Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation.

The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer's disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD.

TDP-43 and Tau Oligomers in Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.

Proteinaceous aggregates are major hallmarks of several neurodegenerative diseases. Aggregates of post-translationally modified transactive response (TAR)-DNA binding protein 43 (TDP-43) in cytoplasmic inclusion bodies are characteristic features in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent studies have also reported TDP-43 aggregation in Alzheimer's disease (AD). TDP-43 is an RNA/DNA binding protein (RBP) mainly present in the nucleus. In addition to several RBPs, TDP-43 has also been reported in stress granules in FTD and ALS pathologies. Despite knowledge of cytoplasmic mislocalization of TDP-43, the cellular effects of TDP-43 aggregates and their cytotoxic mechanism(s) remain to be clarified. We hypothesize that TDP-43 forms oligomeric assemblies that associate with tau, another key protein involved in ALS and FTD. However, no prior studies have investigated the interactions between TDP-43 oligomers and tau. It is therefore important to thoroughly investigate the cross-seeding properties and cellular localization of both TDP-43 and tau oligomers in neurodegenerative diseases. Here, we demonstrate the effect of tau on the cellular localization of TDP-43 in WT and P301L tau-inducible cell models (iHEK) and in WT HEK-293 cells treated exogenously with soluble human recombinant tau oligomers (Exo-rTauO). We observed cytoplasmic TDP-43 accumulation o in the presence of tau in these cell models. We also studied the occurrence of TDP-43 oligomers in AD, ALS, and FTD human brain tissue using novel antibodies generated against TDP-43 oligomers as well as generic TDP-43 antibodies. Finally, we examined the cross-seeding property of AD, ALS, and FTD brain-derived TDP-43 oligomers (BDT43Os) on tau aggregation using biochemical and biophysical assays. Our results allow us to speculate that TDP-43/tau interactions might play a role in AD, ALS, and FTD.

Hoarding and obsessive-compulsive behaviours in frontotemporal dementia: Clinical and neuroanatomic associations.

BACKGROUND: Hoarding and obsessive-compulsive behaviours (OCB) are well documented symptoms in frontotemporal dementia (FTD). While contemporary models consider hoarding and obsessive-compulsive disorder distinct, the related behaviours have not been separately examined in patients with FTD, and the neuroanatomical correlates of hoarding in patients with FTD have not been previously examined (American Psychiatric Association, 2013; Grisham and Baldwin, 2015; Mataix-Cols et al., 2010). METHODS: Patients with FTD who were evaluated between 2004 and 2018 at our centre were included. Cortical thickness and subcortical volumetric analyses were completed on available T1 high resolution anatomic scans using FreeSurfer. RESULTS: Eighty-seven patients met inclusion criteria, and 49 had scans available for quantitative MRI volumetric analysis. New hoarding behaviours were present in 29% of patients and were more common in the semantic variant subtype of FTD, while 49% of individuals had new or increased OCB. Hoarding behaviours were associated with decreased thickness in a factor comprised of left temporal, insular and anterior cingulate cortices. The presence of OCB was predicted by reduced cortical thickness and volumes in a factor comprised of the anterior cingulate and subcortical volumes in the bilateral amygdala and hippocampus. OCB were associated with greater right temporal cortical thickness in comparison to patients with hoarding. DISCUSSION: The association of the semantic variant with hoarding, together with the observed associations between left temporal atrophy and hoarding indicate that degeneration of the left temporal lobe has a role in the emergence of hoarding in FTD. As in current models of Hoarding disorder and Obsessive-Compulsive disorder, our results suggest that in patients with FTD, hoarding and OCB are clinically and anatomically partially dissociable phenomenon. The results may also help to further elucidate the cognitive processes and neural networks contributing to Hoarding disorder and Obsessive-Compulsive disorder in persons without dementia.

Apathy and impulsivity in frontotemporal lobar degeneration syndromes.

Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck's disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal dementia alone. Measures of apathy and impulsivity frequently loaded onto the same components reflecting their overlapping relationship. However, measures from objective tasks, patient-rated questionnaires and carer-rated questionnaires loaded onto separate components and revealed distinct neurobiology. Corticospinal tracts correlated with patients' self-ratings. In contrast, carer ratings correlated with atrophy in established networks for goal-directed behaviour, social cognition, motor control and vegetative functions, including frontostriatal circuits, orbital and temporal polar cortex, and the brainstem. Components reflecting response inhibition deficits correlated with focal frontal cortical atrophy. The dimensional approach to complex behavioural changes arising from frontotemporal lobar degeneration provides new insights into apathy and impulsivity, and the need for a joint therapeutic strategy against them. The separation of objective tests from subjective questionnaires, and patient from carer ratings, has important implications for clinical trial design.awx101media15448041163001.

