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PubMed1993

Mechanism of oxidative stress in skeletal muscle atrophied by immobilization.

To clarify the mechanism of oxidative stress in skeletal muscle atrophied by immobilization, we measured the activities of antioxidant enzymes and xanthine oxidase (XOD) and carried out the cytochemical study of hydrogen peroxide in a typical slow red muscle, the soleus. Male Wistar rats (15 wk old), of which ankle joints of one hindlimb were immobilized in the fully extended position, were killed after 4, 8, or 12 days. The activities of Mn-containing superoxide dismutase (Mn-SOD), Cu-Zn-containing superoxide dismutase (Cu-Zn-SOD), Se-dependent glutathione peroxidase (Se-GSHPx), glutathione S-transferase, catalase, and glutathione reductase were measured spectrophotometrically. The XOD activity and the concentrations of hypoxanthine, xanthine, and urate were measured using a high-performance liquid chromatography. The cytochemical study of hydrogen peroxide in short-term organ culture was performed using an electron microscope. Increased Cu-Zn-SOD and decreased Mn-SOD in atrophy might reflect increased generation of superoxide anions in the cytoplasm rather than in the mitochondria. The source of superoxide anions in the cytoplasm might be the increased superoxide-producing XOD. Enhanced generation of superoxide anions and increased Cu-Zn-SOD activity in atrophy suggested the enhanced generation of hydrogen peroxide in the cytoplasm. Due to the unchanged activity of Se-GSHPx and the unchanged or slightly increased activity of catalase in atrophy, the ability to degrade hydrogen peroxide might not increase so much. Hence, hydrogen peroxide is expected to be increased in atrophy. The cytochemical study supported this expectation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Overexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy.

This study examined the association between local insulin-like growth factor I (IGF-I) overexpression and atrophy in skeletal muscle. We hypothesized that endogenous skeletal muscle IGF-I mRNA expression would decrease with hindlimb unloading (HU) in mice, and that transgenic mice overexpressing human IGF-I (hIGF-I) specifically in skeletal muscle would exhibit less atrophy after HU. Male transgenic mice and nontransgenic mice from the parent strain (FVB) were divided into four groups (n = 10/group): 1) transgenic, weight-bearing (IGF-I/WB); 2) transgenic, hindlimb unloaded (IGF-I/HU); 3) nontransgenic, weight-bearing (FVB/WB); and 4) nontransgenic, hindlimb unloaded (FVB/HU). HU groups were hindlimb unloaded for 14 days. Body mass was reduced (P < 0.05) after HU in both IGF-I (-9%) and FVB mice (-13%). Contrary to our hypothesis, we found that the relative abundance of mRNA for the endogenous rodent IGF-I (rIGF-I) was unaltered by HU in the gastrocnemius (GAST) muscle of wild-type FVB mice. High-level expression of hIGF-I peptide and mRNA was confirmed in the GAST and tibialis anterior (TA) muscles of the transgenic mice. Nevertheless, masses of the GAST and TA muscles were reduced (P < 0.05) in both FVB/HU and IGF-I/HU groups compared with FVB/WB and IGF-I/WB groups, respectively, and the percent atrophy in mass of these muscles did not differ between FVB and IGF-I mice. Therefore, skeletal muscle atrophy may not be associated with a reduction of endogenous rIGF-I mRNA level in 14-day HU mice. We conclude that high local expression of hIGF-I mRNA and peptide in skeletal muscle alone cannot attenuate unloading-induced atrophy of fast-twitch muscle in mice.

Actins↗

PubMed2005

Mechanisms of disuse muscle atrophy: role of oxidative stress.

Prolonged periods of skeletal muscle inactivity lead to a loss of muscle protein and strength. Advances in cell biology have progressed our understanding of those factors that contribute to muscle atrophy. To this end, abundant evidence implicates oxidative stress as a potential regulator of proteolytic pathways leading to muscle atrophy during periods of prolonged disuse. This review will address the role of reactive oxygen species and oxidative stress as potential contributors to the process of disuse-mediated muscle atrophy. The first section of this article will discuss our current understanding of muscle proteases, sources of reactive oxygen in muscle fibers, and the evidence linking oxidative stress to disuse muscle atrophy. The second section of this review will highlight gaps in our knowledge relative to the specific role of oxidative stress in the regulation of disuse muscle atrophy. By discussing unresolved issues and suggesting topics for future research, it is hoped that this review will serve as a stimulus for the expansion of knowledge in this exciting field.

