1. Dr. Gene A. Ferretti Section Chief MRI Section Chief Neuroimaging St. Luke’s University Hospital and Health Network

2.  A neurodegenerative disease is a blanket term encompassing a wide variety of disorders, typically slowly progressive, with variable gradual neurologic dysfunction.

3.  Imaging of the brain in patients with suspected neurodegenerative conditions is common and challenging, the imaging findings are also subtle and equivocal. In many instances, by the time imaging findings are clear cut, the patient has declared themselves clinically, and the diagnosis is already established or at least strongly suggested.  As such the true role of imaging is often to push clinicians towards or away from a particular differential rather than making a firm diagnosis.

4.  Responsible for majority of Dementias  2/3 of dementia cases aged 60-70 yo  Epidemiological risk factors have been identified, including : advanced age female gender apolipoprotein E (APOE) ε 4 allele carrier status current smoking family history of dementia

5.  Alzheimer disease is characterised by the accumulation of senile (neuritic) plaques, neuritic (neurofibrillary) tangles, and progressive loss of neurons within the brain.senile (neuritic) plaquesneuritic (neurofibrillary) tangles  The progression of pathology initially involves the transentorhinal region and then spreads to the hippocampal complex and mesial temporal lobe structures and eventually the temporal lobes and basal forebrain.  The underlying reason for accumulation of senile (neuritic) plaques and neurofibrillary tangles remains poorly understood, as does the reason for non uniform distribution in the cortex.

6.  Clinical diagnosis is made by identifying progressive decline in memory both with clinical examinations and neuropsychologic tests and has been historically based on the the NINCDS-ADRA criteria, which divides patients according to the certainty of the diagnosis different catagories NINCDS-ADRA criteria  Definite: clinical diagnosis and histologic confirmation  Probable: typical clinical syndrome without histologic confirmation  81% sensitive, 73% specific  Possible: atypical clinical features without histologic confirmation but no alternative diagnosis

7.  The only definitive diagnostic test is brain biopsy which in practice is rarely obtained. As such the combination of clinical features and neuroimaging are usually considered sufficient. Although especially with the recognition of variants, this approach undoubtedly misdiagnoses a significant number of cases.  A number of CSF biomarkers are being used which may further help diagnosis. They include beta- amyloid, total tau, and hyperphosphorylated tau

8.  Although CT is able to demonstrate the characteristic patterns of cortical atrophy, MRI is more sensitive to these changes, and better able to exclude other causes of dementia (e.g. multi- infarct dementia) and as such is the favored modality.  Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 33753

9.  The primary role of MRI (and CT for that matter) in the diagnosis of Alzheimer disease is the assessment of volume change in characteristic locations which can yield a diagnostic accuracy of up to 87%  The diagnosis should be made on the basis of two features: mesial temporal lobe atrophy temporoparietal cortical atrophy

10.  Mesial temporal lobe atrophy can be viewed directly by assessing for hippocampal and parahippocampal decrease in volume, or indirectly by examining enlargement of the parahippocampal fissures. The former is more sensitive and specific but ideally requires actual volumetric calculations rather than 'eye- balling' the scan.

11. Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID: 42027

15.  NeuroQuant provides automatic computation of volumes of 11 key neuro structures.  Results are reported in a General Morphometry Report with volumes by hemisphere with an asymmetry index  Age Related Atrophy report for hippocampal and inferior left ventricular volumes plotted against an age related normative database.

16.  Alzheimer’s Disease Neuroimaging Initiative  800 total pts  200 controls  400 pts with Prodromal AD or MCI  200 pts early stage AD  Developed scanning parameters to allow volumetric imaging over multiple platforms  3D T1 weighted data sets with high quality G- W diff.  Approved by FDA

18. vMRI provides information that is not otherwise available and that is complementary to the history, neurological exam, neuropsychological testing, biofluid tests, and nuclear medicine imaging currently available for evaluating cognitive impairment. In addition, the report provides a visual aid for educating patients and their families.

19.  Behavioral, CSF and vMRI biomarkers each predict risk of conversion  Combinations of these substantially improve predictions  Goal of CSF markers to increase certainty that a pt. with MCI has or does not have the underlying AD pathophysiology  Medial T. lobe atrophy alone or in combination was associated with the most rapid rate of conversion, (15 month median survival times)

20.  Atrophy is the pathological event that immediately precedes and underlies, functional decline to dementia  AB develops years or decades prior to cog. imp. But when its assoc with memory impairment it has a sig. higher risk of conversion  Pts. With MCI who test +for AB were likely to convert to AD when hippocampal atrophy was present  Neurology 2011;77:1619-1628

21.  Must say Neuroquant on the Rx  Pts. Scanned at certain sites. (B,AL,AN,Q,W,P)  Pt. motion during scan.  Artifacts affecting overall image quality.  Brains showing gross amount of structural abnormality.  Surgical resections must not be larger than 30 cc.  Tumors must not be larger than 15 cc.  No contrast agents are applied.

