Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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This article includes discussion of tauopathies with dementia and parkinsonism. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The tauopathies are a group of neurodegenerative disorders that manifest as dementias and movement disorders. They have as a common pathological feature, the presence of intracellular accumulation of abnormal filaments of tau protein. The most common tauopathies, Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, Pick disease, and frontotemporal dementia with parkinsonism, present with either dementia, parkinsonism, or both. Clinical features may overlap, and accurate diagnosis may be challenging. In this article, the author reviews the clinical features, pathogenesis, diagnostic work-up, and potential therapies for this group of disorders.
• Tauopathies with dementia and parkinsonism represent a group of disorders with shared underlying pathology of intracellular accumulation of tau protein.
• These pathologically defined disorders can manifest with a broad range of phenotypes, in addition to the classically associated syndromes.
• Classical clinical features can help distinguish these disorders, but there is often marked overlap of clinical features.
• There are no confirmatory diagnostic tests in vivo, but ancillary testing such as imaging may be helpful.
• The diagnostic gold standard for these disorders remains postmortem pathologic confirmation.
Tauopathies are disorders associated with intracellular deposition of abnormally phosphorylated tau (a microtubule-associated protein), usually expressed as neurofibrillary tangles, neuropil threads, or abnormal tau filaments (eg, Pick bodies) (138). These disorders can be classified as sporadic or familial. Depending on the main tau isoform deposit, they can be further divided into 3 major groups:
(a) 4-repeat tauopathies (64 kDa, 68 kDa, and 72 kDa tau bands), including sporadic disorders such as progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and some familial frontotemporal dementias with parkinsonism associated with chromosome-17 (FTDP-17)
(b) 3-repeat tauopathies (60 kDa and 64 kDa tau bands) consisting of sporadic disorders such as Pick disease and some familial frontotemporal dementias with parkinsonism associated with chromosome-17
(c) 3 and 4 tau isoforms tauopathies, in which all isoforms are present in a hyperphosphorylated state (60 kDa, 64 kDa, 68 kDa, and a minor band of 72 kDa), including Alzheimer disease, Lytico-Bodig disease (previously called Parkinsonism-dementia-complex of Guam), and very rare disorders such as Niemann-Pick type C, neurofibrillary tangle dementia, and Gerstmann-Sträussler-Scheinker disease with tangles
Progressive supranuclear palsy. The 1996 National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy (NINDS-SPSP) criteria for a clinical diagnosis of progressive supranuclear palsy included features supporting a diagnosis of possible, probable, and definite progressive supranuclear palsy (90). The criteria for possible progressive supranuclear palsy include a progressive disorder with onset at the age of 40 or older with either vertical supranuclear gaze palsy, or both slowing of vertical saccades and postural instability with falls within the first year of onset. Probable progressive supranuclear palsy requires the presence of vertical supranuclear gaze palsy and postural instability with falls within the first year of onset. Definite progressive supranuclear palsy requires the features of either possible or probable progressive supranuclear palsy as well as pathological findings of typical progressive supranuclear palsy.
Modified clinical diagnostic criteria were proposed by the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) consortium in order to increase diagnostic sensitivity (19). The main differences from the NINDS-SPSP criteria were the inclusion of patients with younger age at onset (≥30 years) and an extension of the occurrence of falls to within 3 years of disease onset. Furthermore, disease duration had to be less than 8 years. A retrospective chart review of 98 pathologically diagnosed progressive supranuclear palsy cases and 46 controls at tertiary care centers evaluated the diagnostic accuracy of the NINDS-SPSP and NNIPPS criteria (126). There was similar sensitivity in the NINDS-SPSP “probable” criteria and the NNIPPS criteria. The highest sensitivity was obtained with a combination of the NINDS-SPSP “probable” and “possible” criteria.
The Movement Disorder Society (MDS) proposed criteria for the clinical diagnosis of progressive supranuclear palsy based on NINDS-SPSP criteria but included 4 domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction (64). This is meant to include the varied presentations of progressive supranuclear palsy and result in higher sensitivity of diagnosis. When compared to the NINDS-SPSP criteria, the MDS-PSP criteria had a greater sensitivity at 87.9% versus 45.5% for the former (Ali F et al 2019). This is likely due to the inclusion of various clinical phenotypes of progressive supranuclear palsy in the MDS criteria.
The pathological entity of progressive supranuclear palsy has been associated with several clinical variants (164). The following nomenclature has been proposed for the common variants: Richardson syndrome, progressive supranuclear palsy—parkinsonism (PSP-P), progressive supranuclear palsy—primary akinesia with gait freezing (PSP-PAGF), progressive supranuclear palsy—corticobasal syndrome (PSP-CBS), progressive supranuclear palsy—progressive nonfluent aphasia (PSP-PNAF). A 2014 retrospective study from 5 brain banks described the phenotypes of 100 pathologically confirmed progressive supranuclear palsy cases (127). During their lifetime, 70% of cases were accurately diagnosed using formal NINDS-SPSP criteria. Only 24 % were classified as Richardson syndrome, and there was a broad spectrum of phenotypes, many cases with atypical features.
The classic form of progressive supranuclear palsy, Richardson syndrome, presents in middle- to late-life with postural instability and falls, axial parkinsonism, frontal cognitive impairment, and ocular motor disturbances. Patients eventually develop a peculiar wide-based, slow, and lurching gait leading to falls, typically backwards (92). There is a supranuclear vertical gaze palsy, particularly down-gaze. Later, horizontal gaze abnormalities also occur. The preservation of the oculocephalic reflex is consistent with a supranuclear gaze palsy. Eyelid abnormalities include apraxia of eyelid opening, leading to functional blindness. The classic “worried” facial expression involves contraction of the frontalis, procerus, and corrugator muscles. Patients usually develop early dysarthria with a slow, growling speech and dysphagia. The parkinsonism is characterized by axial rather than limb involvement, symmetric extremity involvement, as well as its lack of or only transient benefit from levodopa therapy, distinguishing these patients from those with Parkinson disease.
Patients with a PSP-P variant present initially with predominant parkinsonism with limb bradykinesia, rigidity, and tremor (164). Some patients may have a jerky postural tremor or a 4- to 6-Hz reset tremor. Patients with this subtype may have a transient moderate response to levodopa, but eventually become nonresponders. Although falls and cognitive dysfunction do occur, they tend to present later than in Richardson syndrome. The duration of disease to death has been reported to be 3 years longer with PSP-P than Richardson syndrome. The PSP-PAGF variant is characterized by a progressive gait disturbance beginning with start hesitation and progressing to freezing of gait. There may also be freezing of speech and writing. The PSP-CBS variant is characterized by an asymmetric syndrome with limb rigidity, bradykinesia, and dystonia as well as apraxia, cortical sensory loss, and alien limb phenomenon. The PSP-PNFA variant is characterized by nonfluent speech with hesitancy, phonemic errors, and agrammatism as well as apraxia of speech with difficulties with speech initiation, timing, and coordination.