Animals↗

PubMed2005

Changes in PKB/Akt and calcineurin signaling during recovery in atrophied soleus muscle induced by unloading.

Protein kinase B [PKB, also known as Akt (PKB/Akt)] and calcineurin (CaN) are postulated to play important roles in integrating intracellular signaling in skeletal muscle in response to disuse and increased muscle loading. These experiments investigated changes in signal transduction of the downstream pathways of PKB/Akt and CaN during recovery following disuse-induced muscle atrophy. A 10-day period of hindlimb unloading (HLU) via tail suspension (male rats) was used to produce soleus muscle atrophy. Muscle recovery was achieved by returning animals to normal ambulation for 3-10 days. HLU resulted in significant muscle atrophy and a slow-to-fast fiber transition as revealed by appearance of type IId/x and IIb myosin heavy chain (MHC) isoforms. Muscle mass in HLU animals recovered to control (Con) levels after 10 days of reloading, but the fast-to-slow shift in muscle MHC was incomplete, as indicated by the continued presence of type IId/x MHC. Ten days of HLU resulted in a significant decrease (-43%) in muscle levels of phosphorylated PKB/Akt. In contrast, muscle levels of phosphorylated PKB/Akt were greater (+56%) in HLU than in Con animals early after the onset of reloading (3 days). Soleus levels of phosphorylated p70S6K were significantly higher (+26%) in HLU animals after 3 days of muscle reloading. Muscle levels of phosphorylated PKB/Akt and phosphorylated p70S6K returned to Con levels by day 10 of recovery. Moreover, muscle CaN levels were significantly higher than Con levels after 10 days of muscle reloading. These findings are consistent with the hypothesis that PKB/Akt and its downstream mediators are active in the regrowth of muscle mass during the early periods of recovery from muscle atrophy. Our data support the concept that CaN is involved in muscle remodeling during the later phases of recovery from disuse muscle atrophy.

Animals↗

PubMed1992

Rapid but transient atrophy of brown adipose tissue in capsaicin-desensitized rats.

Our previous studies showed atrophy of brown adipose tissue (BAT) in capsaicin-desensitized rats during the period 11-28 days after injections [Cui et al., Am. J. Physiol. 259 (Regulatory Integrative Comp. Physiol. 28): R324-R332, 1990]. The objective of the present studies was to assess the rapidity with which the atrophy occurred and the extent to which recovery had occurred by 8 wk. Rats, either vehicle-injected controls or capsaicin injected, were studied 1, 3, 14, 28, and 52 days after the last injection. BAT was markedly atrophied at 1 day, having less total protein, fewer mitochondria (less total cytochrome oxidase and total uncoupling protein), and fewer cells (less DNA). Atrophy persisted for up to 14 days but had largely disappeared by 28-52 days. A transient reduction in body weight gain and white epididymal adipose tissue weight had also reversed by 28-52 days. We suggest that the rapid atrophy of BAT after capsaicin desensitization is secondary to the loss of sensory neuropeptides in its sensory nerves, neuropeptides that either exert a trophic effect on synthesis of mitochondria or an inhibitory influence on processes that promote degradation of mitochondria. The retardation of the normal age-associated increase in DNA content of BAT in the capsaicin-desensitized rat suggests that sensory neuropeptides might also modulate cell proliferation.

Acclimatization↗

PubMed1977

Time course of muscular atrophy during immobilization of hindlimbs in rats.

The hindlimbs of rats were immobilized, in plaster casts, for varying durations, and the time course for atrophy of muscle and of selected proteins in these muscles was determined. In those muscles whose lengths were at less than resting length during the fixation procedures, exponential decay to a new apparent steady state after atrophy was shown by wet and dry muscle weights and by the amounts of biuret protein, cytochrome c, and citrate synthase. The time taken to decrease to one-half of the final decrease at the new apparent steady state level was about 4-6 days for the above parameters which decayed exponentially. In contrast, the myoglobin concentration increased during atrophy and the amount of myoglobin remain unchanged during atrophy. When fixation procedures on limbs were such that muscles were stretched to lengths greater than resting length, then the onset of atrophy was delayed; indeed, in some cases muscles hypertrophied when fixed in the stretched position.