Typical and atypical pathology in primary progressive aphasia variants.

OBJECTIVE: To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification. METHODS: Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms. RESULTS: A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein (TDP) inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD-TDP type C, 22 of 25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants. INTERPRETATION: Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo. Ann Neurol 2017;81:430-443.

Deep clinical and neuropathological phenotyping of Pick disease.

OBJECTIVE: To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick disease. METHODS: Detailed neuropathological examination using 70µm and traditional 6µm sections was performed using thioflavin-S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity. RESULTS: Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. INTERPRETATION: Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration.

A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies.

Tauopathies are a group of disorders leading to cognitive and behavioral impairment in the aging population. While four-repeat (4R) Tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and Alzheimer's disease, three-repeat (3R) Tau is the most abundant splice, in Pick's disease. A number of transgenic models expressing wild-type and mutant forms of the 4R Tau have been developed. However, few models of three-repeat Tau are available. A transgenic mouse model expressing three-repeat Tau was developed bearing the mutations associated with familial forms of Pick's disease (L266V and G272V mutations). Two lines expressing high (Line 13) and low (Line 2) levels of the three-repeat mutant Tau were analyzed. By Western blot, using antibodies specific to three-repeat Tau, Line 13 expressed 5-times more Tau than Line 2. The Tau expressed by these mice was most abundant in the frontal-temporal cortex and limbic system and was phosphorylated at residues detected by the PHF-1, AT8, CP9 and CP13 antibodies. The higher-expressing mice displayed hyperactivity, memory deficits in the water maze and alterations in the round beam. The behavioral deficits started at 6-8 months of age and were associated with a progressive increase in the accumulation of 3R Tau. By immunocytochemistry, mice from Line 13 displayed extensive accumulation of 3R Tau in neuronal cells bodies in the pyramidal neurons of the neocortex, CA1-3 regions, and dentate gyrus of the hippocampus. Aggregates in the granular cells had a globus appearance and mimic Pick's-like inclusions. There were abundant dystrophic neurites, astrogliosis and synapto-dendritic damage in the neocortex and hippocampus of the higher expresser line. The hippocampal lesions were moderately argyrophilic and Thioflavin-S negative. By electron microscopy, discrete straight filament aggregates were detected in some neurons in the hippocampus. This model holds promise for better understanding the natural history and progression of 3R tauopathies and their relationship with mitochondrial alterations and might be suitable for therapeutical testing.

A case of hyperthymesia: rethinking the role of the amygdala in autobiographical memory.

Much controversy has been focused on the extent to which the amygdala belongs to the autobiographical memory (AM) core network. Early evidence suggested the amygdala played a vital role in emotional processing, likely helping to encode emotionally charged stimuli. However, recent work has highlighted the amygdala's role in social and self-referential processing, leading to speculation that the amygdala likely supports the encoding and retrieval of AM. Here, cognitive as well as structural and functional magnetic resonance imaging data was collected from an extremely rare individual with near-perfect AM, or hyperthymesia. Right amygdala hypertrophy (approximately 20%) and enhanced amygdala-to-hippocampus connectivity (>10 SDs) was observed in this volunteer relative to controls. Based on these findings and previous literature, we speculate that the amygdala likely charges AMs with emotional, social, and self-relevance. In heightened memory, this system may be hyperactive, allowing for many types of autobiographical information, including emotionally benign, to be more efficiently processed as self-relevant for encoding and storage.

The influence of psycholinguistic variables on articulatory errors in naming in progressive motor speech degeneration.

We describe an analysis of speech errors on a confrontation naming task in a man with progressive speech degeneration of 10-year duration from Pick's disease. C.S. had a progressive non-fluent aphasia together with a motor speech impairment and early assessment indicated some naming impairments. There was also an absence of significant phonological or semantic impairment. In order to examine naming difficulties and the factors that influence his speech production errors, we selected 210 words varying in frequency, age of acquisition (AoA), imageability, phonemic length and syllable length and conducted a logistic regression analysis on a range of speech production error types (phone omissions, additions, substitutions, response delays, overall errors). No significant naming errors due to lexical access were found. The only significant predictor of speech articulation errors was phonemic length, with none of the other lexical variables influencing speech production error. The only error type predicted was phone omissions. Results suggest that C.S.'s speech and naming errors indicate compromised speech programming/planning rather than lexical selection and we conclude that this pattern of findings is indicative of problems with motor speech production.

