Clinical, Radiologic, and Pathologic Features of the Globular Glial Tauopathy Subtype of Frontotemporal Lobar Degeneration in Right Temporal Variant Frontotemporal Dementia with Salient Features of Geschwind Syndrome

Abstract

Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman who presented with 3 years of personality changes and behavior symptoms concerning for right temporal variant of frontotemporal dementia with initial and salient features of Geschwind syndrome. Different from most other cases of FTLD-GGT in the literature, clinically, our patient did not have motor abnormalities. MRI showed focal atrophy in the right anterior temporal lobe, with subtle ipsilateral white matter signal abnormalities. The atrophy pattern on neuroimaging was indistinguishable from 5 autopsy-confirmed cases of FTLD-TDP. The presence of white matter signal abnormalities has been previously described as suggestive of a tauopathy. Brain autopsy at age 84 showed GGT type III and A3B3C2 Alzheimer’s neuropathologic changes. Data extraction from previously published cases of GGT showed the presence of co-pathologies such as Alzheimer’s pathology may be a function of advanced age.

Introduction

Frontotemporal Lobar Degeneration (FTLD) is a family of neurodegenerative diseases that tend to affect frontal and anterior temporal brain systems and lead to a variety of Frontotemporal Dementia (FTD) clinical syndromes. The two major types of FTLD are FTLD-TDP and FTLD-tau. Subtypes of FTLD-tau include Pick’s disease, progressive supranuclear palsy (PSP), corticobasal degeneration, and rarer primary tauopathies such as globular glial tauopathy (GGT), a 4-repeat tauopathy with tau globular inclusions in astrocytes and oligodendrocytes.

Three GGT subtypes have been defined according to their neuroanatomical distribution. In type I, the distribution of pathology is predominantly in prefrontal and temporal cortices. In type II, the pathology is mostly in the primary motor cortex with corticospinal tract degeneration. In type III, pathologic changes are found in frontal, temporal, and motor cortices, as well as corticospinal tract (Ahmed, Bigio et al. 2013). Cases with type I and III typically present with cognitive-behavioral syndromes including behavioral variant frontotemporal dementia (bvFTD), while type II most commonly presents as a progressive motor neuron syndrome (Ahmed, Bigio et al. 2013). Several authors have raised questions about this classification system, given there are no definite clinical or radiologic features that would suggest GGT before autopsy examination (Burrell, Forrest et al. 2016, Forrest, Kril et al. 2021). One recent case report of a patient with PSP (Richardson’s syndrome) suggested that if signs of corticospinal tract dysfunction were also present, GGT should be considered (Liu, Chang et al. 2020). Both Liu, Chang et al. (2020) and Ohno, Ikeda et al. (2021) have showed that white matter signal abnormalities not typical of vascular brain injury should also raise the possibility of GGT.

In this article, we present the autopsy findings of GGT Type III, from a case of right temporal variant of frontotemporal dementia (rtvFTD) with initial and salient features of Geschwind syndrome (Veronelli, Makaretz et al. 2017). Geschwind syndrome is an interictal behavioral syndrome, most frequently described in patients with temporal lobe epilepsy, comprising hyper-religiosity, hypergraphia, alterations in sexual behavior, and irritability (Waxman and Geschwind 1975, Bear and Fedio 1977). The clinical and radiographic features from this patient have been previously published (Veronelli, Makaretz et al. 2017). Here, we discuss this case’s characteristics in the context of previously published cases of GGT, their syndromic presentation, frequency of motor features, imaging findings, and coexistent histopathologies. We also perform a comparison of our patient’s imaging with that of pathology-proven FTLD-TDP. We believe that detailed case reports characterizing patients with clinical dementia syndromes arising from rare forms of FTLD, contextualized by the literature, may enable them to be better identified during life, which would facilitate their appropriate participation in biomarker studies and clinical therapeutic trials.