Most progressive supranuclear palsy patients develop marked cognitive deficits and personality changes that are suggestive of frontal lobe dysfunction, leading to the pattern of "subcortical dementia" (07). Progressive supranuclear palsy patients have severe frontal disturbances that can be investigated at the bedside. One bedside test is the 3-clap test, in which the subject is requested to clap 3 times, but no more than 3 times (42). Patients with progressive supranuclear palsy clap many times, whereas patients with Parkinson disease and frontotemporal dementia do not. This so-called “applause sign,” however, is not specific for progressive supranuclear palsy, as it is also present in other neurodegenerative disorders with frontal features, but it seems to differentiate parkinsonian disorders (and Huntington disease) from normal controls (171). Apraxia is not a major disturbance in progressive supranuclear palsy, and its extent is related to the dementia (135).
A European, natural history prospective cohort study involving 362 progressive supranuclear palsy patients evaluated cognitive function using the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and the Mattis Dementia Rating Scale (DRS) (28). The most common impairment was that of initiation, perseveration, and verbal fluency. A multicenter, prospective North American study evaluated the cognitive profiles of 200 progressive supranuclear palsy patients using a number of neuropsychological tests measuring a wide range of cognitive abilities (52). The predominant cognitive deficit was found in executive function, with milder deficits in memory, construction, and naming.
Progressive supranuclear palsy patients also exhibit behavioral symptoms (01). A study of 61 progressive supranuclear palsy patients showed that the majority suffered from continuous apathy, mostly in the moderate-to-severe range, and one third exhibited moderate-to-severe disinhibition (01). However, in contrast to what has been reported in Parkinson disease, depression was infrequent (and mild). A study evaluating behavioral abnormalities in 154 patients with clinically probable progressive supranuclear palsy found that greater than 50% of patients experienced apathy, depression, and sleep disturbances, with apathy as the most common behavioral disturbance (51).
Corticobasal degeneration. In 2013, an international consortium developed new diagnostic criteria for the clinical diagnosis of corticobasal degeneration based on clinical features of greater than 209 pathologically confirmed brain bank and published cases (14). Four corticobasal degeneration phenotypes emerged: corticobasal syndrome, frontal behavioral-spatial syndrome, nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Two sets of criteria were proposed. Probable corticobasal degeneration requires 1) gradual progression for at least 1 year, 2) age at onset ≥ 50 years, 3) no family history or tau mutations, and 4) clinical phenotype of probable corticobasal syndrome or either frontal behavioral-spatial syndrome or naPPA with at least 1 corticobasal syndrome feature. Possible corticobasal syndrome has broader criteria with no age or family history/tau mutation restrictions and includes a PSPS phenotype. The new consensus criteria were applied to a cohort of patients with detailed long-term follow-up including pathological evaluation (08). The criteria were applied to patients with pathology consistent with corticobasal degeneration and those considered corticobasal degeneration mimics without confirmatory pathology. This study addressed 2 questions: whether the criteria identified corticobasal degeneration pathology and what clinical criteria distinguished corticobasal degeneration from corticobasal degeneration mimics. Nine out of 19 patients with confirmed corticobasal degeneration pathology were diagnosed as probable corticobasal degeneration at presentation, and 12 out of 19 were diagnosed by death. This was similar to using the previous criteria and thus did not improve diagnostic accuracy. Fourteen out of 14 patients without corticobasal degeneration pathology met criteria for probable or possible corticobasal degeneration using new diagnostic criteria. Thus, the new criteria identified a broader spectrum of phenotypes for corticobasal degeneration but had a low specificity for clinical diagnosis. No clinical features distinguished the corticobasal degeneration group and corticobasal degeneration mimics.
Alzheimer disease. Clinically, Alzheimer disease may present with not only cognitive but also extrapyramidal symptomatology. The reported prevalence of parkinsonism in clinically diagnosed Alzheimer disease ranges from 12% to 92% (101). Most commonly, rigidity and bradykinesia are seen, as well as gait disturbance, whereas resting tremor is rare and suggests idiopathic Parkinson disease. Parkinsonism in Alzheimer disease usually presents after cognitive deficits. Baseline apathy or subsequent development of apathy in Alzheimer patients has been shown to be associated with greater parkinsonian features in these patients (143). Parkinsonian features in Alzheimer disease heralds a poor prognosis with greater cognitive deficits, earlier institutionalization, and decreased survival (144).
There are difficulties in differentiating Alzheimer disease from dementia with Lewy bodies. Severe memory disturbances affecting both encoding and retrieval are more suggestive of Alzheimer disease, whereas retrieval deficits are more common in dementia with Lewy bodies. Hallucinations and delusions unrelated to medications developing early are also usually suggestive of dementia with Lewy bodies, whereas these features usually develop at later stages in Alzheimer disease. Although the earliest cognitive feature in dementia with Lewy bodies is usually frontal dysfunction, in Alzheimer disease it is amnesia.
Frontotemporal dementia with parkinsonism associated with chromosome-17. Familial frontotemporal dementia with parkinsonism associated with chromosome-17 (FTDP-17) is clinically characterized by frontal behavioral (disinhibition, withdrawal, hyperorality), cognitive disturbances (executive dysfunction, nonfluent aphasia), and parkinsonism (15). The parkinsonism seen in FTDP-17 is classically a symmetric akinetic rigid syndrome that is not responsive to levodopa. Mutations of the tau gene, MAPT, located at position 17q21, were the first identified genetic cause of FTDP-17. However, many kindreds do not harbor a MAPT gene mutation and, thus, do not have tau pathology. There is phenotypic and genetic heterogeneity in the different familial frontotemporal dementias with parkinsonism associated with chromosome-17 kindreds (137; 40; 151; 13).
Kindreds with the N279K mutation of the MAPT gene usually present with parkinsonism. This mutation leads to an increase in the proportion of 4-repeat tau. The pallidopontonigral degeneration family is the largest and best-studied kindred with frontotemporal dementia with parkinsonism associated with chromosome-17 that harbors this mutation (159; 36; 124; 169; 170). Patients with pallidopontonigral degeneration present with an autosomal dominant rapidly progressive disorder characterized by a parkinsonian-dementia syndrome, dystonia, pyramidal signs, and ocular disturbances (167; 166; 159; 172). The average age at disease onset is 43 years, and average survival is 8.6 years. Although all of the affected family members share the N279K mutation, the clinical phenotypes are variable for unclear reasons. Patients present either with parkinsonism or frontal lobe-type dementia. Those with parkinsonism may present clinically with a condition that resembles progressive supranuclear palsy or corticobasal syndrome, but the familial nature and earlier age of presentation assists in the differentiation.
Frontotemporal dementias with a missense MAPT gene mutation (Ser305Asn) may present with hereditary dementia characterized by personality changes followed by memory disturbances but minimal parkinsonism (72).
