1. www.ulss.tv.it Advanced brain imaging and neurodegenerative disorders. Dott.ssa Ingrid Inches

2. Neurodegenerative diseases are conventionally diagnosed using clinical assessment, neuropsychology tests and structural neuroimaging. However, there is an increasing need for using advanced mri techniques in order to better assess early volumetric, methabolic, ultrastructural and functional changes. Understanding the pathophysiology of the diseases may help in planning and monitoring therapy.

3. NEURODEGENERATIVE DISORDERS - DEMENTIAS - EXTRAPYRAMIDAL DISORDERS - MOTOR NEURON DISEASES

4. Dementias have the gratest impact in health management, among all neurodegenerative disorders. It is characterized by cognitive impairment severe enough to interfere with activity of daily living. Prevalence and incidence of dementias increase with age of patients. 2,5 dementia cases x 1000 65 – 69 yrs 9 dementia cases x 1000 75 – 79 yrs 40, 2 dementia cases x 1000 85 – 89 yrs Ramani, et al., Radiology 2006. DEMENTIAS

5. Prevalence of AD Dementia Scheltens, Fox, Barkhof, DeCarli, Lancet Neurology 2002. DEMENTIAS – Alzheimer’s disease

6. Dubois F, Feldman HF, Jacova C, DeKosky ST et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS – ADRDA criteria. Lancet Neurol 2007; 6: 734-46 Probable AD: EARLY AND SIGNIFICANT EPISODIC MEMORY IMPAIRMENT CRITERION A: EARLY AND SIGNIFICANT EPISODIC MEMORY IMPAIRMENT at least one or more supportive biomarker criteria.

7. B. MTL ATROPHY STRUCTURAL NEURO- IMAGING WITH MRI C. GLUCOSE METABOLISM IN BILATERAL TEMPORAL REGIONS MOLECULAR NEURO- IMAGING WITH PET D. β AMYLOID τ PROTEIN CSF ANALYSIS E. PROVEN AUTOSOMAL DOMINANT MUTATION WITHIN THE IMMEDIATE FAMILY SUPPORTIVE CRITERIA at least one or more supportive biomarker criteria.

8. CONVENTIONAL IMAGING – Alzheimer’s disease CONTROLS AD Linear measures of atrophy in mild Alzheimer disease. Frisoni GB et al. AJNR 17 (1996) 913-23 1) MTL atrophy is common in AD (71 – 96%) compared with older NC subjects. 2) Width of the temporal horn could discriminate AD vs NC with sensitivity 86%

9. Mapping local hippocampal changes in Alzheimer’s disease and normal ageing with MRI at 3T. R L L R Frisoni GB,et al. Brain 131 (2008) 3266 - 3276 1)sensitive to MTL atrophy in AD not specific 2) sensitive to progression of the disease 3) volumes of AD patients tended to be lower vs NC 4) medial, lateral regions in body and tail were lower in older NC 5) AD dorsolateral head and presubiculum VBM - Alzheimer’s disease

10. -DTI: white matter damage in AD patients.  MD and  FA in corpus callosum and in WM of frontal, temporal and parietal lobes. Strong correlation between MMSE and WM FA - MD. - In AD patients white matter changes are likely to be secondary to wallerian degeneration due to neuronal loss in cortical areas. DTI - Alzheimer’s disease Bozzali, Falini et al., JNNP 2002.

11. Diffusion Anisotropy an Diffusivity of White Matter Tracts in the Temporal Stem in AD disease: Evaluation of the “Tract of Interest” by Diffusion Tensor Tractography. T.Taoka, MD; et al. AJNR 27 (2006) 1040 -1045. - 15 NC and 15 AD “tract of interest” method TRACTS - Alzheimer’s disease

12. Regional Degradation of White Matter Ultrastructure in Mild cognitive impairment and Alzheimer’s disease by Diffusion Tensor Imaging. Y. Zhang, MD; et al. Neurology 68 (2007 ) 13 - 19. Alzheimer’s disease and MCI -MCI is associated with FA reduction particularly in the cingulum fibers, predominantly in the left posterior cingulate. -In AD, FA is further reduced in the cingulum fibers and FA reduction extend to the splenium. -FA reduction in the posterior cingulate improved the classification of MCI and AD from cognitively normal elderly, compared to the classifications using hippocampal volume loss alone.