Extrapyramidal syndromes in frontotemporal degeneration.

Descriptions of extrapyramidal (EP) involvement in Pick's disease (renamed recently as FTD) appeared 80 years ago. CBD pathology was confirmed as a common substrate for primary progressive aphasia (PPA). We suggested that CBD and PPA should be included with frontal lobe dementia as Pick complex. PSP was prototype for "subcortical dementia", and aphasia and apraxia, considered unusual for PSP, are now seen as a rule. The overlap of PSP and CBD is considerable. We recently reviewed our cohort with EPS in FTD and identified 22 patients with the movement disorder as a first syndrome and another larger group of 48 patients who developed EPS after an initial onset with a cognitive disorder: aphasic, behavioral or both. All cognitive onset CBD/PSP patients and all but two with motor onset developed aphasia during the course of their illness. General cognitive and behavioral measures are similar for each presentation, but language scores are worse in cognitive onset cases, reflecting the frequency of aphasic presentations. Anomic patients become non-fluent, logopenic, agrammatic and mute. Using the Frontal Behavioral Inventory (FBI), a questionnaire specifically designed for the spectrum of apathy and disinhibition displayed by patients with FTD, we have documented the behavior change in CBD/PSP with motor and cognitive onsets. The significant personality changes consisted of apathy, disinhibition, perseveration and inattention, some of the core symptoms of FTD. In 18 autopsied cases, 15 had tau pathology. The overlap of CBD/PSP with PPA and bvFTD suggests a spectrum of related entities and predicts tau-positive pathology. Cross-sectional studies without significant follow-up may not observe the subsequent development language or behavior deficit, or the evolution from PPA and/or FTD-bv to CBD/PSP.

Behavioral variant frontotemporal dementia with corticobasal degeneration pathology: phenotypic comparison to bvFTD with Pick's disease.

Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer's-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed clinical characterization. All patients with CBD pathology and clinical assessment were reviewed (N = 17) and selected if they initially met criteria for bvFTD [bvFTD(CBD), N = 5]. Available bvFTD patients with Pick's [bvFTD(Pick's), N = 5] were selected as controls. Patients were also compared to healthy older controls [N = 53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick's). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick's) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal > ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick's) patients. Despite a remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick's disease neuropathology.

Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau).

A clinically and pathologically heterogeneous type of frontotemporal lobar degeneration has abnormal tau pathology in neurons and glia (FTLD-tau). Familial FTLD-tau is usually due to mutations in the tau gene (MAPT). Even FTLD-tau determined by MAPT mutations has clinical and pathologic heterogeneity. Tauopathies are subclassified according to the predominant species of tau that accumulates, with respect to alternative splicing of MAPT, with tau proteins containing three (3R) or four repeats (4R) of ~32 amino acids in the microtubule binding domain. In Pick's disease (PiD), 3R tau predominates, whereas 4R tau is characteristic of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Depending upon the specific mutation in MAPT, familial FTLD-tau can have 3R, 4R or a combination of 3R and 4R tau. PiD is the least common FTLD-tau characterized by neuronal Pick bodies in a stereotypic neuroanatomical distribution. PSP and CBD are more common than PiD and have extensive clinical and pathologic overlap, with no distinctive clinical syndrome or biomarker that permits their differentiation. Diagnosis rests upon postmortem examination of the brain and demonstration of globose tangles, oligodendroglial coiled bodies and tufted astrocytes in PSP or threads, pretangles and astrocytic plaques in CBD. The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown.

The birth and early evolution of the frontotemporal dementia (FTD) concept.

An historical overview of the development of the concept of frontotemporal dementia is presented, regarding the last 30 years, using as a backbone the conferences held on this theme, with a start in 1986 in Lund, Sweden. Since then, a dramatic increase in research activities and publications has rapidly expanded our knowledge in this field, a step necessary for the ultimate goal to find an effective treatment of this devastating disorder.

Depletion of oxidative and endoplasmic reticulum stress regulators in Pick disease.

