1. Alzheimer’s disease (AD)

• Most common cause of progressive dementia (~60% of cases >65 years)^[1]
• Pathology: Senile gray matter plaques made of neurotoxic deposits of extracellular amyloid–beta (Aβ) 42 protein, intracellular neurofibrillary tangles (NFTs); neuronal death causing decreasing neuronal density. 
• Order of involvement: Transentorhinal cortex → medial temporal lobes → frontal, parietal, and occipital neocortical association areas 
• Clinical features: Memory decline → impaired language, visuospatial, and executive abilities^[1]
• Imaging: 
  • Volumetric grading of medial temporal lobe atrophy (Figure 1)
  • FDG-PET: hypometabolism of temporal lobes, parahippocampal gyri, posterior cingulate cortex (PCC), and precuneus, (involvement of the precuneus, middle and inferior temporal gyri more characteristic); relative sparing of the precentral gyrus, basal ganglia, and occipital cortex (Figure 2); Exception: posterior cortical atrophy variant (Figure 3) ^[2]
  • ASL: Areas of hypoperfusion same as PET
  • Tau selective radiotracers  (Eg: F-18 flortaucipir, )for disease-specific imaging of AD^[3]

Fig 1: Visual grading of medial temporal atrophy (MTA)

Fig 2: 81 year old female who presented with gradual memory decline and moderate depression. A: Axial T2 FLAIR image shows chronic white matter changes of subcortical and periventricular white matter (black arrows). B: Coronal T1 image shows grade 4 atrophy of bilateral medial temporal lobes. C, D, E: Axial, coronal, and sagittal FDG-PET images shows hypometabolism in bilateral temporal, precuneus and posterior cingulate cortices (yellow arrows). Preserved metabolism is seen in basal ganglia, anterior cingulate, sensory-motor and visual cortices. Imaging and clinical findings are consistent with Alzheimer's disease.

Fig 3: 82 year old male who presented with progressive dementia. A: Axial non-contrast CT of brain shows bilateral asymmetrical parietal predominant cortical atrophy (left more than right). B: Fused axial image of 18F-FDG PET-CT shows moderate to severe asymmetrical cortical hypometabolism involving bilateral parietal lobes (red arrows), involving the left parieto-occipital lobe and the left posterior cingulate gyrus C: ASL sequence shows hypoperfusion of the corresponding areas. 99mTc TRODAT SPECT of the same patient showed preserved dopamine receptor binding of bilateral basal ganglia (not shown). Findings are suggestive of posterior cortical atrophy variant of Alzheimer’s disease.

2. Dementia with Lewy Body (DLB)

• Second or third most common dementia
• Pathology: loss of dopaminergic neurons in substantia nigra, reduced striatal dopaminergic activity; neuronal inclusions of alpha-synuclein-positive Lewy bodies in cerebral cortex, substantia nigra, and brainstem^[4]
• Clinical features: Fluctuating cognition, visual hallucinations, REM sleep behavior disorder, parkinsonism; same as Parkinson’s disease (cortical involvement more pronounced in DLB)^[5]
• Imaging:
  • Atrophy of the frontal, temporal lobes, insular cortices (medial temporal lobe less involved)
  • Loss of swallow tail sign
  • DAT (dopamine transporter) imaging: low density of the presynaptic neurons of corpus striatum
  • FDG-PET: Hypometabolism of occipital, temporoparietal, and prefrontal cortices (relative sparing of pre- and post-central gyri, and medial temporal lobes); “cingulate island sign”- preserved metabolism of PCC with hypometabolic cuneus and precuneus ^[6]

Fig 4: 76 year old male who presented with tardive dyskinesia, dementia, and tremors of the left upper limb for last 2 years. A: Axial T1 image shows cerebral atrophy with parietal predominance. B: Axial ASL image shows relative hypoperfusion of bilateral parietal lobes and occipital lobes with relative sparing of the posterior cingulate cortex - "cingulate island sign". C: Axial SWI image shows absence of the normal high SWI signal within the substantia nigra on the left - "absent swallow tail sign" (inset shows magnified image with yellow arrow pointing towards the abnormal finding). Imaging features are suggestive of dementia with Lewy body (DLB).

