Differential Diagnosis in Neurology

16.3. Fronto Temporal Dementias (FTDs)

• General characteristics:
  • Less common and earlier onset compared to AD dementias
  • Approximately 5% of all primary dementias
  • Onset earlier than 65 years of age
• Clinically heterogenous and encompass:
  • Pick's disease
  • Primary progressive aphasia in Pick's disease
  • Familial progressive subcortical gliosis
  • Frontal lobe disorders lacking distinctive histology
  • Progressive aphasia with dementia
  • Frontal lobe degeneration with motor neuron disease
  • DDPAC (disinhibition-dementia-parkinsonism-amyotrophy complex)
  • Hereditary dysphasic disinhibition dementia
  • FTD with parkinsonism linked to chromosome 17
  • PPND (palliopontine nigral degeneration)
• Clinical features:
  • Deficits in behavior and social interaction:
    • Occur early
    • Out of proportion to the memory deficit
    • Loss of personal hygiene and deficient grooming
    • Loss of social graces
    • Social withdrawal
    • Disinhibition
    • Impulsivity
    • Distractibility
    • Hyperorality; hyperphagia
    • Stereotyped and perservative behaviors
    • Depression
    • Apathy
    • Psychosis
    • Obsessive stereotyped behavior
    • Diminished speech output to mutism
    • Decreased executive function
    • Loss of judgment and insight
  • Expressive speech dysfunction:
    • Loss of fluency
    • Stereotypic speech
    • Echolalia
  • Associated neurologic signs:
    • Early and prominent frontal release signs
    • Incontinence after cognitive changes is present
    • Parkinsonism later in the course of the disease
    • Visuospatial memory, orientation functions are preserved
    • Praxis is preserved
  • MRI:
    • Frontal and anterior temporal lobe atrophy
  • AchE inhibitors are ineffective
  • Genetics of FTD:
    • Familial in 40–50% of cases
    • Variant with Parkinsonism:
      • Linked to chromosome 17q 21–22 (FTDP-17)
      • Families with FTD P-17 have:
        • Abnormalities of tau protein
    • Gene for tau:
      • On chromosome 17 close to or within the FTDP17 region
      • Expressed in neurons > glia
      • Has 6 isoforms
      • Important for microtubule stabilization binding and assembly
      • Splicing mutations occur in the FTDs

FTD Variants

• Syndromes linked to FTD P-17:
  • Palliopontine nigral degeneration (PPND)
  • Familial multiple system tauopathy with presenile dementia (FMST)
  • Familial progressive subcortical gliosis

FTD P-17 (Fronto Temporal Dementia and Parkinsonism)

• General characteristics:
  • AD; chromosome q 21
• Clinical features:
  • Age of onset 51 years
  • Parkinsonism
  • No resting tremor
  • Corticospinal tract degeneration without wasting or fasciculation
  • Supranuclear ophthalmoplegia:
    • Apraxia of eyelid opening
  • Autonomic function spared early:
    • Incontinence of bowel and bladder late
  • Seizures rare but may occur late in the course of the illness
  • Mean duration from onset to death is three years
  • Variability of phenotype within families
  • Family linked to chromosome 3 with same clinical features
• EEG:
  • Normal until later in life
• Pathology:
  • Neuronal loss, gliosis and spongiosis:
    • Frontal and temporal lobes
    • Cingulate gyrus
    • Substantia nigra pars compacta
  • Increased CSF tau protein
  • Ballooned neurons in the frontal lobe

FTDP-17 (P302 L) Mutation

• General characteristics:
  • C to T change in exon 10
  • Codes for mRNA with four microtubule binding repeats (4R)
  • 4 R tau repeats aggregated in both gray and white matter

Disinhibition–Dementia–Parkinsonian–Amyotrophy Complex (DDPAC)

