REVIEW ARTICLE
Frontotemporal dementia and parkinsonism linked to chromosome 17

Introduction
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a recently described autosomal dominant inherited disorder caused by mutations in the MAPT gene. The MAPT gene encodes the microtubule-associated tau protein. FTDP-17 is a rare neurological condition. Since the 1996 International Consensus Conference held in Ann Arbor, Michigan, which defined FTDP-17 [17], approximately 200 families with 39 pathogenic mutations in the MAPT gene have been identified. Altogether, about 600 patients have been described, including those who died in the antecedent generations (personal assessment). Families with MAPT gene mutations were identified in North America, Europe, Asia and Australia [80]. There are no documented cases of FTDP-17 in Poland [36,85].
The disorder is thought to be related to the altered proportion of tau protein isoforms or the ability of tau to bind to microtubules and to promote microtubule assembly and organization [22,57]. Tau gene mutations are found in 25% of the cases with familial frontotemporal dementia (FTD), but the prevalence of tau mutations in sporadic cases is only 4% [72].
The clinical picture of FTDP-17, consisting of behavioral and personality changes, cognitive impairment and motor symptoms, varies between families with different mutations as well as between members of the same family [17,57,59,81]. Tau genotype correlates with the type of initial clinical presentation; H1/H1 genotype being associated with parkinsonian phenotype and H1/H2 with the FTD phenotype [3]. The variability of clinical and pathological pictures within one family bearing the same MAPT mutation suggests the existence of other genetic or environmental factors in addition to the mutated MAPT [15,57].
Clinical presentation of FTDP-17 and genotype/
phenotype correlations have previously been described in detail [3,59,80,81].
Recently familial FTD with ubiquitin-positive and tau-negative inclusions was linked to a chromosomal region at 17q21 (FTDU-17) [8,10]. In these cases, mutations in MAPT were not found despite a detailed genetic analysis [10,57]. The clinical symptoms of FTDU-17 are similar to FTDP-17 and include personality changes, memory disturbances, cognitive impairment and parkinsonism [8].
Prior to the Consensus Conference several families known as pallido-ponto-nigral degeneration (PPND), multiple system tauopathy with dementia (MSTD), hereditary dysphasic disinhibition dementia (HDDP), disinhibition-dementia-parkinsonism-amyotrophy complex (DDPC) and others were clinically and pathologically characterized [18,59]. However, their phenotype was somewhat different and they were considered to represent separate syndromes. In 1994, Wilhelmsen et al. found linkage to the locus on the long arm of chromosome 17 (17q21-22) in a DDPC family [79]. Additional genetic studies demonstrated linkage to the same locus in other families [4,78]. The Consensus Conference helped to group all of these kindreds into a single category of FTDP-17. In 1998, it was documented that MAPT gene mutations segregate with disease phenotype [9, 14, 28].

Tau biology
Tau protein is necessary for stabilization and generation of microtubules, cell structures responsible mainly for axonal transport. In the human brain tau protein exists in 6 isoforms, generated by alternative splicing of exons 2, 3 and 10 [39]. Exons 2 and 3 code N-end 29-58 amino acid panels, responsible for three-dimensional orientation of microtubules [25,70]. Exon 10 codes for one of 4 (C-end) microtubule binding domains giving rise to 4R tau isoforms (Fig. 1). Isoforms 3R have a lower affinity to microtubules than isoforms 4R. In physiological conditions all isoforms undergo phopshorylation by specific kinases. The phosphorylation level of tau protein regulates its interactions with microtubules. The same process probably regulates binding protein molecules to each other, which (in specific conditions) could lead to pathological accumulation of tau. The longest tau isoform has 79 serine and threonine potential phosphorous group acceptors. The acceptor group numbers decrease with length of the isoform. Most of these acceptor groups are located outside of microtubule binding domains [6]. The phosphorylation process is regulated by kinases, most of which are proline-dependent. These kinases include mitogen activated protein (MAP) kinases [12], glycogen synthase kinase 3B (GSK3B) [24], cyclin-dependent kinases 2 and 5, and stress-activated proteins’ (SAP) kinases. In the regions without Ser and Thr groups phosphorylation is regulated by class II kinases, such as Ca²⁺/calmodulin-dependent protein kinase II (CaMPKII), cyclic-AMP dependent kinase (CDK) and microtubule-affinity regulating kinases (MARK). In a normal brain the ratio of phosphorylation and dephosphorylation processes is equal. In pathological states this equilibrium is altered [6]. Isoforms 3R are also called ‘fetal’ MAP-tau, because they are predominant forms in the developing brain. Fetal forms of tau are more phosphorylated than ‘adult’ ones. Their binding to microtubules is weaker, allowing axons to grow during the maturation process. In an adult brain the ratio of 3R and 4R isoforms is close to 1 (with minimal dominance of 3R) [70]. MAPT mutations lead to the accumulation of protein and disturbances in microtubule functions. Accumulated tau is mostly insoluble and carries numbers of incorrect post-translational modifications. It also disturbs microtubule transport, leading to cell death through the deficiency of nutrients and structural molecules.
At the present time there are 39 known pathogenic mutations of MAPT gene, mainly localized around a microtubule binding domain area (Figure 2, Table I). The University of Antwerp database [1] also lists a silent L315L mutation. There are 18 non-pathogenic polymorphisms in MAPT gene listed on The University of Antwerp database [1] (not included in this review).

