Progressive subcortical gliosis

Douglas J Lanska MD MS MSPH

Neurobehavioral & Cognitive Disorders

Updated 05.14.2024
Released 05.25.1993
Expires For CME 05.14.2027

Progressive subcortical gliosis

Author: Douglas J Lanska MD MS MSPH

See Contributor Disclosures

Progressive subcortical gliosis

In This Article

Quick Link

Introduction

Overview

The author explains the clinical presentation, etiology, differential diagnosis, and diagnostic workup of progressive subcortical gliosis, a chromosome 17–linked dementia with unique pathologic features. Microscopically, the major pathologic change is a marked fibrillary astrocytosis, particularly in the area of the short cortical association tracts at the junction of cortical lamina VI and the subcortical white matter and in the subpial cerebral cortex. Overall, the survival of patients with progressive subcortical gliosis averages about 10 years and is similar to that of other types of frontotemporal dementia.

Key points

	• Progressive subcortical gliosis is a rare dementing disorder resembling Pick disease but with distinctive neuropathologic features. The clinical manifestations are those of a frontotemporal dementia and overlap with those of other frontotemporal dementias.
	• Progressive subcortical gliosis has an insidious onset, generally in the fifth or sixth decade. The course is progressive, generally over 5 to 15 years, but both fulminant and protracted courses occur.
	• Common initial manifestations include personality and emotional changes, lack of judgment and insight, deterioration in social behavior, delusions, paranoia, auditory and visual hallucinations, and depression.
	• Microscopically, the major pathologic change is a marked fibrillary astrocytosis, particularly in the area of the short cortical association tracts at the junction of cortical lamina VI and the subcortical white matter and in the subpial cerebral cortex.
	• Most cases have been sporadic, but some hereditary forms are recognized, with linkage demonstrated in one kindred to a region on the long arm of chromosome 17 (17q21-22).
	• Overall, the survival of patients with progressive subcortical gliosis averages about 10 years and is similar to that of other types of frontotemporal dementia.

Historical note and terminology

Progressive subcortical gliosis is a rare dementing disorder clinically and pathologically resembling Pick disease but with distinctive neuropathologic features. In 1949, Neumann described three cases under the appellation of "Pick disease, type II" (48). In 1967, Neumann and Cohn reported four additional cases and suggested the designations "primary subcortical gliosis" and "progressive subcortical gliosis" (49); although neither of these terms is ideal, the latter has become established in the literature (10).

Although rare reports of familial cases were reported beginning in the 1940s, it was not until the late 1980s and 1990s that it was recognized that progressive subcortical gliosis could be transmitted as an autosomal dominant trait (16; 36). Progressive subcortical gliosis was linked to a tau mutation in the microtubule-associated protein tau (MAPT) gene on the long arm of chromosome 17 (55; 24) and, thus, it was included in the group of "frontotemporal dementias and Parkinsonism linked to chromosome 17" group (FTDP-17) (21; 10). More than 60 MAPT mutations have since been identified, usually causing behavioral variant frontotemporal dementia (FTD) or parkinsonism clinically (60).

MAPT-related frontotemporal dementia (MAPT-FTD) is a progressive neurodegenerative disorder characterized by frontotemporal dementia, often with parkinsonian manifestations. Most affected individuals have behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) or a parkinsonian syndrome, but there is considerable phenotypic heterogeneity, even between and within families with the same MAPT variant (57). In two families with the c.896_897insACA, p.K298_H299insQ variant in the MAPT gene, affected patients showed symptoms initially resembling Parkinson disease and symptoms of progressive supranuclear palsy later (47).

End-stage disease is characterized by severe dementia often with muteness and profound functional motor impairment (often becoming chairbound or bedbound) (57). Mean disease duration is about 9 years but can be more than 30 years (57).

The concept of "frontotemporal dementias and Parkinsonism linked to chromosome 17" has since been challenged (19). Review of known cases suggested that distinct MAPT mutations result in particular tau subtypes linked to frontotemporal lobar degeneration (FTLD). As such, Forrest and colleagues argued that FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category.

Clinical manifestations

Presentation and course

	• Progressive subcortical gliosis presents as a frontotemporal dementia similar to Pick disease.
	• Progressive subcortical gliosis has an insidious onset, generally in the fifth or sixth decade.
	• Common initial manifestations include personality and emotional changes, lack of judgment and insight, deterioration in social behavior, delusions, paranoia, auditory and visual hallucinations, and depression.
	• Terminal manifestations included profound dementia, akinetic mutism, incontinence, severe dysphagia, and extrapyramidal signs.

Progressive subcortical gliosis has an insidious onset, generally in the fifth or sixth decade, although individuals have developed the disease as early as 30 years and as late as 79 years (36; 38). The distribution of age of onset is similar for familial and sporadic cases. There is no apparent gender predilection.