• General characteristics:
  • FTD variant
    • Chromosome 17
• Clinical features:
  • Mean age at onset is 45 years of age
  • Disinhibition
  • Klüver-Bucy features
  • Schizophrenic behavior
  • Social withdrawal
  • Initial preservation of orientation, speed of processing and calculation
  • Hyperphagia
  • Later symptoms:
    • Perseveration
    • Constructional apraxia
    • Decreased speech
    • Poor calculation ability
  • Parkinsonism:
    • Rigidity
    • Bradykinesia
    • Postural instability
  • Spinal cord:
    • Fasciculation
    • Muscle wasting
• Pathology:
  • Anatomic areas of involvement:
    • Anterior temporal lobes
    • Entorhinal cortex
    • Cingulate gyrus
    • Pyriform cortex
    • Amygdala
  • Circumscribed laminar spongiosis:
    • Limbic areas
    • Association cortices
  • Neural intracytoplasmic inclusions:
    • Phosphorylated neurofilament lattice like formation with ubiquitin
    • Located in brainstem nuclei, hypothalamus, and basal ganglia
    • Negative for amyloid
  • Oligodendroglial cytoplasmic inclusions similar to those seen in multiple system atrophy

Pallido-Ponto-Nigral Degeneration (PPND)

• General characteristics:
  • Missense mutations in exon 10 of the tau gene
  • Mutations in the intron adjacent to the exon 103 splice site:
    • Encodes tau isoform with 4 MT (microtubule) binding repeats
• Clinical features:
  • Stage I:
    • Mild dementia and parkinsonism
  • Stage II:
    • Moderate Parkinsonism
    • Dementia
    • Dysarthria
    • Pyramidal tract dysfunction
    • Extraocular muscle dysfunction
    • Sensory abnormalities
  • Stage III:
    • Severe parkinsonism
    • Dementia
    • Dysphagia
  • Stage IV:
    • Terminal
  • Dementia
  • Rapidly progressive parkinsonism
  • Begins > 30 years of age
  • Dystonia
  • Perservative vocalization
  • Pyramidal tract dysfunction
• Pathology:
  • Neuronal and glial rich tau (inclusions):
    • Formed from aggregated neurofilaments
    • Hyperphosphorylated tau proteins
    • Morphological and biochemical patterns simulate:
      • Sporadic CBD
      • PSP

Familial Progressive Subcortical Gliosis (FPSG)

• General characteristics:
  • Autosomal dominant
• Clinical features:
  • Onset in presenium
  • Slowly progressive course
  • Early clinical features:
    • Personality change
    • Depression
    • Disinhibition
    • Degeneration of social graces
    • Memory impairment
    • Psychotic symptoms
  • Late clinical features:
    • Progressive dementia
    • Verbal stereotypies
    • Decreased speech output
    • Echolalia
    • Features of Klüver Bury syndrome
  • Terminal clinical manifestations:
    • Profound dementia
    • Mutism
    • Dysphagia
    • Extrapyramidal signs
• Pathology:
  • Generalized cerebral atrophy:
    • Frontal and temporal lobes most severely affected
    • Fibrillary astrocytosis in subcortical white matter
    • Subpial and deep layers of frontal and temporal lobe are affected
  • Tau mutation:
    • over expression of soluble four repeat tau isoform
    • causes neuronal and glial tau pathology

Hereditary Dysphasic Disinhibition Dementia (HDDD)

• General characteristics:
  • AD; 17q 21–22
    • Not tangere specific
• Clinical features:
  • Global dementia
  • Disproportionate dysphasia
  • Frontotemporal symptoms
• Pathology:
  • Asymmetric frontotemporal atrophy (left side)
  • Status spongiosis
  • Neuronal loss in layer II of the cortex
  • Astrocytic reaction of the cortex

Progressive Language Disorder Due to Lobar Atrophy of FTD

• Clinical features:
  • Patients are heterogeneous
  • Anomia is a prominent presenting complaint
  • Language dysfunction includes:
    • Nonfluent and agrammatic
    • Fluent aphasia with profound loss of word meaning
  • Associated features in some patients:
    • Associative agnosia
    • Personality change
    • Behavior disorder
• SPECT and CT evaluation:
  • Left hemisphere abnormalities
  • Bilateral fronto temporal cortices are atrophied
• Pathology:
  • Atrophy gliosis and spongiform change
  • No senile plaques or neurofibrillary tangle