A G389R mutation in exon 13 of the MAPT gene can cause a syndrome similar to Pick disease. Progressive aphasia and memory disturbance are the initial signs and begin in the fourth or fifth decade of life, followed by apathy, indifference, hyperphagia, rigidity, pyramidal signs, and dementia. Death occurs after 2 to 5 years. A juvenile presentation of a G389R mutation was reported with the proband developing symptoms at the age of 17 (34).
A variant of familial frontotemporal dementias with parkinsonism associated with chromosome-17 with a G-to-A transition in the intron following exon 10 of the MAPT gene (familial multiple system tauopathy) may also manifest supranuclear gaze palsy in addition to frontal and parkinsonian disturbances and a 4-repeat tauopathy (139). Mutation at codon 301 of the MAPT gene may present in the same family with early-onset dementia and parkinsonism exhibiting either frontal dementia or a corticobasal syndrome phenotype (Bugiani et al 1999; 100; 107). The severity and heterogeneity of the clinico-morphologic phenotypes may reflect the diversity in the primary molecular mechanisms of disease in familial frontotemporal dementias with parkinsonism associated with chromosome-17. Further studies are needed to better understand the phenotypic variations.
Lytico-Bodig disease. Lytico-Bodig (also called Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex) is a neurodegenerative condition endemic to the native Chamorros of Guam, usually occurring in the fifth to seventh decade of age. When it is clinically characterized by a parkinsonism-dementia syndrome, it is called Bodig disease; when it presents with amyotrophic lateral sclerosis, it is called Lytico disease. In addition to parkinsonism (mainly bradykinesia and rigidity, but also tremor without pill-rolling tremor), the Bodig form may also present with pyramidal signs, and supranuclear gaze palsy. Both variants of Lytico-Bodig may present with a retinal pigment epitheliopathy (56% of the subjects), which is also present in 16% of the Chamorros (39).
Guadeloupean parkinsonism. The focus of atypical parkinsonism affecting the natives of Guadeloupe is also a tauopathy that shares some clinical and pathologic features with progressive supranuclear palsy. This focus of atypical parkinsonism is reminiscent of the one described in Guam and the Kii Peninsula. Patients present with various phenotypes including early postural instability, parkinsonism not responding to L-dopa, ophthalmoplegia, pseudobulbar palsy, frontal lobe dementia, and cortical myoclonus (11). Three cases with this phenotype have been examined postmortem. Neuropathologically, 2 cases resembled progressive supranuclear palsy, and 1 exhibited unusual pathological features including absent tufted astrocytes and abundance of tau-positive threads; additionally, tau-positive neurons outnumbered true neurofibrillary tangles (32). They all showed the H1/H1 haplotype without any mutation. Consumption of herbal tea and tropical fruits and plants of the Annonaceae family containing inhibitors of mitochondrial I enzymes have been associated with this disorder (32; 81). Annonacin, a lipophilic inhibitor of this mitochondrial complex, (found in fruit and herbal teas from plants of the Annonaceae family) induces nigral and striatal neurodegeneration in rats and is likely of relevance for the development of the atypical parkinsonism in Guadeloupe (33). It is possible that by studying this disorder the role of gene and environmental interactions in the development of tauopathies manifesting clinically with parkinsonism and dementia could be better understood.
A 72-year-old man presented with 2 years of difficulty walking and frequent falls backwards. His voice was soft, and he had difficulties keeping his eyes open. He had become a messy eater and had difficulty seeing all the food on his plate. He also started to have difficulty swallowing solids and liquids. On examination there was a “worried” facial expression with contraction of the frontalis and corrugator muscles and deep nasolabial folds. There was apraxia of eyelid opening. On primary gaze there were square wave jerks. Optokinetic nystagmus was slowed in the vertical plane, and he had marked difficulty looking downwards. His speech was dysarthric and “growling.” There was marked rigidity of the neck and normal tone in the arms. His gait was wide-based and reckless, and he pivoted when turning. There were impaired postural reflexes. The clinical history and examination were consistent with a diagnosis of probable progressive supranuclear palsy.
The etiopathogenesis of cell degeneration in the sporadic tauopathies is poorly understood. The observation that tau gene coding and splice-site mutations causing familial frontotemporal dementias with parkinsonism associated with chromosome-17 demonstrates that tau dysfunction is sufficient to induce neurodegeneration (71; 122; 136; 139; 140). Research has substantially advanced our understanding of the tauopathies and provided the opportunity to develop transgenic mouse models that hopefully will improve our insight into the pathogenesis of these disorders and will accelerate the discovery of more effective therapies (54; 88; 86; Lewis et al 2005; 165). The causative role of tau filament formation in the pathogenesis of neurofibrillary degeneration has been experimentally shown in vivo (58). Despite this breakthrough, the pathogenesis of the more common sporadic 4-repeat tauopathies, such as progressive supranuclear palsy and corticobasal degeneration, remains unknown. However, even when the tau mutation is identified (familial frontotemporal dementias with parkinsonism) the reasons for both late symptom onset and phenotype variability remain unknown. Several mechanisms have been proposed to explain both issues, including genetic and environmental factors as well as free-radical-mediated oxidative injury.
Genetic factors. In familial frontotemporal dementias with parkinsonism associated with chromosome-17 families, several exonic and intronic tau missense and splice site mutations in the tau gene have been identified, and the gene has been regionally localized to chromosome 17q21- 22 (65; 71; 122; 57; 125; 168; 23; 114). Currently, more than 50 mutations in the MAPT gene have been identified. Many of the known mutations have their primary effect at the protein level. They reduce the ability of tau protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. The other mutations have their primary effect at the RNA level and perturb the normal ratio of 3-repeat to 4-repeat tau isoforms. Where studied, this resulted in a relative overproduction of tau protein with 4 microtubule-binding domains in the brain. Individual tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration, or Pick disease. Known mutations are either in the coding region or are intronic mutations located close to the splice-donor site of the intron downstream of exon 10 (53). Most coding region mutations cause a reduced ability of tau to interact with microtubules, and some promote assembly of tau into filaments. Missense mutations affecting constitutively expressed exons influence all 6 major tau isoforms and result in neurofibrillary tangles similar to those in secondary tauopathies, such as Alzheimer disease. In contrast, mutations exhibiting exon 10 splicing in were shown to increase the ratio of 4-repeat tau, whereas if exon 10 is spliced out, 3-repeat tau outnumbers (71; 122; 139; 152; 70).
A cross-sectional study of 74 patients with frontotemporal dementia compared the clinical and pathological characteristics of patients with MAPT, GRN, and C9orf72 gene mutations (134). Those with MAPT mutations were younger and had more disinhibition, stereotyped behaviors, semantic impairment, and temporal brain atrophy. GRN patients were more likely to present with a nonfluent aphasia and were older at death. Those with C9orf72 mutations were associated with amyotrophic lateral sclerosis and demonstrated more psychotic symptoms. MAPT cases were associated with tau pathology, whereas GRN and C9orf72 were associated with TDP-43 pathology. A review of C9orf72 cases with parkinsonism found a hypokinetic-rigid syndrome to be more common than resting tremor, both symmetric and asymmetric presentations (160). Other presentations included a progressive supranuclear palsy phenotype, cerebellar dysfunction, upper and lower motor neuron signs, cognitive dysfunction, personality change, and psychiatric symptoms. C9orf72 mutations should be considered in atypical parkinsonism cases with a family history of amyotrophic lateral sclerosis or frontotemporal dementia.