Case Presentation

Clinical features for this patient, including detailed neuropsychological testing, have been previously published as a form of sporadic rtvFTD, with initial and predominant symptoms as seen in Geschwind syndrome (Veronelli, Makaretz et al. 2017). Briefly, the patient presented at age 73 with 3 years of personality and behavior symptoms including disinhibition, loss of empathy, and compulsive behavior with the development of hyper-religiosity, hypergraphia, and poor emotional regulation. A framework for the clinical-radiological features of the rtvFTD includes episodic memory problems, prosopagnosia, behavioral disinhibition, apathy or inertia, loss of empathy, egocentrism, and compulsive behavior, as symptoms present in 40 to 60% of patients, and language problems in ~30% of patients (Ulugut Erkoyun, Groot et al. 2020). The patient presented here indeed had several of such features, including behavioral disinhibition, loss of empathy, difficulty recognizing familiar faces, egocentrism, and compulsive behavior. She presented language difficulties later in her disease course. Interestingly, her initial and salient features reminisced those described in Geschwind syndrome, with specific compulsive behavior including hypergraphia, hyper-religiosity, in addition to poor emotional regulation. Overall, her clinical presentation was considered to be that of rtvFTD with initial and salient features of Geschwind syndrome.

Subsequent to the history described in the prior report, she continued to gradually deteriorate with increasing need for assistance with basic activities of daily living. She expired at age 84 from complications of aspiration pneumonia. Throughout the 14-year course of her illness, she did not exhibit motor symptoms or signs on exam. Her MAPT gene was sequenced and no pathogenic variants were identified.

Neuroimaging

Structural and metabolic abnormalities in the patient’s MRI and FDG-PET scans were focally present in the right anterior temporal lobe (Figure 1, and as previously published (Veronelli, Makaretz et al. 2017)). Atrophy progressed in the right temporal lobe and subsequently in homologous regions of the left temporal lobe as previously described. Mild white matter signal abnormalities were observed, predominantly ipsilateral to areas of atrophy, though not specifically matching the areas of highest atrophy. There were very mild peri-ventricular white matter T2 hyperintensities which are suggestive of cerebral small vessel disease, Fazekas scale of 1 (Fazekas, Chawluk et al. 1987).

Figure 1.

Imaging findings in GGT case and comparison to TDP. A. Patient’s T2 FLAIR MRI scan, with right greater than left anterior and medial temporal lobe, as well as bilateral frontal lobe atrophy. Mildly hyperintense signal in the gray and white matter can be observed in the anterior temporal lobes bilaterally and scattered hyperintensities predominantly in the right frontal and temporal lobes. B. Patient’s cortical atrophy maps. C. Representative case from our comparison group of autopsy-confirmed FTLD-TDP Type C. The spatial pattern of atrophy in the case with confirmed GGT pathology was indistinguishable from five cases with FTLD-TDP.

We performed quantitative analysis of cortical thickness from high-resolution T1-weighted 3D structural MR images collected on a 3T Siemens Magnetom Tim Trio system (Siemens Medical Solutions, Erlangen, Germany), using a 12-channel phased-array head coil. Cortical reconstructions and volumetric segmentation of the T1-weighted images were performed using the FreeSurfer analysis suite version 6.1 according to a procedure that has been previously described in detail (Dale, Fischl, & Sereno, 1999; Fischl & Dale, 2000; Fischl, Sereno, & Dale, 1999; Rosas et al., 2002; Salat et al., 2004). Cortical atrophy was assessed using a 2 class general linear model (GLM) as implemented in FreeSurfer, comparing cortical thickness in this patient to a group of 75 age-matched healthy controls (age: M = 72.65 yrs, SD = 4.80). Results were converted to W scores as previously described. We selected 4 cases from our database with focal anterior temporal presentations of frontotemporal dementia (FTD) who were followed to autopsy and found to have FTLD-TDP Type C neuropathologic changes for comparison. The results did not show any distinguishing features with regard to the spatial pattern of atrophy (a representative comparison case is shown in Figure 1.

