Phenotypic presentation of frontotemporal dementia with Parkinsonism-chromosome 17 type P301S in a patient of Jewish-Algerian origin.

A 39-year-old old Jewish woman of Algerian origin developed a rapidly progressive neurocognitive disorder characterized by asymmetric rigidity, spasticity with bilateral Babinski's sign, bradykinesia, altered speech that progressed to mutism, and severe bradyphrenia. She partially responded to levodopa. The family history revealed 4 affected first-degree relatives (3 had already died). Genetic studies carried out in the proband and her living affected sister showed a P301S mutation in chromosome 17.     

Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17

Association between clinical characteristics and types of the tau gene mutation has been observed in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). P301L mutation seldom causes parkinsonism as a leading symptom; instead it usually causes personality changes with aggressiveness and disinhibition. We experienced two patients of FTDP-17 from separate families (designated as patient 1 from family 1 and patient 2 from family 2). They had P301L mutation in common. However, their phenotypes were distinct from each other. Aggressive behaviors and disinhibition were the main symptoms in patient 1, whereas parkinsonism was the most prominent feature in patient 2. Their genotypes of the tau gene were different at three sites, i. e. in exon 6, in intron segment before exon 10, and in exon 13, though they do not bring amino acid change. Patient 1 had more prevalent C/C, C/C, and rare T/C respectively. Patient 2 had less prevalent T/T, A/A, and more prevalent T/T respectively. These findings suggest two things. Firstly, they do not share a common founder for P301L mutation. Secondly, either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism. Accumulation of information as to phenotype-genotype association will settle this hypothesis. Received: 7 May 2001, Received in revised form: 23 October 2001, Accepted: 22 November 2001     

Frontotemporal dementia and parkinsonism linked to chromosome 17 with the N279K tau mutation

We present a case of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) harboring the N279K mutation in the MAPT gene from the family known as pallido‐ponto‐nigral degeneration (PPND). This 49‐year‐old man was followed for 17 years. He presented at age 41 years with left leg stiffness and en‐bloc turning. During the course of his illness he developed a constellation of symptoms including parkinsonism, pyramidal signs, vertical gaze palsy, dysphagia, dystonia, personality and cognitive dysfunction, weight loss and mutism. Gross neuropathological examination showed mild atrophy of the cerebral cortex, hippocampal formation, amygdala, thalamus, subthalamic nucleus and depigmentation of the substantia nigra. Microscopy revealed neuronal loss and gliosis in the same regions. Tau immunohistochemistry showed pretangles, numerous threads, grain‐like structures and oligodendroglial tau‐positive inclusions (“coiled bodies”). In the spinal cord the tau pathology was more abundant in gray than white matter. Pretangles and threads were present in the anterior and, to a lesser extent, in the posterior horns. FTDP‐17 should be suspected in patients with a history of familial parkinsonism combined with behavioral and cognitive changes, onset before age 65 years and an aggressive clinical course.     

Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family

Background: Frontotemporal dementia with parkinsonism linked to chromosome 17q21–22 (FTDP-17) is an autosomal dominant tauopathy manifested by a variable combination of personality changes, cognitive decline and hypokinetic-rigid movement disorder. Significant clinical and pathological heterogeneity of FTDP-17 is related in part to more than 20 different pathogenic mutations identified in the tau gene. Among others, the P301S mutation has been previously reported in three families of European and one of Japanese origin presenting with different clinical phenotypes. Objectives To report a three-generation family of Jewish-Algerian origin with FTDP-17 due to the P301S tau mutation. Methods: Clinical, neuropsychological and neuroimaging evaluation of 3 patients, tau genotyping, and pathological study of the proband. Results: The 3 affected family members had a fairly stereotyped clinical course with early personality changes from their late 30s followed within a period of 1–2 years by a progressive cognitive and motor deterioration eventually leading to a state of akinetic mutism or death 3–5 years after the initial symptoms. The main clinical manifestations included severe dementia and hypokinetic-rigid movement disorder associated with supranuclear gaze impairment, pyramidal signs and frontal release signs. Brain imaging disclosed a variable degree of frontotemporal atrophy, ventriculomegaly and regional cerebral hypoperfusion or glucose hypometabolism. Frontal lobe biopsy in the proband revealed weak tau immunoreactivity in a few cortical neurons, in rare neurites and in some glial cells with no neurofibrillary tangles. Molecular DNA analysis identified a P301S mutation in exon 10 of the tau gene. Conclusions: The observed clinical features further expand the reported P301S phenotype and confirm a more aggressive course of the disease than in the other known tau mutations. Received: 23 September 2002, Received in revised form: 13 January 2003, Accepted: 27 January 2003 Correspondence to: Dr. A. Lossos     