Animals↗

PubMed1997

Nociceptive atrophy of the rat soleus muscle induced by bone fracture: a morphometric study.

Reflex atrophy of the soleus muscle induced by ipsilateral metatarsal bone fracture in Sagatal-anesthetized adult male rats was studied by using two-dimensional stereological methods 7 days after the operation. When compared with contralateral solei, the wet weight of the experimental soleus muscles was decreased by approximately 24% and the area of the entire muscle section by approximately 29%. In atrophied solei, the number of type 1 fibers was lower by approximately 8%, resulting in lower total number of fibers (by approximately 6%). This indicates that slow motor units might be more sensitive to nociceptive stimulation. However, with respect to the fiber area, the reflex atrophy induced by metatarsal bone fracture in the rat soleus muscle resembles simple atrophy after 7 days, as the mean muscle fiber area was decreased by approximately 26% with no significant difference between atrophy in type 1 and type 2a fibers (by 27.3 and 23.0%, respectively).

Animals↗

PubMed2005

Clenbuterol induces muscle-specific attenuation of atrophy through effects on the ubiquitin-proteasome pathway.

The ubiquitin-proteasome pathway is primarily responsible for myofibrillar protein degradation during hindlimb unweighting (HU). Beta-adrenergic agonists such as clenbuterol (CB) induce muscle hypertrophy and attenuate muscle atrophy due to disuse or inactivity. However, the molecular mechanism by which CB exerts these effects remains poorly understood. The aims of this study were to investigate whether CB attenuates HU-induced muscle atrophy through an inhibition of the ubiquitin-proteasome pathway and whether insulin-like growth factor I (IGF-I) mediates this inhibition. Rats were randomized to the following groups: weight-bearing control, 14-day CB-treated, 14-day HU, and CB + HU. HU-induced atrophy was associated with increased proteolysis and upregulation of components of the ubiquitin-proteasome pathway (ubiquitin conjugates, ubiquitin conjugating enzyme E2-14 kDa, and 20S proteasome activity). Upregulation of the ubiquitin proteasome occurred in all muscles tested but was more pronounced in muscles composed primarily of slow-twitch fibers (soleus) than in fast-twitch muscles (plantaris and tibialis anterior). Although CB induced hypertrophy in all muscles, CB attenuated the HU-induced atrophy and reduced ubiquitin conjugates only in the fast plantaris and tibialis anterior and not in the slow soleus muscle. CB did not elevate IGF-I protein content in either of the muscles examined. These results suggest that CB induces hypertrophy and alleviates HU-induced atrophy, particularly in the fast muscles, at least in part through a muscle-specific inhibition of the ubiquitin-proteasome pathway and that these effects are not mediated by the local production of IGF-I in skeletal muscle.

Administration, Oral↗

PubMed2005

Mechanical stimulation of the plantar foot surface attenuates soleus muscle atrophy induced by hindlimb unloading in rats.

Unloading-induced muscle atrophy occurs in the aging population, bed-ridden patients, and astronauts. This study was designed to determine whether dynamic foot stimulation (DFS) applied to the plantar surface of the rat foot can serve as a countermeasure to soleus muscle atrophy normally observed in hindlimb unloaded (HU) rats. Forty-four mature (6 mo old), male Wistar rats were randomly assigned to ambulatory control, HU alone, HU with active DFS (i.e., plantar contact with active inflation), HU with passive DFS (i.e., plantar contact without active inflation), and HU while wearing a DFS boot with no plantar contact groups. Application of active DFS during HU significantly counteracted the atrophic response by preventing approximately 85% of the reduction in type I myofiber cross-sectional area (CSA) in the soleus while preventing approximately 57% of the reduction in type I myofiber CSA and 43% of the reduction in type IIA myofiber CSA of the medial gastrocnemius muscle. Wearing of a DFS boot without active inflation prevented myofiber atrophy in the soleus of HU animals in a fashion similar to that observed in HU animals that wore an actively inflated DFS boot. However, when a DFS boot without plantar surface contact was worn during HU, no significant protection from HU-induced myofiber atrophy was observed. These results illustrate that the application of mechanical foot stimulation to the plantar surface of the rat foot is an effective countermeasure to muscle atrophy induced by HU.