Neuropathological Evaluation

The patient underwent a brain autopsy. The brain weighed 860 grams. On gross inspection, there was marked atrophy of the frontal and temporal lobes, lesser atrophy of the occipital lobes, and sparing of the parietal lobes. Microscopically, the frontal and temporal cortices were moderately thin and gliotic. Immunohistochemistry for hyperphosphorylated tau revealed many globular glial inclusions in the subcortical white matter of the frontal and temporal lobes, and the white matter of the brainstem including the cerebral peduncles, basal pontis, and medullary pyramids (Figure 2). No such inclusions were found in the primary motor cortex. The regional distribution of neuropathological findings with semi-quantitative measures can be observed in Table 1. White matter globular glial inclusions were not only observed in the frontal and temporal cortices, but also in the descending corticospinal tracts (especially cerebral peduncles, pons, and pyramids). As observed in figure 2, the tau deposits sit within the descending corticospinal tracts. Given the presence of globular glial inclusions with a frontotemporal distribution in addition to their presence in the descending corticospinal tracts, these changes are consistent with globular glial tauopathy, type III (Ahmed, Bigio et al. 2013).

Figure 2.

Tau staining of brain regions. A. White matter underlying BA8; B. Cortex from inferior temporal gyrus; C. White matter underlying inferior temporal gyrus; D. Basis pontis highlighting that the tau deposits sit within the descending corticospinal tracts; E. Medullary pyramids.

Table 1.

Regional distribution of neuropathological findings.

Area	Neuropathology
	NFT	NP	DP	GGI	LB/LN
Hippocampal formation	+++	++	++	NA	-
Entorhinal cortex	+++	+++	+++	+++	-
Temporal pole	+	NA	NA	NA	-
Temporal white matter	NA	NA	NA	+++	NA
Superior frontal gyrus	++	+	+++	+++	-
Inferior frontal cortex	+	NA	NA	NA	NA
Cingulate gyrus	++	++	+++	+++	-
Superior and inferior parietal lobules	++	+	+++	+	-
Primary motor/sensory cortex	++	++	NA	NA	-
Primary and association visual cortex	+	+	+++	NA	NA
Amygdala	+	NA	NA	+++	-
Basal ganglia	+	NA	+++	NA	NA
Thalamus	-	-	-	NA	NA
Cerebellum	-	NA	+	+	NA
Midbrain	+	NA	+	+++1	NA
Pons	+	NA	NA	+	-
Medulla	+	NA	NA	+2	NA

DP = amyloid beta diffuse plaques; GGI = white matter globular glial inclusions; LB/LN = Lewy bodies or Lewy body neurites; NFT = neurofibrillary tangles; NP = amyloid beta neuritic plaques; TDP-43 = TDP-43 positive inclusions; +++ = numerous; ++ = scattered/moderate; + = sparse/rare; - = absent; NA = not evaluated

¹Especially in the cerebral peduncle

²Predominantly located in the pyramids

In addition to the findings detailed above, there was amyloid-β plaque deposition in the cortex, basal ganglia, periaqueductal gray midbrain, and cerebellum consistent with Thal stage 5 (Thal, Rüb et al. 2002). Neurofibrillary tangles were present in the cortex (including primary visual cortex) and hippocampus. The frequency and distribution of neurofibrillary tangles are consistent with Braak tangle stage VI/VI (Braak and Braak 1991) and neocortical neuritic plaques were consistent with an age-related CERAD score of moderate (C2) (Mirra, Heyman et al. 1991). By the 2012 NIA-Alzheimer Association guidelines for the neuropathologic diagnosis of Alzheimer Disease, this case received a score of A3B3C2, suggesting high probability of findings diagnostic for Alzheimer Disease (Hyman, Phelps et al. 2012, Montine, Phelps et al. 2012, Nelson, Alafuzoff et al. 2012). Additional neuropathologic changes included that of hypertensive related changes and diffuse, cortical and leptomeningeal Cerebral Amyloid Angiopathy (Vonsattel grade 2 of 4 (Greenberg and Vonsattel 1997)). Alpha-synuclein stains were performed and negative in the hippocampal formation, entorhinal cortex, cingulate gyrus, superior and inferior parietal lobules, temporal pole, superior frontal gyrus, primary motor/sensory cortex, amygdala, and pons. TDP-43 staining was performed and absent in the hippocampal formation and amygdala.

