There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary targets and disease progression in ALS and variants of ALS, (2) brain imaging markers for upper motor neuron lesion, and (3) evidence for ALS being a multisystem disorder. Clinically, upper motor and lower motor neuron symptoms can occur in any order over time. Brain imaging markers show upper motor neuron involvement in early disease. Overlap syndromes of ALS and dementia, and involvement of autonomic and sensory nerves occur frequently. PET/SPECT scans, functional MRI and voxel based morphometry studies clearly show abnormalities in extra-motor areas of the brain. Pathologically, the 43 kDa TAR DNA-binding protein (TDP-43) provides a clue to these overlapping disorders. In conclusion, evidence accumulates that ALS is a multisystem disorder rather than a pure lower and/or upper motor neuron disorder.

Abstract Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.

The aim of this study was to investigate the extent of cortical and subcortical lesions in amyotrophic lateral sclerosis (ALS) using, in combination, voxel based diffusion tensor imaging (DTI) and voxel based morphometry (VBM). We included 15 patients with definite or probable ALS and 25 healthy volunteers. Patients were assessed using the revised ALS Functional Rating Scale (ALSFRS-R). In patients, reduced fractional anisotropy was found in bilateral corticospinal tracts, the left insula/ventrolateral premotor cortex, the right parietal cortex and the thalamus, which correlated with the ALSFRS-R. Increased mean diffusivity (MD) was found bilaterally in the motor cortex, the ventrolateral premotor cortex/insula, the hippocampal formations and the right superior temporal gyrus, which did not correlate with the ALSFRS-R. VBM analysis showed no changes in white matter but widespread volume decreases in grey matter in several regions exhibiting MD abnormalities. In ALS patients, our results show that subcortical lesions extend beyond the corticospinal tract and are clinically relevant.

Background:Increasing neuroimaging studies have revealed gray matter (GM) anomalies of several brain regions by voxel-based morphometry (VBM) studies in patients with amyotrophic lateral sclerosis (ALS). A voxel-wise meta-analysis was conducted to integrate the reported studies to determine the consistent GM alterations in ALS based on VBM methods. Methods:Ovid Medline, Pubmed, Emabase, and BrainMap database were searched for relevant studies.Data were extracted by two independent researchers. Voxel-wise meta-analysis was performed using the effect-size signed differential mapping (ES-SDM) software. Results:Twenty-nine VBM studies comprising 638 subjects with ALS and 622 healthy controls (HCs) met inclusion criteria.The global GM volumes of ALS patients were significantly decreased compared with those of HCs. GM reductions in patients were mainly located in the right precentral gyrus, the left Rolandic operculum, the left lenticular nucleus and the right anterior cingulate/paracingulate gyri. The right precentral gyrus and the left inferior frontal gyrus might be potential anatomical biomarkers to evaluate the severity of the disease, and longer disease duration was associated with more GM atrophy in the left frontal aslant tract and the right precentral gyrus in ALS patients. Conclusion:The results support that ALS is a complex degenerative disease involving multisystems besides the motor system.The mechanism of asymmetric atrophy of the motor cortex and the implication of Rolandic operculum involvement in ALS need to be further elucidated in future studies.

61 We performed meta-analyses of GM anomalies with 20 VBM studies in ALS patients.61 GM atrophy was consistently found in the frontal, temporal, and somatosensory areas.61 Disease duration and severity, and age were correlated with GM loss in ALS patients.61 We provide convergent evidence that ALS is a multisystem degenerative disorder.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with selected both upper and lower motor neuron involvement. Although some inconsistent results exist, both pathological studies and many structural neuroimaging studies have revealed brain volume changes in ALS. To provide an objective overview of structural changes in ALS, a voxel-wise meta-analysis was performed in published voxel based morphometry (VBM) studies. A systematic search of VBM studies was applied in ALS. Five studies met the inclusion criteria, comprising 84 ALS patients and 81 normal controls. A voxel-wise meta-analysis was performed on the retrieved VBM studies using signed differential mapping. Descriptive analysis showed that 25% of ALS patients had right precentral gyrus atrophy (2373 voxels). Group analysis demonstrated regional grey matter loss over the whole brain in the right precentral gyrus (p = 7.96 0103 100908084). Sensitivity analysis showed good sensitivity (157 voxels). In conclusion, right precentral grey matter atrophy was a common finding and prominent feature of brain structural changes in ALS.