Progressive supranuclear palsy and corticobasal degeneration share many pathological features with familial frontotemporal dementias with parkinsonism with defined tau mutations (eg, P-301, N279K) including selective deposition of 4-repeat tau (20; Bugiani et al 1999; 151). Although most cases of progressive supranuclear palsy appear to be sporadic, rare genetically determined forms have been reported (Yebenes et al 1995; 129; 128). A genome-wide association study found significant novel variants associated with progressive supranuclear palsy at TX6, EIF2AK3, and MOBP as well as 2 independent variants in the MAPT gene (63). These genes are involved in the endoplasmic reticulum unfolded protein response, endosomal protein transport, and myelin structure. Genetic studies have shown that progressive supranuclear palsy is associated with inheritance of a specific genotype (H1/H1) in the tau gene (18; 17; 46; 157). The H1 haplotype of tau has been identified as a significant risk factor for progressive supranuclear palsy and corticobasal degeneration. The effect of the H1/H1 susceptibility genotype appeared stronger in the typical progressive supranuclear palsy phenotype, Richardson syndrome, than in progressive supranuclear palsy-parkinsonism (161). Melquist and colleagues identified additional genetic loci involved in conferring the risk of progressive supranuclear palsy through a pooling-based genome-wide association study of more than 500,000 single nucleotide polymorphisms (99). The H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic, genotypic, and haplotypic levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes and both genes could be viable candidates for conferring the risk of developing progressive supranuclear palsy. The H1/H1 genotype dosage does not influence age at onset, severity, or survival of patients with progressive supranuclear palsy (91). It is likely that either both H1 alleles need to be present or alternatively both H2 alleles need to be absent to develop this disease. Whether the H1/H1 genotype is an inherited susceptibility variant or the H2/H2 is a protective variant in progressive supranuclear palsy is unclear, but studies suggest that the latter is likely. Specific H1 variants (subhaplotypes) are associated with this disorder (116; 120). Moreover, whether a relatively rare mutation with low penetrance could contribute to the abnormal tau aggregation observed in progressive supranuclear palsy remains to be determined. Stanford and colleagues identified a novel silent mutation (S305S) in the tau gene in a subject with pathologic features of progressive supranuclear palsy with neurofibrillary tangles concentrating within the subcortical regions of the basal ganglia (142). Another mutation (G303V) on the tau gene was seen in early onset familial autosomal dominant progressive supranuclear palsy, with overexpression of tau isoforms with 4 microtubule-binding repeats in the proband brain (130). The discovery of these mutations provides direct molecular evidence for a functional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic. Variants of the VEGF gene were demonstrated to be a susceptibility factor for progressive supranuclear palsy and corticobasal syndrome (24). A systematic genetic analysis of MAPT in 10 pathologically confirmed corticobasal degeneration cases identified a novel mutation in MAPT in exon 13, p.N410H (77). Functional analysis demonstrated that this mutation interfered with tau homeostasis. A genome-wide association study involving 152 autopsy-proven corticobasal degeneration cases demonstrated shared associations with progressive supranuclear palsy at MAPT and MOBP (myelin-associated oligodendrocyte basic protein) (78). In a study of 802 patients with progressive supranuclear palsy, novel associations with progressive supranuclear palsy were observed for 3 MAPT H1 subhaplotypes, including H1d and H1o, which further supports the role of MAPT haplotypic variation in susceptibility to progressive supranuclear palsy (60).
Environmental factors. Amongst the tauopathies, the majority of cases of progressive supranuclear palsy and corticobasal degeneration are sporadic and it is likely that environmental factors may contribute to the development of these disorders. The most relevant finding in the search for environmental factors was reported by Caparros-Lefebvre and colleagues in a group of related Guadeloupean patients with an atypical parkinsonian and frontal dementia neurodegenerative disorder that resembles progressive supranuclear palsy and Lytico-Bodig disease (31; 32). They also found that patients with these disorders had an increased consumption of tropical fruits (paw paw) and herbal tea (boldo) that contain tetrahydroisoquinolones and acetogenins that are neurotoxic in animal models (33). Neuropathological examination of 3 of these progressive supranuclear palsy patients, homozygous for the H1 tau haplotype, showed an accumulation of 4-repeat tau protein predominating in the midbrain. Cellular studies have shown that tetrahydroisoquinolones and acetogenins exert a direct toxicity to dopaminergic neurons through inhibition of complex 1 enzymes --a mitochondrial mechanism similar to MPTP or rotenone exposure (81). Intravenous administration of annonacin (a major acetogenin from the plant A. muricata) to rats resulted in significant loss of dopaminergic neurons in the substantia nigra and cholinergic, dopaminergic, and cyclic AMP-regulated phosphoprotein (DARPP-32)-immunoreactive GABAergic neurones in the striatum, accompanied by a significant increase in the number of astrocytes and microglial cells (33). The distribution of the lesions was similar to that in patients with atypical parkinsonism.
A case-control study evaluated the association of environmental risk factors and progressive supranuclear palsy and found that a greater number of years of drinking well water was associated with progressive supranuclear palsy (94). No specific environmental toxin, however, was found to be associated with progressive supranuclear palsy.
Oxidative stress. There have been reports of a regionally specific and significant increase of oxidative injury in the substantia nigra, subthalamic nucleus, and superior frontal cortex in postmortem progressive supranuclear palsy-affected tissue as compared to age-matched control tissue. The cerebellum, an area relatively unaffected by the disease process, was unchanged (06). Lipoperoxidation was shown to be selectively involved in progressive supranuclear palsy (113). It is hypothesized that intraneuronal accumulation of toxic aldehydes may hamper tau degradation, leading to abnormal aggregation. Several studies have shown a regionally specific and significant increase of markers of oxidative injury in affected areas, but not in unaffected areas, of postmortem progressive supranuclear palsy tissue as compared to age-matched controls (113; 06). These findings suggest that oxidative damage, precipitated by enhanced free radical production, plays a role in the pathogenesis of this disorder. Hartzler and coworkers have proposed that tau phosphorylation in progressive supranuclear palsy and Pick disease is a result of oxidative stress-induced activation of mitogen-activated protein kinases (59).