Both oxidative and endoplasmic reticulum (ER) stress is associated with multiple neurodegenerative, age-related diseases. The rare disorder Pick disease (PiD) shares some pathological hallmarks of other neurodegenerative diseases that may be related to oxidative stress. Importantly, activation of an ER stress response, which is also involved in aging, has not yet been investigated in PiD. In this study, we assessed the implication of ER stress associated with oxidative stress in PiD as a potential mechanism involved in its pathogenesis. Samples from morphologically affected frontal cortex and apparently pathologically preserved occipital cortex showed region-dependent increases in different protein oxidative damage pathways. The oxidative modifications targeted antioxidant enzymes, proteases, heat shock proteins, and synaptic proteins. These effects were associated with compromised proteasomal function and ER stress in frontal cortex samples. In addition, we observed a depletion in ER chaperones (glucose-regulated proteins Grp78/BiP and glucose-regulated protein 94) and differences in tissue content and distribution of nuclear factor-erythroid 2 p45-related respiratory 2, required for cell survival during the unfolded protein response. These results demonstrate increased region-specific protein oxidative damage in PiD, with proteasomal alteration and dysfunctional ER stress response. We suggest this was caused by complete and specific depletion of Grp78/BiP, contributing to the pathophysiology of this neurodegenerative disease.

[Clinicopathological features of sporadic frontotemporal lobar degeneration with TDP-43-positive inclusions].

Frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) and Pick's disease are common pathological substrates in FTLD patients. Because most Japanese FTLD-TDP patients lack a family history, characterizing clinical features in sporadic FTLD-TDP is important to infer the underlying pathologies in FTLD patients. Our recent study suggested that these two diseases tended to show different clinical pictures. Early impairment of semantic memory was frequent in sporadic FTLD-TDP, but very rare in Pick's disease. In contrast, early impairment of speech output, including non-fluent aphasia and speech apraxia, was more frequent in Pick's disease. Asymmetric motor disturbances (e.g., pyramidal signs, parkinsonism, and contracture) were frequent in sporadic FTLD-TDP, but rare in Pick's disease. The most common first syndrome in FTLD-TDP was semantic dementia (39%), but that in Pick's disease was frontotemporal dementia (64%). Pathologically, consistent with clinical features, the temporal cortex, striatum, globus pallidus, substantia nigra, and pyramidal tract were more severely degenerated in sporadic FTLD-TDP. These findings suggest that the early impairment of semantic memory and asymmetric motor disturbances in sporadic FTLD patients predict FTLD-TDP rather than Pick's disease, while initial behavioral symptoms or non-fluent aphasia without subsequent asymmetric motor disturbances predict Pick's disease rather than FTLD-TDP.

Neuronal and glial tau pathology in early frontotemporal lobar degeneration-tau, Pick's disease subtype.

Frontotemporal lobar degeneration-tau, Pick's disease subtype (PiD) is one of the major types of frontotemporal dementia, but its pathogenesis and disease mechanisms remain unclear. Here, we report a case of very early PiD. The patient was a 63-year-old healthy woman without dementia or any apparent psychosis. She was admitted to the hospital with multiple organ failure, and died three days later. The brain weighed 1050g and showed focal atrophy of the parahippocampal gyrus and right medial temporal lobe. Microscopically, neuronal loss and gliosis were limited to the atrophic areas. Surprisingly, Pick bodies (PiBs) and ballooned neurons were abundant throughout the bilateral temporal cortices, including the dentate gyrus. Cortical lamination of PiBs was predominant in the upper layer (layer II>VI), and the size of early PiBs tended to be smaller than that in severely affected areas. Numerous glial tau-positive inclusions (astrocytic inclusions, oligodendroglial coiled bodies, and threads) were found not only in the cerebral cortex but also in the temporal white matter. The neuropathological findings in this case suggest that PiB formation started long before the appearance of clinical symptoms and that PiB formation originating from small neurons may differ from other tau aggregations such as neurofibrillary tangles.

[The complexes of degenerative dementias: an evolution from disease to spectrum]. / Los complejos de las demencias degenerativas: una evolución de la enfermedad al espectro.