Common initial manifestations include personality and emotional changes, lack of judgment and insight, deterioration in social behavior, delusions, paranoia, auditory and visual hallucinations, and depression (36; 38; 18). Subsequently, affected individuals develop severe memory difficulty, speech output generally declines, and word-finding problems appear. Some patients develop verbal stereotypy, echolalia, or manifestations of the human Klüver-Bucy syndrome (36). Dysarthria and myoclonus have also been reported (18).

Several cases had clinical evidence of relatively localized dysfunction involving visual, motor, or cognitive domains (48; 58; 02; 05; 04; 06); in some, the changes developed rapidly over weeks, prompting a diagnosis of cerebral infarction or hemorrhage (48; 02). Isolated sporadic cases have also been reported with posterior cerebral dysfunction or atrophy (05; 04; 56; 08; 54), or the clinical manifestations of the Steele-Richardson-Olszewski syndrome (78; 01). Terminal manifestations included profound dementia, akinetic mutism, incontinence, severe dysphagia, and extrapyramidal signs (36).

Prognosis and complications

The course is progressive, generally over 5 to 15 years, but both fulminant (3 months to 2 years) and protracted (spanning decades) courses occur. The duration of illness is generally longer in familial cases than in sporadic cases. The most common causes of death are pneumonia, other respiratory infections, and pulmonary emboli.

Overall, the survival of patients with progressive subcortical gliosis is similar to that of other types of frontotemporal dementia (13).

Clinical vignette

In his early 40s, the patient developed personality change, progressive memory impairment, and decreased activity. He retired from his accounting work because of forgetfulness, difficulty making decisions, and frequent errors in performing simple calculations. In his late 40s, he had poor insight and judgment, impaired memory, mild word-finding problems, and difficulty performing serial subtractions. A masked face, slightly increased appendicular and axial tone, and a fine postural tremor were present, but there were no gaze abnormalities. Complete blood count, serum chemistries, thyroid function studies, and serum rapid plasma reagin were normal. Head CT showed mild cerebral atrophy with ventriculomegaly. Radioisotope cisternography was normal. EEG showed well-modulated 10-Hz alpha activity posteriorly, but frequent, rhythmic, low-amplitude delta transients were observed in the right anterior and right midfrontal areas. Cerebrospinal fluid examination showed an opening pressure of 180 mm H2O, a protein level of 27 mg/dL, a glucose level of 55 mg/dL, and no cells.

At age 50, the patient had decreased verbal fluency, mild comprehension impairment, and word-finding difficulty with semantic paraphasic errors. Over the next several years, he became more compulsive, regimented, and perseverative. His affect became progressively blunted. He lost interest in sexual intercourse, was incontinent, and began eating excessively. He stopped speaking spontaneously but had prominent echolalia. Later he developed severe dysphagia and became bed-bound and emaciated. He died at age 58 years from aspiration.

Biological basis

	• Most reported cases of progressive subcortical gliosis have been sporadic, but there are several reports of familial progressive subcortical gliosis.
	• In two large kindreds, progressive subcortical gliosis was transmitted as an autosomal dominant trait.
	• Linkage has been demonstrated in one kindred to a region on the long arm of chromosome 17 (17q21-22), a site previously associated with the disinhibition-dementia-parkinsonism-amyotrophy complex.
	• Overproduction of 4-repeat tau is probably the primary effect of the progressive subcortical gliosis mutation. In a kindred with progressive subcortical gliosis, a tau mutation (at position +16 of the intron after exon 10) leads to an overrepresentation of the soluble 4-repeat tau isoforms that assemble into wide, twisted, ribbon-like filaments.
	• Microscopically, the major pathologic change is a marked fibrillary astrocytosis, particularly in the area of the short cortical association tracts at the junction of cortical lamina VI and the subcortical white matter and in the subpial cerebral cortex.
	• Neuronal cytoskeletal inclusions (Pick bodies, neurofibrillary tangles, Lewy bodies) are absent in progressive subcortical gliosis.

Etiology and pathogenesis

Most reported cases of progressive subcortical gliosis have been sporadic, but there are several reports of familial progressive subcortical gliosis (26; 49; 31; 16; 37; 36; 69). In several of the initial reports of familial progressive subcortical gliosis, family history information is sketchy, and detailed clinical information and pathological confirmation are available only for the index cases (26; 49; 31). In a preliminary report in 1986, Currier and colleagues first demonstrated that progressive subcortical gliosis could be transmitted as an autosomal dominant trait (16). In a large kindred of 90 individuals spanning six generations, 21 of 65 members in four consecutive generations may have been affected, and five members from two generations were proved to have been affected on the basis of autopsy (36).