3. Vascular dementia (VaD)

• Second or third most common dementia
• Pathology: Large vessel infarctions, watershed infarction in dominant hemisphere, small vessel disease
• Clinical features: Variable; decline in frontal lobe tasks including executive function and attention, neuropsychiatric symptoms (depression); subtypes present (Eg: CADASIL)
• Imaging:

• • >=2 large territory, >=3 lacunar infarcts, or strategic infarctions- diagnosis ^[7]
  • >25% of a cerebral hemisphere with white matter abnormalities/hyperintensities (WMHs) - subcortical VaD
  • Dilated VR spaces proportional to degree of severity of subcortical VaD
  • PET-CT: Hypometabolism of anterior cingulate cortex, deep gray nuclei, primary cortices, and middle temporal gyrus

Fig 5: 59 year old female who presented with cognitive decline. A: Axial T2-FLAIR weighted image show multiple chronic infarctions with gliosis in watershed territories (red arrows). B: Axial ASL image shows areas of hypoperfusion in bilateral fronto-parietal cortices, predominantly the perirolandic region (red oval). C: Axial T2-weighted image shows prominent VR spaces bilaterally (yellow oval). Imaging findings are diagnostic of vascular dementia.

Fig 6: 25 year old female who presented with slurring of speech. A, B: Axial DWI and ADC images show acute infarct involving left centrum semiovale (yellow ovals). C,D: Axial DWI and ADC images show subacute infarct involving splenium of corpus callosum on the right (yellow arrows). E: Axial SWI MinIP image shows multiple microhemorrhages in g angliocapsular predominance, pons and left cerebellar hemisphere (red arrows). F: Axial T2 FLAIR weighted image shows chronic white matter changes involving bilateral anterior temporal regions (blue arrows). G: Axial T2 weighted image shows a chronic lacunar infarct in right periventricular location (white arrow). A diagnosis of CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) was made based on patient's age, varying ages of multiple infarcts, involvement of anterior temporal lobe white matter, and microhemorrhages.

4. Frontotemporal dementia (FTD)

• Second most common cause of dementia (<65 years)^[8] 
• Pathology: 3 pathological subtypes- 1. Tau 2. TDP-43 3. FUS 
• Clinical features: 3 subtypes - behavioral variant FTD (bvFTD), semantic dementia (SD), progressive non-fluent aphasia (PNFA) ; social disinhibition, apathy, emotional blunting with loss of sympathy and empathy, repetitive, obsessive and stereotyped behaviors, and dietary changes (eg: gluttony)^[9]
• Imaging: 
  • Volumetry: Marked atrophy of ventromedial, prefrontal and insular cortices; anterior temporal lobes
  • ASL: Hypoperfusion in frontal lobes and anterior cingulate cortex (anterior cingulate cortex involvement help differentiate FTD from AD)
  • PET: hypometabolism of - ventromedial frontal lobe and anterior temporal lobe (bv), left or bilateral temporal poles, middle and inferior temporal gyri, and insula (ssPPA), inferior temporal gyrus, anterior cingulate cortex, and insula with sparing of the amygdala and hippocampi (nfPPA)
  • Lack of tracer uptake in amyloid PET (differentiate FTD from AD)

Fig 7: 70 year old woman who presented with rapidly progressive dementia and behavioural changes. A & B: Axial T2 FLAIR and coronal T2 weighted images show bilateral symmetrical fronto-temporal atrophy (red and yellow arrows) and with corresponding areas showing hypoperfusion in ASL sequence (C) including the anterior cingulate gyrus (red circle). Imaging findings in conjunction with clinical features are suggestive of behavioural variant fronto-temporal dementia (bvFTD).