Abstract In patients with premotor Huntington disease (pmHD), literature has reported decreases in caudate volume. However, the regional vulnerability of the caudate nucleus to pmHD remains to be clarified. We aimed to determine whether regional structural damage of the caudate nucleus was present in pmHD and was correlated with clinical profile using a surface-based morphometric technique applied to T1-weighted MRI. The study cohort consisted of 14 volunteers with genetically confirmed pmHD (6 males; 41.8 13.2 years) and 11 age- and sex-matched controls (5 males; 46.2 卤 11.9 years, p > 0.3). On 3-T T1-weighted images, bilateral caudate volumes were manually delineated. The resulting labels were converted to a surface, triangulated with 1002 points equally distributed across subjects using SPHARM-PDM. Displacement vectors were then computed between each individual and a template surface representing the whole cohort. Computing point-wise Jacobian determinants (JD) from these vectors quantified local volumes. We found decreases in bilateral global caudate volumes in the pmHD group compared to controls (t = 3.4; p = 0.002). Point-wise analysis of local volumes mapped caudate atrophy in pmHD primarily onto medial surface (t > 2.7; FDR < 0.05), with most pronounced changes in anteromedial subdivision. In a combined group of patients and controls, volume within the area presenting significant group difference was positively correlated with scores of executive function (r = 0.7; p < 0.001) and working memory (r = 0.6; p = 0.002). In patients, the caudate atrophy was associated with increase in disease burden (r = 0.7; p = 0.005). Caudate subnuclear atrophy measured using our surface-based morphometric technique is evident in pmHD, correlates with clinical variables, and may provide a more sensitive biomarker than global volumes.

61We examined cortical abnormalities in PD patients using surface-based morphometry.61Cortical thickness was found reduced in the prefrontal cortex of PD patients.61Depressed PD patients showed increased brain area in orbitofrontal-insula region.61These results might be helpful for diagnosis and treatment of depression in PD.

Default mode network (DMN) has been reported to be susceptible to APOEε4 genotype. However, the APOEε4-related brain changes in young carriers are different from the ones in elderly carriers. The current study aimed to evaluate the cortical morphometry of DMN subregions in cognitively normal elderly with APOEε4. 11 cognitively normal senior APOEε4 carriers and 27 matched healthy controls (HC) participated the neuropsychological tests, genotyping, and magnetic resonance imaging (MRI) scanning. Voxel-based morphometry (VBM) analysis was used to assess the global volumetric changes. Surface-based morphometry (SBM) analysis was performed to measure regional gray matter volume (GMV) and gray matter thickness (GMT). Advancing age was associated with decreased GMV of DMN subregions. Compared to HC, APOEε4 carriers presented cortical atrophy in right cingulate gyrus (R_CG) (GMV: APOE carriers: 8475.23 ± 1940.73 mm3, HC: 9727.34 ± 1311.57 mm3,t= 2.314,p= 0.026, corrected) and left insular (GMT: APOEε4 carriers: 3.83 ± 0.37 mm, HC: 4.05 ± 0.25 mm,t= 2.197,p= 0.033, corrected). Our results highlight the difference between different cortical measures and suggest that the cortical reduction of CG and insular maybe a potential neuroimaging marker for APOE 4εsenior carriers, even in the context of relatively intact cognition.

We prospectively investigated pathological modifications in the corticospinal tract (CST), by diffusion tensor imaging (DTI) in 14 patients with sporadic amyotrophic lateral sclerosis (ALS) and 12 healthy volunteers. We used a validated automated method to accurately measure the in vivo thickness of the cerebral cortex. We found a reduction of precentral cortical ribbon thickness in ALS patients with respect to control subjects. DTI metrics demonstrated disorganization of the CST, as characterized by decreased fractional anisotropy (FA) and increased Apparent Diffusion Coefficient in ALS patients with respect to control subjects. Decreased mean FA values along the CST significantly correlated with clinical measures of pyramidal and bulbar impairment.