Progressive subcortical gliosis (family pedigree)

Pedigree of a family with progressive subcortical gliosis transmitted as an autosomal dominant trait, possibly with reduced penetrance. Squares denote males, circles denote females, and diamonds denote either gender. Blackened sym...

Lanska and colleagues subsequently confirmed these findings in a second kindred of 80 individuals spanning four generations.

Progressive subcortical gliosis (pedigree)

Pedigree of family with progressive subcortical gliosis transmitted as an autosomal dominant trait, possibly with reduced penetrance. Squares denote males, circles denote females, and diamonds denote either gender. Blackened symbo...

Ten of 30 members in three consecutive generations may have been affected by the disease, and two siblings were proved to have been affected on the basis of autopsy (37; 36). In 1995, Petersen and colleagues suggested that familial progressive subcortical gliosis may be a prion disease (55), but this conclusion was later retracted (22).

Linkage has been demonstrated in one of the kindreds reported by Lanska and colleagues (36) to a region on the long arm of chromosome 17 (17q21-22) (55; 20; 21; 77), a site previously associated with the disinhibition-dementia-parkinsonism-amyotrophy complex (40; 76; 77). As early as 1995, it was recognized that candidate genes in the region include microtubule-associated protein tau (MAPT) (55). Subsequently, a tau mutation at position +16 of the intron after exon 10 has been identified (24) in one kindred with progressive subcortical gliosis (36; 55). The mutation destabilizes a predicted stem-loop structure and leads to an overrepresentation of the soluble 4-repeat tau isoforms that assemble into wide, twisted, ribbon-like filaments. Overproduction of 4-repeat tau is probably the primary effect of the progressive subcortical gliosis mutation. It may lead to an excess of 4-repeat tau over available binding sites on microtubules, resulting in the hyperphosphorylation of tau and its assembly into filaments (35).

Some other conditions included in the "frontotemporal dementias and Parkinsonism linked to chromosome 17" group (21), but with clinicopathologic differences from progressive subcortical gliosis (21; 41), have mutations in the tau gene (61; 64; 75; 51; 53). Several studies have identified various missense mutations, silent mutations, and amino acid deletions in the tau gene in patients with frontotemporal dementias (65; 66; 67; 39). Mutations have also been described at positions +3, +12, +13, +14, and +16 of the intron after exon 10 of the tau gene, and at the intron 10+11-splice site (62; 14; 39). Detailed tau pathology has been reported for the kindred with the +3 mutation, also known as “familial multiple system tauopathy with presenile dementia” (63; 62); affected individuals have neuronal and glial tau pathology similar to that of progressive subcortical gliosis. It is also characterized by the presence of wide, twisted ribbons made of 4-repeat tau isoforms and an overproduction of soluble 4-repeat tau, indicating that the different mutations in the intron after exon 10 cause disease through the same mechanism. These findings firmly establish that the overproduction of 4-repeat tau alone is sufficient to lead to filamentous tau pathology and a dementing disease (65).

How changes in the ratio of 3-repeat tau to 4-repeat tau produce neuronal and glial dysfunction and cell death is unknown. 3-repeat tau and 4-repeat tau may bind to distinct microtubule sites, and an altered ratio of these isoforms may disrupt microtubule function (65; 39). Also, overproduction of 4-repeat tau may simply produce an excess of free cytosolic tau, which then becomes hyperphosphorylated and is assembled into pathologic filaments (39). Other mutations alter the binding of tau to microtubules and interfere with its ability to promote microtubule assembly (65; 39).

The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.

Another kindred with autosomal dominant subcortical gliosis presenting as a frontotemporal dementia, but without tau- or ubiquitin-containing inclusions and without ubiquitin or TDP-43 staining, has been reported by Swerdlow and colleagues (69). Symptom onset was generally in the fifth or sixth decade, but some individuals did not become symptomatic until their eighth decade. The TDP-43 type C form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss, and gliosis, and the absence of neuronal intranuclear inclusions (29).

The brains of progressive subcortical gliosis cases are moderately to severely atrophic, usually with preferential involvement of the white matter of the frontal and temporal lobes (36), but several cases affected mainly the frontal lobes, and one sporadic case affected predominantly the parietal and occipital lobes (05; 04). Most often, the atrophy is symmetric (36), but in several cases, one side was more affected than the other (48; 79; 58; 73).

Microscopically, the major pathologic change is a marked fibrillary astrocytosis, particularly in the area of the short cortical association tracts at the junction of cortical lamina VI and the subcortical white matter and in the subpial cerebral cortex (49; 58; 42; 59; 73; 36).