Neuropathology
Gross examination reveals brain atrophy with brain weight ranging from 720 to 1420 grams [2,43,58,77]. The degree of atrophy is variable and to some extent correlates with the stage of disease. In advanced stages atrophy may be conspicuous in the frontal and temporal lobes, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus and hypothalamus (Fig. 3A) [17,27,30,48,59,72]. The anterior part of the frontal lobe is especially vulnerable to atrophy. The atrophy is frequently asymmetric, with a “knife-edge” appearance of the cerebral cortex in some cases [19,27,60,74]. The white matter of the temporal lobes and corpus callosum may be decreased in volume. In some cases atrophy of the midbrain and pons is observed (Fig. 3A). There is marked depigmentation of the substantia nigra and locus coeruleus (Fig. 3B) [23,26,30,58,60,62]. Mild atrophy of the cerebellar cortex and loss of pigment in the dentate nucleus may be seen [18,19,58,59,]. Gray and white matter atrophy may be accompanied by enlargement of the lateral and third ventricles [19,26,27,30,74].
Microscopical findings in FTDP-17 include neuronal loss and astrocytic gliosis, present in varied distribution and severity in the cerebral cortex, underlying the white matter, basal ganglia and brainstem [16,69]. The neuronal loss in the cortex may be associated with microvacuolization and spongiosis in the superficial cortical layers [2,16,30,53,74]. Ballooned achromatic neurons can be seen in some cases (Fig.4A) [48,59,71,73]. Pick-like bodies, similar to those seen in Pick’s disease (PiD) were found in some mutations (Fig 4B) [5,27,48,52,69] However, the neuropathologic hallmark of FTDP-17 is the presence of hyperphosphorylated tau protein deposits in neurons or in both neurons and glia of the cerebrum, cerebellum and brainstem [22,59,68]. Tau accumulation may also be seen in motor neurons of the spinal cord [2,15,30]. Neuronal tau pathology consists of neurofibillary degeneration with formation of classic flame- and globose-shaped neurofibrillary tangles (NFT) [17,64] or diffuse, granular deposits, called pretangles (Fig.5A,B) [7,26,84]. Thread-like structures (neuropil threads) and grains, seen in both grey and white matter, represent glial processes and axonal segments (Fig.5C) [11,35]. Astrocytic tau pathology demonstrates the presence of a granular tau staining pattern (Fig 5D), and structures reminiscent of the tufted astrocytes (as also observed in progressive supranuclear palsy, PSP) or astrocytic plaques (typical of corticobasal degeneration, CBD) [17,59,68]. Astrocytic plaques were described only in two mutations: K317M [84] and N279K [58]. The oligodendroglial tau deposits resemble coiled bodies described in other neurodegenartive diseases (Fig 5E) [29,59]. Both neuronal and glial tau inclusions can be identified with silver staining, including Bielschowsky, Bodian or Gallyas. However, they are most reliably identified with immunohistochemistry for tau protein, especially with antibodies specific for phosphorylation-dependent epitopes staining insoluble tau deposits [16]. The intensity and specific location of tau deposits within the CNS regions and different cell types vary depending on the type of MAPT mutation. Mutations in exons 9,11,12 and 13 are characterized by predominant neuronal tau deposits. Mutations in exons 1 and 10 and in the intron following exon 10 are characterized by both neuronal and glial tau deposition [18]. Generally, in cases with neuronal-only deposits, all six tau isoforms are detected, with predominance of 3R tau. In cases with mixed neuronal/glial tau pathology deposits consist predominantly of 4R tau isoform [57].
The detailed characteristic of neuropathological changes in FTDP-17 with regard to their topographical distribution in different mutations of MAPT is presented in table II.
Morphology of tau filaments in FTDP-17, seen in electron microscopy, is markedly heterogeneous and depends on the MAPT mutation type. Tau protein may have an appearance of straight filaments (e.g. in mutations R5L, P301S, E10+3,G389R), twisted filaments (S305S, E10+13, G389R), straight tubules (R5H, N296H, S305N), paired tubules (N279K), twisted ribbons (K257T, P301L, K369I) or paired helical filaments (V337M, G342V, R406W) (Fig. 6) [16,48,59,68]. Two different types of tau filaments may coexist in one particular MAPT mutation, e.g. straight and twisted filaments in G389R or S320F mutation [19,63].

Differential diagnosis
Clinically, FTDP-17 may mimic several other neurodegenerative diseases. In the absence of a positive family history and molecular genetic data FTDP-17 can be mistaken for dementive disorders such as PiD, FTD, argyrophilic grain disease and Alzheimer disease (AD), and movement disorders such as PSP, CBD or Parkinson’s disease [22,41,57,58,59,72,75,80].
The neuronal tau pathology seen in FTDP-17 (NFT and Pick-like bodies) requires differential diagnosis with that of AD or PiD. The glial tau pathology (astrocytic plaques, tufted astrocytes, coiled bodies) resembles that of PSP and CBD [66]. The presence of family history and genetic analysis of tau mutation are of great value in the differential diagnosis of these diseases.
Neuroimaging studies (CT, MRI) can assist in the clinical differential diagnosis of FTDP-17 mainly by excluding other diseases, such as brain tumor, vascular disease or hydrocephalus [80].

Conclusions
The clinical, molecular genetic and pathological characterizations of FTDP-17 led to a much better understanding of basic cellular process dysfunctions occurring in other neurodegenerative disorders, including AD, PiD, PSP and CBD. It is hoped that further work on a FTDP-17 mouse model [65] will lead to the development of specific and perhaps even curative therapies for this condition that can be extrapolated to other dementive and extrapyramidal disorders.

Acknowledgements
This work was supported in part by the grant P01 NS 40256 from the NINDS to the Mayo Clinic (Morris K Udall PD Research Center of Excellence). J.S. is a recipient of the Smith Fellowship.
The authors are grateful for technical assistance of Laura A. Brown, Frances H. Dodge and Jessica C. Milligan.

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