Animals↗

PubMed2004

Regression of capillary network in atrophied soleus muscle induced by hindlimb unweighting.

Little is known about the mechanisms responsible for the adaptation and changes in the capillary network of hindlimb unweighting (HU)-induced atrophied skeletal muscle, especially the coupling between functional and structural alterations of intercapillary anastomoses and tortuosity of capillaries. We hypothesized that muscle atrophy by HU leads to the apoptotic regression of the capillaries and intercapillary anastomoses with their functional alteration in hemodynamics. To clarify the three-dimensional architecture of the capillary network, contrast medium-injected rat soleus muscles were visualized clearly using a confocal laser scanning microscope, and sections were stained by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) and with anti-von Willebrand factor. In vivo, the red blood cell velocity of soleus muscle capillaries were determined with a pencil-lens intravital microscope brought into direct contact with the soleus surface. After HU, the total muscle mass, myofibril protein mass, and slow-type myosin heavy chain content were significantly lower. The number of capillaries paralleling muscle fiber and red blood cells velocity were higher in atrophied soleus. However, the mean capillary volume and capillary luminal diameter were significantly smaller after HU than in the age-matched control group. In addition, we found that the number of anastomoses and the tortuosity were significantly lower and TUNEL-positive endothelial cells were observed in atrophied soleus muscles, especially the anastomoses and/or tortuous capillaries. These results indicate that muscle atrophy by HU generates structural alterations in the capillary network, and apoptosis appears to occur in the endothelial cell of the muscle capillaries.

Animals↗

PubMed2005

Attenuation of skeletal muscle atrophy via protease inhibition.

Skeletal muscle atrophy in response to a number of muscle wasting conditions, including disuse, involves the induction of increased protein breakdown, decreased protein synthesis, and likely a variable component of apoptosis. The increased activation of specific proteases in the atrophy process presents a number of potential therapeutic targets to reduce muscle atrophy via protease inhibition. In this study, mice were provided with food supplemented with the Bowman-Birk inhibitor (BBI), a serine protease inhibitor known to reduce the proteolytic activity of a number of proteases, such as chymotrypsin, trypsin, elastase, cathepsin G, and chymase. Mice fed the BBI diet were suspended for 3-14 days, and the muscle mass and function were then compared with those of the suspended mice on a normal diet. The results indicate that dietary supplementation with BBI significantly attenuates the normal loss of muscle mass and strength following unloading. Furthermore, the data reveal the existence of yet uncharacterized serine proteases that are important contributors to the evolution of disuse atrophy, since BBI inhibited serine protease activity that was elevated following hindlimb unloading and also slowed the loss of muscle fiber size. These results demonstrate that targeted reduction of protein degradation can limit the severity of muscle mass loss following hindlimb unloading. Thus BBI is a candidate therapeutic agent to minimize skeletal muscle atrophy and loss of strength associated with disuse, cachexia, sepsis, weightlessness, or the combination of age and inactivity.

Animals↗

PubMed2006

Spastic tail muscles recover from myofiber atrophy and myosin heavy chain transformations in chronic spinal rats.

Without intervention after spinal cord injury (SCI), paralyzed skeletal muscles undergo myofiber atrophy and slow-to-fast myofiber type transformations. We hypothesized that chronic spasticity-associated neuromuscular activity after SCI would promote recovery from such deleterious changes. We examined segmental tail muscles of chronic spinal rats with long-standing tail spasticity (7 mo after sacral spinal cord transection; older chronic spinals), chronic spinal rats that experienced less spasticity early after injury (young chronic spinals), and rats without spasticity after transection and bilateral deafferentation (spinal isolated). These were compared with tail muscles of age-matched normal rats. Using immunohistochemistry, we observed myofiber distributions of 15.9 +/- 3.5% type I, 18.7 +/- 10.7% type IIA, 60.8 +/- 12.6% type IID(X), and 2.3 +/- 1.3% type IIB (means +/- SD) in young normals, which were not different in older normals. Young chronic spinals demonstrated transformations toward faster myofiber types with decreased type I and increased type IID(X) paralleled by atrophy of all myofiber types compared with young normals. Spinal isolated rats also demonstrated decreased type I myofiber proportions and increased type II myofiber proportions, and severe myofiber atrophy. After 4 mo of complete spasticity (older chronic spinals), myofiber type transformations were reversed, with no significant differences in type I, IIA, IID(X), or IIB proportions compared with age-matched normals. Moreover, after this prolonged spasticity, type I, IIA, and IIB myofibers recovered from atrophy, and type IID(X) myofibers partially recovered. Our results indicate that early after transection or after long-term spinal isolation, relatively inactive tail myofibers atrophy and transform toward faster myofiber types. However, long-term spasticity apparently produces neuromuscular activity that promotes recovery of myofiber types and myofiber sizes.