The extensive application of advanced MR imaging techniques has undoubtedly improved our knowledge of the pathophysiology of amyotrophic lateral sclerosis. Nevertheless, the precise extent of neurodegeneration throughout the central nervous system is not fully understood. In the present study, we assessed the spatial distribution of cortical damage in amyotrophic lateral sclerosis by using a cortical thickness measurement approach.Surface-based morphometry was performed on 20 patients with amyotrophic lateral sclerosis and 18 age- and sex-matched healthy control participants. Clinical scores of disability and disease progression were correlated with measures of cortical thickness.The patients with amyotrophic lateral sclerosis showed a significant cortical thinning in multiple motor and extramotor cortical areas when compared with healthy control participants. Gray matter loss was significantly related to disease disability in the left lateral orbitofrontal cortex (P = .04), to disease duration in the right premotor cortex (P = .007), and to disease progression rate in the left parahippocampal cortex (P = .03).Cortical thinning of the motor cortex might reflect upper motor neuron impairment, whereas the extramotor involvement seems to be related to disease disability, progression, and duration. The cortical pattern of neurodegeneration depicted resembles what has already been described in frontotemporal dementia, thereby providing further structural evidence of a continuum between amyotrophic lateral sclerosis and frontotemporal dementia.

The asymmetric GM atrophy of the motor cortex and extra-motor cortex represents the common MRI structural signatures of spinal-onset ALS, and sole extra-motor cortex atrophy represents the structural signatures of bulbar-onset ALS. The present study also demonstrated that the pattern of GM damage is likely to distribute wider in spinal-onset ALS than in bulbar-onset ALS.

(2000). El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders: Vol. 1, No. 5, pp. 293-299.

Study of functional rating scale for amyotrophic lateral sclerosis : revised ALSFRS (ALSFRS-R) Japanese version No To Shinkei 53(4), 346-355, 2001

Patient’s Name: Date:Instructions: Ask the questions in the order listed. Score one point for each correctresponse within each question or activity.Maximum Patient’sQuestionsScore Score5 “What is the year? Season? Date? Day of the week? Month?”5 “Where are we now: State? County? Town/city? Hospital? Floor?”The examiner names three unrelated objects clearly and slowly, thenasks the patient to name all three of them. The patient’s response is3used for scoring. The examiner repeats them until patient learns all ofthem, if possible. Number of trials: ___________“I would like you to count backward from 100 by sevens.” (93, 86, 79,5 72, 65, …) Stop after five answers.Alternative: “Spell WORLD backwards.” (D-L-R-O-W)“Earlier I told you the names of three things. Can you tell me what those3were?”Show the patient two simple objects, such as a wristwatch and a pencil,2and ask the patient to name them.1 “Repeat the phrase: ‘No ifs, ands, or buts.’”“Take the paper in your right hand, fold it in half, and put it on the floor.”3(The examiner gives the patient a piece of blank paper.)“Please read this and do what it says.” (Written instruction is “Close1your eyes.”)“Make up and write a sentence about anything.” (This sentence must1contain a noun and a verb.)“Please copy this picture.” (The examiner gives the patient a blankpiece of paper and asks him/her to draw the symbol below. All 10angles must be present and two must intersect.)130 TOTAL(Adapted from Rovner & Folstein, 1987)1Source: www.medicine.uiowa.edu/igec/tools/cognitive/MMSE.pdf Provided by NHCQF, 0106-410Instructions for administration and scoring of the MMSEOrientation (10 points):61 Ask for the date. Then specifically ask for parts omitted (e.g., "Can you also tell me what season itis?"). One point for each correct answer.61 Ask in turn, "Can you tell me the name of this hospital (town, county, etc.)?" One point for eachcorrect answer.Registration (3 points):61 Say the names of three unrelated objects clearly and slowly, allowing approximately one second foreach. After you have said all three, ask the patient to repeat them. The number of objects thepatient names correctly upon the first repetition determines the score (0-3). If the patient does notrepeat all three objects the first time, continue saying the names until the patient is able to repeat allthree items, up to six trials. Record the number of trials it takes for the patient to learn the words. Ifthe patient does not eventually learn all three, recall cannot be meaningfully tested.61 After completing this task, tell the patient, "Try to remember the words, as I will ask for them in alittle while."Attention and Calculation (5 points):61 Ask the patient to begin with 100 and count backward by sevens. Stop after five subtractions (93,86, 79, 72, 65). Score the total number of correct answers.61 If the patient cannot or will not perform the subtraction task, ask the patient to spell the word "world"backwards. The score is the number of letters in correct order (e.g., dlrow=5, dlorw=3).Recall (3 points):61 Ask the patient if he or she can recall the three words you previously asked him or her toremember. Score the total number of correct answers (0-3).Language and Praxis (9 points):61 Naming: Show the patient a wrist watch and ask the patient what it is. Repeat with a pencil. Scoreone point for each correct naming (0-2).61 Repetition: Ask the patient to repeat the sentence after you ("No ifs, ands, or buts."). Allow only onetrial. Score 0 or 1.61 3-Stage Command: Give the patient a piece of blank paper and say, "Take this paper in your righthand, fold it in half, and put it on the floor." Score one point for each part of the command correctlyexecuted.61 Reading: On a blank piece of paper print the sentence, "Close your eyes," in letters large enoughfor the patient to see clearly. Ask the patient to read the sentence and do what it says. Score onepoint only if the patient actually closes his or her eyes. This is not a test of memory, so you mayprompt the patient to "do what it says" after the patient reads the sentence.61 Writing: Give the patient a blank piece of paper and ask him or her to write a sentence for you. Donot dictate a sentence; it should be written spontaneously. The sentence must contain a subjectand a verb and make sense. Correct grammar and punctuation are not necessary.61 Copying: Show the patient the picture of two intersecting pentagons and ask the patient to copy thefigure exactly as it is. All ten angles must be present and two must intersect to score one point.Ignore tremor and rotation.(Folstein, Folstein & McHugh, 1975)2Source: www.medicine.uiowa.edu/igec/tools/cognitive/MMSE.pdf Provided by NHCQF, 0106-410Interpretation of the MMSEMethod Score InterpretationSingle Cutoff