Discussion

Clinical Presentation of GGT

We discuss this case in the context of a new literature review of published cases of GGT, aiming to determine whether clinical characteristics or imaging features could be used to predict FTLD-GGT neuropathologic changes.

First, we summarized the presenting clinical syndromes in patients determined at autopsy to have GGT (Table 2). From 87 published cases with GGT on autopsy (Supplementary table 1), age of onset was reported in 86 cases and was 67.13 on average (range 43 to 86); 51.7% female and 48.3% male. Regarding the clinical syndrome, 26 cases (29.9%) had a clinical presentation compatible with behavioral variant FTD (bvFTD), followed in frequency by corticobasal syndrome (16.1%), and primary progressive aphasia (13.8%).

Table 2.

Percentage of motor involvement per syndrome in cases with GGT.

Syndrome	Motor involvement		Total (%)
	Yes (n)	No (n)
bvFTD	15	11	29.9%
CBS (1 case CBS vs PLS)	14	0	16.1%
PPA	8	4	13.8%
PSP	7	0	8.0%
Atypical AD1	2	3	5.7%
AD syndrome	3	2	5.7%
MND + dementia/FTD	5	0	5.7%
MND	3	0	3.4%
PSP and MND	4	0	4.6%
MSA	2	0	2.3%
MSA and MND	1	0	1.1%
CJD2	1	0	1.1%
Other	2	0	2.3%
Total (%)	77%	23%	100% (n=87)

AD = Alzheimer’s disease; bvFTD = behavioral variant Frontotemporal Dementia; CBS = corticobasal syndrome; CJD = Creutzfeldt–Jakob disease; FTD = frontotemporal dementia; MND = motor neuron disease; MSA – multiple system atrophy; PLS = primary lateral sclerosis; PPA = primary progressive aphasia; PSP = progressive supranuclear palsy

¹Included cases of memory decline with prominent behavioral deficits, atypical semantic dementia, progressive executive dysfunction with personality changes and upper motor neuron weakness, AD syndrome with prominent language impairment, and short-term memory loss, rigidity, and incontinence.

²Cognitive impairment, upper motor neuron weakness, tongue thrusting movements, limb apraxia, mute, positive 14-3-3

In the past, there have been conflicting reports on whether motor neuron involvement could be a supportive clinical feature to suggest underlying GGT. Among these 87 cases, 77% of them had motor systems dysfunction of various types, including upper motor neuron signs, extrapyramidal signs, weakness, and changes in gait. In the recent review by Forrest, Kril et al. (2021), motor features were quantified only when present as isolated upper motor neuron signs, which were present in 12.5% of cases. The patient we reported here exhibited the unusual initial and salient features of Geschwind syndrome in the context of rtvFTD. However, she did not have motor neuron or extrapyramidal signs that could clinically suggest GGT.

Our patient did have a later age of onset and death than that typical of FTD, but this is not clearly characteristic of GGT. From our literature review, of the participants who presented with bvFTD or PPA (n=37), the average age of symptom onset was 65.43 years (range 50 to 79), comparable to typical FTD (Onyike and Diehl-Schmid 2013). Disease duration was reported for 34 of these patients and was 7.38 years (range 2 to 17), which is also similar to typical FTD (Onyike and Diehl-Schmid 2013). A summary by syndrome of the age of onset or diagnosis, age at the time of death, and disease duration can be found in Table 2 of the supplementary material.