Aging↗

PubMed2005

[Anorexia nervosa and cerebral atrophy in adolescents].

BACKGROUND AND OBJECTIVE: The incidence of cerebral atrophy in patients with anorexia nervosa and its relation to nutritional parameters has not been considered yet. PATIENTS AND METHOD: The medical records of 55 patients were reviewed. 47 of them underwent a cerebral magnetic resonance, anthropometric and nutritional study. RESULTS: Cerebral atrophy was found in 10 (21.2%) out of the 47 patients studied. Those patients with cerebral atrophy showed an older age and greater percentage of weight loss than patients without atrophy (p = 0.014 and p = 0.001) but lower triceps skinfold average (p = 0.001). CONCLUSIONS: Cerebral atrophy is common in patients with anorexia nervosa, mainly in those with a severe weight loss and lower body fat.

Adolescent↗

PubMed2006

Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion.

NKX3.1 is a homeobox gene located at chromosome 8p21.2, and one copy is frequently deleted in prostate carcinoma. Prior studies of NKX3.1 mRNA and protein in human prostate cancer and prostatic intraepithelial neoplasia (PIN) have been conflicting, and expression in focal prostate atrophy lesions has not been investigated. Immunohistochemical staining for NKX3.1 on human tissue microarrays was decreased in most focal atrophy and PIN lesions. In carcinoma, staining was inversely correlated with Gleason grade. Fluorescence in situ hybridization showed that no cases of atrophy had loss or gain of 8p, 8 centromere, or 8q24 (C-MYC) and only 12% of high-grade PIN lesions harbored loss of 8p. By contrast, NKX3.1 staining in carcinoma was correlated with 8p loss and allelic loss was inversely related to Gleason pattern. Quantitative reverse transcription-PCR for NKX3.1 mRNA using microdissected atrophy revealed a concordance with protein in five of seven cases. In carcinoma, mRNA levels were decreased in 6 of 12 cases but mRNA levels correlated with protein levels in only 4 of 12 cases, indicating translational or post-translational control. In summary, NKX3.1 protein is reduced in focal atrophy and PIN but is not related to 8p allelic loss in these lesions. Therefore, whereas genetic disruption of NKX3.1 in mice leads to PIN, nongenetic mechanisms reduce NKX3.1 protein levels early in human prostate carcinogenesis, which may facilitate both proliferation and DNA damage in atrophic and PIN cells. Monoallelic deletions on chromosome 8p are associated with more advanced invasive and aggressive disease.

Adenocarcinoma↗

PubMed2000

Pontine atrophy in spinocerebellar ataxia type 6.

To investigate the clinical range of spinocerebellar ataxia type 6 (SCA6), we screened CAG repeat expansion in the voltage-dependent alpha 1A calcium channel gene (CACNL1A4) in 71 ataxic patients in 60 families; 54 patients in 43 families with hereditary ataxia and 17 sporadic patients. Thirteen patients with SCA6 were detected to have elongated CAG in CACNL1A4. Of these, 7 patients had been diagnosed as having hereditary cerebellar cortical atrophy, and 6 patients had been found to have sporadic occurrence. One patient showed distinct pontine atrophy with prominent horizontal or oblique gaze nystagmus which is an unusual feature in sporadic olivopontocerebellar atrophy. For the efficient screening of SCA6, we would propose testing CAG repeat expansion in CACNL1A4, in patients with one of two markers: (1) horizontal or oblique gaze nystagmus without other eye movement disorders, (2) pure cerebellar atrophy, even if occurrence is sporadic. We should note that the pontine atrophy could also be caused by CAG repeat expansion in CACNL1A4.

Adult↗

PubMed2004

Clinicopathological staging of frontotemporal dementia severity: correlation with regional atrophy.