78 Cortical thickness estimation and central surface reconstruction 78 Voxel-based projection scheme based on tissue segmentation 78 Phantom creation scheme for thickness and surface validation 78 Third party phantoms and real data for comparison with other software (Freesurfer)

In this study, we have assessed the validity and reliability of an automated labeling system that we have developed for subdividing the human cerebral cortex on magnetic resonance images into gyral based regions of interest (ROIs). Using a dataset of 40 MRI scans we manually identified 34 cortical ROIs in each of the individual hemispheres. This information was then encoded in the form of an atlas that was utilized to automatically label ROIs. To examine the validity, as well as the intra- and inter-rater reliability of the automated system, we used both intraclass correlation coefficients (ICC), and a new method known as mean distance maps, to assess the degree of mismatch between the manual and the automated sets of ROIs. When compared with the manual ROIs, the automated ROIs were highly accurate, with an average ICC of 0.835 across all of the ROIs, and a mean distance error of less than 1 mm. Intra- and inter-rater comparisons yielded little to no difference between the sets of ROIs. These findings suggest that the automated method we have developed for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable. This method may be useful for both morphometric and functional studies of the cerebral cortex as well as for clinical investigations aimed at tracking the evolution of disease-induced changes over time, including clinical trials in which MRI-based measures are used to examine response to treatment.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons. In some ALS patients, dementia or aphasia may be present (ALS-D). The dementia is most commonly a frontotemporal dementia (FTD), and many of these cases have ubiquitin-positive, tau-negative inclusions in neurons of the dentate gyrus and superficial layers of the frontal and temporal lobes. Identical inclusions have been found in cases presenting with FTD and have been designated motor neuron disease (MND)-inclusions. Cases of ALS-D without MND-inclusions have been reported to show neocortical gliosis, neuronal loss, and superficial spongiosis, but there have also been scattered case reports of ALS with Alzheimer鈥檚 disease (AD). To determine whether AD pathology may play a role in the dementia or aphasia syndromes in ALS, we reviewed 30 cases of sporadic ALS diagnosed at the University of Pittsburgh Medical Center. A clinical history of ALS-D was found in 24.1% of the cases, of which 57% had MND-inclusions. Although the ALS-D cases with MND-inclusions typically had amyloid-beta (A尾) plaques, there were no neuritic plaques. Three cases of ALS-D had no MND-inclusions, and two of these fulfilled pathological criteria for AD. One ALS-D case showed severe amyloid angiopathy but no neuritic plaques or MND-inclusions. MND-inclusions were not found in any ALS case without dementia; however, four patients without dementia or aphasia showed moderate or frequent numbers of neuritic plaques. In conclusion, we found that approximately 30% of ALS cases with dementia have AD and that some ALS cases without frank dementia have significant AD pathology.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with selected both upper and lower motor neuron involvement. Although some inconsistent results exist, both pathological studies and many structural neuroimaging studies have revealed brain volume changes in ALS. To provide an objective overview of structural changes in ALS, a voxel-wise meta-analysis was performed in published voxel based morphometry (VBM) studies. A systematic search of VBM studies was applied in ALS. Five studies met the inclusion criteria, comprising 84 ALS patients and 81 normal controls. A voxel-wise meta-analysis was performed on the retrieved VBM studies using signed differential mapping. Descriptive analysis showed that 25% of ALS patients had right precentral gyrus atrophy (2373 voxels). Group analysis demonstrated regional grey matter loss over the whole brain in the right precentral gyrus (p = 7.96 0103 100908084). Sensitivity analysis showed good sensitivity (157 voxels). In conclusion, right precentral grey matter atrophy was a common finding and prominent feature of brain structural changes in ALS.

Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. The total number of neurons in the neocortex and motor cortex from eight patients suffering from amyotrophic lateral sclerosis (ALS) and nine controls was estimated. No attempt was made to estimate subpopulations of neurons such as the number of giant pyramidal cells of Betz. No difference was found in the average number of neurons in neocortex in ALS and controls, 21.7 and 22.3脳10 9, respectively, and 1.33 and 1.29脳10 9 in motor cortex, respectively. In the light of our stereological measurements, results obtained from in-vivo proton magnetic resonance spectroscopy ( 1H-MRS), suggesting neuronal loss in ALS, may instead be due to neuronal metabolic dysfunction and/or alteration in the size or the volume fraction of the neurons.

In , motor neurons in the spinal cord and brainstem shrink before they die. In 12 cases of sporadic , and in 11 control subjects, we have measured the neurons in the second sacral segment and the hypoglossal , and have calculated a 'shape index' that shows the convexity or concavity of the . (The shape index, SI = 100 x C/P, where C is the circumference of the largest circle that can be inscribed in the neuron and P is the perimeter of the perikaryon, including the bases of the dendrites as seen in a Nissl preparation. The shape index increases with increasing convexity of the cell.) In the ventral horn of segment S2 and in the hypoglossal , the surviving motor neurons in showed significantly decreased size and increased shape index (convexity) of the . By contrast, the of Onuf in segment S2, consisting of neurons that supply the pelvic floor muscles, was preserved in . Its cells did not differ significantly in size or convexity between the and control groups. In both the hypoglossal and S2 neuronal populations in , the sizes of the cells were positively correlated with the numbers of surviving motor neurons. However, there was no correlation of the shape index with numbers of cells. This is interpreted as due to shrinkage of neurons still taking place at the time of , when the changes in shape were probably largely completed. These observations indicate that the mechanism of neuronal atrophy in may involve both reduced protein synthesis and enzymatic degradation of the within the larger dendrites.

Abstract The distribution of reactive astrocytes was examined in the cortical gray matter of non-motor and motor regions from cases of familial and sporadic amyotrophic lateral sclerosis (ALS) and compared to that of β-amyloid deposits. By glial fibrillary acidic protein immunocytochemistry, patches of reactive astrocytes, characterized by multiple reactive astrocytes in a circular or patch-like formation, occurred in 12 of 15 ALS cases examined. These patches of reactive astrocytes were not restricted to the motor cortex but were found in the gray matter in ALS in all examined brain regions, including frontal, temporal, inferior parietal, cingulate, occipital, and motor cortices, from both familial and sporadic ALS cases. Reactive astrocytes were also found in the subpial region and at the gray/white matter junction. Because patches of astrocytes can occur in association with senile plaques, β-amyloid was localized. By immunostaining, β-amyloid deposits were observed in five of the 15 ALS cases: three cases had only early plaques, two had both early and classic plaques. The number of ALS cases with both astrocyte patches and amyloid plaques was four of 15, but typically astrocyte patches in ALS occurred without any evidence of an association with β-amyloid deposits. Therefore, the astrocyte patches in ALS are not the result of β-amyloid deposition. The widespread occurrence of reactive astrocytes, as patches in the cortical gray matter and in the subpial region and at the gray/white matter junction, is evidence of a widespread pathology in ALS cortex in both familial and sporadic forms of the disease. 08 1994 Wiley-Liss, Inc.