24.  Chronic traumatic encephalopathy ( CTE ) is a neurodegenerative tauopathy that is thought to result from mild repetitive head trauma.neurodegenerativetauopathy  Most commonly seen in amateur and professional athletes where head contact is common (e.g. boxing, football, rugby, ice hockey), as well as in military personnel exposed to explosive blasts.

25.  Symptoms have an insidious onset, most often years after the initial injuries, with loss of normal attention, concentration and memory. This can progress, in some cases in 2-3 years, to include motor symptoms such impaired gait, impaired, executive function, lack of insight and poor judgement

26.  There is generalized cerebral atrophy with more pronounced atrophy of the frontal and temporal lobes (including mesial temporal lobe) as well as the thalamus, hypotha lamus and mammillary bodies. mesial temporal lobethalamushypotha lamusmammillary bodies  CTE is characterized by the presence of neurofibrillary tangl es and TDP-43 binding protein in subcortical and perivascular regions, often with reactive astrocytes and microglia neurofibrillary

27. Imaging features of CTE are nonspecific but the following may be seen  generalized cortical atrophy  hippocampal atrophy  vermian atrophy  cavum septum pellucidum cavum septum pellucidum  features of diffuse axonal injury (e.g. microhaemorrhagesdiffuse axonal injury

29.  Vascular dementia, also known as vascular cognitive impairment, is the second most common cause of dementia.  It is primarily seen in patients with atherosclerosis and chronic htn and results from the accumulation of multiple white matter or cortical infarcts, although cerebral haemorrhages can be variably includedatherosclerosis

30. Incidence has been variably reported, but is strongly correlated with age, seen in only 1% of patients over the age of 55 years of age, but in over 4% of patients over 71 years of age. To add to the confusion, given the prevalence of Alzheimer's disease, the two are commonly seen together. Additionally some patients develop accelerated vascular changes due to specific underlying disease (e.g. CADASIL and Fabry disease), and thus their demographics will be quite separate from the general population. CADASILFabry disease

31.  Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID : 10674

32.  Overlap of CMH and Dementias.  Seen in Chronic HTN, AA, CTE, Vascular Dem.  CMH, or microbleeds, are usually defined as <5 mm in size, and have a number of underlying causes.  Best seen on Gradient imaging and esp. SWI imaging.

33. CHRONIC HYPERTENSIVE AMYLOID ANGIOPATHY

34.  chronic hypertensive encephalopathy (common) chronic hypertensive encephalopathy  typically involve the basal ganglia, thalami as well as brain stem, cerebellum and corona radiata  cerebral amyloid angiopathy (common) cerebral amyloid angiopathy  typically involves the grey-white matter junction; usually spares the basal ganglia  Vascular dementias  CTE  cavernous malformations cavernous malformations  multiple (familial) cavernous malformation syndrome multiple (familial) cavernous malformation syndrome  post cerebral radiotherapy  septic and fat emboli  cerebral vasculitis (primary or secondary): microhaemorrhages usually located at the corticomedullary junction cerebral vasculitis  haemorrhagic diffuse axonal injury (DAI): typically involves the grey–white matter junction, splenium of the corpus callosum, and dorso-lateral brainstem diffuse axonal injury (DAI)  haemorrhagic micrometastases (rare): melanoma or renal cell carcinoma haemorrhagic micrometastases  CADASIL (rare): microhaemorrhages have been reported to occur in 25–70%of cases without a characteristic distribution CADASIL

35.  Synucleinopathies are a subgroup of neurodegenerative diseases, characterised by impairment of alpha-synuclein metabolism, resulting in abnormal intracellular deposits and can further be divided into those with and those without the formation of Lewy bodies :neurodegenerative diseasesLewy bodies  diseases with Lewy bodiesLewy bodies  Parkinson disease / Parkinson disease dementia Parkinson diseaseParkinson disease dementia  Lewy body disease Lewy body disease  multiple systemic atrophy (MSA) multiple systemic atrophy (MSA)

36.  Parkinson disease (PD), also known as idiopathic parkinsonism, is a neurodegenerative disease and movement disorder characterised by a resting tremor, rigidity and hypokinesia due to progressive degeneration of dopaminergic neurons in the substancia nigra. neurodegenerative diseasemovement disorder

37.  Clinical presentation  Parkinson disease is classically characterized by a triad of features:  resting tremor  rigidity  bradykinesia  postural instability: sometimes added as a cardinal feature

38.  Radiographic features  Initial imaging findings are subtle and only potentially seen on MRI. With advanced disease, non-specific generalized minor cerebral volume loss can be demonstrated.