5. Parkinsonian syndromes

5.a Parkinson’s disease (PD)

• Most common cause of Parkinsonian syndrome  (~80%)^[10]
• Pathology: Same as Lewy Body dementia 
• Clinical features: Bradykinesia, resting tremor, rigidity, postural instability; non-motor symptoms like constipation, anosmia, REM sleep disorder, autonomic dysfunction, dementia etc.
• Imaging:
• Volumetry: No significant brain atrophy
• T2* (SWI): Absent “swallow tail” sign
• I-123 ioflupane SPECT: : Lack of normal uptake in corpus striatum

Fig 8: 61 year old female who presented bradykinesia, gait imbalance, right upper limb rigidity. A: Axial non-contrast CT shows mild age-related atrophy in cerebral hemispheres. B: Axial fused 18F-FDG PET-CT image shows no definite areas of abnormal hypo- or hypermetabolism. C: Axial SWI image of midbrain shows decreased signal in substantia nigra- "absent swallow tail sign". D: Normal swallow-tail sign seen as thin hyperintense region within substantia nigra (yellow arrows). Imaging and clinical findings are suggestive of Parkinson’s disease.

5.b Multisystem atrophy (MSA)

• Clinical features: Parkinsonism + varying cerebellar, autonomic, and pyramidal dysfunction
• 2 clinical subtypes: cerebellar type (MSA-C), parkinsonian type (MSA-P)
• Diagnosis: 2022 Movement Disorder Society criteria (4 diagnostic categories)^[11]

• Imaging:
  • MSA-P: “Lateral putaminal sign”- T2/PD hyperintense lateral rim adjacent to the putamen
  • MSA-C: “Hot cross bun” sign- cruciform T2 hyperintense signal within the basis pontis- hallmark feature
  • Atrophy and T2 hyperintense signal involving pons, medulla, middle cerebellar peduncles, and cerebellar hemispheres
  • FDG-PET: Hypometabolism of putamina and cerebellar hemispheres

Fig 9: 44 year old male who presented with postural instability and dystonia. A: Axial T2 FLAIR weighted image of brain showing high T2 signal in the transverse pontocerebellar tracts and median pontine raphe nuclei of pons- "hot cross bun sign" (yellow circle). B: Axial T2 FLAIR weighted image of brain shows atrophy with high T2 signal of bilateral middle cerebellar peduncles (yellow arrows). C: Sagittal T1 weighted image of brain shows atrophy of pons and cerebellum (red arrows). D: Sagittal reformat of ASL map shows relative hypoperfusion of the cerebellum. The clinical and imaging features are diagnostic of multiple system atrophy cerebellar type (MSA-C).

5.c Progressive supranuclear palsy (PSP)

• Clinical features: Parkinsonism + vertical supranuclear gaze palsy + prominent postural instability
• Pathology: 4R tau isoform NFTs in the basal ganglia, diencephalon, and brainstem
• Imaging: 
  • “Hummingbird” sign- reduced AP diameter of midbrain
  • “Mickey mouse” sign- widened interpeduncular cistern
  • FDG-PET: Hypometabolism of brainstem and midline frontal cortex
  • SPECT: similar to PD

Fig 10: 67 year old male who presented with cognitive decline and Parkinsonian symptoms. A: Axial T2 FLAIR weighted image of brain showing reduced anteroposterior midline midbrain diameter (red arrow) - "Mickey mouse sign", and loss of lateral convex margin of tegmentum of midbrain- "morning glory sign" (yellow arrows). B: Sagittal T1 FLAIR weighted image of brain showing concave outline of the superior aspect of midbrain - "hummingbird sign" (yellow circle) with reduced midbrain to pons width ratio. C: Axial ASL image of brain shows relative hypoperfusion of both frontal lobes. Overall imaging features are suggestive of progressive supranuclear palsy with frontal predominance (PSP-F).