Clinical Similarities of PSG, DDPAC, FTD, PPND

• Presenile age at onset
• Behavioral manifestations
• Variable degrees of frontal lobe atrophy
• Parkinsonism:
  • Most severe in :
    • DDPAC
    • PPND
    • FSG
    • Less severe in FTD
• Degeneration to varying degrees of:
  • Caudate
  • Hippocampus
  • Substantia nigra
• All four disorders may have:
  • Different mutations in the same gene
  • Variant expression of a single mutation
  • Different genes in close proximity

Primary Progressive Apraxia in Pick's Disease

• General considerations:
  • Multimodal apraxia
  • No degradation of intelligence or deterioration of personality until late
• Clinical features:
  • Apraxia:
    • Limb clumsiness
    • Inappropriate positioning and alignment of fingers for specific movements
    • Decreased speed of movement of the hands and fingers
    • Gestural apraxia is evident
  • Pick's disease component:
    • Apraxia of speech:
      • Articulatory difficulty without language breakdown
      • Lesion of the left pars operculum rather than the pars triangularis
      • Buccofacial apraxia and dysarthria

Pick's Disease

• General considerations:
  • AD
  • Chromosome 17
• Clinical features:
  • Early personality changes
  • Deterioration of social skills
  • Prominent language abnormalities:
    • Early nonfluent aphasia
    • Echolalia
    • Isolated word finding difficulty
    • Relative preservation of auditory comprehension
  • Aberrant motor behavior
  • Disinhibition
  • Euphoria
  • Apathy
  • Rare patients:
    • Early memory loss
    • Painful symptomatology
  • Predictors of Pick's disease
    • Frontal dementia
    • Early cortical dementia:
      • Aphasia
      • Apraxia
      • Agnosia
      • Memory (usually preserved)
      • Severe frontal lobe features
    • Marked personality change at onset
    • Klüver–Bucy symptomatology
    • Absence of ideomotor apraxia
    • Absence of gait abnormalities at onset

Frontal Lobe Dementia with Motor Neuron Disease

• General considerations:
  • Occurs in approximately 30% of patients with ALS
• Clinical features:
  • Typical upper and lower motor neuron clinical findings
• Pathology:
  • Cortical degeneration; large cell loss, gliosis and spongiform change
  • Substantia nigra and cranial nerve involvement
  • Anterior horn loss
  • Ubiquitinated inclusions
  • Amygdala, thalamus striatus, substantia nigra are variably involved
  • Regions Lacking Distinctive Pathological Changes
    • Atrophy of the frontal lobes
    • Vacuolated second cortical layer
    • Astrocytosis of deeper layers
    • Hippocampus (CAI; subiculum involved)

Pathologic Changes Common to all Frontal Lobe Dementias

• Frontal and temporal lobe atrophy
• Variable striatal and nigral involvement
• Pick's disease variable:
  • Loss of neurons in all layers of the frontotemporal cortex
  • Microvacuolation
  • Astrocytosis
  • Intraneuronal inclusions (Pick's bodies):
    • Hyperphosphorylated tau
    • Ubiquitin positive
    • Argyrophilic
    • Associated with ballooned neurons which are not int the same neuron as the Pick body

Differential Diagnosis of FTD Vs Alzheimer's Disease

• FTD:
  • Early non-cognitive behavioral change
  • Better calculation abilities than AD
  • Decreased verbal output
  • Reiterative speech
  • Verbal stereotype and echolalia
  • Visuospatial skills
  • Less severe memory impairment less severe