Frontotemporal dementia and parkinsonism linked to chromosome 17 – the first Polish family

Background: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) is a neurodegenerative disorder with various clinical phenotypes. We present the first Central‐Eastern European family (Gdansk Family) with FTDP‐17 because of a P301L mutation in microtubule‐associated protein tau (MAPT). Methods: We have studied a family consisting of 82 family members, 39 of whom were genetically evaluated. The proband and her affected brother underwent detailed clinical and neuropsychological examinations. Results: P301L mutation in MAPT was identified in two affected and five asymptomatic family members. New features included hemispatial neglect and unilateral resting tremor not previously reported for P301L MAPT mutation. Low blood folic acid levels were also detected. Conclusions: Our report suggests that FTDP‐17 affects patients worldwide, but because of its heterogenous clinical presentation remains underrecognized.     

A new case of frontotemporal dementia and parkinsonism resulting from an intron 10 +3-splice site mutation in the tau gene: clinical and pathological features

Hereditary frontotemporal dementia and parkinsonism (FTDP) linked to chromosome 17 (FTDP-17) constitutes a new form of tauopathy, and mutations in the tau gene have recently been reported in some affected families. This report presents clinical and neuropathological data from a member of a British family (SOT 254) with a history of dementia and movement disorder. The medical history of the affected patient, a woman aged 44 years, was reviewed, and a detailed post-mortem examination of the brain was undertaken. A panel of well characterized phosphorylation-dependent and independent anti-tau antibodies was used to assess tau pathology, and inclusions were examined by electron microscopy. Neuronal loss and gliosis were widely distributed, but most severe in neocortical regions, and were associated with abundant neuronal and glial tau inclusions which consisted of a mixture of paired helical filaments (PHFs), similar to those in Alzheimer's disease, and distinct twisted ribbon-like filaments. Genomic DNA was obtained from post-mortem tissue from the index patient, and blood from two unaffected members of the same family. For the index case only, sequencing of intronic sequences flanking exon 10 of the tau gene identified a G to A transition at position +3 of the splice-donor site downstream of exon 10, identical to that reported in multiple system tauopathy with presenile dementia (MSTD). The clinical, neuropathological and genetic findings strongly suggest that SOT 254 represents a new example of FTDP-17 resulting from a mutation in the tau gene. These results are compared with those reported for other FTDP-17 families, i.e. for MSTD.     

<Emphasis Type="Italic">Tau</Emphasis> gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)

Received: October 8, 1999 / Accepted: November 29, 1999 / Published online: February 8, 2000     

Interest in genetic testing in pallido-ponto-nigral degeneration (PPND): a family with frontotemporal dementia with Parkinsonism linked to chromosome 17

The specific mutation on the tau gene responsible for a neurodegenerative disease known as pallido-ponto-nigral degeneration (PPND) was recently located. PPND family members are at risk for an autosomal dominant form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). This study investigated whether individuals in this family would consider presymptomatic genetic testing. Surveys were sent to 66 at-risk individuals in the family; replies were received from 20 (30%). Family members were asked if they would consider having testing now or in the future, and to indicate their reasons for and against proceeding with testing. Fifty per cent (n=10) of those who were at risk and who responded indicated they would consider testing now, and 55% (n=11) would think about it in the future. The most frequently cited reasons to proceed with testing were to 'collaborate with research' (70%) and to 'know if my children are at risk' (45%). The most frequently cited reason not to pursue testing was 'I can enjoy my life more fully by not knowing' (50%). Results suggest that interest in determining whether they will manifest PPND is generally low among at-risk members of this family, despite wide support and participation in other research studies.     

Biochemical and pathological characterization of frontotemporal dementia due to a Leu266Val mutation in microtubule-associated protein tau in an African American individual

Frontotemporal dementia (FTD) is a clinically heterogeneous disorder characterized by alterations in language and/or behavior, often in association with Parkinsonism or motor neuron disease. A familial form of FTD is associated with mutations in the microtubule-associated protein tau (MAPT) gene. We report here on the clinical, neuroimaging, cerebral spinal fluid biomarker, genetic, biochemical and postmortem neuropathological analyses of a case of familial FTD with a Leu266Val MAPT mutation which results in a very early age of onset and a rapid course of disease. This is also the first reported case of any MAPT mutation in an individual of African American ethnicity. Grant Acknowledgement: The research reported here was supported by grants AG17586, AG10124, NS44266, K08 NS14108, and K08 AG20073 from the National Institutes on Aging and Neurological Disorders and Stroke of the National Institutes of Health, Department of Health and Human Services.     