5.d Corticobasal degeneration (CBD)

• Clinical features: Asymmetric movement abnormalities, cortical signs like alien limb phenomenon, cognitive decline, poor response to levodopa
• Imaging:
  • Asymmetric atrophy of posterior frontal and parietal lobes, cerebral peduncles
  • Subcortical T2 FLAIR hyperintensity; normal basal ganglia
  • FDG PET: Hypometabolism involving primary cortices and contralateral basal ganglia
  • SPECT: Asymmetric decreased striatal uptake

Fig 11: 56 year old female who presented with limb dystonia and cognitive decline. A: Axial T2-FLAIR weighted image shows asymmetrical atrophy of bilateral fronto-parietal regions, more on the left (yellow arrow). A few small chronic small vessel ischemic changes are also seen (red circles). B: Axial ASL image of the same patient shows asymmetric areas of hypoperfusion involving bilateral superior fronto-parietal regions, suggestive of corticobasal degeneration (CBD). Note that the brainstem appears structurally normal (C) which helps distinguish this condition from progressive supranuclear palsy (PSP).

6. Cerebral amyloid angiopathy (CAA)

• Pathology: Accumulation of cerebral amyloid-β (Aβ) in small leptomeningeal and cortical vessels
• Diagnosis: Boston criteria 2.0^[12]
• Clinical features: Lobar hemorrhages (headache, stroke etc.), cognitive decline (gradual/step-wise/rapid-progressive)
• Imaging:
  • Hemorrhages (lobar, microhemorrhages sparing basal ganglia and pons, convexity subarachnoid hemorrhage, cortical and cerebellar superficial siderosis
  • Ischemic changes (chronic white matter changes, lacunar infarcts etc.)
  • PET-CT: Normal

Fig 12: 77 year old male with history of gradual cognitive decline who presented with acute onset headache and left-sided weakness. A: Coronal SWI image shows altered susceptibility focus in the right high frontal region consistent with intraparenchymal haemorrhage (yellow arrows). B: Axial SWI image shows curvilinear regions of altered susceptibility in the high fronto-parietal cortex, suggestive of superficial siderosis (red circle). Multiple microhemorrhagic foci are also noted in the cortico-subcortical locations of cerebral parenchyma bilaterally (yellow circle). C: Axial T2 FLAIR weighted image showing discrete and confluent non-diffusion restricting high T2 signals in the periventricular white matter (red arrows), suggestive of chronic small vessel ischaemic changes. Imaging features with clinical findings are suggestive of cerebral amyloid angiopathy (CAA).

7. Amyotrophic lateral sclerosis (ALS)

• Pathology: ubiquitinated TDP-43 inclusions
• Clinical features: progressive weakness, muscle atrophy, and fasciculations starting in the limbs (UMN and LMN degeneration)^[13]
• Imaging:
• T2 hyperintensity involving corticospinal tracts
• FDG-PET: hypometabolism in motor/perirolandic and frontal cortices, occipital lobes

Fig 13: 46 year old male with history of progressive lower limb weakness for 2 years. A: FDG-PET shows severe hypometabolism in bilateral posterior frontal and parietal lobes (left> right) involving the pre and post central gyri (red oval). B: Axial T2 FLAIR weighted image appears grossly unremarkable. C,D: Axial and sagittal CT images of lower limbs show moderate to severe atrophy of thigh and leg muscles, particulary involving posterior compartment of legs (red arrow). Imaging findings with clinical findings are suggestive of Amyotrophic Lateral Sclerosis (ALS).

 8. Huntington’s disease

• Pathology: Atrophy of striatum, subcortical and cortical regions in later stages
• Genetics: CAG trinucleotide repeat expansion on chromosome 4
• Clinical features: chorea, dementia, and psychosis
• Imaging:
  • “Box-shaped ventricles”- Atrophy of striatum with ex vacuo dilation of the frontal horns of the lateral ventricles
  • PET-CT:  Hypometabolism in the striatum, frontal and temporal lobes

Fig 14: 47 year old female with history of cognitive decline for 2 years. Strong family history of seizures and cognitive decline are also present. A: Coronal T2 weighted image shows atrophied caudate nuclei (red arrows) with ex-vacuo dilatation of frontal horns of lateral ventricles- "box shaped ventricle" sign. B: Axial non-contrast CT image shows bilateral caudate nuclei atrophy (decreased frontal horn width to intercaudate distance ratio, increased intercaudate distance to inner table width ratio). Chunky calcifications are seen in bilateral basal ganglia (red ovals). C: Axial T2 FLAIR weighted image shows mild cortical atrophy with chronic white matter changes (yellow arrows).