In most of these disorders, the pathology involves the frontosubcortical circuits. Parkinsonism reflects the involvement of the motor circuit. Frontal cognitive disturbances (impaired execution of sequential actions, shifting between tasks, concreteness in thinking, difficulty in retrieving information and planning, and decreased verbal fluency) depict involvement of the dorsolateral circuit. Involvement of the orbitofrontal circuit is illustrated by depression, disinhibition, and behaviors depending on environmental stimuli (ie, imitation behaviors); apathy and attentional disturbances represent the involvement of the mediofrontal circuit. Studies using MRI PET have shown deficits to correlate with regional cerebral atrophy in progressive supranuclear palsy, suggesting that intrinsic neurodegeneration of specific subcortical nuclei and frontal cortical subregions together contribute to motor and behavioral disturbances in progressive supranuclear palsy (21; 38).
In progressive supranuclear palsy, gross examination of the brain shows midbrain atrophy. The substantia nigra has decreased neuromelanin pigment, and the subthalamus, superior cerebellar peduncle, and dentate nucleus are atrophic. There are neuronal loss and neurofibrillary tangles in the basal ganglia, diencephalon, and brainstem. Progressive supranuclear palsy is characterized by abundant neurofibrillary tangles and neuropil threads particularly in the striatum, especially globus pallidus interna, subthalamic nucleus, substantia nigra, oculomotor complex, reticular formation, periaqueductal gray, superior colliculi, basis pontis, dentate nucleus, and prefrontal cortex (93). There is uniform presence of tau-positive cortical lesions. These were found in highest concentration in the precentral and angular gyrus, primarily affecting the deep cortical layers, and involved both small and large neurons. Neuronal loss and gliosis are variable. Tau-positive glial inclusions, tufted astrocytes, are a consistent pathologic finding. Coiled bodies, which are tau deposits in oligodendrocytes found in the white matter, are also seen in a widespread distribution. Early pathology is evident primarily in the midbrain, perhaps explaining the relatively early vertical eye movement abnormalities. The pontine nucleus raphe interpositus, pedunculopontine, and deep pontine nuclei are also affected. Statistical analysis has suggested that both cortical and subcortical neurofibrillary tangles are linked to the pedunculopontine nucleus, which may play a prominent role in spreading the lesions. The distribution and ultrastructure of neurofibrillary tangles in progressive supranuclear palsy is distinct from those found in Alzheimer disease. Progressive supranuclear palsy is associated with more subcortical involvement, with 15- to 20-nm-wide single tubules, compared to the cortically based paired helicoidal filaments of Alzheimer disease.
There is pathologic heterogeneity in progressive supranuclear palsy associated with the proposed clinical variants. Tau pathology has been shown to be milder in the PSP-P phenotype with less widespread distribution when compared with the Richardson syndrome (162; 73). The pathology associated with PSP-PAGF was demonstrated to also have a more restricted distribution when compared with Richardson syndrome, with less severe tau pathology in the motor cortex, striatum, pontine nuclei, and cerebellum (163; 05). A small series of PSP-CBS patients demonstrated greater tau pathology in the midfrontal and inferior parietal cortices, areas that are commonly affected in corticobasal degeneration (150). Another small series of 4 patients with PSP-PNFA demonstrated less severe tau pathology in subcortical gray matter and brainstem structures and more severe pathology in the superior frontal gyrus and temporal cortex compared to Richardson syndrome (74).
The neuropathology of corticobasal degeneration includes prominent atrophy of the frontoparietal cortex, particularly peri-Rolandic regions, as well as depigmentation of the substantia nigra. In affected regions, there is neuronal loss, gliosis, and prominent glial and neuronal intracytoplasmic filamentous tau-immunoreactive pathology. Achromatic ballooned neurons, which are most numerous in cortical and limbic regions, are strongly immunoreactive for phosphorylated neurofilaments and B-crystallin but variably positive for tau (47). The glial tau pathology consists of characteristic astrocytic plaques as well as numerous tau-immunoreactive inclusions in gray and white matter in astrocytes and oligodendrocytes (coiled bodies). Perhaps the most striking feature of corticobasal degeneration is the extensive accumulation of tau-immunoreactive cell processes throughout both the gray and white matter. Unlike the neuropil threads of Alzheimer disease, the majority of threads do not stain with antibodies to neurofilament, suggesting that many are localized in the glia.
In frontotemporal dementia and parkinsonism, atrophy of frontal and temporal cortex, as well as of basal ganglia and substantia nigra, is seen. In the majority of cases, these features are accompanied by neuronal loss, gliosis, and microtubule-associated protein tau deposits, which can be present in both neurons and glial cells (136). The distribution, structural, and biochemical characteristics of the tau deposits differentiate them from those present in Alzheimer disease, corticobasal degeneration, progressive supranuclear palsy, and Pick disease. Frontotemporal dementia with parkinsonism associated with mutations in MAPT are associated with tau pathology whereas those caused by other gene mutations (GRN, C9orf72) have non-tau pathology (115).
The pathology of Alzheimer disease associated with parkinsonism is heterogeneous (101). Twenty to eighty-five percent of Alzheimer patients with parkinsonism have been shown to have coincident pathology consistent with idiopathic Parkinson disease. In some cases, there are no structural abnormalities of the substantia nigra. Cases without evidence of nigral degeneration may have deposition of neurofibrillary tangles in the nigra or extranigral dopaminergic loss or deposits. A neuropathological study compared Alzheimer disease patients with and without parkinsonism, but without pathological findings consistent with idiopathic Parkinson disease (66). Parkinsonism in Alzheimer disease was associated with cell loss in the substantia nigra and the putamen. Neuronal tau pathology was a less striking feature, with neurofibrillary tangle density in the substantia nigra but not the putamen correlating with parkinsonism.
Bodig disease is characterized neuropathologically by abundant neurofibrillary tangle lesions similar to those of Alzheimer disease, but without the amyloid plaques (98; 29). However, the distribution of the neurofibrillary tangles is similar to that in progressive supranuclear palsy (49). Although several hypotheses have been proposed (eg, neurotoxins, such as beta-N-methylamino-L-alanine from the Cycas circinalis seeds; viral and genetic theories), the etiology of Lytico-Bodig disease remains unknown; however, the tau gene is not the primary cause of this disorder (118).
Progressive supranuclear palsy is the most frequent parkinsonian disorder after Parkinson disease. The average annual incidence rate for progressive supranuclear palsy for ages 50 to 99 years is 5.3 new cases per 100,000 person-years, and the age-adjusted prevalence rate is 6.0 to 6.4 (55; 26; 132; 108). The prevalence of progressive supranuclear palsy increases with age (26).
The incidence and prevalence of corticobasal degeneration are unknown, but it is estimated that approximately 4.9 per 100,000 people are affected in the United States and 1.7 in Japan (147; 105).
The familial frontotemporal dementias with parkinsonism associated with chromosome-17 mutations are rare. A study evaluated their frequency in 3 patient series: a community-based dementia series; a clinicopathological tauopathy referral series (P301L mutations in 3.6% cases but 9.4% familial cases); and a pathologically confirmed familial frontotemporal dementia series (3 splice-site mutations in 13.6% of cases). The data indicated variable but less than 15% of cases with familial frontotemporal dementias with parkinsonism associated with chromosome-17, depending on the sample referral and criteria used (68).