Late-onset frontotemporal dementia associated with a novel <Emphasis Type="Italic">PGRN</Emphasis> mutation

Summary We describe a new mutation in the PGRN gene (A303AfsX57) associated with late-onset frontotemporal dementia and with “cat’s eye” shaped intranuclear and cytoplasmatic ubiquitin immunoreactive inclusions in the neuropathological exam. The A303AfsX57 mutation is consistent with a nucleotide deletion in exon 8 (c908delC). This deletion causes a frameshift at codon 303 that introduces a premature termination codon (A303AfsX57).     

Pick's disease pathology of a missense mutation of S305N of frontotemporal dementia and parkinsonism linked to chromosome 17: another phenotype of S305N

We report the second phenotype of frontotemporal dementia and parkinsonism linked to chromosome 17 with S305N similar to Pick's disease pathology in two brothers. The brain of the older brother showed macroscopic atrophy compatible with Pick's disease, and subsequent tau gene analysis revealed heterozygous S305N mutation in exon 10 of the tau gene. Round-shaped neuronal inclusions similar to Pick's bodies were positive for phosphorylated serine 262 as well as other anti-tau antisera, which is different from immunoexpression of Pick's bodies. Ultrastructurally, these neuronal inclusions consisted of straight, randomly orientated fibrils measuring approximately 10-20 nm in width and 60-600 nm in length. This ultrastructural profile is similar to that of the first case of S305N. S305N reported here can cause another phenotype closely resembling Pick's disease.     

Involvement of puromycin‐sensitive aminopeptidase in proteolysis of tau protein in cultured cells,and attenuated proteolysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) mutant tau

In tauopathies, tau protein is hyperphosphorylated, ubiquitinated, and accumulated in the brain; however, the mechanisms underlying this accumulation remain unclear. To gain an understanding of the role of proteases in the metabolism of tau protein, in the present study we evaluated the effects of protease inhibitors in SH‐SY5Y human neuroblastoma cells and COS‐7 cells transfected with the tau gene. When cells were treated with 0.1–10 µmol/L of lactacystin and 1.0–20 µmol/L of MG‐132 (inhibitors of proteasome), 0.1–10 µmol/L of CA‐074Me (a cathepsin inhibitor), and 0.1–2 µmol/L of puromycin (a puromycin‐sensitive aminopeptidase (PSA) inhibitor) for up to 24 h, there were no significant changes in tau protein levels. However, pulse‐chase experiments demonstrated that the proteolysis of tau protein in SH‐SY5Y cells was attenuated following treatment of cells with 200 nmol/L puromycin. Increased tau protein levels were also observed in SH‐SY5Y cells treated with short interference (si) RNA to PSA to inhibit the expression of PSA. These data suggest that PSA is a protease that catalyses tau protein predominantly in SH‐SY5Y cells. The protein metabolism of tau‐containing mutations of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) was also investigated using pulse‐chase experiments. The results indicate attenuated proteolysis of tau in cells transfected with mutant tau genes after 48 h. Further immunocytochemical analysis and subcellular fractionation experiments revealed that the mutations did not alter the intracellular distribution of tau and suggested that impaired accessibility of tau to PSA is unlikely to account for the attenuated proteolysis of tau protein. Western blotting with phosphorylation‐dependent antibodies revealed that phosphorylation levels of tau at Thr²³¹, Ser³⁹⁶, and Ser⁴⁰⁹ were increased in cells transfected with V337M, R406W, and R406W mutant tau genes, respectively. Together, the data suggest that attenuated proteolysis of FTDP‐17 mutant tau may be explained by increased phosphorylation levels, resulting in resistance to proteolysis.     

From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation.

Frontotemporal dementia is a heterogeneous, often inherited disorder that typically presents with the insidious onset of behavioral and personality changes. Two genetic loci have been identified and mutations in tau have been causally implicated in a subset of families linked to one of these loci on chromosome 17q21-22. In this study, linkage analysis was performed in a large pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutational analysis of the tau coding region identified a C-to-T change in exon 10 that resulted in the conversion of proline to a leucine (P301L) that segregated with frontotemporal dementia in this family. The clinical and pathological findings in the MN family emphasize the significant overlap between Pick's disease, corticobasal degeneration, and frontotemporal dementia and challenge some of the current dogma surrounding this condition. Pathological studies of two brains from affected members of Family MN obtained at autopsy demonstrate numerous tau-positive inclusions that were most prominent in the frontal lobes, anterior temporal lobes, and brainstem structures, as well as Pick-like bodies and associated granulovacuolar degeneration. These Pick-like bodies were observed in 1 patient with motor neuron disease. Because exon 10 is present only in tau mRNA coding for a protein with four microtubule binding repeats (4R), this mutation should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is selectively aggregated in both gray and white matter of affected individuals. Although there was significant pathological similarity between the 2 cases, the pattern of degenerative changes and tau-positive inclusions was not identical, suggesting that other genetic or epigenetic factors can significantly modify the regional topology of neurodegeneration in this condition.     

Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT R406W mutation presenting with a broad distribution of abundant senile plaques

We report the autopsy results of a patient with familial dementia who was diagnosed as having frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17) with an R406W mutation in the microtubule‐associated protein tau (MAPT) gene. This patient showed Alzheimer's disease (AD)‐like clinical manifestations from the age of 59, with reduced β‐amyloid1‐42 (Aβ₄₂) and elevated total and phosphorylated tau levels in the cerebrospinal fluid. He did not present with any apparent parkinsonism throughout the disease course. His autopsy at age 73 showed atrophy and neurodegeneration in many brain regions, particularly in the antero‐medial temporal cortex and hippocampus, followed by the frontal lobes, with abundant neurofibrillary tangles. In addition, a diffuse distribution of Aβ‐positive senile plaques, including many neuritic plaques, was observed and classified as stage C according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. These results suggest that analyzing of the MAPT gene is essential for diagnosing familial dementia, even if amyloid markers such as Aβ₄₂ in the cerebrospinal fluid and amyloid imaging are positive, or if neuropathological findings indicate a diagnosis of AD.     

Lrrk2 and chronic inflammation are linked to pallido-ponto-nigral degeneration caused by the <Emphasis Type="Italic">N279K</Emphasis> tau mutation

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified in families with autosomal dominant late-onset Parkinson disease (PD). Lrrk2 is a phylogenetically conserved, ubiquitous protein, which is constitutively expressed in various cells including neurons and glial cells of human brain. We recently reported that Lrrk2 is identified in Lewy bodies in PD as well as in neuronal and glial inclusions in several other neurodegenerative disorders. Here we show that Lrrk2 is closely associated with the tau-positive inclusions in eight members of a family with frontotemporal dementia of the pallido-ponto-nigral degeneration type linked to the chromosome 17 N279K tau mutation (N279K/FTDP-17/PPND). Lrrk2 is colocalized with tau in oligodendroglial coiled bodies and intracytoplasmic neuronal inclusions. HLA-DR positive reactive microglia and ICAM-1 positive reactive astrocytes accumulated in affected areas demonstrating that inflammatory processes are also involved in the disease pathogenesis. Western blot analysis of soluble extracts of N279K/FTDP-17/PPND brain tissue suggests that C-terminal fragment(s) of apparent 64–75 kDa molecular weight may be the major Lrrk2 species in pathological deposits. The possibility that Lrrk2 is linked with various neurodegenerative disorders through the ubiquitin proteosome pathway is discussed. The results indicate that Lrrk2 is linked to frontotemporal atrophy of PPND type caused by N279K tau mutation. They also show that chronic inflammation is involved in the pathogenesis of N279K/FTDP-17/PPND.     

Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration

BACKGROUND: The neuropathology associated with LRRK2 mutations is heterogeneous but Lewy body (LB) type pathology is the most common substrate encountered. While the prevalence of LRRK2 mutations has been extensively studied in Parkinson's disease (PD), limited information is available on the frequency of LRRK2 mutations in dementia with Lewy bodies (DLB) and in other pathological conditions associated with these mutations, such as non-specific nigral degeneration without LB, tau-immunopositive neurofibrillary tangle pathology, and ubiquitin-positive neuronal inclusions resembling those observed in a subtype of frontotemporal lobar degeneration (FTLD-U). OBJECTIVE: To further investigate the neuropathology associated with LRRK2 mutations. METHODS: We have screened for the LRRK2 G2019S and codon-1441 (R1441G/C/H) mutations in 110 cases from a Spanish Brain Bank, which include: 66 synucleinopathies (33 PD, 25 DLB and 8 multiple system atrophy cases), 29 tauopathies (21 progressive supranuclear palsy, 3 corticobasal degeneration and 5 tau-positive FTLD cases), 3 cases of non-specific nigral degeneration and 12 tau-negative FTLD (9 FTLD-U and 3 dementia lacking distinctive histology cases). RESULTS: The G2019S mutation was found in two cases: One case had a clinical and pathological diagnosis of PD and the other suffered from typical PD and on neuropathological examination had non-specific nigral degeneration without LB. A synonymous variant (R1441R; c.4323C>T) was detected in another PD case. CONCLUSIONS: In this brain bank-based series, LRRK2 G2019S mutation occurred in patients with parkinsonism associated with either typical brainstem LB pathology or non-specific nigral degeneration. LRRK2 mutations were not encountered in other neurodegenerative disorders associated with synuclein and tau deposition.