Radiographic Features

From the 87 published cases, 5 had a reported CT and 57 had a reported MRI. Of these, the predominant atrophy pattern was frontotemporal, described in 21 cases. White matter signal abnormalities (WMSA) were reported in 30 cases. Of these, WMSA in 5 cases were explicitly attributed to chronic small vessel disease (Bigio, Lipton et al. 2001, Ohara, Tsuyuzaki et al. 2002, Powers, Byrne et al. 2003, Clark, Lashley et al. 2015, Rusina, Csefalvay et al. 2019). 6 cases reported WMSA that seemed to preferentially affect the corresponding areas of atrophy (Ferrer, Hernandez et al. 2003, Tan, Piao et al. 2005, Hasegawa, Takeda et al. 2018, Hirano, Iritani et al. 2020, Liu, Chang et al. 2020). Josephs, Katsuse et al. (2006) reported 12 cases of atypical PSP, which all showed an increase in T2 signal in the subcortical white matter. Among the cases with reported subcortical WMSA, there was a disproportional clinical presentation of PSP or corticobasal syndrome. An interesting radiologic finding was reported by Tanaka, Kawakatsu et al. (2019) with a case of motor neuron disease-FTD which had marked anterior temporal atrophy, and bilateral symmetrical T2-weighted high intensity signal in the cerebral peduncles. Lastly, Keller, Kavkova et al. (2022) recently published imaging correlates for 3 cases of GGT Type I (2 of which were not analyzed in this publication); they noted a sagittal callosal T2-hyperintense band and nonspecific WMSA, which in at least one case seemed to coincide with the areas of greatest atrophy.

Changes in white matter have been described in the past as a distinguishing feature between tauopathies and TDP-43 pathology (McMillan, Irwin et al. 2013). Tractography was not performed in the patient presented here. Mild WMSA were present and ipsilateral to regions of atrophy. The pattern of atrophy per se was indistinguishable from that of semantic variant PPA cases with FTLD-TDP neuropathologic changes (Rohrer, Geser et al. 2010, Whitwell, Jack et al. 2010, Collins, Montal et al. 2017, Mesulam, Dickerson et al. 2017). These findings highlight the lack of specificity of atrophy patterns to distinguish within underlying pathologies in FTLD.

Concomitant Pathologies

In the 87 cases summarized in this publication, concomitant pathology was noted in 26 cases. Alzheimer’s disease (AD) pathology was the most frequent co-pathology, described alone in 14 cases, with yet other co-pathologies in an additional 5 cases. α-synuclein was found in 5 cases (of which 3 had concomitant AD pathology, and 1 concomitant neurofibrillary tangles without neuritic plaques). Interestingly, vascular pathology was only described in 5 cases, 2 of which also had AD pathology and 1 TDP-43 (References in table 3 supplementary material). This last finding is interesting given it raises the possibility that not all the subcortical WMSA observed in imaging pre-mortem can be attributed to vascular disease.

When comparing the age of death, cases with any other concomitant pathology had an average age of death of 77.92 years (n= 26), compared to 71.37 years in those without co-pathologies. Average age of death of patients with only AD as a co-pathology was 77.93 years. These findings raise the question of whether co-pathologies are present predominantly as a function of older age.

In our case, neuropathologic examination revealed a combination of GGT Type III, and AD neuropathologic changes. Both neuropathologic processes demonstrated a skewing of the burden of lesions towards the frontal and temporal lobes, mapping well onto the clinical symptomatology. Our patient died at the age of 84, which raises the possibility that AD pathology is present, at least in part, in relation to her older age. Increased frequency of neuropathologic changes with advancing age has been shown in prior studies of GGT (Kovacs, Alafuzoff et al. 2008), but it is unclear whether that is simply a function of age or whether there may be pathophysiologic synergies between the processes that lead to GGT and AD.

In conclusion, we present a case of rtvFTD with the unusual initial and salient features of Geschwind syndrome, who was found to have GGT at autopsy. Of the family of frontotemporal lobar degeneration tauopathies, GGT is rare. Clinically, it should be considered on the differential diagnosis in atypical cases of FTD, especially when motor features are present. Radiologically, white matter hyperintensities subjacent to areas of atrophy could be suggestive, though not specific, of GGT. The pattern of atrophy on neuroimaging in the case presented here was indistinguishable from that of autopsy-confirmed cases of TDP-43. Finally, concomitant pathological changes such as AD pathology can be present, but likely as a function of age. This implies that the presence of AD biomarkers does not necessarily rule out co-pathology with GGT, and should be considered in cases with presentations that include mixed features suggestive of FTLD and AD.

Data Availability Statement

An SPSS file summarizing the characteristics of patients within the cited literature is available from the corresponding author, BCD, upon reasonable request. Otherwise, participants, whose imaging was analyzed in this study, did not agree for their data to be shared publicly, so supporting imaging data is not available.