Progressive subcortical gliosis (parietal cortex)

Section of parietal cortex of a patient with progressive subcortical gliosis stained for glial fibrillary acidic protein. This demonstrates a ribbon of severe fibrillary astrocytosis in the subpial cortical zone and at the junctio...
Progressive subcortical gliosis (parietal cortex section)

Section of parietal cortex of a patient with progressive subcortical gliosis stained for glial fibrillary acidic protein. This demonstrates a ribbon of severe fibrillary astrocytosis in the subpial cortical zone and at the junctio...
Progressive subcortical gliosis (section of parietal cortex)

Section of parietal cortex of a patient with progressive subcortical gliosis stained for glial fibrillary acidic protein. This demonstrates severe fibrillary astrocytosis at the junction of the cortex and white matter. (x100) (Con...

This gliosis is most pronounced in the frontal and temporal lobes, occurs in the absence of identifiable myelin loss, and is out of proportion to the mild neuronal loss in the cortex (73; 36). Lesser degrees of gliosis are observed in the deep white matter, basal ganglia, thalamus, brainstem tegmentum, cerebellum, and central gray matter of the upper cervical spinal cord (36). In addition, variable protoplasmic astrocytic proliferation is evident in all layers of the cerebral cortex (58; 42; 59; 06; 36).

Laminar spongiosis has been variably reported in laminae II and III of the cerebral cortex in cases of progressive subcortical gliosis (49; 58; 42; 59; 73; 36).

Progressive subcortical gliosis (occipital cortex)

Section of occipital cortex of a patient with progressive subcortical gliosis showing spongiform change. (hematoxylin and eosin, x40) (Contributed by Dr. Douglas Lanska.)
Progressive subcortical gliosis (section of occipital cortex)

Section of occipital cortex of a patient with progressive subcortical gliosis showing spongiform change. (hematoxylin and eosin, x100) (Contributed by Dr. Douglas Lanska.)

The spongiosis may be focal and probably occurs late in the disease. It generally spares the deeper layers of the cortex as well as the basal ganglia, thalamus, brainstem, and cerebellum (36). Ultrastructural studies have shown areas of clarification and frequent vacuoles in large postsynaptic dendrites surrounded by glycogen and mitochondria (42). This spongiosis has been attributed variously to neuronal loss, loss of dendritic arborizations of neurons that expand in the second layer, and pathologic alteration and disintegration of astrocytes (42; 59; 73). The spongiosis of progressive subcortical gliosis is similar to that in other neurodegenerative diseases (eg, Pick disease, Alzheimer disease), but it differs from the spongiform change of Creutzfeldt-Jakob disease, which is pancortical, most prominent in the deeper layers, and frequently involves the thalamus, basal ganglia, brainstem, and cerebellum (43; 36).

Neuronal cytoskeletal inclusions (Pick bodies, neurofibrillary tangles, Lewy bodies) are absent in progressive subcortical gliosis (36). Several cases had occasional balloon neurons in the cerebral cortex (48; 79); however, most authors did not identify such cells. Although considered one of the histopathologic hallmarks of Pick disease (52), balloon neurons are nonspecific and do occur in several other neurodegenerative disorders.

In several cases, the pars compacta of the substantia nigra exhibited moderate to marked degenerative changes (36). There was no apparent neuronal loss or gliosis in the nucleus basalis of Meynert in the cases wherein this was examined (36).

Studies in a transgenic mouse model of frontotemporal dementia and parkinsonism linked to chromosome 17 indicate that the L-dopa-resistant parkinsonism in this tauopathy results from early loss of dopaminoreceptive neurons in the striatum (12). Accumulation of mutant tau leads to neurofibril degeneration and apoptosis through caspase-3 activation (12). In the late stages, dopaminergic neurons and dopaminoreceptive neurons decreased equally (12).

Alterations in pro-nerve growth factor and brain-derived neurotrophic factor have been identified in non-Alzheimer disease tauopathies (03). Neurotrophin dysregulation as a result of tau pathology may represent a mechanism by which tau produces neurotoxicity in progressive subcortical gliosis and other non-Alzheimer dementias (03).

Even though the hippocampus is not the primary pathologic site in progressive subcortical gliosis and other tauopathies, there are nevertheless disease-specific regional selective neuronal vulnerabilities that can be demonstrated in the hippocampus for these disorders (45).

Differential diagnosis

Confusing conditions

The clinical manifestations of progressive subcortical gliosis are those of a frontotemporal dementia and overlap with those of Pick disease and other frontotemporal dementias, including Alzheimer disease, corticobasal ganglionic degeneration, Binswanger disease, and similar conditions (33; 74; 11; 70).

Although in many cases the clinical manifestations of progressive subcortical gliosis are similar to those of Pick disease and Alzheimer disease, progressive subcortical gliosis can be distinguished on pathologic grounds (48; 49; 36; 38; 33). Progressive subcortical gliosis shares with Pick disease and other frontotemporal dementias a predilection for the frontal and temporal poles, whereas in Alzheimer disease, the posterior temporal and parietal lobes are preferentially involved. The atrophic process in progressive subcortical gliosis is not sharply demarcated, whereas in Pick disease, there are typically circumscribed areas of severe atrophy with an abrupt transition between severely affected and less affected areas.