13. Regionally-specific diffusion tensor imaging in Mild cognitive impairment and Alzheimer’s disease. M.M.Mielke, MD; et al. Neuroimage 46 (2009) 47 - 55. -75 pts (25 NC, 25 aMCI, 25 AD) -baseline and 3 months follow up -AD vs NC reduction FA in fornix and anterior cingulate -MCI vs AD lower FA in fornix, anterior cingulate, splenium -Over 3 months follow- up further decrease FA in anterior cingulate -Decrease FA well correlated with worse clinical performance. Alzheimer’s disease and MCI

14. A diffusion tensor MRI study of patients with MCI an AD with a 2-year clinical follow-up. Scola E, Bozzali M, Agosta F, Falini A et al. J Neurol Neurosur Psychiatry 2010 8; 798 – 805. - 62 pts (21 aMCI, 21 AD, 20 NC) - baseline and 2 years follow up - aMCI-C had WM and GM changes similar to AD - aMCI-NC showed DTI pattern similar to NC - increase MD in hippocampi, anterior insulae, frontal and parietal WM and decrease FA of temporal WM better distinguished aMCI-C vs aMCI-NC Alzheimer’s disease and MCI

15. Whole-brain N-Acetylaspartate as a surrogate Marker of Neuronal Damage in diffuse Neurologic Disorders. D.J. Rigotti et al. AJNR 28 (2007) 1843 -1849. -NAA (single peak at 2.02) is the most intense in a healthy brain. - 25 NC, 28 AD, 27 MCI significant decrease of WB NAA AD vs NC but not between them (MCI – AD). H MRS - Alzheimer’s disease

16. MCI AD H MR spectroscopy voxel in posterior cingulate, superior-temporal and parietal lobe. -Decrease of NAA peak and increase of Myo peak in AD and MCI vs NC. -Increase of Myo peak in MCI vs NC Kaantarci, Reynolds et al., AJNR 2003. Alzheimer’s disease and MCI

17. - fMRI testing the activation of MTL memory - learning tasks that required the encoding of new information into memory (familiar pictures vs novel pictures) -12 AD 10 NC - Decrease functional signal in MTL areas in AD vs NC Functional MR imaging in Alzheimer’s Disease during Memory Encoding. S. Rombouts, F. Barkhof et al. AJNR 21 (2000) 1869 - 1875. fMRI - Alzheimer’s disease

18. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. B.C. Dickerson, MD et al. Neurology 65 (2005) 404 - 411. - 10 NC, 9 MCI, 10 AD - fMRI with face-name task - Hyperactivation in hippocampal and entorhinal cortex in MCI - This pattern may reflect the need for memory circuits to recruit additional neural resources in order to compensate early MTL memory – networks degeneration. Alzheimer’s disease and MCI

19. -75 subjects - 13 AD - 28 NC - face–name associative memory encoding task : novel face – name pairs familiar face – name pairs  in signal intensity magnitude from NC, MCI, AD in - left anterior cingulate gyrus - left MTL ( hyppocampus)  in signal magnitude from NC, MCI, AD in postero-medial cortices (precuneus and posterior cyngulate gyrus). Cortical Deactivation in Mild Cognitive Impairment: High – Field – Strength Functional MR Imaging. J Petrella, MD et al. Radiology 245 (2007) 224 – 235. Alzheimer’s disease and MCI

20. - Increasing magnitude activation signal from NC to MCI to AD in PMC - Loss of deactivation in PMC: abnormally activation in low default mode network activity region. - PMC: region attending to enviromental stimuli, planning future behaviors and conscious processes.

21. - 41 NC, 18 AD, 28 MCI - MCI patients less deactivation vs NC but more vs AD - Anterior frontal cortex default mode network distinguished MCI from NC and AD. - The response in the precuneus NC vs AD and MCI not MCI vs AD. Altered resting state networks in mild cognitive impairment and mild Alzheimer’s disease: an fMRI study. SA Rombouts, F Barkhof et al. Radiology 256 (2010) 598 – 606. fMRI resting state - Alzheimer’s disease and MCI

22. Post-mortem biochemical studies ( Connor et al, Neurobiol Aging 2004 ) found out eccessive brain iron in cortical and basal ganglia region in AD. SWI - Alzheimer’s disease Oxidative damage to the brain caused by free radical reactions catalized by iron could be implicated in AD.

23. In AD entorhinal cortex could be a marker of iron. SWI has been proposed as a means of measuring regional iron level.

24. Structural imaging based on magnetic resonance is an integral part of the clinical assessment of patients with suspected Alzheimer dementia. Diffusion tensor, functional magnetic resonance imaging, and resting/functional MRI have a relevant role as adjuncts to clinical assessment in early diagnosis and monitoring of progression. New growing interest in SWI-dependent imaging as a potential bio- marker of the presence of iron in AD. Conclusions

26. -75 subjects - 13 AD - 28 NC - face–name associative memory encoding task : novel face – name pairs familiar face – name pairs  in signal intensity magnitude from NC, MCI, AD in - left anterior cingulate gyrus - left MTL ( hyppocampus)  in signal magnitude from NC, MCI, AD in postero-medial cortices (precuneus and posterior cyngulate gyrus). Cortical Deactivation in Mild Cognitive Impairment: High – Field – Strength Functional MR Imaging. J Petrella, MD et al. Radiology 245 (2007) 224 – 235. Alzheimer’s disease and MCI

36. DEMENTIAS – Alzheimer disease Conventionally neurodegenerative diseases are diagnosed using clinical assessment, neuropsychology and structural neuroimaging. However there in an increasing need for using advanced mri technique in order to better asses early volumetric, methabolic, ultrastuctural and functional changes helping to understand the pathophysiology of the diseases and planning and monitoring therapy.