41.  Dementia with Lewy bodies (DLB), also known as Lewy body disease, is a neurodeg disease related to Parkinson's disease (PD). It is reported as the second most common form of neurodegenerative dementia following Alzheimer’s disease (AD), accounting for 15-20% of cases at autopsy. neurodeg diseaseParkinson's disease (PD)Alzheimer’s disease (AD)

42.  Features reported include:  generalized decrease in cerebral volume most marked in  frontal lobes  parietotemporal regions  enlargement of the lateral ventricles  relatively focal atrophy of the  midbrain midbrain  hypothalamus hypothalamus  substantia innominata substantia innominata  Perhaps more importantly the hippocampi remain normal in size, helping to distinguish Lewy body disease from Alzheimer's diseasehippocampiAlzheimer's disease

43.  Multiple system atrophy (MSA) is a sporadic neurodegenerative disease (one of the synucleinopathies) characterised by varying degrees of cerebellar ataxia, autonomic dysfunction, parkinsonism and corticospinal dysfunction. synucleinopathies  MSA-C: predominance of cerebellar symptoms (olivopontocerebellar atrophy)olivopontocerebellar atrophy  MSA-P: predominance of parkinsonian signs and symptoms (striatonigral degeneration)striatonigral degeneration

44.  MRI  T2: hyperintensities typically present in the pontocerebellar tracts  pons: hot cross bun sign (MSA-C)hot cross bun sign  middle cerebellar peduncles  cerebellum  putaminal findings in (MSA-P):  reduced volume  reduced GRE and T2 signal relative to globus pallidus  reduced GRE and T2 signal relative to red nucleus  abnormally high T2 linear rim surrounding the putamen ("putaminal rim sign"), seen at 1.5T (this is normal at 3T) putaminal rim sign

45. Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 5465 Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 28472

47.  Normal pressure hydrocephalus (NPH) remains a controversial entity with often ambiguous imaging findings. It is classically characterized by the triad of gait apraxia, urinary incontinence and dementia, although not all patients with NPH have all three.

48.  In a large study in Norway found a striking increasing incidence with increasing age:  3.3 per 100,000 for people 50 to 59 years of age  49.3 per 100,000 for people 60 to 69 years of age  181.7 per 100,000 for people 70 to 79 years of age

49.  The classical clinical findings of normal pressure hydrocephalus are:  urinary incontinence  deterioration in cognition (dementia)  gait disturbances  These can be remembered with the unkind mnemonic Wet, Wacky and Wobbly. Wet, Wacky and Wobbly  As the name suggests mean CSF opening pressure in patients with NPH is within the normal range (<18 cmH 2 O).

50.  Morphological changes  ventriculomegaly  frontal and temporal horns of the lateral ventricles most affectedlateral ventricles  upward bowing of the corpus callosumcorpus callosum  periventricular high signal on T2 weighted sequences  narrow callosal anglecallosal angle  changes in sulcal size  crowding of the gyri at the vertex (with small sulci)  cingulate sulcus sign: posterior part of cingulate sulcus is narrower than the anterior part, the divider between the two being a line drawn parallel to the floor of the 4th ventricle cingulate sulcus sign  sylvian fissures out of proportion to sulcal enlargement (which is minimal) and hippocampus and mesial temporal lobe volumes (which are near normal) sylvian fissures

51. Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID: 41180 Case courtesy of Dr Ruslan Esedov, Radiopaedia.org, rID: 8401

54.  CSF flow studies increased aqueductal stroke volume CSF flow studies  aqueductal stroke volume is the average volume of CSF moving through the cerebral aqueduct  calculated by summing the absolute values of stroke volume in systole and diastole and dividing by 2  (forward stroke volume + reverse stroke volume)/2  increased aqueductal peak velocity  various publications have set various normal and abnormal ranges  flow rate of > 24.5mL/min 95% specific for NPH 9,11  stroke volume of > 42 microL shown on one paper to predict good response from shunting

55.  A good clinical history is a must if the importance of subtle findings is be appreciated. Unfortunately all too often requests contain only vague details such as "dementia?". If possible further history should be obtained including:  patient demographics  age, gender, ethnicity, occupation  main presenting complaint  characterization of cognitive symptoms  attentional problems  memory problems (e.g. short term / long term / ante-grade / retrograde)  language problems (e.g. receptive, expressive)  visual/constructional problems  apraxia  personality change (e.g. disinhibition, aggression)  characterization of physical symptoms  Tremor, Rigidity, Hyperkinesis, Falls, Dysphagia, Incontinence, eye signs  time course  onset, duration, progression  any relevant family history  any risk factors for differential diagnosis  e.g. smoking, hypertension, diabetes, stroke  clearly stated differential diagnosis.