Criteria for the Diagnosis of FTD

• General considerations:
  • Character change and disordered social conduct are the dominant features
  • They maintain:
    • Spatial skills
    • Perception
    • Praxis
    • Memory
• Core diagnostic features:
  • Insidious onset with gradual progression
  • Decline in social conduct
  • Impairment of personal conduct
  • Emotional blunting
  • Loss of insight
• Associated clinical features of FTD:
  • Behavioral:
    • Decline in hygiene and grooming
    • Mental rigidity or inflexibility
    • Distractibility
    • Impersistence
    • Hyperorality
    • Dietary changes
    • Perseveration
    • Stereotypy
    • Utilization behavior
• Speech and Language:
  • Altered speech output:
    • A spontaneity
    • Economy of speech
    • Pressure of speech
  • Echolalilia
  • Perseveration
  • Mutism
• Neurological Examination:
  • Primitive reflexes
  • Incontinence
  • Akinesia and rigidity
  • Tremor
• Laboratory evaluation:
  • Neuropsychological tests:
    • Impairment of frontal lobe function
    • Absence of:
      • Amnesia
      • Aphasia
      • Perceptual spatial disorder
    • EEG is normal
    • Frontal and anterior temporal abnormalities by MRI, SPECT and PET scanning

Diagnostic Exclusion Features for FTD

• Clinical:
  • Abrupt onset; ictal events
  • Early severe amnesia
  • Spatial disorientation
  • Myoclonus
  • Corticospinal tract weakness
  • Cerebellar ataxia
  • Choreoathetosis
• Diagnostic:
  • Brain imaging:
    • Predominant post central structural or functional deficits
    • Multifocal lesions on CT or MRI
  • Laboratory evaluation:
    • Inflammatory markers
    • Metabolic abnormalities

Progressive nonfluent aphasia vs FTD

• Clinical features:
  • Language:
    • Disorder of expressive language is the dominant feature rather than behavioral change (PPA)
    • Insidious onset and gradual progression
    • Nonfluent spontaneous speech with one of:
      • Agrammatism
      • Phonemic paraphasia
      • Anomia
      • Pressure of speech
      • Idiosyncratic word usage
      • Absence of phonemic paraphasias
      • Surface dyslexia and dysgraphia
      • Preserved calculation
  • Behavior:
    • Loss of sympathy and empathy (FTD)
    • Narrowed preoccupation (FTD)
    • Parsimony (FTD)
    • Normal (PPA)
  • Neurological examination:
    • Absent or late primitive reflexes (PPA)
    • Akinesia and rigidity (FTD)
    • Tremor (FTD)
    • Normal (PPA)
  • Diagnostic evaluation:
    • Neuropsychological testing in temporal component of FTD:
      • Profound semantic loss
      • Failure of word comprehension
      • Poor naming
      • Decreased face and object recognition
    • Preserved:
      • Phonology and syntax
      • Elementary perceptual processing
      • Spatial skills
  • EEG is normal
  • Pathology:
    • Structural and functional anterior temporal lobe defects

Differential Diagnosis of Progressive Nonfluent Aphasia vs. FTD

• May feel that PPA may be a subgroup of FTD

Primary Progressive Aphasia (PPA)

• Behavioral:
  • Early preservation of social skills to a much greater degree than loss of language
• Language:
  • Agrammatism:
    • Omission or incorrect use of grammatical terms:
      • Articles, prepositions, verbs, inflexion and derivatives
    • Phonemic paraphasia:
      • Sound based errors
      • Use of incorrect phoneme
  • Motor deficit of speech:
    • Stuttering or oral apraxia
    • Repetition of parts of a word; particularly the first consonant
  • Impaired repetition
  • Some alexia and agraphia:
    • Phonemic paraphasias

Diagnostic Evaluation of Primary Progressive Aphasia

• Neuropsychology:
  • Presence of normal scores on one or more tests of frontal lobe function
  • No loss of information from immediate to delayed recall
  • Normal face and object recognition
  • Normal scores on spatial cognitive tasks