In progressive subcortical gliosis, cortical neuron loss is mild or inconspicuous, and a characteristically distributed astrogliosis is most prominent subcortically and in the deep cortical laminae. In both Pick disease and Alzheimer disease, cerebral cortical neuron loss is prominent and is associated with a commensurate degree of cortical gliosis and little subcortical gliosis. Cerebrocortical neuronal inclusions are uniformly absent in progressive subcortical gliosis but are pathologic hallmarks of Alzheimer disease and Pick disease, seen even in early or incipient cases (44).

Despite these distinctions, the differentiation of progressive subcortical gliosis from Pick disease may be difficult, and some authors likely lump progressive subcortical gliosis with putative subtypes of Pick disease without Pick bodies (eg, Pick disease "type C" of Constantinidis and colleagues) (15; 71; 28).

Compared with other forms of frontotemporal dementia (27; 30), progressive subcortical gliosis appears to have a distinctive clinicopathologic profile (36; 21; 41), but several specific forms of frontotemporal dementia, including progressive subcortical gliosis, have now been linked to chromosome 17 (21; 14).

Thalamic degenerations involve similar neural structures and have histopathologic similarities to progressive subcortical gliosis (50; 06; 36). Primary thalamic degenerations are frequently accompanied by secondary gliosis in the cerebral cortex, subcortical white matter, basal ganglia, and various brainstem nuclei. Thalamic gliosis and neuron loss occur in progressive subcortical gliosis (79; 49; 06); however, they apparently develop independently of the other pathologic changes because (1) there is prominent gliosis of the short ipsilateral cortical association fibers that have no direct thalamic connections; (2) there is neither demyelination nor axon loss in the thalamic radiations; (3) gliosis in the cerebral cortex generally spares laminae III and IV, where the majority of thalamocortical projection fibers terminate (36).

Some of the "atypical" dementias have features in common with progressive subcortical gliosis. Although progressive subcortical gliosis and "frontal lobe degeneration of non-Alzheimer type" are clinically similar (25), pathologic differences exist between the two conditions (09; Englund and 09; 36). In frontal lobe degeneration, little atrophy occurs, and brain weights are generally greater in frontal lobe degeneration than in progressive subcortical gliosis. In addition, the pathologic changes of frontal lobe degeneration are more evident in the cerebral cortex rather than in the subcortical areas, with prominent cortical neuron loss and mild gliosis involving mainly the outer cortex. Finally, areas typically involved in progressive subcortical gliosis (basal ganglia, thalamus, substantia nigra, inferior olivary nucleus) are either not affected or are much less affected in frontal lobe degeneration. Several other reported cases of familial (32; 46; 34) and sporadic (72; 34) atypical non-Alzheimer dementia had clinical and pathologic similarities to progressive subcortical gliosis, but in all of these cases, there was prominent cortical neuron loss in addition to variable degrees of gliosis.

Diagnostic workup

• Cerebral imaging is normal early in the course, but later shows generalized cerebral atrophy, sometimes preferentially affecting the frontal and opercular areas.

Cerebral imaging is normal early in the course but later shows generalized cerebral atrophy, sometimes preferentially affecting the frontal and opercular areas.

Progressive subcortical gliosis (CT)

CT scan of patient with progressive subcortical gliosis, showing relative frontal and opercular atrophy. (Contributed by Dr. Douglas Lanska.)

Brain MRI may show hyperintensities in the subcortical white matter on T2-weighted images (18). Electroencephalograms remain normal except for mild slowing late in the illness. Screening for tau gene mutations in patients with frontotemporal dementia is still largely a research tool and is unlikely to identify pathogenic mutations in sporadic cases (67).