It is important to stress that before making the diagnosis of a tauopathy, it is crucial to exclude treatable causes of parkinsonism or dementia such as drug-induced, infectious, vascular, and tumoral etiologies. A good history rules out drug-induced parkinsonism in patients with dementia (eg, neuroleptics) or medication-induced cognitive disturbances in those with parkinsonism (eg, anticholinergic agents). Similarly, when suspected by history or examination ancillary tests (eg, metabolic, neuroimaging, or cerebrospinal studies) help to diagnose metabolic, vascular, tumoral, or infectious causes. There are reports of syndromes resembling progressive supranuclear palsy following surgeries on the heart and the great vessels (85; 102). Also, a PSP-like paraneoplastic syndrome has been described in association with B-cell lymphoma (146).
• Neurodegenerative disorders (progressive supranuclear palsy, corticobasal degeneration, Pick disease, frontotemporal dementia with parkinsonism)
• Drug-induced (combination of drugs, anticholinergics in Parkinson disease patients, or both anticholinergics and dopamine blockers)
• Infectious (Whipple disease, Creutzfeldt-Jakob disease, HIV)
• Vascular (multi-infarct, lacunar infarct)
• Toxic (Wilson disease, manganese, Guadeloupean parkinsonism)
• Tumoral (primary, secondary)
• Normal pressure hydrocephalus
• Posttraumatic (dementia pugilistica)
Ancillary testing such as imaging and CSF markers may be helpful to support a clinical diagnosis, especially in early stages when diagnosis can be unclear. Many of the tests described below, however, are not routinely available in clinical practice. The diagnostic gold standard remains postmortem pathologic confirmation.
Magnetic resonance imaging (MRI). Progressive supranuclear palsy has characteristic features on MRI that may help distinguish progressive supranuclear palsy from other parkinsonian disorders (156; 112; 56; 67). The main findings in progressive supranuclear palsy on MRI are midbrain atrophy, third ventricular dilatation, and T2 hyperintensities of the periaqueductal gray. The atrophy of the rostral tegmentum compared to the pontine base is called the “penguin” or “hummingbird” sign (112; 56). The “morning glory” sign, which is a concavity of the lateral margin of the tegmentum suggesting atrophy of the midbrain, is said to be related to the vertical supranuclear gaze palsy seen in progressive supranuclear palsy (02). The MRI Parkinsonism index (MRPI) (pons area/midbrain area x middle cerebellar peduncle width/superior cerebellar peduncle width) has been proposed to distinguish progressive supranuclear palsy from Parkinson disease (104). In 42 clinically diagnosed progressive supranuclear palsy patients, the MRPI was significantly higher in the progressive supranuclear palsy group compared to the probable Parkinson disease, possible Parkinson disease, and healthy control group. The midbrain/pons ratio was significantly lower in progressive supranuclear palsy patients compared to the Parkinson disease and control subjects; however, there was considerable overlap in the values between progressive supranuclear palsy subjects and others. An MRI measure of the sagittal midbrain-to-pons ratio was assessed in a group of pathologically and clinically diagnosed progressive supranuclear palsy, Parkinson disease, and multiple system atrophy patients (97). Midbrain measurement of less than 9.35 mm or a ratio of 0.52 had 100% specificity and positive predicative value for the diagnosis of progressive supranuclear palsy. One study found that the midbrain/pons measurement was affected by increasing age and disease-related changes in Parkinson disease, whereas the MRPI was not affected (103). Brain iron accumulation may show a characteristic pattern on T2-weighted images in progressive supranuclear palsy patients, with iron deposition in the caudate, globus pallidus, and putamen distinguishing progressive supranuclear palsy from Parkinson disease or healthy controls (22).
MRI findings in corticobasal degeneration include asymmetric atrophy of the dorsal prefrontal and perirolandic cortices, corpus callosum, striatum, and brainstem (79; 84). In patients with corticobasal degeneration who demonstrate alien limb syndrome, MRI scans reveal focal abnormalities in the corresponding area of the homunculus (69). A proportion of corticobasal degeneration patients show physiological evidence of impaired callosal motor function and atrophy of the corpus callosum on MRI, possibly correlated to dysphasic and cognitive disorders (149).
Diffusion tensor imaging has compared progressive supranuclear palsy and corticobasal syndrome, looking at patterns of white matter degeneration (158). In progressive supranuclear palsy, the infratentorial regions were most affected, including the bilateral superior cerebellar peduncles and midbrain, compared to controls. In corticobasal syndrome, the supratentorial regions were most affected in an asymmetric fashion, including the body of the corpus callosum, white matter of the premotor, prefrontal, and motor cortices, and middle cingulate bundle, compared to controls. White matter tract damage was assessed in 37 progressive supranuclear palsy patients compared to patients with Parkinson disease and healthy controls (04). Measurements of the corpus callosum and superior cerebellar peduncle distinguished progressive supranuclear palsy from Parkinson disease. Furthermore, severity of damage in the corpus callosum and superior cerebellar peduncles correlated with global disease severity in progressive supranuclear palsy.
Single photon emission computed tomography (SPECT). The early differentiation between Parkinson disease and other neurodegenerative disorders with parkinsonian features has been attempted with SPECT (16). A SPECT study with the dopamine marker beta-CIT demonstrated striatal binding was significantly reduced in multiple system atrophy (-51% of normal mean), progressive supranuclear palsy (-60%), corticobasal degeneration (-35%), and Parkinson disease (-58%) as compared to normal controls (119). Asymmetry of striatal beta-CIT binding was significantly increased in patients with corticobasal degeneration and Parkinson disease. Putamen-caudate nucleus ratios in patients with Parkinson disease, multiple system atrophy, and progressive supranuclear palsy, but not with corticobasal degeneration, were significantly reduced (119). A study using (123I)ioflupane SPECT found more significant reduction of striatal binding in progressive supranuclear palsy cases compared to Parkinson disease and multiple system atrophy patients (10). A study of 123I-FP-CIT SPECT in 36 patients with probable corticobasal degeneration found more uniform reduced uptake throughout the striatum and greater asymmetry in caudate and putamen uptake in corticobasal syndrome compared to Parkinson disease (35). Combined presynaptic and postsynaptic D2 receptor imaging with IBZM SPECT imaging has also been found to be useful in the differentiation between the parkinsonian syndromes. Significant reductions in D2 receptor binding were seen in patients with multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration but not in essential tremor, Parkinson disease or diffuse Lewy body disease (121).
