lack of anxiety (fear) is distinct from lack of frustration (anger), which increased in 2/5 Pick’s and 3/5 CBD patients after disease onset. It is also distinct from mild depression or sadness, which was reported in two bvFTD(Pick’s) and 3/5 bvFTD(CBD) patients at initial presentation.
The relative ventral frontal sparing seen in the bvFTD(CBD) patients may account for this ability to still feel self-concern. There is evidence that anxiety involves a primarily ventral network, including the inferior insula, medial orbitofrontal, and inferior temporal cortex (Liotti et al., 2000
). In direct comparison with bvFTD(CBD) patients, bvFTD(Pick’s) patients showed significantly greater damage to structures in the ventral “anxiety” network, including right medial temporal and inferior insular cortex. It is possible that the comparative sparing of this network in bvFTD(CBD) patients allows them to retain some rudimentary self-concern, manifesting in the ability to feel fearful over the sense that “something is wrong,” and to self-report anxious symptoms, while this capacity is lost in the more ventral-predominant, “disinhibited-subtype” patients like the bvFTD(Pick’s) group.
Summary and Conclusions
Given the substantial clinical overlap between bvFTD presentations arising from different pathologies, it is not surprising that expert neurologists still fail to predict CBD neuropathology in patients who present with bvFTD. At initial presentation, all patients in both bvFTD(CBD) and bvFTD(Pick’s) groups met Neary research criteria for bvFTD (Neary et al., 1998
), showing insidious onset and progression, with disordered personal and interpersonal conduct, and profound loss of insight and emotional blunting. Though some patients in both groups had normal sensory-motor evaluations, several motor findings were seen in both groups, including slowed gait, decreased arm swing, rigidity, tremor, restricted upgaze, and primitive reflexes. The severity and frequency of typical parkinsonism was marginally greater in bvFTD(CBD) than bvFTD(Pick’s) patients; however, no specific motor feature clearly differentiated the groups, and none of the patients demonstrated symptoms consistent with a typical corticobasal syndrome. Neuropsychological testing revealed that both bvFTD groups have equivalent deficits in most cognitive domains, including learning and memory, executive functioning, visuoconstruction, and language skills such as naming and word generation. However, micrographia appeared more frequently in the bvFTD(CBD) patients. Formal neuropsychiatric assessment of the two bvFTD groups showed that while both evidenced substantial apathy, bvFTD(CBD) patients had less severe social disinhibition, as well as less pronounced eating and sleep disturbances, agitation, and irritability. Potentially due to their comparative preservation of ventral frontoinisular rim structures, bvFTD(CBD) patients appeared to have greater retention of the capacity for self-referential anxiety, while this appeared largely absent in the bvFTD(Pick’s) patients. Analysis of the regional atrophy patterns in the two bvFTD groups revealed no significant differences at a corrected level of analysis. Both groups had substantial damage to inferior frontotemporal regions, particularly to the frontal poles, bilateral insula, orbitofrontal and superior medial frontal cortex, and bilateral caudate, areas involved in the “salience network” (Seeley, 2007) central to the control of eating, self-awareness, and social behavior. However, the bvFTD(CBD) patients could all have their pattern of frontal damage classified as dorsal > ventral, and their particular behavioral pattern was predominantly apathetic rather than disinhibited.
Our findings add to an emerging recognition that classical definitions of CBD-associated clinical features, which emphasize parietal dysfunction and atrophy with extrapyramidal deficits, will miss many patients with pathological CBD. bvFTD is a major mode of presentation of CBD, affecting almost one-third of the cases at our dementia speciality clinic found to have CBD at autopsy. CBD patients with bvFTD present in a manner almost indistinguishable from bvFTD due to Pick’s disease. Milder social disinhibition, and rudimentary preservation of anxious self-concern may help distinguish bvFTD from CBD from other bvFTD etiologies. This behavioral phenotype may result from the fact that bvFTD(CBD) patients may lack the degree of ventral frontoinsular damage that emerges early in most bvFTD (Pick’s) patients.
Disease-modifying treatments focused upon abnormal tau aggregation are becoming available in the next year. These therapies, if successful, may exert better efficacy for patients with CBD than for those with tau-negative FTLD pathologies. To maximize success of these trials, clinicians and researchers must continue to refine their sensitivity to pathology-predictive clinical features that occur early in the disease course, when interventions still stand to most positively impact patient lives.