Media

References

01: Armstrong RA. White matter pathology in progressive supranuclear palsy (PSP): a quantitative study of 8 cases. Clin Neuropathol 2013;32(5):399-405. PMID 23587170
02: Auff E, Seitelberger F. Contribution to the problem of presenile glial dystrophy. Neuropathology 1980;1:113-8.
03: Belrose JC, Masoudi R, Michalski B, Fahnestock M. Increased pro-nerve growth factor and decreased brain-derived neurotrophic factor in non-Alzheimer's disease tauopathies. Neurobiol Aging 2014;35(4):926-33. PMID 24112788
04: Benson DF. Posterior cortical atrophy: a new clinical entity, or Alzheimer's disease. In reply. Arch Neurol 1989;46:843-4.
05: Benson DF, Davis RJ, Snyder BD. Posterior cortical atrophy. Arch Neurol 1988;45:789-93. PMID 3390033
06: Bergmann M, Gullotta F, Weitbrecht WU. Progressive subkortikale gliose. Fortschr Neurol Psychiatr 1991;59:328-34. PMID 1937341
07: Boller F, Lopez Ol, Moosey J. Diagnosis of dementia: clinicopathologic correlations. Neurology 1989;39:76-9. PMID 2642615
08: Borruat FX. Posterior cortical atrophy: review of the recent literature. Curr Neurol Neurosci Rep 2013;13(12):406. PMID 24136454
09: Brun A. Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Arch Gerontol Geriatr 1987;6:193-208. PMID 3689053
10: Brun A, Gustafson L. The birth and early evolution of the frontotemporal dementia (FTD) concept. J Mol Neurosci 2011;45(3):324-9. PMID 21647707
11: Bugiani O. The many ways to frontotemporal degeneration and beyond. Neurol Sci 2007;28:241-4. PMID 17972037
12: Chiba S, Takada E, Tadokoro M, et al. Loss of dopaminoreceptive neuron causes L-dopa resistant parkinsonism in tauopathy. Neurobiol Aging 2012;33(10):2491-505. PMID 22169201
13: Chiu WZ, Kaat LD, Seelaar H, et al. Survival in progressive supranuclear palsy and frontotemporal dementia. J Neurol Neurosurg Psychiatry 2010;81:441-5. PMID 20360166
14: Conneally M, Bird TD, Engel AG, et al. Frontotemporal dementia. Neurogenetics part A. Continuum 2000;6(6):59-72.
15: Constantinidis J, Richard J, Tissot R. Pick's disease: histological and clinical correlations. Eur Neurol 1974;11:208-17. PMID 4137107
16: Currier RD, Smith EE, Perry Tl, Bevin J, Gambetti P, Jackson JF. Familial astrocytic dementia. Neurology 1986;36:272. PMID 3748391
17: Englund E, Brun A. Frontal lobe degeneration of non-Alzheimer type. IV. White matter changes. Arch Gerontol Geriatr 1987;6:235-43. PMID 3689056
18: Feng F, Zhang WT, Wang LN. Progressive subcortical gliosis: neurodegenerative dementia should not be ignored. Chin J Contemp Neurol Neurosurg 2017;17(8):626-8.
19: Forrest SL, Kril JJ, Stevens CH, et al. Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain 2018;141(2):521-34. PMID 29253099
20: Foster NL, Wilhelmsen K, Sima AA, et al. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus. Document number 05391:1-30. West Hempstead, New York: National Auxiliary Publication Service, 1996.
21: Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D’Amato C, Gilman S. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference participants. Ann Neurol 1997;41(6):706-15. PMID 9189031
22: Gambetti P. Prion in progressive subcortical gliosis revisited [letter]. Neurology 1997;49:309-10. PMID 9222220
23: Gearing M, Mirra SS, Hedreen JC, Sumi SM, Hansen LA, Heyman A. The Consortium to Establish a Registry for Alzheimer's disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease. Neurology 1995;45:461-6. PMID 7898697
24: Goedert M, Spillantini MG, Crowther RA, et al. Tau gene mutation in familial progressive subcortical gliosis. Nat Med 1999;5:454-7. PMID 10202939
25: Gustafson L. Frontal lobe degeneration of non-Alzheimer type. II. Clinical picture and differential diagnosis. Arch Gerontol Geriatr 1987;6:209-23. PMID 3689054
26: Hassin GB, Levitin D. Pick's disease. Arch Neurol Psychiatr 1941;45:814-33.
27: Hodges JR, Davies RR, Xuereb JH, et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004;56:399-406. PMID 15349867
28: Ikeda K. Where fronto-temporal dementia should be placed in the history of Pick’s disease and related disorders [in Japanese]. Seishin Shinkeigaku Zasshi 2000;102:529-42. PMID 10979314
29: Kawles A, Nishihira Y, Feldman A, et al. Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C. Brain 2022;145(3):1069-78. PMID 34919645
30: Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain 2005;128:1996-2005. PMID 16033782
31: Khoubesserian P, Davous P, Bianco C, Puyirat J. Demence familiale de type Neumann (gliose sous corticale). Rev Neurol (Paris) 1985;141:706-12. PMID 2868516
32: Kim RC, Collins GH, Parisi JE, Wright AW, Chu YB. Familial dementia of adult onset with pathologic findings of a nonspecific nature. Brain 1981;104:61-78. PMID 7470845
33: Kim SY, La DL, Park SH, Koo HS, Chi JG. A case report of progressive subcortical gliosis. J Korean Neurol Assoc 1995;13(3):696-702.
34: Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T. Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 1990;40:251-6. PMID 2300243
35: Krishnamurthy PK, Johnson GV. Mutant (R406W) human tau is hyperphosphorylated and does not efficiently bind microtubules in a neuronal cortical cell model. J Biol Chem 2004;279:7893-900. PMID 14660557
36: Lanska DJ, Currier RD, Cohen M, et al. Familial progressive subcortical gliosis. Neurology 1994;44:1633-43. PMID 7936288
37: Lanska DJ, Lanska MJ, Whitehouse PJ, Gambetti P. Familial progressive subcortical gliosis. Neurology 1989;39:252.
38: Lanska DJ, Markesbery WR, Cochran E, Bennett D, Lanska MJ, Cohen M. Late onset progressive subcortical gliosis. J Neurol Sci 1998;157:143-7. PMID 9619636
39: Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001;24:1121-59. PMID 11520930
40: Lynch T, Sano M, Marder KS, et al. Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. Neurology 1994;44:1878-84. PMID 7936241
41: Mann DM. Dementia of frontal type and dementias with subcortical gliosis. Brain Pathol 1998;8:325-38. PMID 9546290
42: Masse G, Mikol J, Brion S. Atypical pre-senile dementia. J Neurol Sci 1981;52:245-67. PMID 7310435