Positron emission tomography (PET). Imaging with [(18)F]-fluorodeoxyglucose has been used to identify characteristic patterns of regional glucose metabolism in patient cohorts with idiopathic Parkinson disease, as well as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration (44). PET scanning using a postsynaptic D2 receptor ligand fluorine-18 desmethoxyfallypride (18F-DMFP) has shown that patients with multisystem atrophy and progressive supranuclear palsy have decreased postsynaptic tracer binding (133). PET scans have also revealed a pattern of increased microglial activation in progressive supranuclear palsy patients involving cortical and subcortical regions that corresponds well with the known distribution of neuropathological changes and may help in characterizing in vivo the underlying disease activity in progressive supranuclear palsy (50). A study involving 107 atypical parkinsonism patients demonstrated that FDG-PET had greater sensitivity than [¹²³I]IBZM-SPECT in distinguishing Lewy body disease from atypical parkinsonism, and FDG-PET could reliably distinguish subgroups of atypical parkinsonism, including progressive supranuclear palsy and corticobasal degeneration (61). A comparison using FDG-PET between Richardson syndrome and PSP-P demonstrated distinct patterns with predominant frontal and thalamic hypometabolism with Richardson syndrome and putaminal hypometabolism with PSP-P (141).
Brain parenchyma sonography. Brain parenchyma sonography may help distinguish progressive supranuclear palsy from Parkinson disease by focusing on substantia nigra and lentiform nucleus hyperechogenicity. Studies have shown that hyperechogenicity of the substantia nigra is associated with Parkinson disease, whereas a normoechogenic substantia nigra is associated with progressive supranuclear palsy (43). Enlargement of the third ventricle greater than 10 mm in combination with hyperechogenicity of the lenticular nucleus may also help distinguish progressive supranuclear palsy from Parkinson disease (154). When Richardson syndrome patients were compared with PSP-P, hyperechogenicity of the lentiform nucleus and greater enlargement of the third ventricle was associated with Richardson syndrome and substantia nigra hyperechogenicity was more closely associated with PSP-P (76).
A study evaluated patients with progressive supranuclear palsy and corticobasal syndrome via brain parenchyma sonography using a transcranial color-coded phased-array ultrasound system equipped with a 2.5-MHz transducer through preauricular acoustic bone windows using a standardized protocol (155). Marked hyperechogenicity of the substantia nigra was seen in 88% of 8 corticobasal syndrome patients but not in any of 11 progressive supranuclear palsy patients. Marked dilatation of the third ventricle (width less than 10 mm) was found in 83% of 12 progressive supranuclear palsy patients but in none of the corticobasal syndrome patients.
Cerebrospinal fluid biomarkers. Researchers have studied cerebrospinal fluid proteins as potential biomarkers to help distinguish parkinsonian disorders (37). The levels of total CSF tau in progressive supranuclear palsy and corticobasal degeneration have shown mixed results compared with controls. Further studies of different forms of tau protein have also been studied in parkinsonian disorders. One study found a low ratio of light (33 kDa) to heavy (55 kDa) tau protein in the CSF of patients with progressive supranuclear palsy, which differentiated this group from other tauopathies and from synucleinopathies (25). This finding had an 87% sensitivity and 86% specificity, and was validated against MRI voxel-based morphometry of brainstem gray matter. A study evaluating CSF biomarkers in clinically diagnosed progressive supranuclear palsy (n=21), corticobasal syndrome (n=12), and Parkinson disease (n=28) found higher concentrations of tau protein (t-tau), and tau protein phosphorylated at Thr181 (p-tau) in corticobasal syndrome patients compared with progressive supranuclear palsy and Parkinson disease (03). The ratio of p-tau/t-tau had 84.2% sensitivity and 66.7% specificity for distinguishing progressive supranuclear palsy from corticobasal syndrome; t-tau had the greatest sensitivity (75%) and specificity (90.9%) for discriminating corticobasal syndrome from Parkinson disease. A study compared CSF tau in clinically diagnosed progressive supranuclear palsy compared to Alzheimer disease and normal controls (153). There were lower CSF N-terminal and C-terminal tau concentrations in progressive supranuclear palsy compared to normal controls and Alzheimer disease. Alzheimer disease cases had higher total CSF tau concentrations and p-tau levels than progressive supranuclear palsy cases and normal controls. Male patients had lower tau levels in the progressive supranuclear palsy and Alzheimer disease cases.
Neurofilament light chain, a protein associated with neurodegeneration, has been studied as a biomarker to distinguish atypical parkinsonism from Parkinson disease. Elevated levels of neurofilament light chain in CSF have been shown to differentiate atypical parkinsonism (progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy) from Parkinson disease early on in the disease course with a high sensitivity and specificity (48). Elevated serum neurofilament light chain has also been shown to distinguish progressive supranuclear palsy from Parkinson disease and is correlated with levels of CSF neurofilament light chain. Further studies are needed to confirm neurofilament light chain’s role as a diagnostic biomarker for atypical parkinsonism (96).
In general, the tauopathies progress steadily. In progressive supranuclear palsy, most patients eventually require a wheelchair and a feeding tube; speech may become unintelligible, palilalic, or mute. In a study of the progression of progressive supranuclear palsy in patients selected from the research and clinical files of 7 medical centers involving tertiary centers of Austria, England, France, and the United States, the median survival time was 5.6 years (range 2 to 16.6 years) (95). Onset of falls during the first year, early dysphagia, and incontinence predicted a shorter survival time. Age at onset, gender, and early onset of dementia, vertical supranuclear palsy, or axial rigidity had no effect on prognosis of survival. Pneumonia was the most common immediate cause of death (95).
A retrospective study evaluated the clinical predictors of survival in 43 patients with clinically diagnosed progressive supranuclear palsy, 37 with Richardson syndrome and 6 with PSP-P (41). Older age at onset (> age 63), early dysphagia, and early cognitive dysfunction predicted decreased survival. Furthermore, a shorter time to first clinical disability milestone predicted a decreased overall survival.
In corticobasal degeneration, the condition is slow in progression and relentless. In 1 series of pathologically proven cases, dysarthria occurred 40 months after disease onset and dysphagia at a median of 64 months, in contrast to 84 months and 130 months in Parkinson disease (106). Medications do not appear to affect the natural progression of the neurodegenerative process, and the disease usually progresses to death within 6 to 9 years.
Frontotemporal dementias are inexorably progressive. The duration of disease can be as short as a few years to well over a decade. As the frontotemporal dementias progress, gait and balance difficulties may intervene. Eventually, difficulties with swallowing occur, leading to weight loss or aspiration pneumonia.
Currently, no treatments can slow or stop the progression of these disorders. However, an early and accurate diagnosis allows physicians to provide the appropriate care, avoid disease-related complications, and estimate prognosis and survival.
In progressive supranuclear palsy and corticobasal degeneration, trials with dopaminergic drugs and cholinesterase inhibitors have failed to show benefit. The myoclonus in these disorders has been treated with benzodiazepines and sodium valproate with varying degrees of success. Botulinum toxin injections are useful for focal dystonias that may occur in these disorders (80). Palliative therapies include physical, occupational, speech, and swallowing therapies for these patients’ gait instability, dysarthria, and dysphagia. Depression can be treated with SSRIs.
In frontotemporal dementia, a randomized, double-blind, placebo-controlled, crossover study of trazodone produced a significant decrease in the Neuropsychiatric Inventory total score in 26 patients. This change was due mainly to improvements on irritability, agitation, depressive symptoms, and eating disorders (82).