INTRODUCTION: Everyone has a particular combination of risk polymorphisms and occasionally determinant mutations, related to molecular items which are pathogenetic in degenerative dementias. If we add other epigenetic factors to this, we can generate a very heterogeneous base, which explains why these diseases manifest through varied clinical and neuropathological phenotypes, distributed in <> (groups of entities with symptomatic, neurochemical, histopathologic and proteinopathic affinities). METHOD: A review of the current knowledge about phenotype variants of degenerative dementias has been carried out, detecting overlapping and divergent aspects between them and generating groups (complexes) which are more operative to work with, instead of using the current independent entities (diseases). RESULTS: Besides the known Pick complex, there are sufficient data to propose the recognition of the Lewy complex, Alzheimer complex, multisystemic atrophy complex, and polyglutamine complex. Each one of them contains phenotypic variants that overlap with other complex variants, creating links between all the complexes and forming a spectrum in which almost all degenerative dementias can be included. CONCLUSIONS: The progression of medical knowledge has made it more appropriate to locate each patient at a specific point in a complex, in the degenerative dementia spectrum, instead of diagnosing a generic disease. This change makes it recommendable to adjust the diagnostic criteria, and the therapeutic decisions should be designed individually according to their specific location in a complex. Researchers should also take into account this diversity when establishing both the criteria for selecting participants and the objectives of their therapeutic trials.

Los complejos de las demencias degenerativas: una evolución de la enfermedad al espectro / The complexes of degenerative dementias: an evolution from disease to spectrum

Introducción. Cada persona tiene una combinación de polimorfismos de susceptibilidad y ocasionalmente alguna mutación determinante relacionados con elementos moleculares de la cadena patogénica de las enfermedades degenerativas con demencia. Si añadimos otros factores epigenéticos, se genera una base enormemente heterogénea para que estas enfermedades se expresen a través de fenotipos clínicos y neuropatológicos variados que se distribuyen formando «complejos» (grupos con afinidades proteinopáticas, neuroquímicas, histopatológicas y sintomáticas). Método. Revisión en literatura médica de variantes fenotípicas de las demencias degenerativas, detectando aspectos de solapamiento y divergencia entre ellas y formando grupos (complejos) que permitan actuar de un modo operativamente más eficaz que con la consideración actual de entidades independientes (enfermedades). Resultado. Aparte del conocido complejo Pick, existen datos suficientes como para proponer el reconocimiento del complejo Lewy, complejo Alzheimer, complejo de la atrofia multisistémica y complejo de poliglutamina. En cada complejo hay variantes fenotípicas que muestran solapamiento con variantes de otros complejos, creando nexos que los encadenan y forman un espectro que engloba la mayoría de las demencias degenerativas. Conclusiones. La progresión de los conocimientos ha generado la conveniencia de ubicar a cada enfermo en un punto de un complejo, en el espectro de las demencias degenerativas, en vez de diagnosticar enfermedades genéricas. Para ello deberían ajustarse los criterios de diagnóstico y deberá calcularse individualmente la pauta terapéutica con mayor probabilidad de eficacia. Los investigadores también deberían tener en cuenta esta diversidad, tanto al establecer los criterios de selección de los enfermos como los objetivos de los ensayos terapéuticos (AU)

Introduction. Everyone has a particular combination of risk polymorphisms and occasionally determinant mutations, related to molecular items which are pathogenetic in degenerative dementias. If we add other epigenetic factors to this, we can generate a very heterogeneous base, which explains why these diseases manifest through varied clinical and neuropathological phenotypes, distributed in «complexes» (groups of entities with symptomatic, neurochemical, histopathologic and proteinopathic affinities). Method. A review of the current knowledge about phenotype variants of degenerative dementias has been carried out, detecting overlapping and divergent aspects between them and generating groups (complexes) which are more operative to work with, instead of using the current independent entities (diseases). Results. Besides the known Pick complex, there are sufficient data to propose the recognition of the Lewy complex, Alzheimer complex, multisystemic atrophy complex, and polyglutamine complex. Each one of them contains phenotypic variants that overlap with other complex variants, creating links between all the complexes and forming a spectrum in which almost all degenerative dementias can be included. Conclusions. The progression of medical knowledge has made it more appropriate to locate each patient at a specific point in a complex, in the degenerative dementia spectrum, instead of diagnosing a generic disease. This change makes it recommendable to adjust the diagnostic criteria, and the therapeutic decisions should be designed individually according to their specific location in a complex. Researchers should also take into account this diversity when establishing both the criteria for selecting participants and the objectives of their therapeutic trials (AU)