43: Masters CL, Richardson JR. Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease): the nature and progression of spongiform change. Brain 1978;101:333-44. PMID 352478
44: Miki Y, Mori F, Tanji K, et al. An autopsy case of incipient Pick's disease: immunohistochemical profile of early-stage Pick body formation. Neuropathology 2014;34(4):386-91. PMID 24444359
45: Milenkovic I, Petrov T, Kovacs GG. Patterns of hippocampal tau pathology differentiate neurodegenerative dementias. Dement Geriatr Cogn Disord 2014;38(5-6):375-88. PMID 25195847
46: Moossy J, Martinez AJ, Hanin I, Rao G, Yonas H, Boller F. Thalamic and subcortical gliosis with dementia. Arch Neurol 1987;44:510-3. PMID 3579662
47: Morino H, Kurashige T, Matsuda Y, et al. Clinical and pathological features of FTDP-17 with MAPT p.K298_H299insQ mutation. Mov Disord Clin Pract 2024;11(6):720-7. PMID 38605589
48: Neumann MA. Pick's disease. J Neuropathol Exp Neurol 1949;8:255-82. PMID 18153924
49: Neumann MA, Cohn R. Progressive subcortical gliosis, a rare form of pre-senile dementia. Brain 1967;90:405-27.** PMID 5339109
50: Oda M. Thalamus degeneration in Japan. A review from clinical and pathologic viewpoints. Appl Neurophysiol 1976;39(3-4):178-98. PMID 801858
51: Oka Y, Saiki H, Hashimoto Y, et al. Japanese familial cases of frontotemporal dementia and parkinsonism with N279K tau gene mutation. Mov Disord Clin Pract 2020;8(1):126-32. PMID 33426168
52: Okada K, Hata Y, Takayanagi Y, Takahashi T, Takayanagi I, Nishida N. An autopsy case of preclinical/early clinical Pick disease. J Neuropathol Exp Neurol 2019;78(10):971-4. PMID 31504691
53: Olszewska DA, Fearon C, McGuigan C, et al. A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene. Neurobiol Aging 2021;106:343.e1-8. PMID 34274155
54: Ortner M, Kurz A. Posterior cortical atrophy. Pathology, diagnosis and treatment of a rare form of dementia [Article in German]. Nervenarzt 2015;86(7):833-9. PMID 25791802
55: Petersen RB, Tabaton M, Chen SG, et al. Familial progressive subcortical gliosis: presence of prions and linkage to chromosome 17. Neurology 1995;45:1062-7. PMID 7783864
56: Renner JA, Burns JM, Hou CE, McKeel DW Jr, Storandt M, Morris JC. Progressive posterior cortical dysfunction: a clinicopathologic series. Neurology 2004;63:1175-80. PMID 15477534
57: Rohrer J, Ryan B, Ahmed R. MAPT-Related Frontotemporal Dementia. 2000 Nov 7 [updated 2022 Aug 18]. In: Adam MP, Mirzaa GM, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2023. PMID 20301678
58: Seitelberger F. Praesenile gliale dystrophie. Acta Neuropathol 1968;Suppl 4:109-18. PMID 5728980
59: Seitelberger F, Gross H, Pilz P. Pick's disease: a neuropathologic study. In: Hirano A, Miyoshi K, editors. Neuropsychiatric disorders in the elderly. New York: Igaku-Shoin, 1983:87-117.
60: Shafei R, Woollacott IOC, Mummery CJ, et al. Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia. Neurobiol Aging 2020;87:141.e15-20. PMID 31870644
61: Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 1998a;8:387-402. PMID 9546295
62: Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC. Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol 1998b;153:1359-63. PMID 9811325
63: Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Prac Natl Acad Sci U S A 1997;94:4113-8. PMID 9108114
64: Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 1998c;95:7737-41. PMID 9636220
65: Spillantini MG, Swieten JC, Goedert M. Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Neurogenetics 2000a;2:193-205. PMID 10983715
66: Spillantini MG, Toshida H, Rizzini C, et al. A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann Neurol 2000b;48:939-43. PMID 11117553
67: Stanford PM, Brooks WS, Teber ET, et al. Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies. J Neurol 2004;251:1098-104. PMID 15372253
68: Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical diagnosis in primary degenerative dementia: correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 1983;46:9-13. PMID 6842208
69: Swerdlow RH, Miller BB, Lopes MB, et al. Autosomal dominant subcortical gliosis presenting as frontotemporal dementia. Neurology 2009;72(3):260-7. PMID 19153373
70: Tacik P, DeTure M, Hinkle KM, et al. A novel tau mutation in exon 12, p.Q336H, causes hereditary Pick disease. J Neuropathol Exp Neurol 2015;74(11):1042-52. PMID 26426266
71: Tissot R, Constantinidis J, Richard J. Pick's disease. In: Frederiks JA, editor. Neurobehavioral disorders. Handbook of clinical neurology. Vol 2. New York: Elsevier Science, 1985:233-46.
72: Torack RM, Morris JC. Mesolimbocortical dementia: a clinicopathologic case study of a putative disorder. Arch Neurol 1986;43:1074-8. PMID 3753266
73: Verity MA, Wechsler AF. Progressive subcortical gliosis of Neumann: a clinicopathologic study of two cases with review. Arch Gerontol Geriatr 1987;6(3):245-61. PMID 3318744
74: Wada K, Motoi Y, Komatsuzaki Y, et al. An 81-year-old man with personality change, dementia, and gait disturbance with diffuse leukoaraiosis of the cerebral white matter [in Japanese]. No To Shinkei 2006;58:79-90. PMID 16482927
75: Wilhelmsen KC, Forman MS, Rosen HJ, et al. 17q-linked frontotemporal dementia--amyotrophic lateral sclerosis without tau mutations with tau and alpha-synuclein inclusions. Arch Neurol 2004;61:398-406. PMID 15023818
76: Wilhelmsen KC, Lynch T, Nygaard TG. Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22. Am J Hum Genet 1994;55:1159-65. PMID 7977375
77: Wilhelmsen KC, Wszolek ZK, Currier RC, Lanska DJ. The clinical spectrum of chromosome 17q21.22-linked degenerative syndromes. Neurology 1996;46:A188.
78: Will RG, Lees AJ, Barnard RO. A case of progressive subcortical gliosis presenting clinically as Steele-Richardson-Olszewski syndrome. J Neurol Neurosurg Psychiatry 1988;51:1224-7. PMID 3225606
79: Yano K, Nishina Y, Kumano S. Ein beitrag zur histopathologie der Pickschen krankheit mit besonder beruecksichtigung der glioesen elemente. Folia Psychiatr Neurol Jpn 1960;14:123-39. PMID 13787230