A 2009 double-blind, placebo-controlled trial evaluated the effect of riluzole in 760 Parkinson-plus patients, including 362 patients with a clinical diagnosis of progressive supranuclear palsy (19). At 36 months, there was no effect of riluzole on the primary outcome of survival or rate of progression.
A small open-label study evaluated the effect of rivastigmine in 5 patients with progressive supranuclear palsy and dementia over a period of 3 to 6 months (89). With rivastigmine up to 12 mg/day, there was a slight improvement in working memory and verbal fluency. The medication was well tolerated. A larger randomized, placebo-controlled study of rivastigmine 1 mg/day found no effect on disease progression in progressive supranuclear palsy after 1 year (111). Two randomized controlled trials of memantine for frontotemporal dementia showed marginal benefit in the Clinical Global Impression scores, but further trials are needed (75). A multicenter, randomized, placebo-controlled study of high doses of CoQ10 (2400 g/day) did not demonstrate significant improvement in the primary outcome of Progressive Supranuclear Palsy Rating Scale and Unified Parkinson’s Disease Rating Scale at 12 months (12).
Clinical trials with tau-based therapies. There is interest in trying to target the accumulation of abnormal tau by different strategies. Santacruz and colleagues developed a transgenic mouse model expressing mutant tau that could be suppressed with doxycycline (131). After the doxycycline treatment, memory function recovered, and neuron numbers stabilized, but the neurofibrillary tangles continued to accumulate. The authors concluded that the neurofibrillary tangles are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy. Noble and colleagues showed that treatment of tangle-forming transgenic mice (htau line) with minocycline resulted in reduced levels of tau phosphorylation and insoluble tau aggregates (109). The in vivo effects of minocycline were also associated with reduced caspase-3 activation and lowered tau cleavage by caspase-3. The results suggest a possible novel therapeutic role for minocycline in the treatment of Alzheimer disease and related tauopathies.
Another potentially feasible approach at lowering the tau burden involves reducing the activity of the kinases that phosphorylate tau, particularly glycogen synthase kinase 3ß (GSK-3ß) and cyclin-dependent kinase-5. GSK-3 has been proposed as the main kinase able to aberrantly phosphorylate tau in Alzheimer disease and related tauopathies, raising the possibility of designing novel therapeutic interventions based on GSK-3 inhibition. Lithium is a potent inhibitor of GSK-3 and is commonly used for the treatment of bipolar disorder in humans. In a transgenic mouse model expressing tau mutations, chronic lithium treatment decreased glycogen synthase kinase-3-dependent-tau phosphorylation and resulted in a reduction in the abnormal phosphorylation of tau and of filamentous aggregates (117).
Similarly, Noble and colleagues showed that chronic lithium administration in a transgenic mouse model overexpressing tau P301L reduced tau phosphorylation at specific sites targeted by GSK-3ß (110). Chronic lithium treatment of a double transgenic model overexpressing GSK-3ß and tau hyperphosphorylation in hippocampal neurons prevented the progression of the tauopathy in early stages (30). It was still possible to partially reverse tau pathology in advanced stages of the disease, although neurofibrillary tangle-like structures could not be changed. Engel and colleagues also showed the therapeutic efficacy of chronic lithium administration in aged 3xTg-AD mice harboring plaques and tangles (45). Lithium reduced tau phosphorylation but did not significantly alter the amyloid ß load nor did it improve the deficits in working memory. Rametti and colleagues showed that exposure of cultured cortical neurons to lithium decreased tau protein levels due to a reduction in tau mRNA levels (123). Tajes and colleagues treated senescence-accelerated mouse (SAM) P8 mice, a murine model of senescence, and mice of the control SAMR1 strain with lithium (145). The treatment reduced the levels and activity of GSK-3 ß and the activity of cyclin-dependent kinase 5 and reduced hyperphosphorylation of 3 different phosphoepitopes of tau: Ser199, Ser212, and Ser396. It also reduced hippocampal caspase 3 and calpain activation. Taken together, these in vivo and in vitro findings of lithium-mediated reductions in GSK-3ß and cyclin-dependent kinase 5 activities, tau phosphorylation, apoptotic activity, and cell death provide a rationale for the use of lithium as a potential treatment in tauopathies. An open-label trial of lithium in progressive supranuclear palsy and corticobasal degeneration was stopped prematurely because of drug intolerability. A randomized, placebo-controlled study failed to demonstrate benefit of valproate, a GSK-3 inhibitor, on disease progression in progressive supranuclear palsy (83).
The Tau Restoration PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial evaluating tideglusib, a GSK-3 inhibitor, in 146 patients with mild-to-moderate progressive supranuclear palsy (148). At 52 weeks there was no significant difference in the change from baseline on the progressive supranuclear palsy rating scale between tideglusib and placebo. There were no significant differences in secondary endpoints as well. However, in a subset of patients studied with MRI there was lower progression of brain atrophy in the active drug group, especially in the parietal and occipital lobes (62).
A double-blind placebo-controlled trial evaluated intranasal davunetide in 313 patients with progressive supranuclear palsy (27). Davunetide has been shown in preclinical studies to reduce tau phosphorylation and increase microtubule stability. In this study there was no significant difference in the change from baseline between the davunetide and placebo groups in the Progressive Supranuclear Palsy Scale and the Schwab and England Activities of Daily Living Scale at up to 52 weeks.
In conclusion, the tauopathies with dementia and parkinsonism constitute a fascinating group of neurodegenerative disorders, in which considerable overlap between the clinical phenotype often exists and antemortem diagnosis is challenging. Careful clinical profiling, development of diagnostic criteria combined with advances in neuroimaging and genetic testing have helped in categorizing these disorders into definite entities. The discovery of mutations in the tau gene, potential causative environmental factors, and the study of the pathophysiology in animal models have greatly enhanced our understanding of these disorders. Further research is needed to elucidate the pathogenic mechanisms that lead to tau accumulation and neuronal degeneration.
Mary Ann Thenganatt MD
Dr. Thenganatt of the University of Pennsylvania has no relevant financial relationships to disclose.See Profile
Joseph Jankovic MD
Dr. Jankovic, Director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine, received research and training funding from Allergan, F Hoffmann-La Roche, Medtronic Neuromodulation, Merz, Neurocrine Biosciences, Nuvelution, Revance, and Teva and consulting/advisory board honorariums from Abide, Lundbeck, Retrophin, Parexel, Teva, and Allergan.See Profile
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Jan. 18, 2022
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Behavioral & Cognitive Disorders
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Neuroacanthocytosis is a neurologic syndrome characterized by a broad spectrum of movement disorders that often share acanthocytes on the blood smear. A variety of other neurologic symptoms may accompany neuroacanthocytosis, including seizures, motor neuron disease, and dementia. Chorea-acanthocytosis is an autosomal recessive disorder due to mutations in the VPS13A gene (chromosome 9q21), and is among the disorders known to cause neuroacanthocytosis.
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