9. Creutzfeldt–Jakob disease (CJD)

• Pathology: Prion protein driven encephalopathy
• Clinical features: 4 subtypes - sporadic (most common), variant, familial, iatrogenic^[14]
• Imaging:
  • T2/DWI hyperintensity of cortex (“cortical ribboning”) and basal ganglia + thalamus (“hockey stick” sign)
  • FDG-PET: Hypometabolism of affected regions

Fig 15: 57 year old female who presented with rapidly progressive dementia. A: Axial DWI image shows curvilinear hyperintense signal involving the left cerebral cortex (red arrows) with ADC drop (not shown)- "cortical ribbon sign". B & C: Axial DWI and T2 FLAIR weighted images shows hyperintense signals involving bilateral caudate nuclei, putamen and ventromedial thalami. Imaging findings with clinical features are in keeping with Creutzfeldt-Jakob disease (CJD).

10. Wilson’s disease

• Pathology: Deficiency of ceruloplasmin, leading to accumulation of copper in brain, mainly putamen and globus pallidus
• Clinical features: Chronic hepatitis, neuropsychiatric symptoms (dementia, dysarthria, movement disorders, mood disturbances), ocular manifestations (Keyser-Fleischer rings, sunflower cataracts) etc.
• Imaging:
  • T2 FLAIR hyperintensities in putamen (most common), globus pallidi, caudate nuclei, ventrolateral thalami, deep grey nuclei of midbrain
  • “Face of panda” sign- T2 hyperintense midbrain tegmentum
  • “Face of panda cub” sign- involvement of pontine tegmentum
  • White matter changes (frontal predominant)

Fig 16: 36 year old male who presented with abnormal limb movements. A,B: Axial T2 FLAIR and T1 weighted images shows T2 FLAIR hyperintense areas (red arrows) with corresponding T1 hypointensity (yellow arrows) in bilateral putamen and caudate nuclei, with relative sparing of globus pallidi. Mild putaminal atrophy is also noted. C: Axial T2 weighted image shows high signal intensity in the tegmentum of midbrain sparing red nucleus and superior colliculi- "face of panda sign". Lab investigations revealed low ceruloplasmin levels, and diagnosis of Wilson's disease was made.

11. Hallervorden spatz syndrome/Pantothenate kinase-associated neurodegeneration (PKAN)

• Pathology: Neurodegeneration with brain iron accumulation (NBIA)
• 2 clinical phenotypes:
  • Classic PKAN - early onset progressive dystonia, dysarthria, rigidity, and choreoathetosis
  • Atypical PKAN - later onset (>10 years), speech defects, psychiatric disturbances, gradual disease progression
• Imaging:
  • CT- globus pallidi classification (not specific)
  • MRI- “Eye of the tiger” sign- T2 hypointense globus pallidi with central hyperintensity due to gliosis
  • T2 hypointensity in pars reticulata of substantia nigra
  • GRE/T2*: Hypointensities in corresponding areas (iron accumulation)

Fig 17: 16 year old girl who presented with frequent falls, inability to talk fluently, and abnormal limb movements. A: Axial T2 FLAIR weighted image shows hypointense signals in both globus pallidi with subtle central hyperintensities (yellow arrows) and substantia nigra (not shown)- "eye of the tiger sign". Axial SWI images at globus pallidi (B) and substantia nigra (C) show susceptibility artefacts (red arrows), corresponding to areas of iron deposition. Imaging features are consistent with pantothenate kinase-associated neurodegeneration (PKAN), also known as Hallervorden-Spatz syndrome.