title: Hereditary Spastic Paraplegia: Beyond Clinical Phenotypes toward a Unified Pattern of Central Nervous System Damage.
abstract: OBJECTIVE
  To investigate whether specific patterns of brain gray matter (GM) regional volumes and white matter (WM) microstructural abnormalities and spinal cord atrophy occur in patients with pure and complicated hereditary spastic paraplegias (HSPs). Relationships between clinical and cognitive features of patients with HSP who had brain and cervical cord damage were also investigated.
  
  
  METHODS
  This study was approved by the local ethical committees on human studies, and written informed consent from all subjects was obtained prior to enrollment. Forty-four patients with HSP (20 genetically defined cases and 24 without genetic diagnosis) and 19 healthy control subjects underwent clinical, neuropsychological, and advanced magnetic resonance (MR) imaging evaluations. Patterns of GM atrophy and WM microstructural damage obtained by using structural and diffusion-tensor MR imaging were compared between groups. Cervical cord atrophy was also assessed by using an active surface method. Correlations between clinical, cognitive, and diffusion-tensor MR imaging measures were evaluated.
  
  
  RESULTS
  Clinical data showed that spastic paraplegia is accompanied by a number of other features, including sensory disturbances, and verbal and spatial memory deficits, not only in complicated HSP but also in pure HSP. MR imaging demonstrated a similar involvement of motor, association, and cerebellar WM pathways (P < .05, family-wise error corrected for multiple comparisons) and cervical cord (P < .001) in patients with HSP relative to healthy control subjects, regardless of their clinical picture. The severity of WM damage correlated with the degree of spasticity (P < .05, family-wise error corrected) and cognitive impairment (r values, -0.39 to 0.51; P values, .001-.05) in both pure and complicated HSP.
  
  
  CONCLUSIONS
  The detection of a distributed pattern of central nervous system damage in patients with pure and complicated HSP suggests that the "primary" corticospinal tract involvement known to occur in these patients may be associated with a neurodegenerative process, which spreads out to extramotor regions, likely via anatomic connections. This observation is in line with emerging pieces of evidence that, independent of the clinical phenotype, there is a common neurodegenerative cascade shared by different neurologic disorders.
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Federica
authors.initials: F
authors.lastname: Agosta
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Marina
authors.initials: M
authors.lastname: Scarlato
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Edoardo G
authors.initials: EG
authors.lastname: Spinelli
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Elisa
authors.initials: E
authors.lastname: Canu
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Carlo
authors.initials: C
authors.lastname: Casali
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Maria
authors.initials: M
authors.lastname: Sessa
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pagani
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.affiliation: From the Neuroimaging Research Unit (F.A., E.G.S., E.C., E.P., M. Filippi) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M. Scarlato, E.G.S., M. Sessa, G.C., M. Filippi), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; Laboratory of Clinical Molecular Biology and Cytogenetics, San Raffaele Scientific Institute, Milan, Italy (S.B., M. Ferrari); Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy (C.C.); Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.); Vita-Salute San Raffaele University, Milan, Italy (G.C., M. Ferrari, A.F., M. Filippi); and Department of Neuroradiology, San Raffaele Scientific Institute, Milan, Italy (A.F.).
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
mesh_terms: D000328:Adult; D000368:Aged; D002490:Central Nervous System / Q000473:pathology*; D003071:Cognition; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000523:psychology