Patient Profile

Age range of presentation: 45 to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor

heredity typical

autosomal dominant
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Unspecified dementia, including senile dementia: F03

Dementia in Pick disease: F02.0

Pick disease: G31.0
ICD-11: Dementia due to other specified diseases classified elsewhere: 6D85.Y

Frontotemporal dementia: 6D83
OMIM: Pick disease, type II: #172700

Familial progressive subcortical gliosis: #221820

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Progressive subcortical gliosis

Associated Disorders

Atypical dementia
Disinhibition-dementia-parkinsonism-amyotrophy complex
Frontal lobe dementias
Frontotemporal dementia
Frontotemporal dementia with parkinsonism linked to chromosome 17
- Nonspecific dementia
- Steele-Richardson-Olszewski syndrome
- Tauopathy
- Thalamic dementia

Differential Diagnosis

Pick disease
Alzheimer disease
other frontotemporal dementias
corticobasal ganglionic degeneration
Binswanger disease
- thalamic degenerations
- “atypical” dementias
- frontal lobe degeneration of non-Alzheimer type

Progressive subcortical gliosis

Progressive subcortical gliosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Wilson disease

Anti-LGI1 encephalitis

Fatal familial insomnia

Hyperventilation syndrome

Apraxia

Neurologic disorders associated with behavioral symptoms

Cortical blindness

Leukodystrophies

	• Management is supportive.
	• Although antipsychotic medications have been used to control hallucinations and paranoia, such agents may increase the extrapyramidal dysfunction that is commonly present in the later stages of the disorder.

Progressive subcortical gliosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Wilson disease

Anti-LGI1 encephalitis

Fatal familial insomnia

Hyperventilation syndrome

Apraxia

Neurologic disorders associated with behavioral symptoms

Cortical blindness

Leukodystrophies

This is an article preview.
Start a Free Account
to access the full version.