Semantic Aphasia Tasks vs FTD

• General characteristics:
  • Specific posterior speech disorder whereas FTD is primarily an anterior speech dysfunction
• Clinical features:
  • Fluent empty spontaneous speech
  • Reduced use of nominal terms
  • Increased use of broad generic terms
  • Loss of word meaning
  • Disorder of single word comprehension
• Semantic paraphasias:
  • Semantically related words replace correct nominal terms
  • Super ordinate category substitution (e.g. animal for camel)
  • Coordinate category errors (dog for elephant)
• Prosopagnosia:
  • Inability to recognize familiar faces
  • Auditory or somatic modalities confer immediate recognition
• Logo clonic and festinant speech:
  • Logo clonic:
    • Effortless representation of the final syllable
  • Festinant speech:
    • Rapid effortless reiteration of individual phonemes
  • Rapid loss of train of thought
  • Associative agnosia:
    • Impairment of object identity:
      • Tactile and visual sphere is preserved
  • Preserved:
    • Matching and drawing reproduction
    • Single word repetition
    • Relative preservation of repetition of sentences
    • Ability to read aloud and to write to dictation (orthographically regular words)

Associated Clinical Diagnostic Features of Semantic Aphasia

• Pressure of speech
• Idiosyncratic word usage
• Absence of phonemic paraphasias in spontaneous speech
• Preserved calculation
• Parsimony (abnormal preoccupation with money and financial economy)
• Loss of sympathy and empathy

Diagnostic Evaluation of Semantic Aphasia 

• Neuropsychological testing:
  • Profound semantic loss
  • Failure of word comprehension and naming
  • Poor face object recognition
• Preserved
  • Phonology and syntax

Olivo Ponto Cerebellar Atrophy (OPCA)

• General characteristics:
  • Autosomal dominant or recessive forms
• Clinical features:
  • Appendicular ataxia
  • Dysarthria
  • Cranial nerve degeneration and retinal degeneration in variant forms
  • Parkinsonism
  • Mild peripheral neuropathy
• Pathology:
  • Neuronal loss and gliosis
  • Found in oligodendrocytes
  • Ubiquitin positive
  • Inferior olives
    • Atrophy, gliosis, neuronal loss

Cortico Basal Ganglionic Degeneration (CBGD)

• General characteristics:
  • Chromosome 17; H haplotype
• Clinical features:
  • Asymmetric
  • Akinetic rigid syndrome
  • Apraxia (ideomotor, ideational)
  • Parietal cortical sensory loss associated with:
    • Limb akinesias (loathness to move)
    • Cataleptic posture:
      • Usually levitation of an extremity
  • Alien hand syndrome:
    • Posterior type
    • Failure to recognize the hand as one's own
    • Groping movements (usually anterior alien hand)
    • Complex involuntary movement
  • Atypical clinical features:
    • Marked speech disturbance
    • Dementia
    • Complex tremor
    • Rarely the hand is aggressive (attempts to strangle the patient)
• Pathology:
  • Ballooned achromatic neurons:
    • Neurofilament protein positive
  • Astrocytic plaques:
    • Annular clusters of thick short tau positive deposits
    • Within distal processes of cortical astrocytes
  • Pick's type b:
    • Cortical degeneration with swollen chromatolytic neurons

Progressive Supranuclear Palsy (PSP)

• General characteristics:
  • Chromosome 17q21–q22
  • AO/AO allele
  • Hi haplotype
• Clinical features:
  • Akinesia and axial rigidity
  • Head held in extended position (to utilize vestibular ocular reflexes for downgaze)
  • Dysarthria
  • Pyramidal tract dysfunction
  • Failure of downgaze (primarily)
  • Frequent falls (severe loss of postural reflexes)
  • Deep nasolabial folds
  • Sexual disinhibition
  • Frontal lobe dementia
  • Arm levitation
  • Eye lid apraxia (inability to open eyes on command)
  • Fall backwards
  • Stimulus sensitive myoclonus
  • Bilateral grasp reflex
  • Increased reflexes
  • Extensor posturing
• Pathology:
  • Neurofibrillary tangles:
    • Flame straight filaments, distinct from those of AD
    • Astrocytic gliosis which are paired filaments
  • Lesions noted in the:
    • Superior colliculi
    • Pretectal areas
    • Periaqueductal gray
    • Reticular formation
    • Subthalamic nucleus