The pattern and degree of brain atrophy in frontotemporal dementia (FTD) has the potential for use as an aid in the diagnosis of this disorder and its differentiation from other neurodegenerative diseases. However, before this can occur, the sequence and progression of atrophy needs to be fully elucidated. Recently, we have described a four-point scheme for staging the severity of degeneration in FTD, which correlates with both duration of disease and severity of dementia [Broe M., et al.: Neurology 2003;60:1005-1011]. When volumetric analysis is performed in post-mortem-confirmed cases of FTD, atrophy of all lobes is present by stage 2 and then progresses with successive stages. Within each lobe, there is variation in the degree of atrophy between different functionally discreet brain regions with some regions showing marked atrophy and others showing little. Much of the frontal lobe, the amygdala and hippocampus are severely atrophic by stage 2, suggesting that they are some of the earliest areas affected in FTD.

Atrophy↗

PubMed2006

Topographical patterns of lobar atrophy in frontotemporal dementia and Alzheimer's disease.

BACKGROUND/AIMS: Fronto-temporal dementia (FTD) designates a group of relatively common neurodegenerative disorders. The aim of this study was to characterize the patterns of brain atrophy in FTD compared to Alzheimer's disease (AD). METHODS: A novel semiautomatic volumetric MRI analysis method was applied to measure regional brain volumes in FTD (n = 15; behavioural variant n = 9, language variant n = 6) in contrast with AD patients (n = 15) and age-matched controls (NC) (n = 15). FTD and AD patients were matched on demographic measures and Mini Mental State Examination scores. RESULTS: Significant atrophy was present in the frontal and anterior temporal lobes of subjects with FTD compared to AD (p = 0.02; effect size = 1.11) and compared to NC (p < 0.001; effect size = 1.86). Severe atrophy of the left anterior temporal region distinguished the language variant. AD patients, by contrast, did not differ from NC for frontal lobe volume but had smaller anterior temporal lobes (p = 0.03). Both dementia groups had medial temporal lobe atrophy of similar magnitude. A logistic regression model including 4 regional measures correctly classified 100% of subjects. CONCLUSION: FTD can be reliably differentiated from AD by virtue of a topographical pattern of atrophy involving the frontal lobes and anterior temporal regions. Medial temporal lobe volumes do not distinguish FTD from AD.

Aged↗

PubMed2006

Patterns of frontal lobe atrophy in frontotemporal dementia: a volumetric MRI study.

OBJECTIVES: Frontotemporal dementia (FTD), the second commonest degenerative cause of dementia under the age of 65, often presents with striking changes in behaviour and personality in association with frontal lobe atrophy. Based on the behavioural changes observed in FTD, it is commonly assumed that the orbitofrontal cortex is the earliest and most severely affected frontal sub-region. However, evidence to support this assumption has to date been largely lacking. METHODS: Using a novel volumetric MRI method, we performed a detailed volumetric analysis of six frontal regions in 12 subjects with the frontal or behavioural variant of FTD (fvFTD) and 12 age-, education- and sex-matched normal controls. The regions studied were: the orbitofrontal and insula regions (representing the orbitobasal cortex); the inferior and middle frontal regions (representing the dorsolateral prefrontal areas); and the superior frontal and anterior cingulate regions (representing the medial prefrontal areas). RESULTS: As a group, the fvFTD patients showed atrophy involving all six regions. We then segregated the 12 patients into three sub-groups according to their overall degree of atrophy. In the mildest group (n = 3) all regions fell within 2 standard deviations of normal. In the intermediate group (n = 6) only the orbitofrontal region (bilaterally) fell clearly outside the control range (>2 z scores below the control mean); the next most atrophic region in this group was the right insular region. The severe group (n = 3) had generalized atrophy throughout the frontal regions measured. CONCLUSIONS: In conclusion, patients with the earliest stages of fvFTD show no significant loss of volume in any frontal lobe area as measured by a novel MRI volumetric technique. When volume loss does occur, changes are initially seen in the orbitofrontal cortex before atrophy becomes more widespread. These results provide some partial support for the often-quoted assumption that the orbitofrontal cortex is the locus of earliest pathology in fvFTD, although these findings must be regarded as preliminary in view of the small numbers of patients involved.

Atrophy↗