Differential Diagnosis of Spontaneous Arm Levitation

• Parietal lobe lesion (posterior alien hand)
• CBGD (cortico basal ganglionic degeneration)
• PSP
• Dorsal column lesions (associated with flailing movements)
• Hemiatrophy hemiparkinsonism

Differential Clinical Features between CBGD and PSP

• PSP:
  • Vertical gaze (down gaze) abnormality early
  • Unilateral dystonia early
• CBGD:
  • Striking asymmetry at presentation
  • Cortical parietal sensory loss
  • Stimulus sensitive and action induced myoclonus
  • Severe limb apraxia
  • Vertical gaze paresis is late

Tauopathies

FTD-17 Parkinsonism

• FTD-17 chromosome dementia variants:
  • PPND (pedunculo pallidal pontine nigral degeneration)
  • DDDAC (depression-disinhibition amyotrophy complex)
  • FSCG (familial subcortical gliosis)
  • HDDD
  • FTDP-17 (missense mutations):
    • Exons 9, 10, 12
    • 3 intronic mutations (regulate alternative splicing of exon 10)
  • PPA (primary progressive aphasia)
• CGBD (corticobasal ganglionic degeneration)
• PSP:
  • Classic atypical form missense mutism (R406W)
• Parkinson's disease ALS dementia complex of Guam
• Head trauma
• Postencephalitic parkinsonism

Lesion Common Diseases with Dementia as a Major Clinical Feature

Hallervorden Spatz Disease

• General characteristics:
  • AR; chromosome 20p12.3-p13
  • Pantothenic acid kinase 2 deficiency (PANK2 gene)
• Clinical features:
  • Onset in childhood, teens, adult
  • Basal ganglionic type rigidity
  • Dysarthria
  • Athetosis
  • Pyramidal tract dysfunction
• Pathology:
  • Neuronal loss in SNPC and the GPi/GPe
  • Pigment deposition in the same neurons (SN/GP)
    • Iron pigment deposition
    • Axonal swelling and dystrophic changes
    • Spheroids
    • Fe⁺⁺ deposition in the same areas seen in infantile neuroaxonal dystrophy

Post Encephalic Parkinsonism

• General characteristics:
  • Pandemic of 1918 (apparently of specific virus)
  • Rare sporadic cases
• Clinical features:
  • Autonomic storms (fluctuating blood pressure, sweating, pupillary dilatation)
  • Oculogyric, crisis, ophthalmoplegia
  • Volatile personality changes
  • Akinetic rigid state
  • Prominent tremor
  • Sleep inversion
  • Central respiratory irregularities
  • Obsessive compulsive behavior
  • Somnolence
• Pathology:
  • Midbrain atrophy
  • Neurofibrillary tangles
  • Gliosis

Wilson's Disease

• General considerations:
  • AR; chromosome 13
• Clinical features:
  • Onset in teenage years
  • Kayser–Fleisher ring (copper-deposition on Descemet's membrane)
  • Slow mental deterioration
  • Wing beating tremor (proximal flinging of the arms)
  • Hypotonia
  • Hyperreflexia
• Deficiency of ceruloplasmin:
  • Copper deposition in the brain
  • Destruction of the liver by copper induced cirrhosis
• Pathology:
  • Hepatolenticular degeneration
  • Spongiform degeneration:
    • Necrosis
    • Cavitation
    • Putamen > globus pallidus > thalamus > cortex
    • Alzheimer's type I glia (large, pale, multilobulated astrocytic nuclei)
    • Opalski cells:
      • Found in the BG
      • Large astrocytes
      • Eccentric small nuclei
      • Abundant foamy cytoplasm
      • Copper deposits